OncoTrials - мониторинг клинических исследований

Описание

Selinexor, a first-in-class, oral selective exportin 1 (XPO1) inhibitor, has shown promise in pre-clinical and clinical studies. It functions by inhibiting the nuclear export protein XPO1, resulting in the accumulation of tumor suppressor proteins and inhibition of oncoprotein mRNAs, which is selectively lethal to myeloma cells. Selinexor has demonstrated activity in combination with various drugs, including glucocorticoids and proteasome inhibitors, leading to its FDA approval for the treatment of relapsed or refractory multiple myeloma.

Критерии включения

• Patients must meet all the following inclusion criteria to be eligible to enroll in this study:
• 1. Has a diagnosis of MM based on standard criteria as follows:
• Myeloma criteria: Must be At least 1 of 2 1. Clonal bone marrow plasma cells />10% 2. Biopsy-proven bony or extramedullary plasmacytoma
• Active Myeloma criteria: Active Myeloma criteria: Must Meet At Least ONE of the Following:
• Meet at least one of the sub-criteria for #1 Evidence of End Organ Damage (a, b, c, or d), OR Meet sub-criteria #2. 60% or greater bone marrow plasma cells, OR Meet sub-criteria #3 Serum free light chain ratio, OR Meet sub-criteria #4 More than one focal lesion on MRI /> 5mm in size.
• 1. Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically
• 1. Hypercalcemia: serum calcium />0.25 mmol/L (/>1mg/dL) higher than the upper limit of normal or />2.75 mmol/L (/>11mg/dL)
• 2. Renal insufficiency: creatinine clearance /<40 mL per minute or serum creatinine />177mol/L (/>2mg/dL)
• 3. Anemia: hemoglobin value of />20g/L below the lowest limit of normal, or a hemoglobin value /<100g/L
• 4. Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or PET/CT. If bone marrow has /<10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement
• 2. 60% or greater clonal plasma cells on bone marrow examination
• 3. Serum involved / uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved light chain is at least 100 mg/L (a patient`s involved free light chain either kappa or lambda is the one that is above the normal reference range; the uninvolved free light chain is the one that is typically in, or below, the normal range)
• 4. More than one focal lesion on MRI that is at least 5mm or greater in size
• The patient must have met the criteria for Active Myeloma at some stage following the diagnosis of Myeloma. Source documentation for both Myeloma and Active Myeloma will be required.
• 2. Patients with relapsed/refractory multiple myeloma with at least three prior lines of therapy 3. Received an
• 1. Anti-CD38 antibody
• 2. Immunomodulatory agent (IMiD)
• 3. Proteasome inhibitor (PI) 4. Currently has MM with measurable disease, defined as:
• * a monoclonal immunoglobulin spike on serum electrophoresis of at least 0.5 g/dL and/or urine monoclonal protein levels of at least 200 mg/24 hours
• * for patients without measurable serum and urine M-protein levels, an involved SFLC /> 100 mg/L or abnormal SFLC ratio
• * for patients with IgD MM, a monoclonal immunoglobulin IgD of at least 5500 mg/L or meet other measurable disease eligibility criteria
• * for patients with IgA MM, total IgA of /> 700 mg/dL 5. Currently has progressive MM: MM patients that are relapsed or have refractory disease from at least 3 regimens or lines of therapy are eligible for enrollment provided they fulfill the other eligibility criteria:
• * patients are considered relapsed, when they progress greater than 60 days from their last dose of treatment
• * patients are refractory when they progress while currently receiving the treatment or within 8 weeks of its last dose 6. Adequate hepatic function within 14 days prior to C1D1: Total bilirubin /< 1.5 × upper limit of normal (ULN) (except patients with Gilbert`s syndrome who must have a total bilirubin of /< 3 × ULN), and Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) normal to /< 2 × ULN.
• 7. Adequate renal function within 14 days prior to C1D1 as determined by OR estimated CrCl of /> 60 mL/min, calculated using the Cockcroft and Gault formula (140 - Age) • Mass (kg)/ (72 • creatinine mg/dL); multiply by 0.85 if female (87)(Appendix 5).
• 8. Adequate hematopoietic function within 14 days prior to C1D1: total WBC count ≥1500/mm3, ANC ≥1000/mm3, hemoglobin ≥8.5 g/dL and platelet count ≥75,000/mm3 (patients for whom /<50% of BM nucleated cells are plasma cells) or ≥50,000/mm3 (patients for whom ≥50% of BM nucleated cells are plasma cells).
• 9. Patients receiving hematopoietic growth factor support, including erythropoietin, darbepoetin, G-CSF, GM-CSF, and platelet stimulators (e.g., eltrombopag, romiplostim, or interleukin-11) must have a 2-week interval between growth factor support and the Screening assessments, but they may receive growth factor support during the study.
• 10. Patients must have:
• * At least a 2-week interval from the last red blood cell (RBC) transfusion prior to the start of study treatment
• * At least a 1-week interval from the last platelet transfusion prior to the start of study treatment
• * However, patients may receive RBC and/or platelet transfusions as clinically indicated per institutional guidelines during the study 11. Female patients of childbearing potential (FCBP) must have a negative serum pregnancy test at Screening. Female patients of childbearing potential and fertile male patients who are sexually active must use highly effective methods of contraception throughout the study and for one month following the last dose of study treatment. Male patients must agree not to donate sperm during the study treatment period. Specifically:
• * FCBP† must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting treatment and must either commit to continued abstinence from heterosexual intercourse or use acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, and at least 28 days before she starts therapy. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy. All subjects must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure.
• † A FCBP (female of childbearing potential) is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) 12. Able to take antiplatelet therapy if platelet count is above 30 x 109/L. Options include aspirin (acetylsalicylic acid, ASA) at 81 or 325/mg/daily, warfarin low molecular weight hepairin, Pradaza, Eliquis, or Xarelto.
• 13. Patients with history of human immunodeficiency virus (HIV) are eligible if they have CD4+ T cell counts ≥350 cells/µL, negative viral load per institutional standard, and no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the last year.
• 14. Patients with untreated hepatitis C virus (HCV) are eligible if there is a documentation of negative viral load per institutional standard.
• 15. Age ≥ 18 years of age. 16. Willing and able to provide written informed consent in accordance with federal, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure.
• 17. Able to adhere to the study visit schedule and other protocol requirements.

Критерии исключения

• Patients meeting any of the following exclusion criteria are not eligible to enroll in this study:
• 1. Patients who had prior exposure to ruxolitinib or selinexor
• 2. Prior malignancy that required treatment or has shown evidence of recurrence (except for non-melanoma skin cancer or adequately treated cervical carcinoma in situ) during the 3 years prior to randomization. Cancer treated with curative intent for />5 years previously and without evidence of recurrence will be allowed.
• 3. Have light chain amyloidosis
• 4. Have plasma cell leukemia
• 5. Have history of active tuberculosis
• 6. Have any concurrent medical condition or disease (e.g., uncontrolled active hypertension, uncontrolled active diabetes, active systemic infection, POEMS syndrome /[polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes/], primary amyloidosis, etc.) that is likely to interfere with study procedures.
• 7. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week prior to Cycle 1 Day 1 (C1D1). Patients on prophylactic antibiotics or with a controlled infection within 1 week prior to C1D1 are acceptable.
• 8. Received the following prior therapy:
• * Chemotherapy within 3 weeks of study drugs
• * Corticosteroids (/>20 mg/daily prednisone or equivalent) within 3 weeks of study drugs to ensure that steroid dose intensity at the beginning of the treatment is not altered by administration of steroids prior to the study. Consumption of steroids within 3 weeks of the treatment may interfere with efficacy and side effects due to differences of steroid intensity.
• * Immunotherapy, immunomodulatory drugs, or proteasome inhibitors within 3 weeks before administration of study drugs
• * Extensive radiation therapy within 28 days before study drugs. Receipt of localized radiation therapy does not preclude enrollment.
• * Use of any other experimental drug or therapy within 28 days of study drugs
• * Strong CYP3A4 inhibitors, strong CYP3A4 inducers and fluconazole doses />200 mg daily within 5 half-lives before study drugs. (For example, clarithromycin has half-life of 4 hours so washout period for clarithromycin is 20 hours.)
• 9. Known intolerance, hypersensitivity, or contraindication to glucocorticoids.
• 10. Known hypersensitivity to compounds of similar chemical or biological composition to ruxolitinib or steroids.
• 11. Concurrent use of other anti-cancer agents or treatments.
• 12. Severe hypercalcemia, i.e., serum calcium ≥ 12 mg/dL (3.0 mmol/L) corrected for albumin
• 13. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
• 14. Pregnant or breastfeeding females.
• 15. Body surface area (BSA) /<1.4 m2 at baseline, calculated by the Dubois or Mosteller method.
• 16. Life expectancy of less than 3 months.
• 17. Major surgery within 4 weeks prior to C1D1.
• 18. Active, unstable cardiovascular function, as indicated by the presence of:
• 1. Symptomatic ischemia, or
• 2. Uncontrolled clinically significant conduction abnormalities (e.g., patients with ventricular tachycardia on anti-arrhythmic are excluded; patients with first degree atrioventricular block or asymptomatic left anterior fascicular block/right bundle branch block will not be excluded), or
• 3. CHF of New York Heart Association Class ≥3 or known left ventricular ejection fraction /< 40%, or
• 4. Myocardial infarction (MI) within 3 months prior to C1D1 or
• 5. Stroke and other thrombosis, such as, pulmonary embolism (PE) or deep vein thrombosis (DVT) within 3 months prior to C1D1.
• 19. Any active GI dysfunction interfering with the patient`s ability to swallow tablets, or any active GI dysfunction that could interfere with absorption of study treatment.
• 20. Inability or unwillingness to take supportive medications such as anti-nausea and anti-anorexia agents as recommended by the National Comprehensive Cancer Network® (NCCN) Clinical Practice Guidelines in Oncology (CPGO) (NCCN CPGO) for antiemesis and anorexia/cachexia (palliative care).
• 21. Any active, serious psychiatric, medical, or other conditions/situations that, in the opinion of the Investigator, could interfere with treatment, compliance, or the ability to give informed consent.
• 22. Contraindication to any of the required concomitant drugs or supportive treatments.
• 23. Patients unwilling or unable to comply with the protocol.

Описание

The primary purpose of this study for Part 1 (Dose Escalation) is to identify the safe effective dose (recommended Phase 2 doses /[RP2Ds/]) and schedule for JNJ-79635322 treatment regimen in combination with either daratumumab or pomalidomide; and for Part 2 (Dose Expansion) is to further define the safety and tolerability of JNJ-79635322 combination treatment regimens at selected RP2D(s).

Критерии включения

• * Have documented initial diagnosis of multiple myeloma according to IMWG diagnostic criteria
• * Meet treatment regimen-specific requirements as follows: Treatment regimen A (JNJ-79635322+daratumumab):Treatment regimen A1: Have been treated with 1 to 3 prior lines of therapy, including a proteasome inhibitor (PI) and an inhibitor, immunomodulatory drug (IMiD) therapy for the treatment of multiple myeloma (MM); Treatment regimen A2: Newly diagnosed MM naïve to multiple myeloma (or other related plasma cell neoplasm)-directed treatments; Treatment regimen B (JNJ-79635322+pomalidomide): Have received greater than or equal to (/>=) 1 prior line of therapy, including a PI and lenalidomide, and are lenalidomide refractory OR />=2 prior lines of therapy, including a PI and lenalidomide
• * Have a weight />=40 kilograms
• * Must have an Eastern Cooperative Oncology Group status of 0 or 2
• * Have measurable disease at screening as defined by at least 1 of the following: a) Serum monoclonal protein (M-protein) level />= 0.5 gram per deciliter (g/dL); or b) Urine M-protein level />=200 milligram (mg)/24 hours; or c) Light chain multiple myeloma: Serum immunoglobulin (Ig) free light chain (FLC) />= 10 mg/dL and abnormal serum Ig kappa lambda FLC ratio. d) For participants without measurable disease in the serum, urine, or involved FLC: presence of 1 or more focus of extramedullary disease which meets the following criteria: extramedullary plasmacytoma not contiguous with a bone lesion, at least 1 lesion />=2 centimeter (cm) (at its greatest dimension) diameter on whole body positron emission tomography-computed tomography (or whole-body magnetic resonance imaging approved by sponsor), and not previously radiated

Критерии исключения

• * Any serious underlying medical conditions, such as: a) Evidence of active viral, bacterial, or systemic fungal infection requiring ongoing antiviral, antibacterial, or antifungal treatment. b) Active autoimmune disease requiring systemic immunosuppressive therapy within 6 months before start of study treatment. c) Cardiac conditions (myocardial infarction, unstable angina, or coronary artery bypass graft /<=6 months prior to enrollment; New york heart association stage III or IV congestive heart failure etcetera)
• * Prior antitumor therapy as follows, in the specified time frame prior to the first dose of study treatment: a) Targeted therapy, epigenetic therapy, monoclonal antibody (mAb) treatment, or treatment with an investigational drug or an invasive investigational medical device within 21 days or 5 half-lives, whichever is less. b) Gene-modified adoptive cell therapy (example, chimeric antigen receptor /[CAR/] modified T cells, natural killer cells) within 90 days. c) Prior anti-CD38 directed therapy within 90 days (for treatment regimen A only; within 21 days for treatment regimen B). d) Conventional chemotherapy within 21 days. e) PI therapy within 14 days. f) Immunomodulatory agent therapy within 7 days. g) Radiotherapy within 14 days
• * Stem cell transplantation: a) Allogeneic stem cell transplant within 6 months before the first dose of study treatment. b) Received an autologous stem cell transplant less than or equal to (/<=)12 weeks before the first dose of study treatment
• * Nonhematologic toxicity from prior anticancer therapy that has not resolved to baseline level or to grade /<=1 (except alopecia, tissue post-RT fibrosis /[any grade/] or peripheral neuropathy grade /<=3)
• * Prior treatment with CD3-redirecting therapy
• * The following medical conditions: pulmonary compromise requiring supplemental oxygen use to maintain adequate oxygenation, human immunodeficiency (HIV) infection, active hepatitis B or C infection, stroke or seizure within 6 months prior to first dose of study treatment

Описание

This is a non-interventional, national, multicenter prospective non-profit observational study aiming at improving the accuracy of risk prediction in multiple myeloma (MM) by applying machine-learning tools for data processing to develop model(s) predicting response to therapy and the probability of early relapse for MM patients.

Критерии включения

• * Age ≥ 18 years
• * Signed Informed Consent form for study participation and personal data processing
• * Diagnosis of active multiple myeloma

Критерии исключения

• * None

Описание

The purpose of this Phase 3 study is to evaluate if BRd prolongs progression free survival (PFS) and/or improves minimal residual disease (MRD) negative status compared with DRd in participants with TI-NDMM.

Критерии включения

• 1. Is at least 18 or the legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the informed consent.
• 2. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and in the protocol.
• 3. NDMM with a requirement for treatment as documented per IMWG criteria.
• 4. Must have at least 1 aspect of measurable disease, as assessed by the central laboratory, defined as 1 of the following:
• 1. Urine M-protein excretion ≥200 mg/24 hours (≥0.2 g/24 hours) And/or
• 2. Serum M-protein concentration ≥0.5 g/dL (≥5.0 g/L) And/or
• 3. Serum free light-chain (FLC) assay: involved FLC level ≥10 mg/dL (≥100 mg/L) and an abnormal serum FLC ratio (/<0.26 or />1.65).
• 5. Newly diagnosed and not considered candidate for high-dose chemotherapy with autologous stem cell transplant (ASCT) due to any of the following:
• 1. ≥70 years of age, OR
• 2. Age 18 to 69 years with presence of comorbid condition(s) likely to have a negative impact on tolerability of high-dose chemotherapy with ASCT, (or for whom national guidelines do not permit transplant due to a cut-off age below 70 years), OR
• 3. Who refuse high-dose chemotherapy with ASCT as an initial treatment.
• 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
• 7. Adequate organ system function as defined by the laboratory assessments.
• 8. Male participants:
• * Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• * Male participants are eligible to participate if they agree to the following during the Treatment Period and for at least 6 months after the last dose of study intervention to allow for clearance of any altered sperm:
• * Refrain from donating fresh unwashed semen
• PLUS either:
• * Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent.
• OR
• * Must agree to use contraception/barrier as detailed below
• * Agree to use a male condom, even if they have undergone a successful vasectomy, and female partner to use an additional highly effective contraceptive method with a failure rate of /<1% per year when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant. Male participants should also use a condom when having sexual intercourse with pregnant females.
• 9. Female participants
• * Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• * A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:
• * Is not a WOCBP OR
• * Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of /<1% per year), preferably with low user dependency during the Treatment Period and for 4 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
• * A WOCBP must have 2 negative highly sensitive serum pregnancy tests before starting treatment, the first may be performed within 14 days from C1D1, the second within 24 hours before the first dose of study intervention.
• * Should pregnancy occur in a female on treatment or the female partner of a male on treatment, treatment must be stopped, and it is advised to seek advice from a physician specialized or experienced in teratology.

Критерии исключения

• 1. Diagnosis of systemic amyloid light chain amyloidosis, Waldenstrom`s disease, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes) or Primary Plasma Cell Leukemia (defined as circulating plasma cells />5%).
• 2. Prior systemic therapy for multiple myeloma, or smoldering multiple myeloma.
• 3. Signs of meningeal or central nervous system involvement with multiple myeloma.
• 4. Major surgery within 2 weeks prior to the first dose of study drugs or has not recovered fully from surgery. Kyphoplasty is not considered major surgery.
• 5. Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions (including lab abnormalities) that could interfere with participant`s safety, obtaining informed consent, or compliance with study procedures.
• 6. Current active liver or biliary disease (except for Gilbert`s syndrome or asymptomatic gallstones, or otherwise stable chronic liver disease as per the investigator`s assessment).
• 7. Participants with previous or concurrent malignancies other than multiple myeloma are excluded. Exceptions are any other malignancy that has been considered medically stable for at least 2 years, after discussion with the GSK Medical Monitor. The participant must not be receiving active therapy, other than hormonal therapy for this disease.
• 8. Evidence of cardiovascular risk including any of the following:
• 1. Evidence of current clinically significant untreated arrhythmias, including clinically significant electrocardiogram abnormalities including second-degree (Mobitz Type II) or third-degree atrioventricular block.
• 2. Recent history (within 3 months of screening) of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty or stenting, or bypass grafting.
• 3. Class III or IV heart failure as defined by the New York Heart Association functional classification system.
• 9. Known human immunodeficiency virus (HIV) infection, unless the participant can meet all of the following criteria:
• 1. Established antiretroviral therapy for at least 4 weeks and HIV viral load /<400 copies/mL within Screening Period.
• 2. CD4+ T-cell (CD4+) counts ≥350 cells/μL.
• 3. No history of acquired immune deficiency syndrome-defining opportunistic infections within the last 12 months.
• 10. Positive hepatitis C antibody test result or positive hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study intervention unless the participant can meet the following criteria:
• 1. RNA test negative.
• 2. Successful antiviral treatment (usually 8 weeks duration) is required, followed by a negative hepatitis C viral load RNA test after a washout period of at least 4 weeks.
• 11. Participants with hepatitis B will be excluded unless the defined criteria can be met.
• 12. Current corneal epithelial disease except for mild punctate keratopathy.
• 13. Intolerance or contraindications to antiviral prophylaxis.
• 14. Unable to tolerate antithrombotic prophylaxis.
• 15. Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs chemically related to belantamab mafodotin, or any of the components of the study intervention.
• 16. Plasmapheresis within 7 days prior to the first dose of study intervention.
• 17. Participants must not have received a live or live-attenuated vaccine within 30 days prior to first dose of belantamab mafodotin.

Описание

This is an open label, single-arm, Phase 2 study to evaluate the efficacy and safety of Anti-BCMA/FcRL5 CAR-T in subjects with relapsed and refractory multiple myeloma. A leukapheresis procedure will be performed to manufacture. Anti-BCMAFcRL5 chimeric antigen receptor (CAR) modified T cells. Prior to Anti-BCMA/FcRL5 infusion subjects will receive lymphodepleting therapy with fludarabine and cyclophosphamide.

Критерии включения

• Age is 18/~70 years old; Expected survival period of/>12 weeks; Multiple myeloma was diagnosed by physical examination, pathological examination, laboratory examination and imaging; Patients with refractory multiple myeloma; Patients with multiple myeloma recurrence; ALT and AST /<3 times normal; bilirubin /<2.0mg / dl; Quality of survival score (KPS)/> 50%; The patient has no serious heart, liver, kidney and other diseases; Recurrence or no disease remission after hematopoietic stem cell transplantation or cellular immunotherapy; Is not suitable for stem cell transplantation conditions or to abandon transplantation due to conditional restrictions; Blood can be obtained intravenously, without other contraindications to leukapheresis; Understand and voluntarily sign a written informed consent form.

Критерии исключения

• Women who are pregnant or breastfeeding, or who have a pregnancy plan within six months; Infectious diseases (such as HIV, active tuberculosis, etc.); Active hepatitis B or hepatitis C infection; Feasibility assessment screening demonstrated /<10% transfection of targeted lymphocytes or underamplification under CD3 / CD28 costimulation (/<5-fold); Abnormal vital signs, and unable to cooperate with the examination; Have mental or mental illness who cannot cooperate with the treatment and efficacy evaluation; Highly allergic constitution or have a history of severe allergies, especially allergic to IL-2; Subjects with a systemic infection or a severe local infection requiring anti-infective treatment; Subjects with severe autoimmune disease; The doctor believes there were other reasons for inclusion

Описание

This is a single center, open-label, dose-escalation/expansion clinical study to evaluate the safety and effectiveness of Fourth-Generation CAR-T, and determine the recommended dose of the CAR T-cells for patients with Multiple Myeloma，B-cell lymphoma and other hematologic malignancies.

Критерии включения

• Subjects must meet all of the following criteria to be enrolled:
• 1. Voluntarily participate in this clinical study and sign the informed consent form; 2. 18 to 75 years old (including cut-off value), Male and female;; 3. Expected survival of at least 3 months; 4.1 CD19-positive B lymphocyte-derived hematologic malignancies; 4.2 Multiple myeloma patients; 4.3 Non-B cell-derived hematologic malignancies patients with CD7 or other target molecules; 5. The clinical trial values during the screening period meet the following criteria:
• 1. White blood cell count ≥ 3.0 × 10e9/L; Absolute neutrophil ≥ 1.0 × 10e9/L; Lymphocyte count ≥ 0.5 × 10e9/L. (The growth factor support is allowed, but growth factor must not have been received within 7 days prior to laboratory testing);
• 2. Platelet count ≥ 50 × 10e9/L (No blood transfusion support within 7 days prior to laboratory tests.); Note: Patients with leukemia, multiple myeloma, and lymphoma are not subject to the above blood picture requirements;
• 3. Biochemical indicators Serum total bilirubin (TBIL) ≤ 2.5 ULN, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 ULN, or 5 ULN if liver dysfunction is primarily due to tumor invasion); 6. Cardiac function: Subjects must have good hemodynamic stability, left ventricular ejection fraction (LVEF) ≥ 55%; 7. Lung condition: Subjects are not serious infections such as severe pneumonia; 8. ECOG activity status score: 0-2 points; 9. Female subjects must use effective contraception (such as oral prescription contraceptives, injectable contraceptives, intrauterine devices, double blockade, contraceptive patches, male partner sterilization) throughout the study period; Must have a negative serum or urine pregnancy test result at screening and throughout the study.

Критерии исключения

• Any one of the following conditions cannot be selected as a subject:
• 1. Having received CAR-T therapy targeting the same molecule;
• 2. Having received other immunotargeted therapy targeting the same molecules;
• 3. Pregnant or lactating women;
• 4. Subjects who have previously suffered from other malignancies, with the following exceptions:
• 1. Having received curative therapy, and no known active disease in the ≥ 3 years prior to the enrollment;
• 2. Non melanoma skin cancer subjects who have completed sufficient treatment and no evidence of thecurrent disease;
• 5. Subjects with a severe mental disorder;
• 6. Subjects with active autoimmune disease requiring immunotherapy;
• 7. Having received allogeneic hematopoietic stem cell transplantation;
• 8. Subjects with significant cardiovascular diseasesa.uncontrolled or symptomatic arrhythmias, congestive heart failure, or any heart disease with cardiac function grade 3 or grade 4 (according to the functional classification method of the New York Heart Association NYHA); b. Myocardial infarction or coronary artery bypass grafting within 6 months prior to screening); c. Clinically significant history of ventricular arrhythmia or unexplained syncope (non vaso-vagal or not due to dehydration);
• 9. Subjects with active infectious disease including positive Hepatitis B surface antigen (HBsAg) or Hepatitis B core antibody (HBcAb) and peripheral blood Hepatitis B virus(HBV) DNA titer is ≥500IU/mL, hepatitis C virus (HCV) antibody positive and peripheral blood HCV RNA positive, human immunodeficiency virus(HIV) antibody positive, syphilis primary screening antibody positive, active pulmonary tuberculosis; or with any significant infection requiring high-grade antibiotics Event;
• 10. Subjects with dysfunction of important organssuch as organ function in the following abnormalities:
• 1. Serum AST or ALT /> 2.5×ULN, or /> 5ULN if liver function is predominantly due to tumor invasion; TBIL /> 2.5 × ULN, unless the subject is Gilbert`s syndrome;
• 2. Serum creatinine/>2.5mg/dl;
• 3. Partial prothrombin time or activated partial thromboplastin time or international normalized ratio /> 1.5×ULN in the absence of anticoagulant therapy;
• 11. Participation in other clinical studies or prior treatment with any gene therapy product in the past three months;
• 12. Subjects with uncontrolled diabetes mellitus (glycosylated hemoglobin HbAlc />8% at screening);13. Highly allergic constitution or history of severe allergies, and having contraindications to cyclophosphamide or fludarabine;
• 14. Feasibility assessment screening demonstrated /<10% transfection of targeted lymphocytes or underamplification under CD3 / CD28 costimulation (/<5-fold); 15. Subjects who are considered unsuitable to participate in this trial by the investigator.

Описание

This is a single center, single arm, open-label, dose escalation, phase 1 study to evaluate the safety, tolerability, preliminary efficacy and immunogenicity of ESO-T01 for patients with relapsed/refractory multiple myeloma.

Критерии включения

• 1. Age ≥ 18 years；
• 2. Diagnosis of multiple myeloma (MM) confirmed according to the IMWG diagnostic criteria, with BCMA expression on MM cells determined by flow cytometry or pathology immunohistochemistry;
• 3. Previously treated with at least 2 lines of anti-MM therapy, with at least 1 complete treatment cycle for each line, and evidence of disease progression within 12 months after the most recent anti-myeloma treatment, or being refractory to both immunomodulatory drugs and proteasome inhibitors, with disease progression within 2 months after the most recent anti-myeloma treatment (according to the IMWG diagnostic criteria);
• 4. Disease must be measurable at screening, meeting at least one of the following criteria:Serum M-protein level ≥ 0.5 g/dL; Urinary M-protein level ≥ 200 mg/24h; Serum involved free light chain ≥ 10 mg/dL and an abnormal serum free light chain κ/λ ratio;
• 5. ECOG score 0-2, with an expected survival time ≥ 3 months;
• 6. Bone marrow function at screening (or within 2 months prior to screening) meets the following criteria: a.Hemoglobin ≥ 6 g/dL (no red blood cell transfusion within 1 week before screening), recombinant human erythropoietin is allowed; for patients who meet the ≥6 g/dL criterion at screening, red blood cell transfusion is allowed to maintain hemoglobin ≥ 6 g/dL; b.Absolute neutrophil count (ANC) ≥ 600/μL (no use of granulocyte colony-stimulating factor (G-CSF) within 1 week or pegylated G-CSF within 2 weeks prior to screening); c. Platelet count ≥ 50,000/μL; d. Lymphocyte count ≥ 500/μL; e. Absolute CD3-positive T cell count ≥ 150/μL;
• 7. Renal function at screening (or within 2 months prior to screening) should be normal, with a creatinine clearance ≥ 45 mL/min;
• 8. Liver function at screening (or within 2 months prior to screening) must meet the following criteria: a. Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 3.0 × the upper limit of normal (ULN); b. Total bilirubin (TBIL) and alkaline phosphatase (AKP or ALP) ≤ 2.0 × ULN (except for congenital hyperbilirubinemia, such as Gilbert`s syndrome, where direct bilirubin can be ≤ 1.5 × ULN); c. Albumin ≥ 3 g/dL;
• 9. Cardiac function at screening (or within 2 months prior to screening) must meet the following criteria: a. Left ventricular ejection fraction ≥ 40% (measured by echocardiogram or MUGA scan); b. No clinically significant pericardial effusion detected; c. No clinically significant ECG abnormalities detected;
• 10. Pulmonary function at screening (or within 2 months prior to screening) must meet the following criteria: Oxygen saturation ≥ 90%;No clinically significant pleural effusion detected;
• 11. For women of childbearing potential, a negative pregnancy test must be obtained at screening and prior to drug infusion, and they must not be breastfeeding;
• 12. Male and female subjects of childbearing potential must agree to use effective contraception from the time of informed consent until 1 year after the study drug administration;
• 13. Male and female subjects of childbearing potential must agree not to donate sperm or eggs (oocytes) or other reproductive cells from the time of informed consent until 1 year after the study drug administration;
• 14. The participant or their legally authorized representative must provide written informed consent (ICF), indicating their understanding of the purpose and procedures of the study and their willingness to participate.

Критерии исключения

• 1. Previous anticancer treatment (as determined by the investigator): a. Received targeted therapy, epigenetic therapy, other investigational drugs, or treatment using invasive investigational medical devices within 5 half-lives; b. Received immune/non-immune-directed systemic therapy within 1 week; Received cytotoxic therapy within 1 week; c. Received proteasome inhibitors or immunomodulatory agent therapy within 2 weeks; d. Received radiotherapy within 4 weeks (if the radiation field covered ≤5% of bone marrow reserve, the subject is eligible regardless of the date of radiotherapy completion);
• 2. Received allogeneic HSCT within 6 months prior to infusion, or autologous HSCT within 3 months prior to infusion;
• 3. Other malignancies prior to screening (except the following): Malignancies treated with curative intent and no evidence of active disease ≥2 years before enrollment; Adequately treated non-melanoma skin cancer with no evidence of disease;
• 4. Previously treated with any viral therapy using VSVG pseudotype virus;
• 5. Serious uncontrolled infections during screening: Bacterial, viral, fungal, etc. infections;
• 6. Positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with elevated peripheral blood HBV DNA levels within 6 months prior to infusion; Positive for hepatitis C antibody (HCV Ab) with elevated peripheral blood HCV RNA levels; Positive for HIV antibody; Positive for syphilis;
• 7. Symptomatic heart failure or significant arrhythmias: NYHA Class III or IV congestive heart failure; Myocardial infarction or coronary artery bypass grafting (CABG) or coronary stent implantation within ≤6 months prior to signing ICF; Clinically significant ventricular arrhythmias or unexplained syncope (except when caused by vasovagal or dehydration); Significant non-ischemic cardiomyopathy history;
• 8. Other significant diseases: Primary immunodeficiency; Stroke or seizure within 6 months prior to screening; Obvious clinical evidence of dementia or altered mental status; History of Parkinson`s disease or Parkinsonism;
• 9. Surgery within 2 weeks prior to treatment or planned surgery within 2 weeks post-treatment, except for local anesthesia procedures;
• 10. Use of live-attenuated vaccines within 1 month before treatment;
• 11. Known severe allergic reaction to ESO-T01 or its formulation components;
• 12. Known severe allergic reaction to Tocilizumab;
• 13. Inability to establish venous access;
• 14. Any other condition deemed by the investigator as unsuitable for participation in the study.

Описание

This study is designed to evaluate if treatment with adjuvant nivolumab improves depth of response in patients with relapsed refractory multiple myeloma (RRMM) who achieve a less-than-ideal response to idecaptagene vicleucel.

Критерии включения

• 1. Written informed consent and HIPAA authorization for release of personal health information signed by the participant or his/her legally authorized representative
• 2. Age ≥ 18 years at the time of consent
• 3. ECOG Performance Status (PS) of ≤ 1 at the time of enrollment. PS must be evaluated within 14 days prior to enrollment.
• 4. Measurable disease according to IMWG 2016 criteria present within 28 days prior to ide-cel infusion. Note that patients will NOT be required to have measurable disease at time of enrollment. Measurable disease is defined as:
• 1. Serum M-protein ≥1 g/dL (/> 0.5 g/dL for IgA or IgM) OR
• 2. Urine M-protein ≥200 mg/24 h OR
• 3. Involved free light chain (FLC) level ≥10 mg/dL provided serum FLC ratio is abnormal
• 5. Previous treatment with idecabtagene vicleucel according to the FDA approved US prescribing information with a response of CR/sCR, VGPR or PR by IMWG 2016 criteria evaluated no sooner than 3 weeks after idecabtagene vicleucel infusion when compared to baseline disease evaluations collected no earlier than 28 days prior to ide-cel infusion. Note: The 28-day window applies to all assessments, even if assessments were performed on different days.
• Note: Participants who received non-conforming idecabtagene vicleucel who were originally prescribed idecabtagene vicleucel according to the FDA approved label may be considered for inclusion per the investigator`s discretion.
• 6. Participants must be enrolled no sooner than 3 weeks and no later than 6 weeks from the date of the idecabtagene vicleucel infusion.
• 7. Recovered from all non-hematologic reversible acute toxic effects of prior therapy (other than alopecia) to ≤ grade 1 or baseline. Participants with grade ≤ 2 treatment induced peripheral neuropathy are eligible. Participants with hematologic reversible acute toxic effects are allowed to participate if laboratory values meet eligibility parameters.
• 8. Demonstrate adequate organ function as defined in the table below; all screening labs to be obtained within 28 days prior to enrollment. The most recent labs prior to enrollment will be used to evaluate for eligibility if labs drawn more than once during screening.
• 9. Females of childbearing potential (FCBP) must have a negative serum pregnancy test within 72 hours prior to enrollment. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are postmenopausal (at least 12 consecutive months with no menses without an alternative medical cause).
• FCBP must be willing to use a highly effective contraceptive method (i.e., achieves a failure rate of /<1% per year when used consistently and correctly) from the time of informed consent until 5 months after last dose of nivolumab. Contraceptive methods with low user dependency are preferable but not required (see table, adapted from: 2020_09_HMA_CTFG_Contraception_guidance_Version_1.1_updated.pdf)
• 10. Ability of the participant to understand and comply with study procedures for the entire length of the study, as determined by the enrolling investigator

Критерии исключения

• 1. Diagnosis of Waldenstrom macroglobulinemia, POEMS syndrome, or amyloidosis
• 2. History of/or active infection listed below:
• 1. Active infection requiring systemic therapy (NOTE: at discretion of investigator, participants receiving treatment for an uncomplicated urinary tract infection or localized cellulitis may be eligible.)
• 2. Uncontrolled Human Immunodeficiency Virus (HIV) or hepatitis B infection. Well controlled HIV infection (as defined by an undetectable viral load) and chronic hepatitis B infection on appropriate prophylaxis can be considered per enrolling investigator discretion
• 3. Active hepatitis C infection. Participants with previously treated hepatitis C infection with documented eradication of their infection will be allowed to enroll.
• 4. Known history of active TB (Bacillus Tuberculosis)
• 3. Pregnant or breastfeeding (Note: breast milk cannot be stored for future use while the mother is being treated on study.)
• 4. Current evidence of active cytokine release syndrome or neurotoxicity (any grade)
• 5. Participants previously diagnosed with an additional malignancy must be disease-free for at least 2 years prior to enrollment. Exceptions include basal cell or squamous cell skin cancer and in situ cervical or bladder cancer.
• 6. Treatment with any anti-myeloma therapy or investigational drug within 30 days prior to cycle 1 day 1 of nivolumab other than ide-cel with the exception of lymphodepleting chemotherapy or steroids for ide-cel therapy. Investigational includes drugs approved for human use but not approved for the indication.
• 7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements as determined by the investigator
• 8. History of transplant:
• 1. Autologous stem cell transplant within 12 weeks of C1D1
• 2. Allogeneic stem cell transplant
• 3. Solid organ transplant
• 9. Active known or suspected autoimmune disease. Participants with Type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• 10. Known history of interstitial lung disease or known history of non-infectious pneumonitis
• 11. Inability to take Pneumocystis jirovecii (PJP) prophylaxis (either trimethoprim-sulfamethoxazole, dapsone, or pentamidine)
• 12. A condition requiring systemic treatment with either corticosteroids (/>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of C1D1 (Note: Inhaled or topical steroids, and adrenal replacement steroid doses /> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease)
• 13. Prisoners or participants who are involuntarily incarcerated
• 14. Known history of myocarditis, regardless of etiology
• 15. Known history of allergy or hypersensitivity to study drug components
• 16. History of serious side effects to nivolumab or ipilimumab, as defined by the enrolling investigator

Описание

This study evaluates an individualized approach combining highly active maintenance treatment with elranatamab with peripheral blood-based clonotypic measurable residual disease (MRD) testing in patients with newly diagnosed multiple myeloma. The overall goal is to generate efficacy data for a personalized maintenance approach using bone marrow-based MRD testing (clonoSEQ) to guide post-autologous hematopoietic cell transplant (AHCT) maintenance with elranatamab for this patient population.

Критерии включения

• Criteria for Pre-Screening Blood Draw
• * Newly diagnosed multiple myeloma (either untreated or receiving first line therapy).
• * Potentially eligible for autologous hematopoietic cell transplant (with or without tandem transplant) for frontline therapy.
• * At least 18 years of age.
• * Ability to understand and willingness to sign an IRB approved written informed consent document. (Legally authorized representatives may sign and give informed consent on behalf of study participants.)
• Inclusion Criteria:
• * Received autologous hematopoietic cell transplantation (with or without tandem transplant) as part of frontline therapy for newly diagnosed IgG or IgA multiple myeloma.
• * Received induction treatment with at least a triplet regimen including a PI and an IMID (+/- an anti-CD38 antibody)
• * Disease response of ≥ partial response (PR) by IMWG criteria at time of study screening (post-transplant).
• * MRD-positive on Day 100 landmark assessment (80 to 140 days after AHCT), defined as />1 x 10-5 myeloma cells/cell by clonoSEQ assay (Adaptive Biotechnologies, Seattle, WA) performed on bone marrow aspirate.
• * ECOG performance status ≤ 2
• * All toxicities from prior treatment should have resolved to Grade ≤ 1 prior to enrollment.
• * Adequate bone marrow and organ function within 28 days prior to start of treatment as defined below:
• * Platelets ≥ 75 k/cumm
• * Absolute neutrophil count ≥ 1.0 k/cumm
• * Hemoglobin ≥ 8 g/dL without the use of growth factors or transfusion for at least 2 weeks.
• * Total bilirubin ≤ 2 × upper limit of normal (ULN; ≤ 3 x ULN if documented Gilbert`s syndrome)
• * Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 × ULN
• * Creatinine clearance ≥ 30 ml/min.
• * The effects of elranatamab on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 5 months after end of treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, or should a man suspect he has fathered a child, s/he must inform her treating physician immediately.

Критерии исключения

• * Inability to identify a trackable clonoSEQ ID.
• * A history of other malignancy with the exception of non-melanoma skin cancers, low or very low risk prostate cancer by NCCN criteria status post definitive therapy or currently on active surveillance, and malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease.
• * Currently receiving any other investigational agents.
• * Prior BCMA-based treatment.
• * CNS involvement of disease.
• * A history of allergic reactions attributed to compounds of similar chemical or biologic composition to elranatamab or other agents used in the study.
• * Uncontrolled intercurrent illness including, but not limited to, plasma cell leukemia, POEMS syndrome, systemic amyloidosis, ongoing or active infection (bacterial, fungal, or viral).
• * Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test within 28 days prior to first dose of elranatamab.
• * HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing not required in the absence of known history of infection.

Описание

The goal of this clinical trial is to find out how well a combination of two medicines (mezigdomide and elranatamab) works in treating patients with refractory/relapsed multiple myeloma.

Критерии включения

• * Subjects must satisfy the following criteria to be enrolled in the study:
• * Subject is ≥ 19 years of age at the time of signing the informed consent form (ICF).
• ② Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
• * Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
• ④ Subject has documented diagnosis of MM and measurable disease, defined as any of the following: A. M-protein ≥ 0.5 g/dL by serum protein electrophoresis (sPEP) or B. M-protein ≥ 200 mg/24-hour urine collection by urine protein electrophoresis (uPEP) or C. For subjects without measurable disease in sPEP or uPEP: serum free light chain (sFLC) levels /> 100 mg/L (10 mg/dL) involved light chain and an abnormal kappa/lambda FLC ratio.
• /*Patients with measurable disease and extramedullary disease will be allowed to participate if there is a measurable extramedullary lesion. These patients require PET-CT follow-up for response evaluation. Those with extramedullary disease (EMD) only will not be allowed to participate: i.e, Patients with plasmacytoma as the only measurable disease are not eligible. For the definition of EMD, refer to Section 8.1.3.
• ⑤ Subject has received 2 or more prior lines of antimyeloma therapy. (Note: One line can contain several phases /[e.g., induction, (with or without) hematopoietic stem cell transplant, (with or without) consolidation, and/or (with or without) maintenance therapy).
• ⑥ Subject must have received at least one proteasome inhibitor and lenalidomide.
• ⑦ Subject achieved minimal response or better to at least 1 prior antimyeloma therapy.
• * Subject must have documented disease progression during or after their last antimyeloma regimen.
• ⑨ Subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.
• ⑩ Individual of childbearing potential (IOCBP) must: A. Have two negative pregnancy tests as verified by the Investigator prior to starting study treatment. She must agree to ongoing pregnancy testing during the course of the study, and after the end of study treatment. This applies even if the subject practices true abstinence/* from heterosexual contact.
• B. Either commit to true abstinence/* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, 2 forms of contraception: one highly effective, and one additional effective (barrier) measure of contraception without interruption 28 days prior to starting study treatment, during the study treatment (including dose interruptions), and for at least 28 days after the last dose of mezigdomide or 150 days after the last dose of elranatamab, whichever is longer.
• Note: A IOCBP (Individual of childbearing potential): an individual who: 1) has achieved menarche (first menstrual cycle) at some point; 2) has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral salpingectomy (the surgical removal of the fallopian tubes) or oophorectomy (the surgical removal of both ovaries) or 3) has not been naturally postmenopausal (without an alternative medical cause eg, amenorrhea following cancer therapy does not rule out childbearing potential) for at least 12 consecutive months (ie, has had menses at any time during the preceding 12 consecutive months).
• ⑪ Male subjects must: A. Practice true abstinence/* (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant individual or an individual of childbearing potential while participating in the study, during dose interruptions and for at least 28 days after the last dose of mezigdomide whichever is longer, even if he has undergone a successful vasectomy.
• * True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. /[Periodic abstinence (e.g., calendar, ovulation, post-ovulation methods) and withdrawal are not acceptable methods of contraception/].
• * Male subjects must agree to refrain from donating sperm while on study treatment, during dose interruptions and for at least 28 days following last dose of mezigdomide,
• * Females must agree to refrain from donating eggs while on study treatment and for at least 28 days after last dose of mezigdomide.
• * Subjects must agree to refrain from donating blood while on study treatment, during dose interruptions and for at least 28 days following the last dose of mezigdomide.
• * Subjects must agree to refrain from receiving live vaccines while on study treatment, during dose interruptions and for at least 90 days following the last dose of the study treatment.

Критерии исключения

• The presence of any of the following will exclude a subject from enrollment:
• * 1 Subject who has had prior treatment with mezigdomide. 2 Patients with gastrointestinal disease or surgery (eg, gastric bypass surgery) that may significantly alter the absorption of mezigdomide and/or other oral study intervention.
• 3 Subject who has had prior treatment with anti-BCMA agents (including CAR T-cell therapy, bispecifics and antibodies).
• 4 Subject who has had any investigational agents within 28 days or 5 half-lives (whichever is shorter) of initiating study treatment.
• A. Participation in another interventional clinical trial concurrent with this study is not permitted, except for those who have completed treatment with the prior investigational agent(s) and are currently in Long-term Follow up.
• 5 Subject has received any of the following. A. Plasmapheresis within the last 28 days of initiating study treatment B. Major surgery (as defined by the Investigator) within 28 days of initiating study treatment.
• C. Radiation therapy, other than local palliative therapy, for myeloma associated bone lesions within 14 days of initiating study treatment.
• D. Use of any systemic antimyeloma drug therapy within 14 days of initiating study treatment.
• E. Use of potassium competitive acid blockers (eg. tegoprazan, vonoprazan) within 7 days of initiating study treatment.
• 6 Subject has previously received allogeneic stem cell transplantation within a year during prior therapy or received autologous stem cell transplantation within 12 weeks of initiating study treatment. Patients who received allogeneic stem cell transplantation should not have evidence of active GVHD.
• 7 Subject has plasma cell leukemia defined by IMWG definition for primary plasma cell leukemia, Waldenstrom`s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or clinically significant light-chain amyloidosis.
• 8 Subject with known central nervous system (CNS) involvement with myeloma. 9 Subject has any significant medical condition, including active or uncontrolled infection, presence of laboratory abnormality, or psychiatric illness that places the subject at an unacceptable risk for treatment-related complications, if he/she were to participate in the study.
• 10 Coronavirus disease 2019 (COVID-19) within 7 days for mild or asymptomatic infections or 14 days for moderate/severe infections prior to initiating study intervention. A longer duration may be needed based on the investigator`s clinical judgment.
• i) Acute symptoms must have resolved and there are no sequelae that would place the participant at a higher risk of receiving study intervention, based on investigator Assessment. No repeat/follow-up COVID-19 testing is required
• 11 Subject has any condition that confounds the ability to interpret data from the study.
• 12 Subject has any of the following laboratory abnormalities: A. Absolute neutrophil count (ANC) /< 1,000/µL. It is not permissible to administer GCSF to achieve minimum ANC levels within 7 days prior to screening complete blood count (CBC) (or within 14 days prior for pegfilgrastim)./* B. Platelet count: /< 75,000/µL for subjects in whom /< 50% of bone marrow nucleated cells are plasma cells; or a platelet count /< 50,000/µL for subjects in whom ≥ 50% of bone marrow nucleated cells are plasma cells (transfusions are not permitted within 7 days prior to screening CBC)./* C. Hemoglobin /< 8 g/dL (/< 4.9 mmol/L)./*
• /* Participants who do not meet criteria for hematologic function because of MM-related cytopenias (e.g. due to extensive marrow involvement by MM) may receive transfusions and be screened after 1 week of transfusion.
• D. Estimated glomerular filtration rate (eGFR) /< 30 mL/min or requiring dialysis. eGFR will be calculated using the Modification of Diet in Renal Disease (MDRD) formula.
• E. Corrected serum calcium /> 13.5 mg/dL (/> 3.4 mmol/L) F. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) /> 2.5 × upper limit of normal (ULN) G. Serum total bilirubin /> 1.5 × ULN, or for participants with documented Gilbert`s syndrome /> 3.0 mg/dL 13 Subject has peripheral neuropathy ≥ Grade 2 14 Subject with gastrointestinal disease or surgery (e.g., gastric bypass surgery) that may significantly alter the absorption of mezigdomide and/or other oral study treatment.
• A. Subject has a prior history of malignancies other than MM, except if the participant has been free of the disease for ≥ 3 years. Patients with CIS treated with curative intent are not excluded if less than 3 years. Exceptions would include basal cell and squamous cell cancer of the skin treated with curative intent.
• 15 Subject has received immunosuppressive medication within the last 14 days of initiating study treatment. The following are exceptions to this criterion: a. Intranasal, inhaled, topical or local corticosteroid injections (e.g., intra-articular injection). b. Systemic corticosteroids at doses that do not exceed 10 mg/day of prednisone or the equivalent. c. Steroids as premedication for hypersensitivity reactions (e.g., computed tomography /[CT/] scan premedication).
• 16 Administration of strong CYP3A modulators; administration of proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole) within 2 weeks of starting study treatment.
• 17 Impaired cardiovascular function or clinically significant cardiovascular diseases, defined as any of the following within 6 months prior to enrollment: A. Acute myocardial infarction or acute coronary syndromes (eg, unstable angina, coronary artery bypass graft, coronary angioplasty or stenting, symptomatic pericardial effusion); B. Clinically significant cardiac arrhythmias (eg, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia); C. Thromboembolic or cerebrovascular events (eg, transient ischemic attack, cerebrovascular accident, deep vein thrombosis /[unless associated with a central venous access complication/] or pulmonary embolism); D. Prolonged QT syndrome (or QTcF /> 470 msec at screening); E. LVEF /<40% as determined by a MUGA scan or echocardiography. 18 Subject has uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment.
• 19 Subject who has had a live vaccine within 3 months of start of study therapy.
• 20 Subject is unable or unwilling to undergo protocol required thromboembolism or antiviral prophylaxis.
• 21 Subject is positive for human immunodeficiency virus (HIV), chronic or active hepatitis B, active hepatitis A, or active hepatitis C: A. Known positive HIV status. B. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen /[HBsAg/] either acute or chronic hepatitis). Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen /[anti-HBcAb/] and/or antibodies to hepatitis B surface antigen /[anti-HBsAb/]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be excluded.
• EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
• EXCEPTION: Subjects with positive anti-HBcAb but negative HBsAg and negative anti-HBsAb profiles are eligible if HBV DNA PCR is negative.
• C. Known to be seropositive for hepatitis C virus (HCV); anti-HCV antibody positive and HCV- ribonucleic acid (RNA) quantitation positive.
• 22 Subject has a history of anaphylaxis or hypersensitivity to thalidomide, lenalidomide, pomalidomide (including ≥ Grade 3 rash during prior IMiD therapy), or dexamethasone or the excipients contained in the formulations, or subject has any contraindications per local PI.
• 23 Ongoing Grade 3 or higher peripheral sensory or motor neuropathy, history of Guillan-Barre syndrome (GBS) or GBS variants, or history of any Grade /> 3 peripheral motor polyneuropathy.
• 24 Subject is an individual who is pregnant, nursing or breastfeeding, or who intends to become pregnant during participation in the study.

Описание

The purpose of this study is to determine the recommended phase 2 dose(s) (RP2D/[s/]) of JNJ-87562761 in Part 1 (dose escalation), and to determine the safety and tolerability at RP2D in Part 2 (dose expansion) in participants with multiple myeloma (MM) whose disease has come back after treatment (relapsed) or hasn`t responded to treatment (refractory).

Критерии включения

• * Relapsed, refractory multiple myeloma with measurable disease defined as: (a) Serum monoclonal paraprotein (M-protein) level greater than (/>)0.5 grams per deciliter (g/dL); or (b) Urine M-protein level />200 milligrams per 24 hours (mg/24 hours); or (c) Light chain multiple myeloma: serum immunoglobulin free light chain (FLC) />10 milligrams per deciliter (mg/dL) and abnormal serum immunoglobulin kappa-lambda FLC ratio
• * Must have had prior therapy including a proteasome inhibitor, immunomodulatory agent and anti-CD38 therapy
• * Have an eastern cooperative oncology group (ECOG) performance status of 0 to 1
• * Have an estimated glomerular filtration rate (eGFR), of /> 30 millilitres (mL)/min/1.73 meter square (m/^2) computed with the online calculator on the chronic kidney disease epidemiology collaboration (CKD-EPI) by use of the CKD-EPI serum creatinine (cr) result
• * While on study treatment and for 6 months after the last dose of study treatment, a participant must: (a) Not breastfeed or be pregnant; (b) Not donate gametes (that is, eggs or sperm) or freeze for future use for the purposes of assisted reproduction; (c) Wear an external condom

Критерии исключения

• * Active plasma cell leukemia, Waldenström`s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes), or immunoglobulin light chain amyloidosis
• * Prior allogeneic transplant within 6 months before the start of study treatment administration or autologous transplant within 12 weeks before the start of study treatment administration
• * Live, attenuated vaccine within 4 weeks before the first dose of study treatment
• * Central Nervous System (CNS) involvement or clinical signs of meningeal involvement of multiple myeloma. If either is suspected, brain magnetic resonance imaging (MRI) and lumbar cytology are required
• * Non-hematologic toxicity from prior anticancer therapy that has not resolved to baseline level or to less than or equal to (/<=) Grade 1 (except alopecia, tissue post-RT fibrosis, or Grade /< 3 peripheral neuropathy)
• * Received a cumulative dose of corticosteroids equivalent to greater than (/>) 140 mg of prednisone within the 14-day period before the start of study treatment administration
• * Prior antitumor therapy in the specified time frame prior to the first dose of study treatment: (Targeted therapy, epigenetic therapy, monoclonal antibody treatment, or treatment with an investigational drug or an invasive investigational medical device or conventional chemotherapy within 21 days, gene-modified adoptive cell therapy or treatment with anti-CD38 directed therapies within 3 months, proteasome inhibitor /[PI/] therapy or radiotherapy within 14 days, or immunomodulatory drug (IMiD) agent therapy within 7 days)
• * Following medical conditions: pulmonary compromise requiring supplemental oxygen use to maintain adequate oxygenation, human immunodeficiency (HIV) infection (participants with a detectable viral load or low CD4 count), active hepatitis B or C infection, active autoimmune disease requiring systemic immunosuppressive therapy within 6 months before start of study treatment, serious uncontrolled ongoing viral or bacterial or systemic fungal infection, cardiac conditions (myocardial infarction /<=6 months prior to enrollment, New York Heart Association stage III or IV congestive heart failure, et cetera /[etc./] )

Описание

Patients with relapsed/refractory symptomatic multiple myeloma who meet all inclusion criteria, will be randomized 1:1 to receive either standard of care chemotherapy (IKEMA or ICARIA) and dexamethasone until disease progression ("dexamethasone arm", arm A) or standard of care chemotherapy (IKEMA or ICARIA) and dexamethasone with dexamethasone discontinuation from the 3rd cycle of treatment (after 8 weeks) ("dexamethasone-free arm", arm B).

In most centers, IKEMA and ICARIA schema can be adapted according to the standard of care in each center Choice between the ICARIA and IKEMA schema is at the discretion of the investigator, in compliance with each drug`s SmPC, but must be performed before randomisation for the purpose of stratification.

Критерии включения

• 1. Adult patients (≥18 years old)
• 2. Documented MM in relapse according to standard criteria.
• 3. All patients must have received between 1 to 3 prior therapies for MM (a prior therapy is defined as 2 or more cycles of therapy given as a MM treatment plan)
• * Eligible for one of the following antibody-based approved combinations:
• 1. ICARIA schema: isatuximab, pomalidomide and dexamethasone.
• 2. IKEMA schema: isatuximab, carfilzomib and dexamethasone
• 4. Subject must have achieved a response (PR or better) to the prior regimen.
• 5. ECOG Performance Status score of 0, 1, or 2.
• 6. For subjects experiencing toxicities resulting from previous therapy (including peripheral neuropathy), the toxicities must have been resolved or stabilized.
• 7. Signed informed consent

Критерии исключения

• 1. Contraindications to investigational medicinal products or auxiliary medicinal product
• 2. Evidence of refractoriness or intolerance to anti-CD38 monoclonal antibodies.
• 3. Previous treatment according to the ICARIA schema with pomalidomide or IKEMA schema with carfilzomib
• 4. Allogenic hematopoietic cell transplant (HCT, regardless of timing).
• 5. Planned to undergo an hematopoietic cell transplant prior to progression of disease ie, these patients should not be enrolled in order to reduce disease burden prior to transplant.
• 6. History of malignancy (other than MM) within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix, or malignancy that in the opinion of the Investigator is considered cured with minimal risk of recurrence within 3 years).
• 7. Known MM meningeal Involvement.
• 8. Plasma cell leukemia (/>2.0 × 109/L circulating plasma cells by standard differential) or Waldenström`s macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or amyloidosis.
• 9. Any concurrent medical condition or disease (e.g., active systemic infection) that is likely to interfere with study procedures or results, or that, in the opinion, of the Investigator would constitute a hazard by participating in this study.
• 10. Uncontrolled chronic obstructive pulmonary disease (COPD)
• 11. Clinically significant cardiac disease.
• 12. Seropositive for hepatitis B with positive PCR
• 13. Seropositive for human immunodeficiency virus (HIV) or hepatitis C
• 14. Lactation
• 15. Participation to another interventional clinical trial
• 16. Inability to give written informed consent

Описание

This is a prospective, descriptive study designed to assess the feasibility of administering CAR T therapy among patients with moderate to severe renal impairment using dose adjusted lymphodepleting chemotherapy.

Критерии включения

• * Receiving lymphodepleting chemotherapy prior to commercial CAR-T administration for multiple myeloma, leukemia, or lymphoma
• * Adequate bone marrow function to receive lymphodepleting chemotherapy
• * Renal function /</= 60mL/min/1.73m2
• * ECOG 0-2

Критерии исключения

• * Relative CNS disorders
• * Active uncontrolled infection or any other concurrent disease or medical condition that was deemed to interfere with the conduct of the study as judged by the investigator
• * Use of therapeutic dose systemic corticosteroids (defined as />20mg/day prednisone or equivalent) within 72 hours of CAR-T administration

Описание

This is a single arm, open-label, dose escalation clinical study to evaluate the safety and tolerability of autologouschimeric antigen receptor T (CAR-T) cells targeting CD19/CD22/BCMA in patients with relapsed/refractory multiple myeloma.

Критерии включения

• * Participants must meet all of the following criteria in order to be enrolled:
• 1. Understand and voluntarily sign an informed consent form (ICF) before conducting any research related evaluations/procedures;
• 2. Age range: 18-75 years old;
• 3. Expected survival period is not less than 12 weeks;
• 4. ECOG score ≤ 2 points;
• 5. The bone marrow flow cytometry results showed positive BCMA antigen (including weak positive, moderate positive, and strong positive);
• 6. According to the IMWG criteria, a diagnosis of multiple myeloma with measurable lesions must meet at least one of the following criteria:
• 1. Serum M protein (SPEP) ≥ 5g/L
• 2. 24-hour urinary M-protein excretion rate ≥ 0.2g (200mg)
• 3. Serum free light chain (sFLC) ≥ 100 mg/L and abnormal free light chain ratio
• 4. The ratio of primitive plasma cells to immature plasma cells in bone marrow cytology examination is greater than 5%, or the flow cytometry detection of monoclonal plasma cells is greater than 5%
• 7. Those who have received treatment with at least three different mechanisms of action (including anti-CD38 monoclonal antibodies, protease inhibitors, immunosuppressants, etc.) but have failed, and have experienced relapse (within 12 months), difficulty in treatment, or intolerance to the last line treatment regimen, including primary difficulty in treatment (subjects who have not achieved minimal remission /[MR/] or developed disease progression /[PD/] during treatment) or secondary difficulty in treatment (subjects who develop disease progression within 60 days after completion of treatment);
• 8. There is no significant abnormality in lung function, and the oxygen saturation is greater than 92% in the absence of oxygen inhalation;
• 9. The blood biochemistry test results meet the following criteria:
• 1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN)
• 2. Total bilirubin ≤ 1.5 × ULN
• 3. 24-hour serum creatinine clearance rate ≥ 30 mL/min
• 4. Lipase and amylase ≤ 2 × ULN
• 10. The blood routine test meets the following criteria:
• 1. Lymphocyte count/>0.5 × 10 /^ 9/L
• 2. Neutrophil count ≥ 1.0 × 10 /^ 9/L
• 3. Hemoglobin ≥ 60g/L
• 4. Platelets ≥ 40 × 10 /^ 9/L
• 11. Men with fertility and women of childbearing age must agree to use effective contraceptive measures from the signing of the informed consent form until 2 years after the use of the study drug. Women of childbearing age include premenopausal women and women within 2 years after menopause. The blood pregnancy test for women of childbearing age must be negative during screening.

Критерии исключения

• * Any of the following situations cannot be selected as a subject:
• 1. Asymptomatic (smoking type) multiple myeloma;
• 2. Multiple myeloma with only extramedullary lesions present;
• 3. Plasma cell leukemia;
• 4. Merge amyloidosis;
• 5. Central nervous system (CNS) metastasis, leptomeningeal disease, or metastatic central compression;
• 6. Pregnancy or lactation period;
• 7. Individuals who are HBsAg positive or HBcAb positive, unless HBV-DNA is less than 100 IU/ml or below the minimum detectable value; Individuals who are positive for hepatitis C virus (HCV) antibodies and HCV-RNA; Individuals who are HIV antibody positive; Individuals who are positive for syphilis specific antibodies and have a positive TRUST (toluidine red unheated serum test) test; Individuals who test positive for Cytomegalovirus (CMV) DNA;
• 8. Cardiovascular diseases with clinical significance, including any of the following:
• 1. QT interval (QTcF) after heart rate correction:/>470 milliseconds;
• 2. New York Heart Association Grade II and above heart failure;
• 3. Left ventricular ejection fraction (LVEF) ≤ 50%;
• 4. Poorly controlled hypertension (systolic blood pressure ≥ 150 mm Hg and/or diastolic blood pressure ≥ 95 mm Hg)
• 5. Arrhythmias that have clinical significance or require antiarrhythmic treatment (such as persistent ventricular tachycardia, ventricular fibrillation, apical torsion tachycardia, and complete left bundle branch block);
• 9. Has experienced unstable angina or acute myocardial infarction within the 6 months prior to signing the ICF;
• 10. Previously received any anti-CD45 or anti-CD3 treatment;
• 11. Individuals who are allergic to any of the components of the drugs used in this study, including but not limited to Qing Lin drugs (cyclophosphamide, fludarabine), etc;
• 12. Received any investigational drug or systemic anti-tumor treatment within 4 weeks (or 5 half lives of the drug, whichever the researcher deems more appropriate) prior to single collection;
• 13. History of other primary malignant tumors within 5 years prior to treatment, except for the following situations:
• 1. Fully treat cured cervical carcinoma in situ;
• 2. Localized basal cell carcinoma or squamous cell carcinoma of the skin;
• 14. Any uncontrolled active infection within 4 weeks prior to single collection requires parenteral antibiotics, antiviral or antifungal treatment;
• 15. Individuals with a history of active pulmonary tuberculosis infection within one year prior to single sampling (excluding subjects with a history of active pulmonary tuberculosis infection more than one year ago who, according to the researcher`s judgment, currently have no evidence of active pulmonary tuberculosis);
• 16. Accompanying or having a history of interstitial lung disease or interstitial pneumonia;
• 17. Subjects who receive autologous hematopoietic stem cell transplantation (ASCT) within 8 weeks of signing the ICF, or who plan to undergo ASCT during the study period;
• 18. Subjects who have received allogeneic stem cell therapy in the past; The researchers believe that complications or other conditions in the subjects may affect their compliance with the protocol or make them unsuitable to participate in this study.

Описание

This study will evaluate efficacy and tolerability of iberdomide, bortezomib, dexamethasone and isatuximab on demand administered in combination.

Критерии включения

• 1. Must understand and voluntarily sign informed consent form
• 2. Age ≥ 65 years at the time of signing consent
• 3. Must be able to adhere to the study visit schedule and other protocol requirements.
• 4. Previously untreated, transplant ineligible, symptomatic multiple myeloma as defined by the criteria below.
• Both criteria a and b must be met:
• 1. Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma
• 2. Any one or more of the following myeloma defining events (MDE):
• I. Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: i.Hypercalcemia: serum calcium />0.25 mmol/L (/>1 mg/dL) higher than the upper limit of normal or />2.75 mmol/L (/>11 mg/dL) ii. Renal insufficiency: creatinine clearance 177 μmol/L (/>2 mg/dL) iii. Anemia: hemoglobin value of />2 g/dL below the lower limit of normal, or a hemoglobin value /<10g/dL iv. Bone lesions: one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography-CT (PET-CT)
• II. Biomarker criteria or MDE:
• i. Clonal bone marrow plasma cell percentage ≥ 60% ii. Involved: uninvolved serum free light chain (FLC) ratio ≥100 (involved FLC level must be ≥100 mg/L) iii. /> 1 focal lesions on magnetic resonance imaging (MRI) studies (at least 5 mm in size)
• 5. Must have Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2.
• 6. Females of child-bearing potential (FCBP) must have a negative serum test and follow the guidelines in the pregnancy prevention program. FCBP and males must either commit to continued abstinence from heterosexual intercourse or must abide by birth control requirements as described in Appendix 9 for the pregnancy prevention program.
• 7. Men must practice complete abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 28 days following study drug discontinuation, even if he has undergone a successful vasectomy as described in Appendix 9 of the pregnancy prevention program.
• 8. Life expectancy of ≥ 3 months.
• 9. Able to take oral medications.
• 10. The following laboratory results must be met within 10 days prior to first study drug administration:
• 1. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L. Growth factors cannot be given within 10 days of study drug administration.
• 2. Serum AST and ALT ≤ 1.5 x upper limit of normal (ULN).
• 3. Creatinine clearance ≥ 30 mL/min either directly measured via 24-hour urine collection or calculated using MDRD (Appendix 1).
• 4. Platelet count ≥ 50 x 109/L. Platelet transfusions to help subjects meet eligibility criteria are not allowed within 10 days before study enrollment.
• 5. Hemoglobin ≥ 80 g/L.

Критерии исключения

• 1. Previous treatment with anti-myeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid /[i.e. less than or equal to the equivalent of dexamethasone 40 mg/day for 4 days; such a short course of steroid treatment must not have been given within 14 days of treatment start/]).
• 2. Any serious medical condition that places the patient at an unacceptable risk if he or she participates in this study. Examples of such a medical condition are, but are not limited to, patient with unstable cardiac disease as defined by: Cardiac events such as MI within the past 6 months, NYHA heart failure class III-IV, uncontrolled atrial fibrillation or hypertension; patients with conditions requiring chronic steroid or immunosuppressive treatment, such as rheumatoid arthritis, multiple sclerosis and lupus, that likely need additional steroid or immunosuppressive treatments in addition to the study treatment.
• 3. Pregnant or lactating females.
• 4. Renal failure requiring hemodialysis or peritoneal dialysis.
• 5. Prior history of malignancies, other than multiple myeloma, unless the patient has been free of the disease for ≥ 3 years. Exceptions include the following:
• 1. Basal cell carcinoma of the skin
• 2. Squamous cell carcinoma of the skin
• 3. Carcinoma in situ of the cervix
• 4. Carcinoma in situ of the breast
• 5. Incidental histological finding of prostate cancer (TNM stage of T1a or T1b)
• 6. Patients who are unable or unwilling to undergo antithrombotic therapy.
• 7. Peripheral neuropathy of ≥ grade 2 severity.
• 8. Known HIV positivity or active infectious hepatitis, type A, B, or C.
• 9. Primary AL (immunoglobulin light chain) amyloidosis and myeloma complicated by amyloidosis.
• 10. Plasma Cell Leukemia
• 11. Evidence of cardiovascular risk including any of the following:
• 1. QTc interval ≥ 470 msecs. Note that the QT interval should be corrected for heart rate by Fridericia`s formula (QTcF)
• 2. Evidence of current clinically significant uncontrolled arrhythmias; including clinically significant ECG abnormalities; including 2nd degree (Type II) or 3rd degree atrioventricular (AV) block.
• 3. History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within six months of screening.
• 4. Class III or IV heart failure as defined by the New York Heart Association functional classification system (Appendix 2)
• 5. Uncontrolled hypertension
• 12. Patients with hypersensitivity to boron or any of its excipients or to the active substance of Iberdomide or its excipients
• 13. Patients requiring strong inhibitors or inducers of CYP3A4/5. See Appendix 10 for a list of these drugs
• 14. Any concurrent severe and/or uncontrolled medical condition or psychiatric disease that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study or that confounds the ability to interpret data from the study.
• 15. Patients that have had severe acute respiratory syndrome coronavirus 2 infection within 14 days for mild or asymptomatic infections or 28 days for severe/critical illness prior to initiating study treatment.
• 16. Patients that have undergone major surgery (as defined by the investigator) within 28 days of initiating study treatment.
• 17. Active systemic infection that is likely to interfere with the study procedures or results or that, in the opinion of the investigator, would constitute a hazard for participating in this study.
• 18. Patients with a gastrointestinal disease that may significantly alter the absorption of iberdomide
• 19. Patients that have received a live vaccine within 3 months of initiating study treatment.

Описание

The purpose of this study is to identify preventive treatments that can minimize the occurrence, severity, and duration of talquetamab-related distorted taste (dysgeusia), during the prophylaxis (preventive) treatment phase, and to better characterize the signs or symptoms of talquetamab-related distorted taste.

Критерии включения

• * Multiple myeloma (MM) according to IMWG diagnostic criteria
• * Were triple-class exposed (received prior treatment with a PI, an IMiD, and anti CD38 mAb)
• * Documented evidence of progressive disease based on investigator`s determination of response by IMWG criteria on or after their last regimen
• * Have an Eastern Cooperative Oncology Group-performance status (ECOG-PS) of 0 or 1 at screening. Participants with ECOG-PS 2 or 3 are eligible for the study if the ECOG-PS score is related to stable physical limitations (e.g., wheelchair-bound due to prior spinal cord injury) and not related to multiple myeloma or associated therapy
• * Be willing and able to adhere to the lifestyle restrictions specified in the protocol

Критерии исключения

• * Contraindications or life-threatening known allergies, hypersensitivity, or intolerance to any study drug or its excipients
• * Stroke, transient ischemic attack, or seizure within 6 months prior to enrollment
• * Any of the following within 6 months prior to the first dose of study treatment: severe or unstable angina, myocardial infarction; major thromboembolytic event (e.g., pulmonary embolism, cerebrovascular accident), clinically significant ventricular arrythmia or heart failure New York Heart Association functional classification Class III or IV. Uncomplicated deep vein thrombosis is not considered exclusionary
• * Major surgery or had significant traumatic injury within 2 weeks prior to the start of administration of study treatment, or will not have fully recovered from surgery, or has major surgery planned during the time the participant is expected to be treated in the study or within 2 weeks after administration of the last dose of study treatment
• * A WETT score suggesting severe dysgeusia at screening. Also unresolved/severe dysgeusia referred by the participant or a finding in the physical examination/oral cavity inspection. Some examples include leukoplakia, prior mouth cancers, extensive dental caries, severe periodontitis, active oral infections, candidiasis, parotic gland removal, or radiotherapy with resultant xerostomia

Описание

This is a study to evaluate the maximum tolerated dose (MTD), dose limiting toxicity (DLT), occurrence of all adverse events (AEs) and serious adverse events (SAEs), pharmacokinetic parameters, pharmacodynamic parameters, immunogenicity, and anti-tumor effects of TQB2029 for injection in Chinese adult subjects with multiple myeloma. The study is divided into Phase Ia and Ib, Phase Ia: dose escalation phase, to evaluate the safety and tolerability of TQB2029 for injection, and determining DLT and MTD; Phase Ib: Dose extension phase, to evaluate the effectiveness of TQB2029 for injection in subjects with multiple myeloma.

Критерии включения

• * Subjects who voluntarily join the study, sign the informed consent form, and have good compliance.
• * Aged from 18 to 75 years; Eastern Cooperative Oncology Group performance status score: 0-2; at least 12 weeks expected survival period.
• * Multiple myeloma with diagnostic records and meeting the International Myeloma Working Group (IMWG) diagnostic criteria
• * There are measurable lesions present
• * The function of main organs is normal.
• * Subjects need to adopt effective methods of contraception.

Критерии исключения

• * Subjects who have taken Chinese patent medicines with anti-tumor indications in the drug instructions that National Medical Products Administration approved within 2 weeks before the first administration.
• * Subjects who received targeted therapy or immunotherapy within 3 weeks before the first medication
• * Subjects who is known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
• * Subjects who has had or currently has other malignant tumors within the past 3 years prior to the first use of medication
• * Subjects who with unrelieved toxic reactions above Common Terminology Criteria for Adverse Events (CTC AE) grade 1 caused by any previous treatment
• * Subjects who have undergone major surgical treatment, significant traumatic injury, or are expected to undergo major surgery during the expected study treatment period within 4 weeks prior to the first use of medication
• * Subjects who have experienced arterial/venous thrombotic event occurred within 6 months prior to the first administration
• * Subjects with a history of psychotropic drug abuse unable to quit or with mental disorders;
• * Subjects with any severe and/or uncontrolled disease
• * According to the judgment of the investigators, there are accompanying diseases that seriously endanger the safety of patients or affect the completion of the study.

Описание

This study is a single-arm, open-label, exploratory dose-escalation and dose-finding clinical trial to evaluate the safety, efficacy, cellular pharmacokinetics and pharmacodynamics of CT0596 cells in patients with R/R MM and PCL.RRMM and RRpPCL

Критерии включения

• Participants must meet all of the following criteria to be enrolled:
• 1. Patients must voluntarily sign the informed consent form (ICF) and must be willing and be able to adhere to the trial visit schedule and other protocol requirements and agree to be in long term follow-up (LTFU) for up to 15 years as mandated by the regulatory guidelines.
• 2. Age ≥ 18 years;
• 3. Patients with R/RMM who have received at least 3 prior lines of therapy, including at least 1 proteasome inhibitor and at least 1 immunomodulator (IMiD). Patients with RRpPCL had received at least 1 prior line of therapy. Number of lines of therapy was defined according to the guidelines provided in Rajkuma/[1/]r 2015 . Patients must have received at least 1 complete cycle of therapy for each line of therapy.
• 4. According to multiple myeloma IMWG 2016 and plasma cell leukemia IMWG 2013, patients must have progressive disease following or during the last treatment.
• 5. Patients must have measurable disease based on at least one of the following parameters:
• 6. Expected survival /> 12 weeks;
• 7. Eastern Cooperative Oncology Group (ECOG) score 0- 1 ;
• 8. Patients should meet the following test results
• 9. Female patients of childbearing potential must have a negative pregnancy test at screening and prior to receiving lymphodepletion therapy and are willing to use a highly effective and reliable method of contraception for 1 year after receiving study treatment and are absolutely prohibited from donating eggs for 1 year after receiving study treatment infusion during the study ;Male patients are willing to use a highly effective and reliable method of contraception for 1 year after receiving study treatment if they are sexually active with a female of childbearing potential. Sperm donation is absolutely prohibited within 1 year following study treatment infusion for all male patients during the study.

Критерии исключения

• 1. Pregnant or lactating women;
• 2. Patient has any significant condition(s), laboratory abnormality or psychiatric illness that would impair the ability of the patient to receive or tolerate the planned treatment or in the opinion of the investigator, participation would not be in the best interest of the patient (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments
• 3. Patients seropositive for HIV, active hepatitis C virus (HCV), or active hepatitis B virus (HBV) infection. History of treated hepatitis B or C is permitted if the viral load is undetectable per qPCR and or nucleic acid testing;
• 4. Patients with any uncontrolled active infection, including but not limited to patients with active tuberculosis (investigator `s judgment);
• 5. Toxicities caused by previous treatment have not recovered to Common Terminology Criteria for Adverse Events (CTCAE) ≤ Grade 1, except alopecia and other events that are judged tolerable by the investigator;
• 6. Previous allogeneic stem cell transplantation; autologous stem cell transplantation within 12 weeks prior to signing informed consent;
• 7. Have received treatment for the disease within 14 days before informed consent
• 8. Have received cell therapy within 28 days before informed consent.
• 9. Systemic glucocorticoids equivalent to /> 15 mg/day prednisone within 7 days prior to informed consent, with the exception of topical glucocorticoids;
• 10. Vaccination with live attenuated vaccines , inactivated vaccines or RNA vaccines within 4 weeks prior to informed consent;
• 11. Allergic or intolerant to lymphodepletion, tocilizumab, or allergic to components (DMSO) in CT0596 CART cell infusion preparation; or previous history of other serious allergies such as anaphylactic shock;
• 12. Patients Waldenström macroglobulinemia, POEMS syndrome, or primary light chain amyloidosis at Screening;
• 13. Patients with any of the following cardiac conditions within 6 months prior to screening:
• 14. Patients who require supplemental oxygen to maintain oxygen saturation /> 92%; or Patients with known or suspected COPD who have Forced Expiratory Volume in 1 second (FEV1) /< 50% of predicted normal on spirometry;
• 15. Patients with active autoimmune diseases, including but not limited to psoriasis, rheumatoid arthritis and other diseases requiring long-term immunosuppressive therapy;
• 16. Patients with second primary malignancies are not eligible if the second primary malignancy has required treatment within the past 2 years or is not in complete remission. Exceptions include the following that have been successfully treated - nonmetastatic basal cell or squamous cell skin carcinoma, non-metastatic prostate cancer, carcinoma-in-situ of breast or cervix, non-muscle invasive bladder cancer
• 17. Patients with symptomatic central nervous system (CNS) disease or suspected CNS metastases;
• 18. Major surgery within 2 weeks before informed consent or planned during the study period or within 4 weeks after giving study treatment (excluding local anesthesia such as cataract)

Описание

Treatment for relapsed/refractory multiple myeloma continues to evolve with the approval of highly effective anti-BCMA CAR T therapies in recent years. However, despite the high prevalence of renal insufficiency in this population, pivotal clinical trials have excluded patients with impaired renal function, leading to an urgent, unmet clinical need to develop safe and effective lymphodepleting regimens prior to CAR T administration for this population. In addition, renal insufficiency is linked to poor disease-related outcomes and is highly associated with several underserved populations.

This study is testing the hypotheses that:

1. low-dose total body irradiation (TBI) in combination with cyclophosphamide (Cy) as lymphodepletion prior to administration of cilta-cel will be safe and tolerable in patients with multiple myeloma who have impaired renal function
2. low-dose TBI-Cy as lymphodepletion prior to cilta-cel will result in comparable CAR T expansion/persistence and disease response rates as those seen with standard lymphodepleting chemotherapy (fludarabine / cyclophosphamide).

Критерии включения

• * Histologically confirmed diagnosis of multiple myeloma.
• * Renal insufficiency, defined as eGFR /< 45 by MDRD formula.
• * At least 18 years of age.
• * ECOG performance status ≤ 1.
• * Meets standard of care indication for cilta-cel (per FDA approval).
• * Women of childbearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study or should a man suspect he has fathered a child, s/he must inform her treating physician immediately.
• * Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Критерии исключения

• * Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial.
• * Currently receiving any other investigational agents.
• * Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or unstable cardiac arrhythmia. Patients with a known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Function Classification; to be eligible for this trial, patients should be a class 2B or better.
• * Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.
• * HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible.
• * Evidence of chronic hepatitis B virus (HBV) that is detectable on suppressive therapy. Patients with evidence of chronic HBV infection with undetectable HBV viral load on suppressive therapy are eligible.
• * History of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible.

Описание

The aim of this study is to assess the clinical efficacy and safety of the anti-BCMA/CD3 bispecific antibody teclistamab (Tecvayli®) in a prospective, real-life setting in Belgium.

Критерии включения

• * Age 18 years or older
• * Written informed consent
• * Has a diagnosis of relapsed and refractory multiple myeloma
• * Has already received at least three previous treatments
• * Is refractory to at least 1 proteasome inhibitor, at least 1 immunomodulatory agent, and an anti-CD38 monoclonal antibody
• * Evidence of disease progression on the last line of therapy, based on determination of response by the IMWG response criteria
• * Anticipated to start treatment with teclistamab per routine clinical care or has started with teclistamab treatment ≤14 days before intended screening visit

Критерии исключения

• * Has participated in a teclistamab trial (teclistamab or control arm) or teclistamab Single Patient Request (SPR) program
• * Has started teclistamab treatment />14 days before intended screening visit.

Описание

Respiratory syncytial Virus (RSV) causes respiratory infections worldwide and typically presents with a seasonal pattern peaking in autumn/winter in temperate climate zones. Apart from infants and elderly individuals, patients with underlying substantial respiratory, cardiovascular, endocrinological diseases and immunocompromised patients are at increased risk to develop lower respiratory tract infection (LRTI) requiring intensive care associated with increased mortality. For certain risk groups such as patients after hematologic stem cell transplantation (HSCT) in-hospital mortality may be as high as 70 %. A causally related, RSV specific treatment does not exist and treatment is therefore usually supportive and non-specific.

The study is aiming to determine if immunocompromised patients benefit from two doses of a RSV subunit vaccine as opposed to one dose. The additional dose will be administered off label.

Критерии включения

• General inclusion criteria
• 1. Participants who, in the opinion of the investigator, can understand and will comply with the requirements of the protocol.
• 2. Participants living in the general community or in an assisted-living facility that provides minimal assistance can be enrolled, such that the participant is primarily responsible for self-care and activities of daily living.
• 3. Participants who can give written informed consent prior to study entry and performance of any study-specific procedure.
• 4. Female participants of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as hysterectomy, post-menopause, premenarche, bilateral oophorectomy, or bilateral salpingectomy
• 5. Female participants of childbearing potential may be enrolled in the study if the participant has practiced adequate contraception from 1 month prior to first Arexvy vaccination and agreed to continue adequate contraception for at least 1 month after completion of the last study intervention administration, and has a negative pregnancy test on the day of first vaccination prior to vaccine application.
• 6. Participants with chronic medical conditions with or without specific treatment are allowed to participate in this study if considered by the investigator as medically stable.
• 7. Additional inclusion criteria for "group 1":
• 7.1. Age ≥18 years at the time of signing the Informed consent form (ICF). 7.2. Diagnosis of a hemato-oncological disease: multiple myeloma including early stage disease or lymphoma in participants medically stable in the opinion of the investigator at study inclusion.
• 7.3. Participants without SCT or ≥3 months after autologous SCT until 24 months after SCT. SCT />24 months, if they have ongoing immunomodulatory/suppressive treatment.
• 7.4. Immunosuppressive or modulating medication related to the hemato-oncological disease are allowed.
• 8. Additional inclusion criteria for "group 2":
• 8.1. Age ≥18 years at the time of signing the Informed consent form (ICF). 8.2. Diagnosis of lung cancer ≥ stage 1. 8.3. Ongoing cancer treatment (including chemotherapy and immunotherapy) or initiation planned within 14 days and treatment initiation/vaccinations preferentially scheduled between treatment cycles.
• 9. Additional inclusion criteria for "group 3":
• 9.1. Age ≥18 years at the time of signing the Informed consent form (ICF). 9.2. Diagnosis of an autoimmune/chronic inflammatory disease with chronic inflammatory bowel disease (IBD) or rheumatoid arthritis (RA).
• 9.3. Treatment with biologicals such as TNF-alpha blocker, anti-CD20, JAK-inhibitors or other biological treatment (combinations with DMARDs, immunomodulators or steroidal or non-steroidal anti-inflammatory drugs are allowed).
• 9.4. Stable disease at time of study entry.
• 10. Additional inclusion criteria for "group 4":
• 10.1. Age ≥60 years at the time of signing the Informed consent form (ICF). 10.2. Healthy, as established by medical history before entering the study with medically stable/controlled chronic conditions such as diabetes, hypertension or cardiac disease allowed.

Критерии исключения

Описание

This phase Ib trial tests the safety, side effects and best dose of ST-067 in combination with teclistamab and how well it works in treating patients with multiple myeloma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). ST-067 is an engineered variant of the human cytokine interleukin-18 that may help the immune system kill cancer cells. Teclistamab is a bispecific antibody that can bind to two different antigens at the same time. Teclistamab binds to B-cell maturation antigen (BCMA), a protein found on some B-cells and myeloma cells, and CD3 on T-cells (a type of white blood cell) and may interfere with the ability of cancer cells to grow and spread. Giving ST-067 in combination with teclistamab may be safe, tolerable and/or effective in treating patients with relapsed or refractory multiple myeloma.

Критерии включения

• * Multiple myeloma, as defined by the presence of at least one International Myeloma Working Group (IMWG) MM-defining event
• * Measurable disease as defined by IMWG criteria, requiring one or more of the following:
• * Serum M-protein ≥ 0.5 g/dL
• * Urine M-protein ≥ 200 mg/24h
• * Involved serum free light chain ratio ≥ 10 mg/dL with abnormal kappa/lambda ratio
• * Measurable plasmacytoma, defined as ≥ 1 lesion with cross-sectional diameter ≥ 2 centimeters)
• * Bone marrow plasma cell percentage ≥ 30%
• * Eligibility to receive commercial tec per the Food and Drug Administration (FDA) package insert. This requires (1) at least 4 prior lines of therapy including a proteasome inhibitor (PI), immune modulatory imide drug (IMID), and CD38 monoclonal antibody (mAb); and (2) refractoriness, intolerance, or ineligibility (as deemed by the patient`s treating physician) to other established therapies known to provide clinical benefit in MM
• * If the FDA package insert for tec is changed to allow for its use in earlier lines of therapy, the above-mentioned stipulations still apply until a protocol modification is approved
• * Age ≥ 18 at study screening
• * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2
• * Anticipated survival of /> 3 months
• * Estimated glomerular filtration rate (eGFR) ≥ 40 mL/min using the Modification of Diet in Renal Disease equation
• * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) both ≤ 3 x the lab`s upper limit of normal (ULN)
• * Total bilirubin ≤ 2 x ULN
• * Platelets ≥ 25,000/μL at screening (no more than 1 transfusion in the 7-day period leading up to screening labs)
• * Hemoglobin ≥ 7 g/dL at screening (no more than 1 transfusion in the 7-day period leading up to screening labs)
• * Absolute neutrophil count (ANC) ≥ 1000 cells/mm/^3 at screening (no more than one administration of growth factor in the 7-day period leading up to screening labs)
• * For patients of reproductive potential only: Willingness to use an effective contraceptive method before, during, and for at least 5 months after the last dose of study therapy
• * Ability to understand and provide informed consent as well as willingness to comply with study requirements including visits and biopsies

Критерии исключения

• * History of prior BCMA-directed therapy in the past 12 months
• * History of another primary malignancy that has not been in remission for at least 1 year
• * However, the following diagnoses are eligible for inclusion: non-melanoma skin cancer, localized prostate cancer, superficial bladder cancer, cervical carcinoma in situ, or any prior malignancy with an estimated /> 90% 1-year cure rate per sponsor-investigator
• * Any condition requiring systemic treatment with corticosteroids (/> 10mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study drug administration. This includes active cytokine release syndrome (CRS), active graft-versus-host disease, or autoimmune conditions
• * Inhaled or topical steroids are allowed, as are replacement corticosteroids for adrenal insufficiency
• * Concurrent use of other anti-MM agents, including investigational drugs, within 7 days of study screening
• * Known central nervous system (CNS) involvement of MM at time of study screening
• * Active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) at time of study screening
• * Current pregnancy or breastfeeding, or planned pregnancy or breastfeeding within the next 12 months
• * Corrected QT (QTc) interval (Bazett formula) ≥ 500 milliseconds on screening electrocardiogram (ECG)
• * Uncontrolled or concurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

Описание

Patients who receive a chemotherapy called melphalan are at high risk of having nausea and vomiting. A medication called olanzapine has been shown to decrease nausea and vomiting after chemotherapy. A previous research study found the 10 mg dose of olanzapine (combined with 3 standard medications used routinely to prevent nausea/vomiting) to be effective for patients who received melphalan chemotherapy, but several other studies have shown many patients have a side effect of sleepiness (e.g., sedation) with that dose of the medication. Our study will compare two lower doses of olanzapine (5 mg and 2.5 mg) in combination with the 3 standard medications used to prevent nausea/vomiting in the patients who receive melphalan chemotherapy to determine which dose is effective in preventing nausea and vomiting with the lowest amount of sleepiness side effect.

Критерии включения

• * Receipt of high-dose melphalan 140-200 mg/m2
• * Autologous stem cell transplantation recipient

Критерии исключения

• * Allergy to olanzapine
• * Documented nausea or vomiting within 24 hours prior to enrollment
• * Treatment with other antipsychotic agents such as risperidone, quetiapine, clozapine, phenothiazine, or butyrophenone within 30 days prior to enrollment or planned during protocol therapy
• * Chronic alcoholism
• * Pregnant
• * Decline or unable to provide informed consent

Описание

The purpose of this study is to monitor the long-term safety of participants who received idecabtagene vicleucel treatment as part of the KarMMa-9 (CA089-1043) Phase 3 clinical trial.

Критерии включения

• * Adult participants ≥19 years of age
• * Korean participants with newly diagnosed multiple myeloma who had a suboptimal response after autologous stem cell transplantation (ASCT) and who were treated with idecabtagene vicleucel (assigned to Arm A) in the KarMMa-9 trial (CA089-1043)
• * Participants must understand and voluntarily sign and informed consent form (ICF) for the Korea long-term follow-up surveillance study prior to any surveillance-related procedures being conducted

Критерии исключения

• * Participants who participate in KarMMa-9 trial (CA089-1043) but disagree with long-term follow-up surveillance in Korea
• * Participants who are not possible to treat with Ide-cel within 9 days post-completion of lymphodepleting chemotherapy (LDC), if delays occur. However, depending on the participants recovery status, whether idecabtagene vicleucel is administered or not, should be discussed with a medical monitor

Описание

This study evaluates the maintenance strategy based on risk stratification and MRD status after stem cell transplantation.

This is a single-arm, multicenter, prospective study. Participants who are R2-ISS 1,2 and MRD negative receive the single drug lenalidomide maintenance. In other circumstances, for example, patients who are R2-ISS 3 or 4 will receive daratumumab combined with lenalidomide regardless of MRD status, while patients with MRD positivity will also receive daratumumab plus lenalidomide maintenance.

Критерии включения

• 1. Newly diagnosed multiple myeloma with a history of a minimum of 4 cycles of induction therapy, have received high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) within 12 months of the start of induction therapy, and be within 6 months of ASCT.
• 2. Must have a partial response (PR) or better response before maintenance.
• 3. Must have an Eastern Cooperative Oncology Group performance status score of 0, 1, or 2.
• 4. This study allows for post-ASCT consolidation therapy.
• 5. ANC ≥ 1.0 x 10/^9/L, Hb ≥ 85 g/L PLT ≥ 75 x 10/^9/L (if BMPC /< 50%) or PLT ≥ 50 x 10/^9/L (if BMPC ≥ 50%).
• 6. No active infection.
• 7. a).TBIL/<1.5 x upper limit of normal (ULN) (/<3 x ULN in patients with Gilbert`s syndrome); b).AST and ALT /<3 x ULN.; c. Creatinine clearance ≥ 45mL/min.

Критерии исключения

• 1. Must not refractory or non-tolerate to lenalidomide in Arm A.
• 2. Must not refractory or non-tolerate to lenalidomide and daratumumab in Arm B.
• 3. Must not have progressed on multiple myeloma (MM) therapy before screening
• 4. Chronic obstructive pulmonary disease (COPD) with FEV1 less than 50 % of predicted normal；
• 5. Have known moderate or severe persistent asthma within the past 2 years or current uncontrolled asthma of any classification
• 6. History of stroke or serious thrombotic event within 12 months prior to screening.

Описание

The aim of this research study is to evaluate the efficacy of Elotuzumab and Iberdomide therapy post-Idecabtagene Vicleucel in participants with relapsed and refractory multiple myeloma.

The names of the study drugs involved in this study are:

* Iberdomide (a type of cereblon E3 ligase modulator)
* Elotuzumab (a type of monoclonal antibody)
* Dexamethasone (a type of steroid)

Критерии включения

• * Previously diagnosed with MM based on standard IMWG criteria
• * Patient has given voluntary written informed consent before any study-related procedures not part of normal medical care are performed, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.
• * Patient who has been treated with at least 4 prior lines of anti-myeloma treatment including immunomodulating agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.
• * In addition, to at least 4 prior lines of anti-myeloma treatment, patient has received ide-cel in accordance with the FDA approved US Prescribing Information and has achieved at least a partial response, and is within 90 days of infusion
• * ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
• * Screening Laboratory evaluations within the following parameters
• * Absolute neutrophil count (ANC) ≥ 1,000 cells/dL (1.0 x 109/L) (Growth factors cannot be used more recently than 7 days prior to initiation of therapy)
• * Platelet count ≥ 75,000 cells/dL (75 x 109/L) (without transfusions during the 7 days prior to initiation of therapy)
• * Hemoglobin ≥ 8.0 g/dL (RBC transfusions are permitted)
• * Total Bilirubin ≤ 1.5 X upper limit of normal (ULN) (except subjects with Gilbert Syndrome, who can have total bilirubin /< 3.0 mg/dL)
• * AST or ALT ≤ 3x ULN
• * Creatinine clearance ≥ 30 ml/min according to the Cockroft-Gault formula:
• * Female CrCl = /[(140 - age in years) x weight in kg x 0.85/] / /[72 x serum creatinine in mg/dL/]
• * Male CrCl = /[(140 - age in years) x weight in kg x 1.00/] / /[72 x serum creatinine in mg/dL/]
• * Age ≥18 years.
• * Ability to understand and the willingness to sign a written informed consent document.
• * A Female of childbearing potential (FCBP) must:
• * Have two negative pregnancy tests before enrollment and randomization into the clinical studies and prior to each re-supply of study drug during the clinical studies based on the frequency outlined in the Pregnancy Prevention Plan (PPP, Appendix D).
• * Sexually active FCBP must agree to use protocol-specified contraceptive methods during participation in the clinical studies and for at least 28 days after the last dose of study drug.
• * Sexually active males (including those who have had a vasectomy) must agree to use protocol specified contraceptive methods during participation in the clinical studies and for at least 28 days after the last dose of study drug.
• * All participants (male and female with or without childbearing potential) must agree to abstain from donating blood products for at least 28 days after the last dose of study drug and semen or sperm while taking study drug and for at least 28 days after the last dose of study drug.

Критерии исключения

• * Prior exposure to Iberdomide
• * Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial.
• * Diagnosed or treated for another malignancy within 3 years prior to enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in-situ malignancy, or low risk prostate cancer after curative therapy
• * Known central nervous system involvement.
• * Systemic treatment, within 14 days before the first dose of treatment, with strong CYP3A or inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John`s wort OR systemic treatment within 14 days of the first dose of treatment with a strong inhibitor of CYP1A2 (ciprofloxacin, fluvoxamine, cimetidine, enoxacin, ethynyl estradiol, mexiletine)
• * Any medical or psychiatric illness/social situation that in the Investigator`s opinion, would impose excessive risk to the patient, would adversely affect his/her participating in this study or would limit compliance with study requirements.
• * Currently active graft versus host disease of any stage or grade after allogeneic stem cell transplantation
• * Prior major surgical procedure or radiation therapy within 14 days of initiation of therapy.
• * Those who require a limited course of radiation for management of bone pain more than 14 days out from initiation of therapy are not excluded
• * Any active, or uncontrolled cardiovascular conditions, including but not limited to uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, grade 3 thromboembolic event or myocardial infarction within the past 6 months.
• * The following therapies within the stated time frames prior to initiation of therapy:
• * Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma within 21 days (42 days for nitrosoureas).
• * The use of live vaccines within 30 days.
• * IMiDs or proteasome inhibitors within 14 days.
• * Other investigational therapies and/or monoclonal antibodies within 4 weeks.
• * Prior peripheral stem cell transplant within 12 weeks.
• * Prior allogeneic stem cell transplantation with active graft-versus-host-disease.
• * Those who require a limited course of daily requirement for corticosteroids (equivalent to />10 mg/day prednisone, though />10mg/day is acceptable if physiological levels require, so long as the dose is stable for at least 7 days prior to initiation of therapy. Inhalation corticosteroids are exempt from this criterion.
• * Lower amounts of corticosteroids that are not part of a daily requirement within 14 days prior to initiating therapy
• * Concurrent symptomatic amyloidosis or plasma cell leukemia
• * POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes)
• * Infection requiring systemic antibiotic therapy or other serious infection within 7 days of starting therapy.
• * Those who are on prophylactic antibiotics only, or on antibiotics and have confirmation of resolution of active infection are eligible.
• * Known seropositive for active viral infection with human immunodeficiency virus (HIV) hepatitis B (HBV) or hepatitis C viral (HCV). Those who are seropositive because of hepatitis B vaccine are eligible. Patients who are positive for HBV core antibody or HBV surface antigen must have a negative polymerase chain reaction (PCR) result prior to enrollment. Those who are PCR positive will be excluded
• * Female patients who are pregnant or lactating.
• * Participants who are receiving any other investigational agents for any indication
• * History of erythema multiforme or severe hypersensitivity to prior IMiD`s® or those who have a known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
• * Inability to tolerate thromboprophylaxis
• * Failure to have fully recovered (≤ Grade 2 according to CTCAE v 5) from the reversible effects of prior chemotherapy

Описание

This is an observational case-control study, aiming to systematically analyze the gut microbiome characteristics of patients with monoclonal gammopathy of undetermined significance (MGUS). The study will collect blood and stool samples from MGUS patients, non-MGUS patients (with similar diseases), and healthy controls, and perform multi-omics detection including microbiomics, peptidomics, and biochemical immunology. It will comprehensively analyze the abnormal features of the gut microbiome in MGUS patients, which may help provide new biomarkers and potential mechanisms for the diagnosis, prognosis evaluation, and treatment strategies of MGUS.

Критерии включения

• (I) Inclusion Criteria:
• 1. Age 45 years or older;
• 2. Negative screening for monoclonal protein by MALDI-TOF MS;
• 3. No significant diseases found upon medical examination, and confirmed not to have any diseases related to this study;
• 4. Sufficient whole blood, plasma, serum, and stool samples available, and relevant case data can be provided.
• (II) Exclusion Criteria:
• 1. History of intestinal tumors, irritable bowel syndrome, or inflammatory bowel disease, or diagnosed during hospitalization;
• 2. Antibiotic treatment received in the past month; Presence of severe systemic diseases, including malignant tumors;
• 3. Insufficient sample volume, or presence of severe hemolysis, lipemia, jaundice, or other unqualified sample conditions.

Критерии исключения

Описание

This is an open-label, single-arm, prospective study conducted in real-world clinical practice. It aims to evaluate the efficacy and safety in Chinese patients with newly diagnosed multiple myeloma who switch to carfilzomib-based regimens after bortezomib-based triple-drug regimen intolerance happens.

Критерии включения

• 1. ≥ 18 years of age
• 2. Diagnosed with multiple myeloma according to IMWG criteria.
• 3. Patients who have received only first-line bortezomib-based triple therapy, including bortezomib/lenalidomide/dexamethasone (VRD), bortezomib/thalidomide/dexamethasone (VTD）,bortezomib/ cyclophosphamide/dexamethasone (VCD), and bortezomib/adriamycin//dexamethasone (PAD).
• 4. Eastern cooperative oncology group(ECOG) score 0-2
• 5. Patients who develop toxicities associated with bortezomib therapy evaluated by the investigator, including the presence of Grade 1 with pain or Grade 2 peripheral neuropathy (PN), Grade 3 hepatic impairment, Grade 3 diarrhea, and any other Grade 3 non-hematologic adverse events and resulting in bortezomib dose reduction or discontinuation.
• 6. Patients who agree to and sign informed consents to participate in this study.

Критерии исключения

• 1. Patients currently participating in other interventional clinical studies (except those currently participating in non-interventional observational studies)
• 2. Patients who have received prior carfilzomib treatment or participated in carfilzomib associated studies (with or without carfilzomib treatment).
• 3. Patients with a primary diagnosis of MM combined with plasma cell leukemia (peripheral blood monoclonal plasma cells ≥5% of the total number of differentiated mature leukocytes)
• 4. Patients who have not fully recovered from the reversible effects of prior chemotherapy (i.e., /<= grade 1 toxicity).
• 5. Patients with other malignancies diagnosed prior to the MM diagnosis, excluding squamous and basal cell carcinomas of the skin, and carcinoma in situ of the cervix or breast, which can be cured within 3 years with minimal risk of recurrence.
• 6. Patients with an active systemic infection, active hepatitis B or C virus infection, or known positive test results for human immunodeficiency virus.
• 7. Evidence of current uncontrolled cardiovascular disease, including hypertension, arrhythmias (prolonged QT interval, ventricular tachycardia, ventricular flutter, ventricular fibrillation, frequent ventricular premature beats (24-hour premature loading of ≥15% of the total number of beats), grade Ⅲ atrioventricular block, and a heart rate of /<30-40 bpm congestive heart failure, unstable angina, or myocardial infarction in the past 3 months,. New York Heart Association (NYHA) class III and IV heart failure. left ventricle ejection fraction（LVEF） /<40% on cardiac ultrasound.
• 8. Participants with known chronic obstructive pulmonary disease (COPD) (defined as forced expiratory volume in 1 second /[FEV1/] /<50% of predicted normal value), persistent asthma, or a history of asthma within the past 2 years (controlled intermittent asthma or mild persistent asthma that is allowed). Participants with known or suspected COPD must undergo FEV1 testing during screening.
• 9. Inability to comply with protocol/procedure.
• 10. Patients with hypersensitivity to the active ingredient or excipients of carfilzomib.
• 11. Pregnant or lactating women

Описание

The purpose of this study is to see if siltuximab plus population pharmacokinetic (PK)-dosed melphalan works as well as the usual approach (body surface area /[BSA/]-dosed melphalan) in people with multiple myeloma (MM) who are receiving an autologous stem cell transplant (ASCT) as part of their standard treatment. The researchers will also see if siltuximab in combination with population PK-dosed melphalan works to decrease symptoms after an ASCT, and will study the safety of siltuximab.

For the run-in, 15 patients will receive siltuximab, 11 mg/kg, seven days before and 14 days after autologous hematopoietic stem cell infusion (+/-2 day).

Критерии включения

• * Histologically-confirmed symptomatic multiple myeloma undergoing autologous HCT with plan off study for melphalan 140 or 200 mg/m2 undergoing HCT within 12 months of diagnosis.
• * At least 60 years of age
• * Have at least 3 million x 10/^6 CD34+ cells/kg to be infused
• * KPS performance status />60% or ECOG Performance Status score of 0-2
• Within 6 weeks prior to enrollment:
• * Diffusion capacity />45% (adjusted for hemoglobin) as predicted by pulmonary function testing.
• * LVEF />45% by MUGA or rest ECHO
• * Clinical laboratory values meeting the following criteria
• * Platelet count ≥ 20 x 10/^9/L
• * ALT and AST ≤ 2.5 x ULN o Total bilirubin ≤ 2.5 x ULN; except if the elevation is due to Gilbert`s syndrome
• * Calculated creatinine clearance /> 40 mL/min
• * Before enrollment, all women are expected to be not of childbearing potential as they will be age 60+.
• * A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the study and for 3 months after receiving the last dose of study drug

Критерии исключения

• * Prior exposure to agents targeting IL-6 or the IL-6 receptor
• * Other malignancy within the past 2 years, except for the following if treated and not active: basal cell or nonmetastatic squamous cell carcinoma of the skin, cervical carcinoma in situ or International Federation of Gynecology and Obstetrics (FIGO) Stage 1 carcinoma of the cervix. Prostate cancer under observation may be enrolled after discussion with the MSK Principal Investigator.
• * Concurrent medical condition or disease (eg, autoimmune disease, active systemic Infection) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in the study
• * Ischemic heart disease requiring intervention in the prior 3 months or uncontrolled heart failure or an uncontrolled arrhythmiaQTc is />460ms by Fridericia. If they have a right or left bundle branch block or intraventricular conduction delay then exclusion will be for />500ms by Friderica.
• * Vaccination with live attenuated vaccines within 4 weeks of first study agent administration
• * Clinically significant infection, including known HIV or hepatitis C infection, or known hepatitis B (Hep B) surface antigen positivity. Patients with Hep B Core positivity can be enrolled if the Hep B PCR is negative, and they are on antiviral suppression. Patients with Hepatitis C Ab positive who are PCR negative and have completed Hepatitis C treatment can be enrolled. HIV with negative viral load on HAART can be enrolled.
• * Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 14 days or 5 half lives before enrollment or is currently enrolled in the treatment stage of an investigational study
• * Had hospitalization for infection or major surgery (eg, requiring general anesthesia) within 2 weeks before enrollment or have not fully recovered from surgery. Note: subjects with surgical procedures conducted under local anesthesia may participate
• * A man who plans to father a child while enrolled in this study or within 3 months after the last dose of study agent.

Описание

This is a first-in-human study of SAR446523 conducted in patients with RRMM.

The study consists of two parts:

Dose escalation (Part A): In this part, up to 6 dose levels (DLs) of SAR446523 will be explored to determine the maximum administered dose (MAD), maximum tolerated dose (MTD), and recommended dose range (RDR) of 2 dose regimens which will be tested in the dose optimization part.

Dose optimization (Part B): In this part, participants will be randomly assigned in a 1:1 ratio using interactive response technology (IRT) to either one of the chosen dose regimens of SAR446523 (determined from data coming from Part A), to determine the optimal dose as the recommended phase 2 dose (RP2D) of SAR446523.

Критерии включения

• * Participants with a documented diagnosis of multiple myeloma (MM) with measurable disease.
• * Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Dose escalation (Part A)
• * Participants must have received at least 3 prior lines of antimyeloma therapy, and must be either relapsed or refractory to the above therapies, or are intolerant to them.
• * Note: In Part A, prior exposure to anti g-protein-coupled receptor, class c, group 5, member d (GPRC5D) therapy and anti B-cell maturation antigen (BCMA) therapy is allowed.
• Dose optimization (Part B)
• * Participants must have received at least 3 prior lines of antimyeloma therapy and be either relapsed or refractory to immunomodulator (IMiD), proteasome inhibitor (PI), anti CD38 monoclonal antibody (mAb), and anti BCMA targeting agent or are intolerant to them.
• * Note: In Part B, prior exposure to antiGPRC5D therapy is not allowed.

Критерии исключения

• -Participants are excluded from the study if any of the following criteria apply: Eastern cooperative oncology group performance status (ECOG PS) of 2 or greater.
• * Primary systemic and localized amyloid light chain (AL) amyloidosis, active polyneuropathy, organomegaly, endocrinopathy, myeloma protein, and skin changes (POEMS) syndrome, active plasma cell leukemia. Participants with central nervous system involvement or with clinical signs of meningeal involvement of multiple myeloma.
• * Systemic antimyeloma treatment within 14 days before the first study treatment administration.
• * Prior treatment with natural killer (NK)-cell engaging therapy (such as monoclonal antibody with antibody-dependent cellular cytotoxicity as primary mechanism of action) within 90 days of the first study treatment administration.
• * Inadequate organ and marrow function.
• * Participants with significant concomitant illness.
• The above information is not intended to contain all considerations relevant to the potential participation in a clinical trial.

Описание

This study includes extended CD34+ profiling on the apheresis product of multiple myeloma patients undergoing standard-of-care quad-induction followed by motixafortide + G-CSF mobilization, and in addition, assesses the pharmacodynamics (PD) of motixafortide following "standard" (/~12 hours) vs "early" (/~16 hours) dosing. The investigators hypothesize that quad-induction may alter the stem cell subsets within the mobilized graft. The investigators further hypothesize that standard and early dosing strategies will result in comparable mobilization and stem cell collection rates.

Критерии включения

• * Subjects must be between the ages of 18 and 78 years, inclusive.
• * Histologically confirmed multiple myeloma expected to receive high-dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT)
• * Received ≥3 cycles but ≤6 cycles of daratumumab-based quadruplet induction therapy (quadruplet induction therapy: combining daratumumab, a proteasome inhibitor, an IMiD, and dexamethasone) before ASCT
• * At least one week (7 days) from last induction cycle prior to the first dose of G-CSF for mobilization
• * The subjects should be in first or second CR (including CR and SCR) or PR (including PR and VGPR)
• * ECOG performance status 0 or 1
• * Adequate organ function at screening as defined below:
• * White blood cell (WBC) counts /> 2.5 × 10/^9/L
• * Absolute neutrophil count /> 1.5 K/cumm
• * Platelet count />100 K/cumm
• * GFR value of ≥15 mL/min/1.732 (by MDRD equation)
• * ALT and/or AST ≤2.5 × ULN
• * Total bilirubin ≤2.0 × ULN unless the participant has Gilbert disease
• * INR or PT: ≤1.5 × ULN unless participant is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants
• * aPTT: ≤1.5 × ULN unless participant is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
• * Female subjects must be of non-childbearing potential or, if of childbearing potential, must have a negative serum pregnancy test at screening and negative urine or serum pregnancy test within 7 days prior to G-CSF first administration.
• Non-childbearing potential is defined as (by other than medical reasons):
• * ≥45 years of age and has not had menses for over 2 years
• * Post hysterectomy, bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation at least 6 weeks prior to screening
• * Women of childbearing potential must agree to use 2 methods of effective contraception: One barrier method (e.g., diaphragm, or condom or sponge, each of which are to be combined with a spermicide) and one hormonal method, unless she uses a highly effective method. Highly effective methods of contraception include:
• * Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal
• * Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable, intrauterine device (IUD)
• * Intrauterine hormone-releasing system (IUS)
• * Bilateral tubal occlusion
• * Vasectomized partner
• * Sexual abstinence These methods must be used starting at study enrollment and for the duration of study participation through 8 days after the last dose of motixafortide.
• Male subjects must agree to use an adequate method of contraception (barrier method) starting with the first day of G-CSF administration through 8 days after the last dose of motixafortide.
• * Ability to understand and willingness to sign an IRB approved written informed consent document.

Критерии исключения

• * Previous history of autologous or allogeneic-HCT
• * Failed previous HSC collections or collection attempts
• * Taken any of the listed below concomitant medications, growth factors or stimulating agents within the designated washout period:
• * Dexamethasone: 7 days
• * Thalidomide: 7 days
• * Lenalidomide: 7 days
• * Pomalidomide: 7 days
• * Bortezomib: 7 days
• * Carfilzomib: 7 days
• * Ixazomib: 7 days
• * G-CSF: 14 days
• * GM-CSF or pegfilgrastim: 21 days
• * Erythropoietin or erythrocyte-stimulating agents: 30 days
• * Eltrombopag, romiplostim or platelet-stimulating agents: 30 days
• * Carmustine (BCNU): 42 days/6 weeks
• * Received />6 cycles lifetime exposure to an IMiD
• * Received />8 cycles of alkylating agent combinations
• * Received />6 cycles of melphalan
• * Received prior treatment with radioimmunotherapy (e.g., radionuclides, holmium)
• * Received prior treatment with venetoclax
• * Has received a live vaccine within 30 days of the planned start of G-CSF administration. Seasonal flu vaccines that do not contain live virus are permitted.
• * Known active CNS metastases or carcinomatous meningitis
• * A history of allergic reactions attributed to compounds of similar chemical or biologic composition to motixafortide, G-CSF or other agents used in the study
• * Has an active or uncontrolled infection requiring systemic therapy
• * Has a known additional malignancy that is progressing or requires active treatment
• * Has a known underlying medical condition that, in the opinion of the treating physician or Principal Investigator, would preclude study participation.
• * Is currently participating in an investigational treatment study, or has participated in a study of an investigational agent and received study therapy, or has been treated with an investigational device, within 4 weeks prior to the first dose of treatment.
• * O2 saturation /< 92% (on room air)
• * Personal history or family history of long QT syndrome or torsade de pointes
• * History of unexplained syncope, syncope from an uncorrected cardiac etiology, or family history of sudden cardiac death.
• * History of myocardial infarction, CABG, coronary or cerebral artery stenting and/or angioplasty, stroke, cardiac surgery, or hospitalization for congestive heart failure within 3 months prior to study enrollment, Angina Pectoris Class />2 or NYHA Heart Failure Class />2.
• * ECG at screening showing QTcF />470 msec and/or PR />280 msec
• * Mobitz II 2nd degree AV Block, 2:1 AV Block, High Grade AV Block, or Complete Heart Block, unless the participant has an implanted pacemaker or implantable cardiac defibrillator (ICD) with backup pacing capabilities.
• * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial, in the opinion of the treating physician or Principal Investigator.
• * Is pregnant or breast-feeding or expecting to conceive or women of childbearing potential unless consent to use two contraceptive methods or highly effective contraception as detailed above, within the projected duration of the trial, starting with the Screening Visit through 8 days after the last dose of study drug.
• * HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible.
• * Evidence of chronic hepatitis B virus (HBV) that is detectable on suppressive therapy. Patients with evidence of chronic HBV infection with undetectable HBV viral load on suppressive therapy are eligible.
• * History of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible.

Описание

This trial is an adaptive platform trial. The structure of the protocol allows the trial to evolve over time. Multiple investigational arms will be included within the trial under a Master Protocol (MP). These investigational arms may be added as appendices at different times depending on whether they are trial-ready and whether accrual in the trial will support another arm. Accrual to an arm will terminate in accord with the arm`s appendix to the Master Protocol.

The purpose of this proposed structure is to support the recurrent research challenge of efficiently evaluating what is the best therapy for a particular patient.

Критерии включения

• * For inclusion in the trial, all the following inclusion criteria must be fulfilled, as no waivers will be permitted:
• Voluntarily agree to participate by giving written informed consent
• ≥18 years of age
• Histologically confirmed multiple myeloma that has relapsed from, is considered refractory to, or is intolerant to regimens containing any of the following:
• A proteasome inhibitor
• An immunomodulating agent
• A CD38-monoclonal antibody
• Measurable disease, defined as one of the following:
• M-protein ≥ 0.5g/dL (0.3 g/dL or above if IgA subtype)
• Urine M-protein ≥ 200 mg/24hours
• Serum free light chain difference /> 100 mg/L
• Serum free light chain ratio (involved/uninvolved) ≥ 8
• Biopsy proven plasmacytoma
• Bone marrow involvement />10%
• ECOG performance status of 0-2
• Adequate organ function, as indicated by the following laboratory values:
• Adequate hematological function, defined as ANC ≥ 1000/µL, platelet count ≥ 75,000/µL, and hemoglobin ≥ 8 g/dL (transfusion and/or growth factor support is allowed for hematologic parameters as long as the investigator deems the patient otherwise fit for screening)
• Adequate hepatic function, defined as total bilirubin level ≤ 1.5 x institutional upper limit of normal (IULN) except in participants with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤1.5 x IULN is required), AST ≤ 2.5 x IULN, and ALT ≤ 2.5 x IULN
• Adequate renal function, defined as calculated creatinine clearance ≥ 30 mL/min per institutional standard (assessment method should be recorded, measured or C-G acceptable)
• Adequate coagulation, defined as international normalized ratio (INR) or prothrombin time ≤ 1.5 x IULN and activated partial thromboplastin time (aPTT) ≤ 1.5 x IULN (unless patient is receiving anticoagulant therapy)
• Persons of childbearing potential must have a negative serum pregnancy test at screening (within 72 hours of first dose of trial medication). Non-childbearing potential for a person assigned as female at birth is defined as 1 of the following:
• ≥ 45 years of age and has not had menses for />1 year
• Amenorrheic for /> 2 years without a hysterectomy and/or oophorectomy and follicle-stimulating hormone value in the postmenopausal range upon pretrial (screening) evaluation
• Status is post-hysterectomy, -oophorectomy, or -tubal ligation
• Persons of childbearing potential must be willing to use highly effective contraceptive measures during sexual contact with a person assigned as male at birth starting with the Screening visit through 90 days after last dose of trial treatment.
• Note: Abstinence is acceptable if this is the established and preferred contraception for the participant.
• Persons assigned as male at birth with a partner(s) of childbearing potential must agree to use highly effective contraceptive measures throughout the trial starting with the Screening visit through 90 days after the last dose of trial treatment is received. Persons assigned as male at birth with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.
• Note: Abstinence is acceptable if this is the established and preferred contraception method for the participant.
• Known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using New York Heart Association Functional Classification. To be eligible for this trial, patients should be Class 2 or lower. Class 2 is defined as slight limitation of physical activity, in which ordinary physical activity leads to fatigue, palpitation, or dyspnea; the person is comfortable at rest.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessments of the investigational arms are eligible for this trial.
• Patients with known HIV infection who are on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• Patients with evidence of chronic hepatitis B virus (HBV) infection must have an undetectable HBV viral load on suppressive therapy, if indicated.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with known HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• Willing and able to comply with the requirements of the protocol.

Критерии исключения

• * For inclusion in the trial, all the following inclusion criteria must be fulfilled, as no waivers will be permitted:
• Voluntarily agree to participate by giving written informed consent
• ≥18 years of age
• Histologically confirmed multiple myeloma that has relapsed from, is considered refractory to, or is intolerant to regimens containing any of the following:
• A proteasome inhibitor
• An immunomodulating agent
• A CD38-monoclonal antibody
• Measurable disease, defined as one of the following:
• M-protein ≥ 0.5g/dL (0.3 g/dL or above if IgA subtype)
• Urine M-protein ≥ 200 mg/24hours
• Serum free light chain difference /> 100 mg/L
• Serum free light chain ratio (involved/uninvolved) ≥ 8
• Biopsy proven plasmacytoma
• Bone marrow involvement />10%
• ECOG performance status of 0-2
• Adequate organ function, as indicated by the following laboratory values:
• Adequate hematological function, defined as ANC ≥ 1000/µL, platelet count ≥ 75,000/µL, and hemoglobin ≥ 8 g/dL (transfusion and/or growth factor support is allowed for hematologic parameters as long as the investigator deems the patient otherwise fit for screening)
• Adequate hepatic function, defined as total bilirubin level ≤ 1.5 x institutional upper limit of normal (IULN) except in participants with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤1.5 x IULN is required), AST ≤ 2.5 x IULN, and ALT ≤ 2.5 x IULN
• Adequate renal function, defined as calculated creatinine clearance ≥ 30 mL/min per institutional standard (assessment method should be recorded, measured or C-G acceptable)
• Adequate coagulation, defined as international normalized ratio (INR) or prothrombin time ≤ 1.5 x IULN and activated partial thromboplastin time (aPTT) ≤ 1.5 x IULN (unless patient is receiving anticoagulant therapy)
• Persons of childbearing potential must have a negative serum pregnancy test at screening (within 72 hours of first dose of trial medication). Non-childbearing potential for a person assigned as female at birth is defined as 1 of the following:
• ≥ 45 years of age and has not had menses for />1 year
• Amenorrheic for /> 2 years without a hysterectomy and/or oophorectomy and follicle-stimulating hormone value in the postmenopausal range upon pretrial (screening) evaluation
• Status is post-hysterectomy, -oophorectomy, or -tubal ligation
• Persons of childbearing potential must be willing to use highly effective contraceptive measures during sexual contact with a person assigned as male at birth starting with the Screening visit through 90 days after last dose of trial treatment.
• Note: Abstinence is acceptable if this is the established and preferred contraception for the participant.
• Persons assigned as male at birth with a partner(s) of childbearing potential must agree to use highly effective contraceptive measures throughout the trial starting with the Screening visit through 90 days after the last dose of trial treatment is received. Persons assigned as male at birth with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.
• Note: Abstinence is acceptable if this is the established and preferred contraception method for the participant.
• Known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using New York Heart Association Functional Classification. To be eligible for this trial, patients should be Class 2 or lower. Class 2 is defined as slight limitation of physical activity, in which ordinary physical activity leads to fatigue, palpitation, or dyspnea; the person is comfortable at rest.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessments of the investigational arms are eligible for this trial.
• Patients with known HIV infection who are on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• Patients with evidence of chronic hepatitis B virus (HBV) infection must have an undetectable HBV viral load on suppressive therapy, if indicated.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with known HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• Willing and able to comply with the requirements of the protocol.
• For inclusion in the trial, patients will not be eligible to participate in Horizon if any of the following criteria are met, as no waivers will be permitted:
• Major concurrent illness or organ dysfunction including but not limited to the following:
• Plasma cell leukemia (the presence of ≥5% circulating plasma cells in peripheral blood smears)
• Waldenström`s macroglobulinemia
• POEMS syndrome
• primary light-chain amyloidosis
• History of allergy or known hypersensitivity to any of the trial treatments or any of their excipients, or contraindication to any of the trial treatments as outlined in the local prescribing information (e.g., United States Prescribing Information /[USPI/]).
• Complete spinal cord compression or CNS involvement
• Allogeneic tissue/solid organ transplant recipients with chronic GVHD requiring steroid equivalent dose of /> 20 mg prednisone
• Active infection requiring treatment
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient`s participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator
• Psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial
• Legally incapacitated or has limited legal capacity
• Persons who are pregnant or lactating

Описание

This study is a single-arm, investigator-initiated clinical trial. The primary objective is to evaluate the safety and preliminary efficacy of administering universal BCMA CAR-T cells to subjects with refractory and relapsed multiple myeloma. Eligible participants will undergo FC preconditioning after signing an informed consent form, followed by a one-time injection of universal UWD-00B cells to assess its safety and efficacy. Subjects will be hospitalized for a period, and after discharge, they will undergo periodic efficacy assessments and long-term survival follow-up for at least five years.

Критерии включения

• * The patient or their guardian understands and voluntarily signs the informed consent form and is expected to complete the study`s follow-up assessments and treatments.
• Age between 18 and 75 years, with no gender restrictions. Diagnosis of multiple myeloma according to the International Myeloma Working Group (IMWG) criteria.
• Documented evidence of relapsed/refractory or primary refractory multiple myeloma, defined as follows:
• Relapsed/Refractory: Lack of response to salvage therapy (defined as no minimal response (MR) or disease progression during treatment), or disease progression within 60 days of the last treatment, or progression after achieving MR or better.
• Primary Refractory: No response (MR or better) to any previous treatment, with no clinical progression or minimal M-protein change, or meeting criteria for primary refractory progression.
• Presence of measurable disease at screening by any of the following criteria: serum M-protein ≥ 1.0 g/dL, urine M-protein ≥ 200 mg/24 hours, or for light-chain myeloma without measurable disease in serum or urine, serum free light chain (FLC) ≥ 10 mg/dL with abnormal serum immunoglobulin κ/λ FLC ratio.
• Resolution of prior treatment-related toxicities to Grade /<2 per CTCAE (unless related to underlying malignancy or deemed stable and not impacting safety or efficacy).
• ECOG performance status 0-2 and an expected survival of more than 3 months.
• Laboratory values meeting the following standards, indicating adequate organ and marrow function, with no severe hematological or organ impairment:
• Serum albumin ≥ 25 g/L Hemoglobin ≥ 8.0 g/dL (without RBC transfusion in the prior 7 days; recombinant human erythropoietin permitted) Absolute neutrophil count ≥ 0.75×10⁹/L (growth factor support allowed if discontinued ≥7 days before test) Platelet count ≥ 60×10⁹/L (no platelet transfusion within 7 days) Creatinine clearance ≥ 30 mL/min/1.73 m² (using kidney disease formula or 24-hour urine collection) ALT and AST ≤ 3.0×ULN Total bilirubin ≤ 2.0×ULN (Gilbert`s syndrome exception with direct bilirubin ≤ 1.5×ULN) PT and APTT /< 2×ULN Blood oxygen saturation ≥ 95%

Критерии исключения

• * Diagnosis or treatment of other invasive malignancies within 3 years, with the exception of curatively treated non-melanoma skin cancer or malignancies with no active disease for ≥ 3 years.
• Prior anti-cancer treatments within 14 days or 5 half-lives (whichever is shorter) including targeted therapy, epigenetic therapy, or investigational drugs, monoclonal antibody therapy within 21 days, proteasome inhibitor therapy within 14 days, immunomodulators within 7 days, or radiotherapy (except if the radiotherapy field covers ≤5% of bone marrow).
• Known active CNS involvement or clinical evidence of myelomatous meningitis. Diagnosis of Waldenström macroglobulinemia, POEMS syndrome, or primary AL amyloidosis at screening.
• Positive for HBsAg or HBcAb with HBV DNA />1000 copies/mL; positive for HCV antibodies, HIV antibodies, CMV DNA, syphilis, or EBV DNA.
• History of severe allergies, including anaphylaxis, or known allergy to any study drugs, their components, or murine proteins.
• Serious cardiac conditions, including but not limited to severe arrhythmias, unstable angina, recent myocardial infarction (within 6 months), NYHA Class III/IV heart failure, recent CABG, unexplained syncope, severe non-ischemic cardiomyopathy, or uncontrolled hypertension.
• Unstable systemic diseases deemed significant by the investigator, including severe liver, renal, or metabolic disorders.
• History of acute or chronic graft-versus-host disease (GVHD) or currently on immunosuppressive therapy for GVHD within 6 months prior to screening.
• Active autoimmune or inflammatory neurologic diseases such as Guillain-Barré syndrome, ALS, or clinically significant cerebrovascular diseases.
• Presence of urgent tumor-related emergencies requiring immediate treatment, such as spinal cord compression, bowel obstruction, leukostasis, or tumor lysis syndrome.
• Uncontrolled bacterial, fungal, viral, or other infections requiring antibiotics.
• Major surgery within 4 weeks prior to lymphodepletion, or planned major surgery during the study period.
• Live virus vaccinations within 4 weeks prior to screening. Severe psychiatric illness. History of alcohol or substance abuse. Pregnant or lactating women, or females and males planning to conceive within 2 years post-cell infusion.
• Any contraindication to study procedures or conditions deemed by the investigator to pose an unacceptable risk.

Описание

This is an open-label, single arm, multicenter, interventional study with Dara-VRD followed by cilta-cel in high-risk smoldering multiple myeloma (SMM) patients.

The primary objectives of this trial, related with efficafy and safety of the treatment, are i) to evaluate the proportion of high-risk SMM patients with undetectable minimal residual disease (MRD) at 6 months, 12 months, and thereafter every 12 months up to 5 years after cilta-cel administration as well as the sustained undetectable MRD rate in the intent-to-treat (ITT) population; ii) to annotate frequency and severity of adverse events (AE) and serious adverse events (SAE), as well as data from laboratory tests aslo related with safety such as Immunoglobulin (Ig) G levels, complete blood count (CBC) cytopenia adn T-cell populations. Secondary objectives are related with response to therapy and will measure different categories of response and survival.

Критерии включения

• - Be ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent.
• - High-risk SMM defined as having 1 of the following 2 criteria: i) High-risk per "Mayo 20-2-20" criteria defined as presence of any ≥2 of the following:
• 1. Serum M-protein ≥2 gm/dL
• 2. Involved to uninvolved FLC ratio ≥20
• 3. BMPC % ≥20% to /<40% OR ii) Presence of ≥95% of BMPC with an aberrant phenotype within the BMPC compartment and immunoparesis present defined as a reduction of at least 25% below the lower normal limit for ≥1 uninvolved immunoglobulin isotype (only IgG, IgA and IgM will be considered).
• - Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤1.
• - Have an estimated glomerular filtration rate (eGFR), based on the Modified Diet in Renal Disease (MDRD) 4-variable formula or 24-hour urine collection of ≥40 mL/min during the screening period.
• - Laboratory values obtained /<21 days prior to Screening: i) Total bilirubin ≤2.0 mg/dL ii) Aspartate aminotransferase (AST) ≤3 x upper limit of normal (ULN) iii) Alanine transaminase (ALT) ≤3 x ULN
• - Hemoglobin ≥8.0 g/dL (≥5 mmol/L) (without prior red blood cell /[RBC/] transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted). For subjects who meet the inclusion criteria at screening, transfusion of RBCs is permitted after screening as needed to maintain a hemoglobin level ≥8.0 g/dL.
• - Neutrophils ≥1.0 × 109/L (prior growth factor support is permitted but must be without support in the 7 days prior to the laboratory test)
• - Platelets ≥75 × 109/L (must be without transfusion support in the 7 days prior to the laboratory test)
• - Lymphocyte count ≥0.3/*109/L
• - Participants should be seronegative for human immunodeficiency virus (HIV) or have controlled disease if seropositive.
• - A female participant of childbearing potential must have a negative serum pregnancy test at screening and within 72 hours of the first dose of study treatment and must agree to further serum or urine pregnancy tests during the study.
• - A female participant must be either of the following: i) Not of childbearing potential ii) Of childbearing potential and practicing at least 1 highly effective method of contraception throughout the study and through 6 months after the last dose of study treatment. If a female participant becomes of childbearing potential after the start of the study, the female participant must comply with ii).
• - A female participant using oral contraceptives should use an additional barrier contraceptive method.
• - A female participant must agree not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study and for a period of 6 months after receiving the cilta-cel infusion. Female participants should consider preservation of eggs prior to study treatment as anti-cancer treatments may impair fertility.
• * A male participant must wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study and for 1 year after receiving the cilta-cel infusion. If the male participant`s partner is a female of childbearing potential, the male participant must use condoms (with or without spermicide) and the female partner of the male participant must also be practicing a highly effective method of contraception. A male participant who is vasectomized must still use a condom (with or without spermicide), but the partner is not required to use contraception.
• * A male participant must agree not to donate sperm for the purposes of reproduction during the study and for 1 year after receiving the last dose of study treatment. Male participants should consider preservation of sperm prior to study treatment as anti-cancer treatments may impair fertility.
• * A male participant must agree not to plan to father a child while enrolled in this study or within 1 year after the last dose of study treatment.
• * Must sign an informed consent form (ICF) indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study
• * An additional ICF will be collected to get participants authorization to collect the necessary samples for performing the Biological studies indicated in this protocol.
• * Be willing and able to adhere to the lifestyle restrictions specified in this protocol.
• Exclusion Criteria:
• - History of uncontrolled illness, including but not limited to MGUS, standard risk smoldering myeloma, active myeloma by current IMWG definition, light chain amyloidosis with organ involvement or patients with extramedullary disease.
• - Non-muscle-invasive bladder cancer treated within the last 24 months that is considered completely cured.
• - Skin cancer (nonmelanoma or melanoma) treated within the last 24 months that is considered completely cured.
• * Noninvasive cervical cancer treated within the last 24 months that is considered completely cured.
• * Localized prostate cancer (N0M0):
• i) with a Gleason score ≤6, treated within the last 24 months or untreated and under surveillance.
• ii) with a Gleason score of 3+4 that has been treated more than 6 months prior to full study screening and considered to have a very low risk of recurrence.
• iii) history of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence).
• - Adequately treated lobular carcinoma in situ or ductal carcinoma in situ.
• - History of localized breast cancer and receiving antihormonal agents and considered to have a very low risk of recurrence.
• - Known allergies, hypersensitivity, or intolerance to cilta-cel or its excipients.
• - Participant had major surgery or had significant traumatic injury ≤14 days prior to Cycle1Day1.
• * If any of the following exist at screening, participant will be excluded because this trial involves an investigational agent whose genotoxic, mutagenic, and teratogenic effect on the developing fetus and newborn are unknown:
• i) Pregnant women ii) Nursing women iii) Men or women of childbearing potential who are unwilling to employ adequate contraception
• * Other comorbidity which would interfere with subject`s ability to participate in trial, eg, uncontrolled infection, uncompensated heart, or lung disease.
• * Any medical or psychiatric illness that could, in the investigator`s opinion, potentially interfere with the completion of treatment according to this protocol.
• * History of neurodegenerative disease (eg, Parkinson or stroke within 6 months).
• * Medical history of treatment for another malignancy /<2 years before trial enrollment, other concurrent chemotherapy, or any ancillary therapy considered investigational. Note: Bisphosphonates are considered supportive care rather than therapy and are thus allowed while on protocol treatment.
• * Known seropositive for or active viral infection with HIV, HBV, hepatitis C virus (HCV), or SARS-CoV-2 (Coronavirus Disease 2019 /[COVID-19/]).
• i) Participants who are positive for SARS-COV-2 antibody, HIV1 and 2 antibody, hepatitis B core antibody (HBc), or hepatitis B surface antigen (HBsAg) must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.
• ii) Participants who are positive for HIV1 or 2 infections, with undetectable viral load and on stable antiretrovirals, will not be excluded.
• iii) Participants with past HCV infection need at least 12 months of sustained virologic response and be negative for RNA to enter.
• iv) Patients with a high-risk of HBV reactivation (eg, negative for HBV antigen but positive for chronic HBV, with or without anti-serum HBV) must be monitored with DNA and ALT/AST).
• - Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
• NOTE: Investigators must ensure that all study enrollment criteria have been met at screening. If a participant`s clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study intervention is given such that the participant no longer meets all eligibility criteria, then the participant must be excluded from participation in the study.

Критерии исключения

Описание

This phase Ib trial tests the safety, side effects, and best dose of iberdomide in combination with teclistamab in treating multiple myeloma that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory). Iberdomide is a medication that belongs to a group of drugs known as cereblon E3 ligase modulators. Iberdomide works by targeting and destroying proteins that help myeloma cancer cells to survive. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Immunotherapy with monoclonal antibodies, such as teclistamab, may help the body`s immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Giving iberdomide in combination with teclistamab may be safe and tolerable in treating patients with relapsed or refractory multiple myeloma.

Критерии включения

• * Patients must have histologically or cytologically confirmed multiple myeloma (MM), as defined in the International Myeloma Working Group (IMWG) criteria
• * If patients have undergone stem cell transplant (SCT), day 0 of SCT must be /> 100 days to be eligible for the study
• * Patients must have had disease progression after ≥ 4 prior lines of anti-myeloma treatments including one proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib), one immunomodulatory imide drug (ImiD) (e.g., thalidomide, lenalidomide, pomalidomide /[POM/]), and one anti-CD38 monoclonal antibody (e.g., daratumumab, isatuximab)
• * Patients must have measurable disease, defined as:
• * Serum M-protein ≥ 0.5 g/dL (≥ 5 g/L)
• * Urine M-protein ≥ 200 mg/24 h
• * Serum free light chain (FLC) assay: "involved" FLC level ≥ 10 mg/dL (≥ 100 mg/L) and an abnormal serum free light chain ratio (/< 0.26 or /> 1.65)
• * Note: Patients with non-secretory disease will be allowed to participate
• * Age ≥ 18 years
• * Because no dosing or adverse event data are currently available on the use of iberdomide in combination with teclistamab in patients /< 18 years of age, children are excluded from this study
• * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60)
• * Hemoglobin ≥ 7.0 g/dL (≤ 28 days prior to registration) (Without growth factor support, blood transfusion, or platelet stimulating agents for the past 7 days, excluding erythropoietin)
• * Absolute neutrophil count ≥ 1,000/mcL (≤ 28 days prior to registration) (Without growth factor support, blood transfusion, or platelet stimulating agents for the past 7 days, excluding erythropoietin)
• * Platelets ≥ 50,000/mcL (≤ 28 days prior to registration) (Without growth factor support, blood transfusion, or platelet stimulating agents for the past 7 days, excluding erythropoietin)
• * Total bilirubin ≤ 2 x institutional upper limit of normal (ULN) (≤ 28 days prior to registration)
• * Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase /[SGOT/])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase /[SGPT/]) ≤ 3 x institutional ULN (≤ 28 days prior to registration)
• * Estimated glomerular filtration rate (eGFR) /> 30 mL/min (≤ 28 days prior to registration)
• * Spot urine (albumin/creatine ratio) ≤ 500mg/g (56 mg/mmol) OR urine dipstick negative/trace (if /> 1+ only eligible if confirmed ≤ 500 mg/g (56 mg/mmol) by albumin/creatinine ratio (spot urine from first void) (≤ 28 days prior to registration)
• * Note: Laboratory results obtained during screening should be used to determine eligibility criteria. In situations where laboratory results are outside the permitted range, the investigator may re-test the subject and the subsequent within range screening result may be used to confirm eligibility
• * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• * Patients with treated brain metastases are eligible if follow-up brain imaging done a minimum of 28 days after completion of central nervous system (CNS)-directed therapy shows no evidence of progression
• * Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy
• * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• * Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better
• * Based on the mechanism of action, teclistamab may cause fetal harm when administered to a pregnant woman. Females of child-bearing potential (FCBP): should use effective contraception during treatment with teclistamab and for 5 months after the last dose. FCBP should not breast feed during treatment with teclistamab and for 5 months after the last dose. Should a FCBP become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. The effects of iberdomide on the developing human fetus are unknown. However, IMiDs are known to be teratogenic. FCBP must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days prior to starting iberdomide, and again within 24 hours. FCBP must either commit to continued abstinence from heterosexual intercourse or begin two acceptable methods of birth control-one highly effective method and one additional effective method-at the same time, at least 28 days before starting iberdomide, while taking iberdomide, and for 28 days following discontinuation from the study. Examples of highly effective methods are intrauterine device, hormonal contraceptives, tubal ligation, or partner`s vasectomy. Examples of barrier method are male condom, diaphragm, or cervical cap. FCBP must also agree to ongoing pregnancy testing. Men must practice complete abstinence or agree to use a condom during sexual contact with FCBP while participating in the study, during dose interruptions, and for at least 28 days following discontinuation from the study, even if he has undergone a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risk of fetal exposure
• * Men must agree to abstain from donating and semen or sperm while taking iberdomide, during dose interruptions, and for at least 28 days after the last dose of iberdomide. FCBP must agree not to donate eggs (ova, oocytes) for the purpose of reproduction during this period
• * All patients must agree to abstain from donating blood products while taking iberdomide and for at least 28 days after the last dose of iberdomide
• * Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study subjects
• * Willingness to adhere to the study visit schedule and other protocol requirements and provide mandatory blood and bone marrow specimens for correlative research
• * Willingness to return to the enrolling institution for follow-up

Критерии исключения

• * Patients who have active plasma cell leukemia, active amyloid light chain (AL) (primary) amyloidosis, active polyneurophathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, myeloma protein, and skin changes), and Waldenstrom macroglobulinemia are ineligible
• * If a patient develops recurrent/refractory (R/R) disease while receiving the most recent line of therapy, there is no need for a washout period. Patients who develop R/R disease while not on treatment must have received an investigational drug or approved systemic anti-myeloma therapy (including systemic steroids) ≤ 14 days or 5 half-lives (whichever is shorter) prior to registration. This includes prior treatment with a monoclonal antibody ≤ 30 days before receiving the first dose of a study drug. The only exception is emergency use of a short course of systemic corticosteroids (equivalent to, or less than: dexamethasone 40 mg/day for a maximum of 4 days) before treatment
• * Patients who have had prior anti-BCMA directed BsAb therapy exposure (prior treatment with anti-BCMA directed antibody drug conjugate, or anti-BCMA-directed CAR T cell therapy are permitted)
• * Patients who have had prior treatment with a cereblon E3 ligase modulator, including mezigdomide, iberdomide, and CFT7455 (all currently in clinical development)
• * Patients who received plasmapheresis ≤ 7 days prior to registration
• * Patients who received a prior allogeneic stem cell transplant. Autologous stem cell transplantation (SCT) is allowed
• * Patients who received a live or live-attenuated vaccine ≤ 30 days prior to registration. Patients are allowed to receive a COVID-19 vaccine at any timepoint during protocol treatment
• * Systemic active infection requiring treatment
• * Any unresolved toxicity ≥ grade 2 from previous treatment except for alopecia or peripheral neuropathy up to grade 2
• * Patients who have had any major surgery ≤ 4 weeks prior to registration
• * Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make this protocol unreasonably hazardous
• * Patients with evidence of active mucosal or internal bleeding
• * Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. Stable chronic liver disease (including Gilbert`s syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if participant otherwise meets entry criteria
• * Patients with known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs chemically related to teclistamab or iberdomide, or any of the components of the study treatment
• * Patients who are taking any anticancer therapy other than hormonal therapy (for prostrate or breast cancer) and palliative radiotherapy (defined as radiation to ≤ 3 sites of active multiple myeloma)
• * Patients who require immunosuppressive medications including, but not limited to, systemic corticosteroids at doses exceeding 10 mg/day of prednisone or equivalent. Use of immunosuppressive medications for the management of iberdomide-related adverse events (AEs) or in subjects with contrast allergies is acceptable. In addition, use of inhaled, topical, intranasal corticosteroids or local steroid injection (e.g., intra-articular injection) is permitted. Temporary use of corticosteroids for concurrent illnesses (e.g., food allergies, computed tomography /[CT/] scan contrast hypersensitivity, pneumonia, etc.) are acceptable
• * Patients who require medications that are strong inhibitors or inducers of CYP3A4/5
• * Patients who are receiving any other investigational agents
• * Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous
• * Pregnant women are excluded from this study because iberdomide is a thalidomide analog and thalidomide is a known human teratogen. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with iberdomide, breastfeeding should be discontinued if the mother is treated with iberdomide. These potential risks may also apply to other agents used in this study
• * Patients who are unable or unwilling to undergo protocol required thromboembolism prophylaxis are excluded

Описание

This clinical trial aims to characterize the safety of OL-101 and establish the recommended dose for future research and to evaluate the efficacy of OL-101 (Dose expansion).

Критерии включения

• * Documented diagnosis of multiple myeloma according to the 2014 IMWG diagnostic criteria
• * Relapsed/refractory multiple myeloma as defined by:
• 1) Received at least 3 prior lines of MM treatment (must include a PI, an IMiD, and an anti-CD38 antibody).
• 2）Disease progression within 12 months of the most recent anti-MM therapy; or disease progression within the past 6 months and subsequently lack response to the most recent line of therapy.
• * Measurable disease at screening as defined by any of the following:
• 1. Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or
• 2. Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.
• * Positive expression of either BCMA or GPRC5D on bone marrow plasma cells; must be GPRC5D expression positive if previously received BCMA targeted therapy
• * ECOG 0-1
• * Expected life expectancy exceeds 12 weeks
• * Adequate bone marrow reserve or organ function meeting the following criteria:
• 1. Hemoglobin ≥ 70 g/L
• 2. Platelet count ≥ 50 × 10/^9/L
• 3. Absolute lymphocyte count ≥ 0.3×10/^9/L
• 4. Absolute neutrophil count ≥ 1.0 × 10/^9/L
• 5. Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤ 2.5 times the upper limit of normal (ULN)
• 6. Total bilirubin ≤ 2 times ULN; except in subjects with congenital bilirubinemia (such as Gilbert syndrome, in which case the direct bilirubin ≤1.5 × ULN is required)
• 7. Creatinine clearance ≥ 60 mL/min (calculated by Cockcroft-Gault equation).
• 8. corrected serum calcium ≤12.5 mg/dL (≤3.1 mmol/L) or free ionized calcium ≤6.5 mg/dl (≤1.6 mmol/L)
• 9. SpO2/>92% on room air
• 10. Left ventricular ejection fraction (LVEF) ≥ 50% as assessed by echocardiogram; no clinically meaningful pericardial effusion by ultrasound

Критерии исключения

• * Solitary plasmacytoma
• * Known active central nervous system (CNS) involvement or exhibits clinical signs of CNS involvement of multiple myeloma.
• * Received allogeneic stem cell transplant; received autologous stem cell transplant within 12 weeks before screening
• * Active second primary malignant tumor, exclude the following: cured non- melanoma skin cancer, non-metastatic prostate cancer, cervical carcinoma in situ, ductal or lobular carcinoma in situ of the breast
• * Any other significant medical disease, abnormality, or condition that, in the investigator judgment, may make the patient unsuitable for participation in the study or put the patient at risk.
• * Plasma cell leukemia, Waldenström`s macroglobulinemia, POEMS syndrome, or primary AL amyloidosis.

Описание

This research is being done to investigate the safety and effectiveness of Darzalex Faspro (daratumumab and hyaluronidase-fihj) (a monoclonal antibody that targets plasma cells that make antibodies) and whether it can lower donor specific antibodies (DSA) levels to low enough levels to permit patients to proceed with allogeneic peripheral blood transplant (alloBMT). Those being asked to participate have high DSA levels that puts those being asked to participate at high risk of rejecting the available donor`s blood stem cells and making those being asked to participate ineligible to receive a stem cell transplant.

Критерии включения

• 1. Participates must meet all other institutional criteria for the planned reduced intensity conditioning allogeneic peripheral blood stem cell transplant (RIC alloHSCT) as defined in Johns Hopkins BMT Policy; all potential non-cord blood donor sources are included: matched related, haploidentical, matched unrelated, mismatched unrelated.
• 2. Participants must be ≥18 years of age.
• 3. Participants must have adequate organ function for undergoing RIC allogeneic peripheral blood stem cell transplant, and for undergoing a clinical trial.
• a. Hematologic. i. White blood cell (WBC). ANC ≥ 500/mm3 (growth factor support allowed). ii. Hemoglobin. No specific cut-off. (PRBC transfusion allowed). iii. Platelets. Platelets ≥ 10,000/mm3 (platelet transfusion allowed). b. Liver. Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert`s syndrome or hemolysis), and Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) /< 5x Upper limit of normal (ULN) c. Renal. Serum creatinine ≤ 2.0 mg/dL. d. Cardiac. Left ventricular ejection fraction ≥ 35%. e. Pulmonary. FEV1 ≥ 50%.
• 4. Subjects are eligible if there are high levels of Donor Specific Antibody levels based on protocol specific scoring system regardless of prior attempts at standard desensitization.
• 5. Participants must have a no other readily available suitable alternative donor.
• 6. All potential Participants must be pre-approved by BMT faculty consensus.
• 7. Participants must have adequate willingness to participate in a clinical trial.

Критерии исключения

• 1. Previous exposure to Daratumumab-SC or other anti-CD38 therapy
• 1. Exposure to Daratumumab-SC or other anti-CD38 therapies (unless a re-treatment study)
• 2. Exposure to an investigational drug (including investigational vaccine) or invasive investigational medical device for any indication within 4 weeks or 5 pharmacokinetic half-lives, whichever is longer.
• 3. Focal radiation therapy within 14 days prior to beginning of planned RIC allogeneic peripheral blood stem cell transplant regimen with the exception of palliative radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma
• 2. Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) /< 50% of predicted normal. Note that FEV1 testing is required for participants suspected of having COPD and participants must be excluded if FEV1 is /< 50% of predicted normal.
• 3. Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate.
• 4. Known hypersensitivity or intolerance to boron or mannitol, sorbitol, corticosteroids, monoclonal antibodies or human proteins, or the excipients
• 5. Diagnosis of multiple myeloma or Amyloid light-chain (AL) amyloidosis
• 6. A planned myeloablative alloBMT or the planned use of bone marrow or cord blood as a stem cell source
• 7. History of HIV infection at any time in past.
• 8. Seropositive for hepatitis B (HBV) (defined by a positive test for hepatitis B surface antigen /[HBsAg/] positive, or antibodies to hepatitis B surface and/or core antigens /[antiHBs or antiHBc, respectively/] with hepatitis B virus /[HBV/]- DNA quantitation positive). Patients who are positive for antiHBs and/or antiHBc must have a negative polymerase chain reaction (PCR) for HBV-DNA quantitation result during screening. Patients with serologic findings suggestive of HBV vaccination (antiHBs positivity as the only serologic marker) AND a known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR. Those who are PCR positive will be excluded.
• 9. Seropositive for hepatitis C (except in the setting of a sustained virologic response (SVR), defined as aviremia at least 12 weeks after completion of antiviral therapy)
• 10. Clinically significant cardiac disease, including:
• 1. Myocardial infarction within 6 months before RIC alloHSCT or unstable or uncontrolled disease/condition related to or affection cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV)
• 2. Uncontrolled cardiac arrhythmia

Описание

This is a phase 1/2 multicenter, open-label, first-in-human study of IBI3003. It includes a phase 1 dose escalation and expansion section to identify maximum tolerated dose(MTD)/recommended Phase 2 Dose(RP2D) of IBI3003, plans to enroll 23/~116 subjects, and a phase 2 stage to explore efficacy, safety and tolerability of IBI3003 at RP2D in multiple myeloma.

Критерии включения

• * Subjects in Parts 1(dose escalation) /& 2 (dose expansion) must satisfy all of the following criteria to be enrolled into the study:
• 1. Age ≥18 years. For Part 1, age ≥18 years and ≤75 years.
• 2. Documented initial diagnosis of multiple myeloma according to IMWG diagnostic criteria. Multiple myeloma is defined as clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma-defining events in protocol
• 3. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
• 4. Life expectancy ≥3 months.
• 5. Subjects with the ability to understand and give written informed consent for participation in this trial, including all evaluations and procedures as specified by this protocol.

Критерии исключения

• 1. Known active CNS involvement or exhibits clinical signs of meningeal involvement of multiple myeloma.
• 2. Have amyloidosis, plasma cell leukemia, Waldenstrom macroglobulinemia, POEMS syndrome, or solitary plasmacytoma, or smoldering MM as defined by the International Myeloma Working Group(IMWG) criteria.
• 3. Spinal cord compression that results in limited self-care occurs within 6 months prior to informed consent, or is expected to occur in the near future.
• 4. History of primary immunodeficiency.
• 5. Current or previous other malignancy within 3 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy.

Описание

The primary purpose of the study is to understand how well the study drug can eliminate abnormal plasma cells and laboratory signs of high-risk monoclonal gammopathy of undetermined significance (HR-MGUS) and non high-risk smoldering multiple myeloma (NHR-SMM). This requires understanding the safety and tolerability of the study drug (how the body reacts to linvoseltamab) as well as the effectiveness of the study drug (how well linvoseltamab eliminates plasma cells). All participants will start treatment with gradually increasing doses of linvoseltamab (step-up doses) before they start receiving the assigned full dose.

The study is split into 2 parts:

* In Part 1, separate groups of 3-6 patients will receive different full doses of linvoseltamab to evaluate the short-term side effects (safety) and tolerability of the study drug within the first 5 weeks after starting treatment. The data collected will help to make a decision about the dosing regimens chosen for Part 2.
* In Part 2, a larger number of participants will be randomized to different dosing regimens to further assess the side effects of linvoseltamab, and to evaluate the ability of linvoseltamab to eliminate abnormal plasma cells in HR-MGUS and NHR-SMM.

The study is looking at several other research questions, including:

* How many participants treated with linvoseltamab have improvement of their HR-MGUS or NHR-SMM?
* What side effects may happen from taking the study drug?
* How much study drug is in the blood at different times?
* Whether the body makes antibodies against the study drug (which could make the drug less effective or could lead to side effects).

Критерии включения

• 1. HR-MGUS or NHR-SMM as defined in the protocol
• 2. Eastern Cooperative Oncology Group (ECOG) performance status ≤1
• 3. Adequate hematologic and hepatic function, as described in the protocol
• 4. Estimated glomerular filtration rate (GFR) ≥30 mL/min/1.73 m2 by the modification of diet in renal disease (MDRD) equation

Критерии исключения

• 1. High-risk SMM, as defined in the protocol
• 2. Evidence of any of myeloma-defining events, as described in the protocol
• 3. Diagnosis of systemic light-chain amyloidosis, Waldenström macroglobulinemia (lymphoplasmacytic lymphoma), solitary plasmacytoma, or symptomatic MM
• 4. Clinically significant cardiac or vascular disease within 3 months of study enrollment, as described in the protocol
• 5. Any infection requiring hospitalization or treatment with IV anti-infectives within 28 days of the first dose of linvoseltamab
• 6. Uncontrolled human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection; or other uncontrolled infection or unexplained signs of infection
• NOTE: Other protocol defined inclusion/exclusion criteria apply

Описание

Study QXL138AM-001 is a Phase 1a/1b study to investigate the safety, pharmacokinetics, and preliminary activity of QXL138AM in subjects with locally advanced un-resectable and/or metastatic solid tumors and multiple myeloma. The study is an open-label, multicenter, first in human study to be conducted in two major parts which are further organized into two sub-parts. Part A Dose Escalation is a modified 3+3 with the first two cohorts consisting of one subject each based on the low clinical starting dose. Dose escalation in solid tumors (Part A1) will be followed by dose finding in multiple myeloma (Part A2). Part B consists of dose expansion in solid tumors (Part B1) and multiple myeloma (Part B2) using the recommended dose for expansion from Part A

Критерии включения

• 1. Participants with Solid Tumors
• * Histopathologically confirmed diagnosis of an advanced, unresectable, or metastatic solid tumor (ovarian, pancreatic, urothelial, renal, hepatocellular, gastrointestinal (GI), lung, prostate, and breast cancer).
• * Have progressed despite standard therapies, or for whom conventional therapy is not effective or tolerable, as judged by the Investigator. Patients must have no available therapeutic options known to confer clinical benefit for their tumor type.
• 2. Participants with Multiple Myeloma
• * Have progressed despite standard therapies, or for whom conventional therapy is not effective or tolerable, as judged by the Investigator.
• * Patients must have failed at least 3 prior therapies for myeloma and should have had prior exposure to a proteosome inhibitor, an IMiD, and an anti-CD38-directed therapy.
• 2. Male or female participants ≥18 years of age at the time of informed consent 3. An Eastern Cooperative Oncology Group (ECOG) performance status scale of 0, 1, or 2 at Screening 4. Must have at least 1 measurable lesion by RECIST version 1.1 (solid tumors only), or evaluable disease by IMWG Uniform Response Criteria (multiple myeloma only) 5. Adequate organ function and bone marrow reserve 6. Adequate cardiac function as estimated by left ventricular ejection fraction 7. Female participants of child-bearing potential must:
• * Have a negative serum pregnancy test at screening and a negative pregnancy test at Week 1 Day 1 prior to first dose of QXL138AM, AND
• * Agree to use at least 1 highly effective method of contraception for the duration of study participation, and for 120 days after last dose of QXL138AM.
• 8. Male participants of child-bearing potential must:
• * Agree to use at least 1 highly effective method of contraception for the duration of study participation, and for 120 days after last dose of QXL138AM, AND
• * Refrain from sperm donation prior to the first dose of investigational product through 120 days following the last dose of QXL138AM.

Критерии исключения

• 1. New York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmia, a history of risk factors for Torsades de Pointes (TdP), including heart failure, hypokalemia, and family history of long QTc syndrome, or evidence of ischemia on ECG.
• Symptomatic ischemic heart disease or unstable angina pectoris; or history of cardiac angioplasty, cardiac stenting, or coronary artery bypass graft. A clinically significant baseline prolongation of QT/QTcF interval at screening.
• 2. The use of concomitant medications that may significantly prolong the QT/QTc interval.
• 3. Active, uncontrolled bacterial, viral, or fungal infections requiring systemic therapy.
• 4. Known hypersensitivity to the investigational product or components (anti-CD138 IgG1 antibody, Interferon A2a and/or the formulation excipients: histidine, sucrose, arginine, polysorbate 80).
• 5. Female participant is lactating.
• 6. Any other clinically significant comorbidities.
• 7. Received prior anticancer therapy within 28 days or 5x the half-life (whichever is shorter) prior to the first dose of investigational product.
• 8. Participants who received wide-field radiation therapy within 4 weeks prior to first dose of investigational product, (2 weeks for limited field radiation therapy)
• 9. Major surgery within 30 days before first dose of investigational product
• 10. Chronic use of systemic corticosteroids of more than 20 mg/day of prednisone or equivalent.
• 11. Active, clinically significant liver disease such as Hepatitis B or C, autoimmune hepatitis, or cirrhosis (Child Hugh Stage B or C).
• 12. Current or history of mood disorder such as major depression per DSM-5 within past two years not controlled with current therapy.
• 13. Active autoimmune disorders not controlled with current therapy.
• 14. Active endocrine disorders including hypothyroidism, hyperthyroidism, hypoglycemia, hyperglycemia, and diabetes mellitus not controlled with current therapy.

Описание

To evaluate the safety and tolerability of chimeric antigen receptor gene-modified T cells targeting BCMA for the treatment of relapsed/refractory multiple myeloma

Критерии включения

• 1. Age 18-80 years, no gender restrictions;
• 2. Diagnosed with refractory/relapsed multiple myeloma through physical examination, pathological examination, laboratory tests, and imaging studies;
• 3. Flow cytometry or histology confirms positive BCMA expression in myeloma cells;
• 4. As judged by the investigator, the expected survival time is />3 months;
• 5. ECOG performance status score ≤2, KPS />60%;
• 6. The patient has good liver, kidney, heart, and lung function: ALT and AST ≤2.5×ULN, those with liver involvement can be relaxed to ≤5×ULN; serum total bilirubin /<34 μmol/L; creatinine clearance rate />30 mL/min; heart ejection fraction (EF) ≥40%, no pericardial effusion and significant arrhythmia; indoor SpO2 ≥92%;
• 7. Peripheral blood lymphocyte absolute count ALC ≥0.5 ×10/^9/L, PLT />30×10/^9/L, Hb />80 g/L and has a single collection venous access, and there are no other contraindications for hematopoietic cell separation;
• 8. Those with fertility must agree to use highly effective contraceptive methods;
• 9. The subject or their legal guardian can understand and is willing to sign a written informed consent form voluntarily.

Критерии исключения

• 1. Pregnant or nursing women, as well as women planning to become pregnant within the next six months;
• 2. Positive virology tests for hepatitis B, hepatitis C, HIV, syphilis, or cytomegalovirus;
• 3. History of other tumors (except for those with skin or cervical in situ cancers that have been cured by radical treatment and show no evidence of disease activity);
• 4. Previously received treatment targeting BCMA;
• 5. Underwent autologous hematopoietic stem cell transplantation within the last 6 weeks;
• 6. Presence of uncontrolled active bacterial or fungal infection;
• 7. Allergic to research-related drugs or cell components;
• 8. Presence of active autoimmune diseases;
• 9. Currently have unstable or active ulcers or gastrointestinal bleeding;
• 10. Unable to cooperate with treatment and efficacy evaluation due to mental or psychological disorders;
• 11. Received other experimental drug treatments within the last 3 months;
• 12. The researcher believes that for other reasons, the individual is not suitable for the clinical trial.

Описание

The purpose of this study is to evaluate the rate of response (how effectively treatment is working) with signs of potential cure at 5 years after the start of induction treatment. This is defined as a composite of sustained (at least 2 years) minimal residual disease (MRD) negativity with complete response/stringent complete response (CR/sCR) and a positron emission tomography/computed tomography (PET/CT) scan that does not show any signs of cancer at 5 years. MRD negativity and CR/sCR is defined as no detectable signs of remaining cancer cells after the treatment. This study will also characterize how well the treatments administered work in the study through progression-free survival (PFS). PFS is defined as the length of time during and after the treatment of a disease, that a participant lives with the disease, but it does not get worse.

Критерии включения

• * Participants with documented new diagnosis of multiple myeloma (MM) according to international myeloma working group (IMWG) diagnostic criteria
• * Participants must have standard-risk MM (stage I and II) based on revised International Staging System (R-ISS)
• * Participants must be considered fit (score equals to /[=/] 0) or intermediate-fit (score=1) according to IMWG Frailty Index assessment (based on the Charlson Comorbidity Index, the Katz Activity of Daily Living and the Lawson Instrumental Activities of Daily Living)
• * Measurable disease defined as: Serum monoclonal paraprotein (M-protein) level greater than or equal to (/>=) 1.0 gram per deciliter (g/dL) or urine M-protein level />= 200 milligrams per 24 hours (mg/24 hours); Light chain MM without measurable disease in the serum or the urine: Serum immunoglobulin free light chain />=10 milligrams per deciliter (mg/dL) and abnormal serum immunoglobulin kappa lambda free light chain ratio
• * Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1

Критерии исключения

• * Any ongoing myelodysplastic syndrome or B-cell malignancy (other than MM). Any history of malignancy, other than MM, which is considered at high risk of recurrence requiring systemic therapy
• * Peripheral neuropathy or neuropathic pain of Grade />= 2, as defined by National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
• * Known active or prior history of central nervous system (CNS) involvement or exhibits clinical signs of meningeal involvement of MM
• * Stroke or seizure within 6 months of signing the informed consent form (ICF)
• * Plasma cell leukemia at the time of screening (/>= 5 percent /[%/] circulating plasma cells in peripheral blood smears), Waldenstrom macroglobulinemia, polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes(POEMS) syndrome, or primary amyloid light chain amyloidosis with associated organ dysfunction
• * Presence of high-risk disease features: (a) Cytogenetic high risk lesions by MM fluorescence in situ hybridization (FISH) including deletion 17p (del/[17p/])/, t(4;14), t(14;16), amplification 1q (amp/[1q21/]) (/>= 4 copies); (b) Presence of 1 or more extramedullary plasmacytomas
• * Seropositive for human immunodeficiency virus (HIV)

Описание

All subjects will receive GR1803 injection until intolerable toxicity or investigator-assessed disease progression occurs (except in cases of disease progression due to discontinuation of the drug as a result of an adverse event) or until the subject has been administered the drug for 2 years or until the subject withdraws consent or until the investigator determines that the subject needs to be discontinued.

Критерии включения

• * 1、ECOG score 0-2 2、≥18 years of age 3、Multiple myeloma must be measurable by central laboratory assessment: Serum monoclonal paraprotein (M-protein) level ≥0.5 g/dL or urine M-protein level ≥200 mg/24 hours; or
• Light chain multiple myeloma without measurable disease in the serum or the urine:
• Serum immunoglobulin free light chain (FLC) ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio.

Критерии исключения

• * 1、Prior treatment with any BCMA-targeted therapy 2、Known active CNS involvement or exhibits clinical signs of meningeal involvement of multiple myeloma 3、Known allergies, hypersensitivity, or intolerance to the study drug (teclistamab) or its excipients 4、Plasma cell leukemia , Waldenström`s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or primary amyloid light-chain amyloidosis.

Описание

Despite recent therapeutic advances, multiple myeloma (MM) remains an incurable disease. Although survival has improved, there are nevertheless diminishing durations of response to each subsequent line of therapy. This highlights the need for further therapeutic innovation. BCMA-targeting CAR-T cells show impressive response rates; however, their median duration of response is disappointing. The investigators propose that CS1(SLAMF7)-targeting CAR-T cells will fill a gap in the MM armamentarium.

CS1 is an attractive target in MM because it is expressed in most patients. Elotuzumab (Empliciti®), an approved anti-CS1 antibody, has proven the clinical efficacy of this target. CAR-T cells are an ideal modality to target CS1, given that two approved treatments, ide-cel (idecabtagene vicleucel, AbecmaTM) and cilta-cel (ciltacabtagene autoleucel, Carvykti™), have proven the potential for cellular immunotherapy in MM.

The investigators are testing the safety and preliminary anti-myeloma efficacy of WS-CART-CS1, a CAR-T cell therapy targeting CS1.

Критерии включения

• * Relapsed or refractory multiple myeloma after 3 or more prior lines of therapy, including proteasome inhibitor (e.g. bortezomib or carfilzomib), anti-CD38 therapy (e.g. daratumumab), and anti-BCMA therapies (e.g. BCMA bispecific antibodies or BCMA CAR-T)
• * Measurable disease, defined as meeting at least one of the following criteria:
• * Serum M-protein ≥ 0.5 g/dL
• * Urine M-protein ≥ 200 mg/24 h
• * Serum FLC assay: involved FLC level ≥10 mg/dL (100 mg/L) with abnormal serum FLC ratio
• * A biopsy-proven plasmacytoma
• * Bone marrow plasma cells /> 30% of total bone marrow cells
• * At least 18 years of age.
• * ECOG performance status ≤ 1
• * Adequate renal, hepatic, respiratory, and cardiovascular function, as defined below:
• * Renal function:
• * calculated creatinine clearance ≥ 50 mL/min/1.73 m2 OR
• * radioisotope glomerular filtration rate ≥ 50 mL/min/1.73 m2 OR
• * normal serum creatinine based on age/gender per institutional normal range
• * Hepatic function:
• * ALT (SGPT) ≤ 5 x ULN for age
• * Total bilirubin ≤ 2.0 x IULN (unless the patient has Grade 1 bilirubin elevation due to Gilbert`s disease or a similar syndrome involving slow conjugation of bilirubin)
• * Respiratory function:
• * Minimum level of pulmonary reserve defined as oxygen saturation /> 91% measured by pulse oximetry on room air
• * Cardiovascular function:
• * LVEF ≥ 45% confirmed by echocardiogram or MUGA within 28 days of screening
• * The effects of CS1 CAR-T on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (at least 2 forms of contraception, including one barrier method) prior to study entry and for 12 months after CS1 CAR-T infusion. If a female subject or female partner of a male subject becomes pregnant during therapy or within 12 months following WS-CART-CS1 infusion, the investigator must be notified in order to facilitate outcome follow-up.
• * Ability to understand and willingness to sign an IRB-approved written informed consent document (or that of legally authorized representative, if applicable).

Критерии исключения

• * Any prior systemic therapy for multiple myeloma within 14 days before planned day of leukapheresis.
• * A history of other malignancy with the exception of treated non-melanomatous skin cancers and malignancies for which all treatment was completed at least 2 years before registration and the subject has no evidence of disease.
• * Currently receiving any other investigational agents.
• * Receipt of any cellular therapy within 8 weeks prior to the planned start of conditioning.
• * A history of allergic reactions attributed to compounds of similar chemical or biologic composition to CS1 CAR-T or other agents used in the study.
• * History of Grade 3 CRS or ICANS with other CAR-Ts (including BCMA CAR).
• * Active hepatitis B, active hepatitis C, any uncontrolled infection, or HIV infection.
• * Ongoing or active infection or other serious underlying medical condition that would impair the ability to receive protocol treatment.
• * Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.

Описание

This clinical trial evaluates the impact of a plant-based whole-foods delivery service on the microbiome in patients with multiple myeloma undergoing an autologous hematopoietic cell transplant. An autologous hematopoietic cell transplant is a procedure in which blood-forming stem cells (cells from which all blood cells develop) are removed, stored, and later given back to the same person. Loss of microbial diversity within the intestinal tract has been associated with poor outcomes for patients receiving autologous stem cell transplantation. A plant-based whole meal delivery service may increase the intake of foods high in fiber and nutrients therefore improve microbial health during the peri-transplant period. In this pilot study, study investigators will explore the feasibility of this approach.

Критерии включения

• * Able to provide written informed consent prior to initiation of any study procedures
• * Planned first autologous stem cell transplantation for multiple myeloma
• * Planned outpatient treatment for the duration of transplantation (if admitted, the investigators will request that caregivers bring the meals/snacks to the hospital as they might with other food prepared at home)
• * Access to a refrigerator
• * Ability to reheat foods
• * Able to consume an oral diet at enrollment
• * Able to communicate clearly regarding aspects of the study: e.g. Give feedback on logistics and meals, in order to maximize the operational data the investigators can gather in this pilot study
• * At least 18 years of age

Критерии исключения

• * Major psychiatric diagnosis that impairs cognitive functioning or is not controlled at the time of the approach, as judged by the patient`s medical team
• * Planned inpatient transplantation

Описание

The purpose of this study is to define the safety of Ciltacabtagene Autoleucel (Cilta-cel) and Talquetamab in participants with high-risk multiple myeloma (MM).

Критерии включения

• * Documented diagnosis of MM according to the IMWG diagnostic criteria and is defined as a measurable disease at screening
• * Cohorts 1 and 3: Received at least 3 prior lines of antimyeloma therapy and have undergone greater than or equal to (/>=) 1 complete cycle of the therapy. Cohort 2: Be newly diagnosed MM and considered ineligible for high-dose chemotherapy with autologous stem cell transplant (ASCT)
• * Cohorts 1 and 3: Documented evidence of progression of disease (PD) or failure to achieve a response to the last line of therapy
• * Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
• * Participant of childbearing potential (POCBP) must have a negative pregnancy test using a highly sensitive β-human chorionic gonadotropin (hCG) serum pregnancy test at screening

Критерии исключения

• * Cohorts 1 and 3: Prior treatment with chimeric antigen receptor T cell (CAR-T) therapy directed at any target or any prior B cell maturation antigen (BCMA)-directed therapy/prior G protein-coupled receptor family C Group 5 member D (GPRC5D)-directed therapy. Cohort 2: Received any prior therapy for MM or smoldering myeloma other than a short course of corticosteroids
• * Cohorts 1 and 3: Received either of the following: An allogenic stem cell transplant within 6 months before apheresis/first dose of study drug and no immunosuppressive medications administered before the start of study treatment. And secondly, received an autologous stem cell transplant less than (/<)12 weeks before apheresis/first dose of study treatment
• * Cohort 2: Received a strong cytochrome P450 (CYP450) inducer within 5 half-lives prior to daratumumab, lenalidomide and dexamethasone (DRd) induction therapy
• * Receive live, attenuated vaccine within 4 weeks of enrollment
• * Toxicity from previous anticancer therapy not resolved to baseline levels or to Grade 1 or less except for alopecia or peripheral neuropathy

Описание

This is a Phase IB/II trial that will investigate the safety, tolerability and efficacy of combination therapy using All-Trans Retinoic Acid (ATRA) with Carfilzomib based therapies in plasma cell myeloma also commonly referred as Multiple Myeloma (MM), in patients considered refractory to proteasome inhibitors (PIs). Multiple myeloma is an incurable clonal plasma cell disorder that comprises 10% of all hematologic malignancies. Over the past 30 years the global prevalence of multiple myeloma has risen to 126%, with 85% of diagnoses occurring in patients />55 years of age. In the past 15 years, survival has improved considerably, which is attributed to the development of multiple different classes of medications, including proteasome inhibitors. Proteasome inhibitors are the foundation of many multiple myeloma treatments in both transplant eligible and ineligible patients for the past 2 decades. While proteasome inhibitors have improved both progression free survival (PFS) and overall survival (OS), many patients eventually develop disease progression arising from resistance to therapies. As a result, there is an unmet need to overcome resistance and find ways to enhance multiple myeloma sensitivity to proteasome inhibitor toxicity. Carfilzomib, a modified peptide epoxyketone that selectively targets intracellular proteasome enzymes, is approved in combination with dexamethasone in patients that have received ≥1 line of therapy or in combination. There are few studies assessing ways to enhance carfilzomib-mediated multiple myeloma toxicity. All-Trans Retinoic Acid (ATRA) is an oxidative metabolite of retinol (vitamin A) and plays an important role in the regulation of cellular proliferation and differentiation. In a recent pre-clinical study, ATRA was found to enhance sensitivity of carfilzomib-mediated apoptosis in vitro via an interferon beta (IFN-β) response pathway. In the clinical setting, ATRA is a well-tolerated drug that has shown little change in the rate of adverse events in early clinical trials with multiple myeloma. The investigators hypothesize that ATRA enhances sensitivity of multiple myeloma to carfilzomib therapy.

Критерии включения

• 1. Age ≥ 18 years with relapsed/refractory multiple myeloma documented according to International Myeloma Working Group (IMWG) criteria.
• 2. Previously treated with three lines of therapy which would include Immunomodulatory drugs (IMiDs), Proteosome inhibitors (including carfilzomib), anti-CD 38 antibodies and failed to achieve a minor response after completing at least 2 cycles of carfilzomib-based therapy or are relapsed while on therapy.
• 3. Patient or legal guardian voluntarily can sign informed consent.
• 4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2
• 5. Adequate organ function defined as:
• 1. Hemoglobin ≥8 g/dL (baseline or after Peripheral Red Blood Cell transfusion), Platelet count />75,000 and Absolute Neutrophil Count />1000/ micro liter.
• 2. Left Ventricular Ejection fraction />50%
• 3. Creatinine Clearance ≥ 30 ml/min
• 4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN)
• 5. Total bilirubin ≤ 1.5 × ULN
• 6. Measurable disease requiring treatment defined as patients having one or more of the criteria below:
• 1. Serum M protein ≥ 0.5 g/dL or
• 2. Urine M-protein ≥ 200 mg/24 hours or
• 3. Serum free light chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum
• 4. kappa lambda ratio.
• 7. If previous autologous stem cell transplantation, must have fully recovered from transplant related toxicities and be />60 days from transplant and have had hematologic recovery independent of growth factor support.
• 8. Willingness to undergo interim bone marrow biopsy as scheduled or if felt to be medically indicated.
• 9. Life Expectancy ≥ 6 months
• 10. Women with childbearing potential and men should practice at least one of the following methods of birth control:
• 1. Total abstinence from sexual intercourse (periodic abstinence not acceptable);
• 2. Surgically sterile partner(s) including vasectomy, bilateral tubal ligation, bilateral oophorectomy, or hysterectomy;
• 3. Intrauterine device with an additional method of contraception to make two effective methods of contraception during treatment with Vesanoid;
• 4. Double-barrier method (condom + diaphragm or cervical cap with spermicide, contraceptive sponge, jellies, or cream);
• 5. Hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) for at least 3 months prior to study drug administration. If hormonal contraceptives are used, the specific contraceptive must have been used for at least 3 months prior to study drug administration. If the patient is currently using a hormonal contraceptive, she should also use a barrier method during this study Women of child-bearing potential must have a negative results of a pregnancy test performed at initial screening on a serum sample obtained within 21 days prior to C1D1, and prior to dosing on a urine sample obtained within 72 hours of the first study drug administration. Males must refrain from sperm donations from date of C1D1 to 90 days after the last date of the study drug.

Критерии исключения

• 1. Non-secretory or hyposecretory multiple myeloma, defined as /<0.5 g/dL M-protein in serum, /<200 mg/24-hour urine M-protein, or disease only measured by serum free light chain.
• 2. Plasma Cell Leukemia
• 3. Concurrent light chain amyloidosis
• 4. Central nervous system involvement (patients with known brain metastases have poor prognosis and often develop progressive neurologic dysfunction that may confound the evaluation of neurologic and other Adverse Events while on ATRA).
• 5. Pregnant or breast feeding
• 6. Severe, active, recurrent, or intercurrent infection (viral, bacterial, fungal), or diagnosis of neutropenia and fever within one week of C1D1.
• 7. History of Allogeneic hematopoietic cell transplantation or solid organ transplantation.
• 8. Unstable angina pectoris, cardiac arrhythmia or /> New York Heart Failure association class II cardiac failure, defined as comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.
• 9. Patient has a significant history of renal, neurologic (peripheral neuropathy), psychiatric, endocrinologic (diabetes mellitus), metabolic, immunologic, cardiovascular, pulmonary, hepatic disease, or significant social situation within the past 6 months that, in the opinion of the investigator, would impede his/her ability to fully participate in the study. For patients who have required an intervention for the above diseases within the past 6 months, a case-by-case discussion with the investigator must occur.
• 10. On investigational therapies within 12 weeks of enrollment.
• 11. Previous allergic reaction or intolerance to a proteasome inhibitor, including carfilzomib, bortezomib, or ixazomib.
• 12. Or deemed unfit for the study on evaluation by Investigator.

Описание

This project will evaluate the efficacy and safety of the conditioning regimen bortezomib-bendamustine-melphalan (BBM) in combination with autologous hematopoietic stem cell transplantation (ASCT) in relapsed multiple myeloma given from 2011 to 2018 at Uppsala University Hospital. This approach will be retrospectively compared to high dose melphalan (HDM) in the same setting in the years prior to, and following the BBM-period. Data on efficacy and safety data will be collected through systematic analysis of electronic medical records and from the Swedish Cancer Registry.

Критерии включения

• * Diagnosis of first relapse after previous ASCT for multiple myeloma according to the International Myeloma Working Group.
• * Treated with a second ASCT (ASCT2) as part of second line treatment at UUH.
• * Conditioning at ASCT2 with bortezomib-bendamustine-melphalan or high-dose melphalan only.

Критерии исключения

• * Double (tandem) ASCT in first or second line treatment
• * Allogenic haematopoietic stem cell transplantation as part of first or second line therapy
• * Failure to meet the minimal dataset, defined as: (date of ASCT1 and ASCT2, date of start of induction treatment for relapsed myeloma prior to ASCT2, medical records from hospitalization for ASCT2, at least one follow-up visit (unless early death before first follow-up visit), date of progression and first treatment of relapsed multiple myeloma after ASCT2.

Описание

This is a prospective, randomized, two-arm, multicenter, exploratory study aimed at evaluating the efficacy and safety of the combination of etoposide, cytarabine and Pegfilgrastim (EAP regimen) for mobilizing hematopoietic stem cells in patients with newly diagnosed multiple myeloma (NDMM). A total of 99 NDMM patients will be enrolled and randomly assigned to receive either the EAP regimen or the GC regimen (cyclophosphamide+ G-CSF) to mobilize hematopoietic stem cells. Subsequently, the mobilization effects and adverse reactions of all patients will be observed and compared.

Критерии включения

• * 1. Patients newly diagnosed as multiple myeloma.
• * 2. Indication for ASCT.
• * 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0/~1.
• * 4. Life expectancy ≥ 3 months.
• * 5. Subjects must be able to understand the protocol and sign the informed consent.

Критерии исключения

• * 1. Cardiac function class II or higher or cardiac ejection fraction /<40%.
• * 2. Serum direct bilirubin (DBIL)/>2× upper limit of normal (ULN).
• * 3. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) />3× ULN.
• * 4. Serum creatinine clearance rate≤30%.
• * 5. Patients with active infection.
• * 6. Previously received hematopoietic stem cell mobilization.

Описание

The primary purpose of this study is to see if individuals with Multiple Myeloma are able and interested in taking part in a tailored exercise program while undergoing their chemotherapy prior to a stem cell transplant. We also hope to learn if this type of program, along with a flexible delivery format (in-person and virtual), helps in maintaining or improving physical fitness, muscle mass and strength, and quality of life during chemotherapy.

Критерии включения

• 1. Have a diagnosis of Multiple Myeloma
• 2. Be transplant eligible
• 3. Be undergoing chemotherapy prior to an autologous stem cell transplant as part of their cancer treatment
• 4. Be an Alberta resident
• 5. Be ≥18 years of age
• 6. Be able to read and understand English.

Критерии исключения

• 1. Their disease status/comorbidities preclude exercise testing or participation
• 2. They are unable to commit to the 10-week exercise program and/or testing sessions at the Cancer Rehabilitation Clinic at the University of Alberta
• 3. They do not have regular access to the internet and/or an electronic device in the home.

Описание

This study is researching an experimental drug called linvoseltamab ("study drug").

This study is focused on patients who have AL amyloidosis that has returned or have failed other therapies and need to be treated again.

The study consists of 2 phases (Phase 1 and Phase 2):

* In Phase 1, linvoseltamab will be given to a small number of participants to study the side effects of the study drug and to determine the recommended doses of the study drug to be given to participants in Phase 2.
* In Phase 2, linvoseltamab will be given to more participants to continue to assess the side effects of the study drug and to evaluate the ability of linvoseltamab to treat AL amyloidosis.

The study is looking at several other research questions, including:

* How many participants treated with linvoseltamab have improvement in the abnormal proteins that cause organ problems and for how long
* How many participants treated with linvoseltamab have improvement in the heart or kidney and for how long
* What the right dosing regimen is for linvoseltamab
* What side effects may happen from taking linvoseltamab
* How much linvoseltamab is in your blood at different times
* Whether the body makes antibodies against linvoseltamab (which could make the drug less effective or could lead to side effects)

Критерии включения

• 1. Confirmed diagnosis of AL amyloidosis, as described in the protocol
• 2. Measurable disease as defined by serum difference between involved and uninvolved free light chains (dFLC) concentration, as described in the protocol
• 3. Previously treated after at least 1 prior therapy and no more than 4 lines of therapy (including autologous stem cell transplant) and requiring further treatment as assessed by the Investigator
• 4. N-terminal pro b-type natriuretic peptide (NT-proBNP) ≤8500 ng/L during screening
• 5. Adequate hepatic, hematologic, renal, and cardiac function, as described in the protocol
• 6. Eastern Cooperative Oncology Group (ECOG) performance score ≤2 at screening

Критерии исключения

• 1. History of other non-AL amyloidosis
• 2. Greater than 60% plasmacytosis on a bone marrow biopsy and/or aspirate during screening
• 3. Presence of lytic bone lesion(s) or extramedullary plasmacytoma on imaging during screening
• 4. Myocardial infarction within the past 6 months prior to the first screening visit
• 5. Known active infection requiring hospitalization or treatment with IV anti-infectives within 28 days of first administration of study drug
• NOTE: Other protocol defined inclusion/exclusion criteria apply

Описание

Patients with multiple myeloma experience a wide range of physical and psychological symptoms from the time of their diagnosis. Meanwhile, patients with aggressive lymphomas undergo unpredictable illness courses, resulting in goals of care conversations occurring late in the illness trajectory and aggressive care being received in the last 30 days of life. Early palliative care alongside usual cancer care has been shown to improve patient outcomes such as symptom burden, mood, and quality of life in patients with solid tumours (e.g. lung, breast or gynecological cancers), but has not been explored among patients with blood cancers to date.

The goal of this clinical trial is to a brief early palliative care intervention for patients with multiple myeloma and aggressive B cell lymphoma attending the Princess Margaret Cancer Centre. The main goals of the study are:

* To see if it is possible to apply the early palliative care intervention for patients with multiple myeloma and aggressive lymphoma
* To see if this early palliative care intervention works well for these patients
* To compare patient experiences with early palliative care and usual care.

Participants will be randomly assigned to one of two groups: one group will receive early palliative care in addition to usual care from their blood cancer doctor, and the other group will receive usual care from their blood cancer doctor only. All participants will be asked to fill out questionnaires about their symptom burden, mood, quality of life, and satisfaction with care throughout the study. Some participants will also be asked to take part in interviews at the end of the trial to answer questions about their experience taking part in the study. Researchers will compare the results between the two groups to see if there are any improvements in quality of life for the patients who received early palliative care. The researchers will use the results of this study to guide in the development of a larger clinical trial.

Критерии включения

• * age ≥18 years;
• * a new diagnosis of multiple myeloma or at time of progression of disease necessitating a change in treatment plan, or relapsed/refractory aggressive B cell lymphomas after one prior line of therapy;
• * Eastern Cooperative Oncology Group (ECOG) performance status 0-3; and
• * willingness to complete symptom screening.

Критерии исключения

• * insufficient English literacy to complete study procedures;
• * hematologist-determined poor cognitive status;
• * current palliative care team involvement at Princess Margaret Cancer Centre or elsewhere;
• * referred to the Princess Margaret Cancer Centre for once-off a second opinion and not receiving ongoing follow up with hematology team at the Princess Margaret Cancer Centre; and
• * failure to score a single item at ≥3 of the ESAS-r-plus at time of recruitment.

Описание

This study is a multicenter, open-label, dose-escalation/dose-expansion clinical Phase I trial designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy profile of SHR-9539 Injection in patients with multiple myeloma.

Критерии включения

• 1. Age ≥ 18 years on day of signing the Informed Consent Form;
• 2. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status Scale；
• 3. Documented initial diagnosis of multiple myeloma according to IMWG diagnostic criteria ；
• 4. Have a life expectancy of at least 3 months；
• 5. Male and female subjects with fertility must agree to use efficient contraceptive measures with their partners within 3 months after the last administration of the test drug from the time of signing the informed consent form, and have no fertility plan and avoid donating sperm / eggs. The pregnancy test during the screening period must be negative.

Критерии исключения

• 1. Central nervous system (CNS) involvement of MM；
• 2. Diagnosis of amyloidosis, plasma cell leukemia, Wahl`s macroglobulinemia, or POEMS syndrome;
• 3. Prior Grade 3 or higher CRS (Per ASTCT standards) related to any T cell redirection (eg, CD-3 redirection technology or CAR-T cell therapy).
• 4. Have other factors that may force the termination of the study, e.g., non-compliance with the protocol, other serious illnesses (including psychiatric illnesses) that require comorbid treatment, serious laboratory abnormalities, associated family or social factors, which would affect the safety of the subjects or the collection of data and samples, as determined by the investigator.

Описание

Multiple myeloma (MM) is a malignancy characterized by uncontrolled proliferation of plasma cells for which there is an urgent and unmet need to develop new, effective therapeutics. Onconova Therapeutics has developed a first-in-class oral inhibitor of CDK4 and ARK5 ON 123300 (NARAZACICLIB) which shows potent anti-myeloma activity in vitro and in vivo in preclinical models, and is undergoing evaluation in Phase 1-2 trials worldwide.

In this study, the researchers will test the safety and preliminary efficacy of inhibition of CDK4 and ARK5 by ON 123300 (NARAZACICLIB) in combination with dexamethasone in myeloma patients in a Phase I/II clinical trial.

Критерии включения

• In order to be eligible to participate in this study, an individual must meet all of the following criteria:
• * Able to provide a signed Written Informed Consent: Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care
• * Male or female patients ≥18 years
• * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• * Symptomatic MM having progressed on ≥2 prior line of therapies - including 1 proteasome inhibitor (bortezomib, carfilzomib etc.), 1 immunomodulatory drug (lenalidomide, pomalidomide, thalidomide etc.), and 1 CD38 targeting monoclonal antibody (daratumumab, isatuximab) either as monotherapy or in combination. Refractoriness (progression while on therapy or ≤60 days after discontinuation of therapy) to prior line of therapy is not required.
• * Subjects who received BCMA-targeted immune-effector therapies like CAR-T cells and/or bispecific antibodies prior can be enrolled provided they are ≥60 days out of the treatment.
• * Subjects must not be candidates for treatment regimens known to provide clinical benefit to be eligible for this study.
• * Subjects must have measurable disease defined by at least 1 of the following 4 measurements:
• * Serum M-protein /> 0.5 g/dL or Urine M-protein /> 200 mg/24 hours
• * Light chain MM without measurable disease in serum or urine: Serum immunoglobulin free light chain assay: involved free light chain level />10 mg/dL (/> 100 mg/L) provided the serum free light chain ratio is abnormal
• * For oligo/non-secretory myeloma, measurable by standard imaging (PET/CT or MRI) ± bone marrow biopsy if myeloma biomarkers are inconclusive or non-contributory
• * Able to swallow and absorb oral medication
• * All previous therapies for cancer, including radiotherapy, major surgery and investigational therapies discontinued for ≥ 14 days before study entry, and all acute effects of any prior therapy resolved to baseline severity or Grade ≤ 1 Common Terminology Criteria for Adverse Events (CTCAE v5.0) excluding alopecia or fatigue.
• * Adequate organ or marrow function
• * CrCl (Cockcroft-Gault equation) ≥ 45ml/min
• * ALT/AST ≤2 times upper limit of normal
• * Total bilirubin ≤2 times upper limit of normal (/<3 x ULN for congenital hyperbilirubinemia states like Gilbert Syndrome)
• * Corrected serum calcium ≤12.5mg/dL or free ionized calcium ≤6.5mg/dL
• * ANC ≥1 x 109/L (prior growth factor permitted but must be without support 7 days before screening test)
• * Hemoglobin ≥8g/dL (without blood transfusion in 7 days prior to test, recombinant erythropoietin permitted)
• * Platelets ≥50 x 109/L
• * No active infections (including but not limited to HIV, Hepatitis B, Hepatitis C, tuberculosis) or chronic health conditions which may interfere in the study in the opinion of the investigator.
• * HIV: undetectable HIV viral load and CD4 counts />200 for />6 months on continuous antiretroviral therapy may be screened.
• * Hepatitis B: If HbcAb positive and HBV PCR-, may be screened
• * Hepatitis C: if completed anti-viral therapy and in sustained virological response />6 months, may be screened
• * Tuberculosis: Quantiferon or skin prick test positive but with negative chest imaging
• * (CXR or CT) and asymptomatic, may be screened
• * Note: A line of therapy consists of ≥1 complete cycle of a single agent, a regimen consisting of a
• * combination of several drugs, or a planned sequential therapy of various regimens3.
• * A treatment is considered a new line of therapy if any one of the following three conditions are met:
• * Start of a new line of treatment after discontinuation of a previous line: if the treatment regimen is discontinued for any reason, and a different regimen is started, it should be considered a new line of therapy. A regimen is considered to have been discontinued if all the drugs in that given regimen have been stopped. The regimen is not considered to have been discontinued if some of the drugs of the regiment, but not all, have been discontinued.
• * The unplanned addition or substitution of one or more drugs in an existing regimen: Unplanned addition of a new drug, or switching to a different drug, or combination of drugs due to any reason, is considered a new line of therapy.
• * Stem cell transplant (SCT): In patients undergoing />1 SCT, except in the case of a planned tandem SCT with a predefined interval such as 3 months, each SCT (autologous or allogeneic, should be considered a new line of therapy, regardless of whether the conditioning regime used is the same or different.

Критерии исключения

• * Active plasma cell leukemia at screening (/>5% plasma cells by standard differential), Waldenstroms macroglobulinemia, PEOMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes), known active or prior CNS involvement or exhibits meningeal signs (extradural skull or spinal mass causing extrinsic mass effect is not excluded) or clinically significant amyloidosis.
• * History of allogeneic hematopoietic cell transplantation (HCT), or other cellular therapy product, within 60 days.
• * Inability to tolerate oral medication, presence of poorly controlled gastrointestinal disease, or dysfunction that could affect study drug absorption including but not limited to:
• * Diarrhea /> Grade 1, based on the NCI CTCAE grading, in the absence of antidiarrheals.
• * Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of study drug, including difficulty swallowing.
• * Following cardiac conditions:
• * New York Heart Association (NYHA) stage III or IV congestive heart failure
• * myocardial infarction or coronary artery bypass graft (CABG) /<6 months prior to enrollment
• * History of clinically significant ventricular arrhythmia or unexplained syncope not believed to be vasovagal in nature or due to dehydration
• * History of severe nonischemic cardiomyopathy e. Impaired cardiac function (LVEF /<45%) as assessed by echocardiogram or multi gated acquisition (MUGA) scan.
• * Stroke or seizure within 6 months of enrollment
• * Are at risk for Torsades de pointes (TdP): Patients who have a marked baseline prolongation of QT/QTc interval (eg, repeated demonstration of a QTc interval />470 msec) using Fredericia`s QT correction formula, or who have a history of additional risk factors for TdP (eg, heart failure, hypokalemia, family history of Long QT Syndrome), or who are currently taking medications that prolong the QT/QTc interval.
• * Are currently taking or within 5 half-lives of taking strong inducers and inhibitors of cytochrome P450 enzyme (CYP) 2C8 and CYP3A4.
• * Have had major surgery within 14 days prior to screening to allow for postoperative healing of the surgical wound and site(s).
• * Have received recent (within 28 days prior to screening) live attenuated vaccines.
• * Active pregnancy or breastfeeding females
• * Known chronic alcohol or drug abuse
• * Lack of capacity to sign consent and/or participate in the trial
• * Any other condition deemed by the investigator to make the patient a poor candidate for clinical trial and/or treatment with investigational agents.
• * Any altered mental status or any psychiatric condition that would interfere with the understanding of the informed consent or limit compliance with study requirements.
• * Prior or concurrent malignancy, except for the following:
• * Adequately treated non-melanoma skin cancer (basal cell or squamous cell skin carcinoma) ≥1 year
• * Cervical carcinoma in situ adequately treated ≥1 year
• * Adequately treated Stage I or II cancer from which the subject is currently in complete remission ≥2 years
• * Any other cancer from which the subject has been disease-free for ≥ 3 years
• * Males or females of childbearing potential who do not agree to practice 2 highly effective methods of contraception. Highly effective method of contraception has a failure rate of less than 1% per year when used consistently and correctly, and agree to remain on a highly effective method of contraception from the time of signing the informed consent form through 90 days after the last dose of study drug. For women, examples of highly effective contraceptives include A) user independent methods: 1. implantable progesterone only hormonal contraception 2. intrauterine device/intrauterine hormone releasing system 3. vasectomized partner B) user dependent methods: 1. combined estrogen and protestor hormonal contraception (oral intravaginal or transdermal) 2. progesterone only hormone contraception (oral or injectable). For men, highly effective barrier method of contraception include - condom with spermicidal foam/gel/film/cream/suppository from the time of signing the ICF until 90 days after receiving the last dose of treatment. Intercourse with a pregnant woman must involve the use a condom. Women and men must agree not to donate eggs or sperm while on the study drug or up to 90 days after the last dose of drug.
• * Uncontrolled, untreated or active infections, including but not limited to HIV, Hepatitis B, Hepatitis C, tuberculosis.

Описание

The purpose of this study is to determine whether Linvoseltamab therapy in patients with newly diagnosed multiple myeloma will convert the disease status from minimal residual disease (MRD)-positive to MRD-negative, and increase the length of time that the disease is controlled. The researchers also want to find out the effects (good and bad) that Linvoseltamab has on participants and the condition.

Критерии включения

• 1. Diagnosis of newly-diagnosed multiple myeloma (NDMM) per International Myeloma Working Group (IMWG) criteria documented initially prior to induction treatment.
• 2. Documentation of having received a triplet or quadruplet based initial combination therapy containing at least two of the following: Immunomodulatory drug (IMiD), proteosome inhibitor (PI), and/or anti-cluster of differentiation 38 (anti-CD38).
• 3. Documentation of attaining a best response of very good partial response (VGPR) or better but MRD+ (sensitivity: ≤10/^-5) after at least 4 cycles of combination therapy.
• Note: Patients who at baseline prior to initial combination therapy did not have IMWG evaluable disease and therefore a response assessment of VGPR was unable to be made but currently have residual MM by M-protein and/or involved light chains and/or MRD positivity may enroll. Also, patients who have no apparent bone marrow (BM) residual disease but rather extramedullary disease as evidenced by positron emission tomography (PET)/computed tomography (CT) may enroll.
• 4. Age ≥18 years.
• 5. Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 1. Patients with ECOG 2 solely due to local symptoms of myeloma (eg, pain) may be allowed after discussion with the PI (APPENDIX A).
• 6. Adequate organ function, which is defined as follows:
• * a. Absolute neutrophil count (ANC) ≥1,000 cells/microliter (mcL) (unless patient has ethnic/cyclic neutropenia or if neutropenia is thought to be due to MM)
• * b. Platelets ≥50,000 platelets/mcL
• * c. Hemoglobin ≥8 g/dL (transfusions permitted)
• * d. Serum total bilirubin ≤ 1.5 X upper limit of normal (ULN) or direct bilirubin ≤ ULN for patients with total bilirubin levels /> 1.5 ULN (except patients with Gilbert`s syndrome who must have a total bilirubin of /<3 X ULN)
• * e. Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT)) and alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase (SGPT)) ≤ 2.5 X ULN
• * f. Serum creatinine ≤ 1.5 X ULN (except if due to myeloma) or estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 (note that measured glomerular filtration rate /[GFR/], ie, 24-hour urine, can also be used) based on institutional standard
• * g. Female patients of childbearing potential must have a negative serum pregnancy test at Screening. Female patients of childbearing potential and fertile male patients who are sexually active with a female of childbearing potential must use highly effective methods of contraception throughout the study and for 6 months following the last dose of study treatment. For more information on contraception requirements, please refer to Section 4.11.
• * h. Willing and able to provide written informed consent in accordance with federal, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure. For more information on the informed consent process, please refer to Section 15.1.
• 7. Willing and able to comply with clinic visits and study-related procedures.

Критерии исключения

• 1. Patients who have received prior systemic therapies for MM other than initial IMiD/PI/anti-CD38-based combination therapy (receiving limited cycles of other induction therapies, eg, cyclophosphamide, bortezomib and dexamethasone (CyBorD) or pulse dexamethasone prior to main induction is allowed). Exclusions include high-dose melphalan with autologous stem cell transplant (HDM-ASCT) and allogeneic stem cell transplant (SCT).
• Note: Continuous systemic corticosteroid treatment with more than 10 mg per day of prednisone or anti-inflammatory equivalent within 72 hours of start of study drug is not permitted.
• 2. Patients who are receiving any other investigational agents for any reasons.
• 3. Patients who receive a live attenuated vaccine within 4 weeks of scheduled study treatment administration.
• 4. Contraindication to any concomitant medication, including those medications administered for infusion reaction, antiviral, antibacterial, anticoagulation, tumor lysis, or hydration prophylaxis given prior to therapy (Sections 4.8, 4.9, and 7).
• 5. Patient has any of the following:
• 1. Human immunodeficiency virus (HIV)-positive with 1 or more of the following:
• * i. History of acquired immune deficiency syndrome (AIDS)-defining conditions cluster of differentiation 4 (CD4) count /<350 cells/mm3
• * ii. Detectable viral load during screening or within 6 months prior to screening
• * iii. Not receiving highly active anti-retroviral therapy
• * iv. Had a change in anti-retroviral therapy within 6 months of the start of screening
• * v. Receiving anti-retroviral therapy that may interfere with study treatment as assessed after discussion with the Sponsor-Investigator in consultation with study pharmacist
• 2. Hepatitis B infection (ie, hepatitis B surface antigen (HBsAg) or hepatitis B virus (HBV)-deoxyribonucleic acid /[DNA/] positive). Patients with resolved infection (ie, patients who are HBsAg negative but positive for antibodies to hepatitis B core antigen (anti-HBc) and/or antibodies to hepatitis B surface antigen (anti-HBs)) must be screened using real-time polymerase chain reaction (PCR) measurement of HBV DNA levels. Those who are PCR positive will be excluded. In the event the infection status is unclear, quantitative viral levels are necessary to determine the infection status. EXCEPTION: Patients with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR.
• 3. Active hepatitis C infection as measured by positive hepatitis C virus (HCV)-ribonucleic acid (RNA) testing. Participants with a history of HCV antibody positivity must undergo HCV-RNA testing. If a participant with history of chronic hepatitis C infection (defined as both HCV antibody and HCV RNA positive) completed antiviral therapy and has undetectable HCV-RNA 12 weeks following the completion of therapy, the participant is eligible for the study.
• 6. History of allergic reactions attributed to compounds of similar chemical or biologic composition to the experimental agents used in study.
• 7. Female patient refuses to discontinue breastfeeding her infant during study treatment or within 6 months after receiving the last dose of study treatment (Section 4.11).
• 8. Women of childbearing potential (WOCBP) and men who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose.
• * Highly effective contraceptive measures for women include: stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening intrauterine device (IUD); intrauterine hormone-releasing system (IUS) bilateral tubal ligation vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the study participant and that the partner has obtained medical assessment of surgical success for the procedure) and/or sexual abstinence.
• * WOCBP are defined as women who are fertile following menarche until becoming post-menopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A post-menopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a post-menopausal state.
• * Male study participants with WOCBP partners are required to use condoms unless they are vasectomized or practice sexual abstinence. Male study participants should not donate sperm during the study, and for at least 6 months after the last dose. Vasectomized partner or vasectomized study participant must have received medical assessment of the surgical success.
• * Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient.
• Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together (Section 4.11).
• 9. Presence of the following cardiac conditions:
• * e. New York Heart Association stage III or IV congestive heart failure
• * f. Myocardial infarction or coronary artery bypass graft ≤ 6 months prior to study enrollment
• * g. History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration. Uncontrolled cardiac arrhythmia or clinically significant electrocardiogram (ECG) abnormalities
• * h. Unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina)
• 10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, venous thromboembolic disease, hemorrhage, pulmonary fibrosis, pneumonitis, neurological condition, active autoimmune disease or a documented history of autoimmune disease with the exception of vitiligo, type I diabetes, and prior autoimmune thyroiditis that is currently euthyroid based on clinical symptoms and laboratory testing, or psychiatric illness/social situations within 2 weeks that would limit compliance with study requirements.
• 11. Active malignancy other than MM requiring treatment in the past 12 months. Malignancies treated within the past 12 months that are considered cured with minimal risk of recurrence are allowed.
• 12. Have any condition that, in the opinion of the Investigator, would compromise the well-being of the patient or the study or prevent the patient from meeting or performing study requirements.
• 13. Patients with impaired decision-making capacity will not be enrolled on this trial.

Описание

Phase 1b, open-label study evaluating the safety, tolerability, pharmacokinetics, preliminary antitumor activity, and pharmacodynamics of OPN-6602 monotherapy and in combination with dexamethasone in subjects with relapsed and/or refractory MM.

Критерии включения

• * Confirmed diagnosis of multiple myeloma (MM)
• * Relapsed or refractory to 3 or more different prior lines of therapy for MM that included immunomodulatory agents, proteosome inhibitors, and anti-CD38 antibody and not a candidate for or intolerant to established therapy known to provide clinical benefit
• * Adequate hematologic, renal, liver, cardiac function

Критерии исключения

• * Monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, Waldenström`s macroglobulinemia, or IgM myeloma
• * Active plasma cell leukemia
• * Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes (POEMS syndrome)
• * Prior Stevens Johnson syndrome
• * Localized radiation therapy to disease site(s) within 2 weeks of the first dose
• * Prior autologous peripheral stem cell transplant or prior autologous bone marrow transplantation within /<90 days of the first dose of study drug
• * Prior allogeneic stem cell transplantation or solid organ transplantation within 12 months of screening; subjects receiving immunosuppressive medication for active graft vs host disease will be excluded.
• * Prior chemotherapy, targeted anticancer or radiation therapy within 2 weeks prior to first dose of study drug
• * Concomitant high-dose corticosteroids (except subjects on chronic steroids given for disorders other than myeloma)
• * Known central nervous system involvement by multiple myeloma
• * Active known second malignancy with exception of adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer; adequately treated Stage 1 cancer from which the subject is currently in remission and has been in remission for ≥2 years; low-risk prostate cancer with a Gleason score /<7 and a PSA level /<10 ng/mL; any other cancer from which the subject has been disease-free for ≥3 years
• * Ongoing systemic infection requiring parenteral treatment
• * Poorly controlled Type 2 diabetes

Описание

The goal of this study (iMMagine-3) is to compare the study drug, anitocabtagene autoleucel to standard of care therapy (SOCT) in participants with relapsed/refractory multiple myeloma who have received 1 to 3 prior lines of therapy, including an anti-CD38 monoclonal antibody and an immunomodulatory drug.

The primary objective of this study is to compare the efficacy of anitocabtagene autoleucel versus SOCT in participants with RRMM as measured by progression-free survival (PFS) per blinded independent review committee (IRC).

Критерии включения

• * Documented historical diagnosis of multiple myeloma (MM)
• * Received 1 to 3 prior lines of antimyeloma therapy, including an immunomodulatory drug (IMiD) and an anti-cluster of differentiation 38 (CD38) monoclonal antibody (mAb). A minimum of 2 consecutive cycles of an IMiD and an anti-CD38 mAb in any prior line of therapy is required. The IMiD and anti-CD38 mAb do not need to be from the same regimen in the prior line(s) of therapy.
• * Documented evidence of progressive disease by IMWG criteria based on the investigator`s determination on or within 12 months of the last dose of the last regimen
• * Measurable disease at screening per IMWG, defined as any of the following:
• * Serum M-protein level ≥ 0.5 g/dL or urine M-protein level ≥ 200 mg/24 hours; or
• * Light chain MM without measurable disease in the serum or urine: serum free light chain ≥ 10 mg/dL and abnormal serum free light chain ratio
• * Only individuals who are candidates to receive at least 1 of the 4 SOCT regimens (PVd, DPd, KDd, or Kd), as determined by the investigator, should be considered for this study
• * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• * Females of childbearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential)

Критерии исключения

• * Prior B-cell maturation antigen (BCMA)-targeted therapy
• * Prior T-cell engager therapy
• * Prior CAR therapy or other genetically modified T-cell therapy
• * Active or prior history of central nervous system (CNS) or meningeal involvement of MM
• * Cardiac atrial or cardiac ventricular MM involvement
• * History of or active plasma cell leukemia, Waldenstrom`s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or amyloidosis
• * Active malignancy (other than MM) requiring ongoing treatment for disease control within the last 24 months. Myelodysplastic syndrome (even without ongoing treatment) is not permitted.
• * Prior auto-SCT within 12 weeks before randomization
• * Prior allogeneic stem cell transplant (allo-SCT)
• * High-dose (eg, cumulative /> 70 mg prednisone or equivalent) systemic steroid therapy or any other form of immunosuppressive therapy within 14 days before randomization
• * Live vaccine ≤ 4 weeks before randomization
• * Contraindication to fludarabine or cyclophosphamide
• * History of allergy or hypersensitivity to any study agent or study drug components. Individuals with a history of severe hypersensitivity reaction to dimethyl sulfoxide (DMSO) are excluded.
• * Life expectancy /< 12 weeks
• Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Описание

A Phase 1b, Multicenter, Open-Label, Study to Investigate the Safety and Efficacy of CLN-619 (anti-MICA/MICB Antibody) in Patients with Relapsed and Refractory Multiple Myeloma

Критерии включения

• 1. Aged ≥ 18 years at the time of signing the ICF.
• 2. Willing and able to give written informed consent and adhere to protocol requirements.
• 3. Patient has a history of multiple myeloma with relapsed and refractory disease as defined by the protocol.
• 4. Patients must have measurable disease (as determined by the local laboratory) as defined by the protocol.
• 5. Performance status of 0 to 2 based on the Eastern Cooperative Oncology Group (ECOG) performance scale.
• 6. Estimated life expectancy of 12 weeks or longer.
• 7. Prior palliative radiotherapy must have been completed at least 14 days prior to dosing on Cycle 1 Day 1.
• 8. Toxicities related to prior study therapy should have resolved to Grade 1 or less according to criteria of NCI CTCAE v5.0, except for alopecia. Patients with chronic but stable Grade 2 toxicities may be allowed to enroll after an agreement between the Investigator and Sponsor.
• 9. Have adequate liver and kidney function and hematological parameters within a normal range as defined by the protocol.

Критерии исключения

• 1. Patient has symptomatic central nervous system involvement of MM.
• 2. Patient has nonsecretory MM, plasma cell leukemia, Waldenstrom`s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or amyloidosis.
• 3. Patient had a prior autologous stem cell transplant ≤ 3 months prior to first dose of study drug on Cycle 1 Day 1.
• 4. Patient had a prior allogeneic stem cell transplant with either standard or reduced intensity conditioning ≤ 6 months prior first dose of study drug on Cycle 1 Day 1 or is on systemic immunosuppression for graft-versus-host disease.
• 5. Patients with concomitant second malignancies (Except adequately treated non-melanomatous skin cancers, ductal carcinoma in situ, superficial bladder cancer, prostate cancer, Grade 1 stage 1A/1B endometrioid endometrial cancer or cervical cancer in situ) are excluded unless in complete remission three years prior to study entry, and no additional therapy is required or anticipated to be required during study participation.
• 6. Patients with any active autoimmune disease or a history of known or suspected autoimmune disease, or history of a syndrome that requires systemic corticosteroids treatment or immunosuppressive medications, except for patients with vitiligo, resolved childhood asthma/atopy or autoimmune thyroid disorders on stable thyroid hormone supplementation.
• 7. A serious uncontrolled medical disorder that would impair the ability of the patient to receive protocol therapy or whose control may be jeopardized by the complications of this therapy.
• 8. Treatment with systemic antiviral, antibacterial or antifungal agents for acute infection within ≤ 7 days of first dose of study drug on Cycle 1 Day 1.
• 9. Patient has active peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the NCI-CTCAE v5.0.
• 10. Diagnosed with HIV, Hepatitis B, or Hepatitis C infection.
• 11. Treatment with non-oncology vaccines for the control of infectious diseases (i.e., HPV vaccine) within 28 days of first dose of study drug on Cycle 1 Day 1.
• 12. Active SARS-CoV-2 infection based on positive SARS-CoV-2 test within 4 weeks prior to enrollment or patients with suspected active infection based on clinical features or pending results.
• 13. Has received immunosuppressive medications including but not limited to CellCept, methotrexate, infliximab, anakinra, tocilizumab, cyclosporine, or corticosteroids (≥ 10 mg/day of prednisone or equivalent), within 28 days of first dose of study drug on Cycle 1 Day 1.
• 14. Patient has history of drug-related anaphylactic reactions to any components of CLN-619. History of Grade 4 anaphylactic reaction to any monoclonal antibody therapy.
• 15. Certain treatment with investigational agents and other anti-neoplastic therapy as defined by the protocol
• 16. Female of child-bearing potential (FOCBP) who is pregnant or breast-feeding, plans to become pregnant within 120 days of last study drug administration or declines to use an acceptable method to prevent pregnancy during study treatment and for 120 days after the last dose of study drug administration.
• 17. Male patients who plans to father a child or donate sperm within 120 days or 5 half-lives of CLN-619, whichever comes later, of last study drug administration, or who has a partner who is a FOCBP, and declines to use an acceptable method to prevent pregnancy during study treatment and for 120 days or 5 half-lives of CLN-619, whichever comes later, after the last dose of study drug administration.

Описание

This phase II trial compares iberdomide maintenance therapy to disease monitoring for improving survival in patients who have received idecabtagene vicleucel (a type of chimeric antigen receptor T-cell /[CAR-T/] therapy) for multiple myeloma. The usual approach after treatment with idecabtagene vicleucel is to monitor the multiple myeloma without giving myeloma medications. There is currently no medication approved specifically for use after idecabtagene vicleucel treatment. Upon administration, iberdomide modifies the immune system and activates immune cells called T-cells, which could enhance the effectiveness of idecabtagene vicleucel. Iberdomide may keep multiple myeloma under control for longer than the usual approach (disease monitoring) after idecabtagene vicleucel, and may help multiple myeloma patients live longer.

Критерии включения

• * PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0):
• * All patients must be pre-registered. For patients who consent to biobanking, submit the bone marrow and blood specimens
• * Note: Patients who do not consent to the optional biobanking must be pre-registered, but specimens should not be submitted for these patients
• * Please ensure patient has suspected diagnosis of multiple myeloma and meets on study guidelines prior to informed consent and biospecimen collection
• * In cases where the bone marrow aspiration may be inadequate at Step 0 registration, the patient may still register on study
• * ELIGIBILITY CRITERIA (STEP 1):
• * Patients must have diagnostically confirmed MM in response status of stable disease or better by International Myeloma Working Group (IMWG) criteria at day 80-110 post-infusion of ide-cel. Patients in deep remission (e.g., CR, MRD-negative, etc.), are eligible
• * All patients are required to have received ide-cel CAR-T within 80-110 days of registration
• * Adverse events related to ide-cel are required to have resolved to grade =/< 1 except fatigue, alopecia, and other events that are unlikely to interfere with study assessments or pose a safety risk to participants
• * Patients must have had ≥ 4 lines of therapy for MM (this includes proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody)
• * Prior therapy with iberdomide is permitted but prior iberdomide refractoriness is prohibited. Refractoriness is defined as per published IMWG criteria; progression while on iberdomide or within 60 days of stopping iberdomide
• * Patients who have received MM-directed therapy since ide-cel infusion are not eligible, with the exception of short-course steroids for managing ide-cel toxicity as described below
• * Age ≥ 18 years
• * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• * Absolute neutrophil count (ANC) ≥ 1,500/mm/^3
• * Platelet transfusions or use of growth factors for neutropenia (e.g., filgrastim, tbo-filgrastim, sagramostim) are not permitted to meet enrollment criteria
• * Platelet count ≥ 75,000/mm/^3
• * Platelet transfusions or use of growth factors for neutropenia (e.g., filgrastim, tbo-filgrastim, sagramostim) are not permitted to meet enrollment criteria
• * Calculated (calc.) creatinine clearance />= 30 mL/min by Modification of Diet in Renal Disease (MDRD)
• * Platelet transfusions or use of growth factors for neutropenia (e.g., filgrastim, tbo-filgrastim, sagramostim) are not permitted to meet enrollment criteria
• * Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
• * Platelet transfusions or use of growth factors for neutropenia (e.g., filgrastim, tbo-filgrastim, sagramostim) are not permitted to meet enrollment criteria
• * Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase /[SGOT/])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase /[SGPT/]) ≤ 3 x upper limit of normal (ULN)
• * Platelet transfusions or use of growth factors for neutropenia (e.g., filgrastim, tbo-filgrastim, sagramostim) are not permitted to meet enrollment criteria
• * Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effect on the developing fetus and newborn are unknown.
• * FCBP (female of childbearing potential) is a female who: 1) has achieved menarche (first menstrual cycle) at some point, 2) has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time during the preceding 24 consecutive months).
• * Females of childbearing potential (FCBP):
• * Must use a contraceptive method that is highly effective (with a failure rate of /< 1% per year), preferably with low user dependency during the intervention period and for at least 28 days after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
• * The effects of iberdomide on the developing human fetus are unknown. Immunodulatory derivative (IMiD) agents as well as other therapeutic agents used in this trial are known to be teratogenic. Females of child-bearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days prior to, and again within 24 hours of starting iberdomide, and must either commit to continued abstinence from heterosexual intercourse or begin two acceptable methods of birth control, one highly effective method and one additional effective method at the same time, at least 28 days before she starts taking iberdomide. Examples of highly effective methods are intrauterine device, hormonal contraceptives, tubal ligation, or partner`s vasectomy. Examples of barrier method are male condom, diaphragm, or cervical cap. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risk of fetal exposure.
• * Should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study, she should inform her treating physician immediately. FCBP must use adequate contraception for at least 28 days after discontinuation from study. Because of the potential for serious adverse reactions in a breastfed child, women are advised not to breastfeed during treatment and for at least 28 days after the last dose.
• * The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with a nearly undetected pregnancy.
• * Non-childbearing potential is defined as follows (by other than medical reasons):
• * ≥ 45 years of age and has not had menses for /> 1 year
• * Patients who have been amenorrhoeic for /< 2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation
• * Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure
• * Male patients must agree to use an adequate method of contraception for the duration of the study and for 28 days afterwards.
• * Male participants: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies:
• * Male participants are eligible to participate if they agree to the following during the intervention period and for 28 days after the last dose of study treatment to allow for clearance of any altered sperm:
• * Refrain from donating sperm
• PLUS, either:
• * Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR
• * Must agree to use contraception/barrier as detailed below:
• * Agree to use a male condom, even if they have undergone a successful vasectomy, and female partner to use an additional highly effective contraceptive method with a failure rate of /< 1% per year as when having sexual intercourse with a woman of childbearing potential (including pregnant females)
• * Patients may not have polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome or amyloidosis involving any vital organ; amyloidosis found in skin or lymph nodes ("non-vital organs"), or incidental observation of amyloidosis on bone marrow biopsy, are both permissible. Plasma cell leukemia is permissible for study enrollment
• * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial
• * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load
• * Patients may not have other, active infections at time of study registration. Recent infections are not exclusionary if antibiotics have been completed and infection is considered to be resolved / controlled. (Chronic maintenance antibiotics for prior infections, such as fungal, are permissible.)
• * No known allergy to iberdomide
• * No known medical condition causing an inability to swallow oral formulations of agents
• * Patients receiving other active therapies for MM since ide-cel infusion are prohibited from participating in the study
• * Corticosteroids used for the purpose of managing ide-cel toxicity (often neurotoxicity) soon after ide-cel administration are acceptable, provided that the participant will have been off corticosteroids for /> 30 days by cycle 1 day 1. Physiologically dosed chronic steroids are permitted
• * Given the potential for interaction with iberdomide, patients who take strong CYP3A4 inducers or inhibitors may enroll after switching to a different agent and after an appropriate washout period for that particular medication, ideally three half-lives, prior to cycle 1 day 1

Критерии исключения

Описание

This phase II trial compares the combination of selinexor, daratumumab, velcade (bortezomib), and dexamethasone (Dara-SVD) to the usual treatment of daratumumab, lenalidomide, bortezomib, and dexamethasone (Dara-RVD) in treating patients with high-risk newly diagnosed multiple myeloma. Selinexor is in a class of medications called selective inhibitors of nuclear export (SINE). It works by blocking a protein called CRM1, which may keep cancer cells from growing and may kill them. Daratumumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD38, which is found on some types of immune cells and cancer cells, including myeloma cells. Daratumumab may block CD38 and help the immune system kill cancer cells. Bortezomib blocks several molecular pathways in a cell and may cause cancer cells to die. It is a type of proteasome inhibitor and a type of dipeptidyl boronic acid. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body`s immune response to help lessen the side effects of chemotherapy drugs. Lenalidomide is in a class of medications called immunomodulatory agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells in the bone marrow. The drugs daratumumab, lenalidomide, bortezomib, dexamethasone and selinexor are already approved by the FDA for use in myeloma. But selinexor is not used until myeloma comes back (relapses) after initial treatment. Giving selinexor in the initial treatment may be a superior type of treatment for patients with high-risk newly diagnosed multiple myeloma.

Критерии включения

• * Presence of newly diagnosed (dx) MM as defined by standard International Myeloma working group (IMWG).
• * Presence of high risk cytogenetics using fluorescent in situ hybridization (FISH) /[del(17p), t(4;14), t(14;16), t(14;20), chromosome 1 abnormalities, MYC translocation, tetrasomies, complex karyotype, high lactate dehydrogenase (LDH), or extramedullary MM.
• * Patients are allowed to have received one cycle of bortezomib-based doublet or triplet therapy. For instance, if a newly diagnosed patient with MM is in need of urgent therapy, they may be enrolled after having received one cycle of bortezomib, cyclophosphamide, dexamethasone.
• * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%).
• * Absolute neutrophil count ≥ 1,000/mcL (/> 500 if bone marrow /[BM/] clonal plasma cell involvement greater than 50%).
• * Platelets ≥ 100,000/mcL (/> 50,000 if BM clonal plasma cell involvement greater than 50%).
• * Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (with the exception of patients with Gilbert`s syndrome who have a high baseline bilirubin).
• * Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase /[SGOT/])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase /[SGPT/]) ≤ 3 × institutional ULN.
• * Glomerular filtration rate (GFR) ≥ 30 mL/min.
• * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
• * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• * Patients with treated brain involvement are eligible if follow-up brain imaging performed within 10 days after central nervous system (CNS)-directed therapy shows no.
• * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
• * Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
• * The effects of selinexor (KPT-330) on the developing human fetus are unknown. For this reason and because selective nuclear export inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men with partners of women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men (with partners of women of childbearing potential) treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of study treatment administration. Adequate contraception should continue for 7 months for females and for 4 months for males after completion of the study treatment.
• * Female of childbearing potential (FCBP) must have a negative pregnancy test during screening. They must either commit to continue abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 4 weeks before therapy, while taking lenalidomide, during dose interruptions, and for 7 months after study treatment. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. Lenalidomide treatment must be discontinued during this evaluation.
• * Men who are sexually active with FCBP must agree to use a latex or synthetic condom while taking lenalidomide, during dose interruptions and for up to 4 weeks after discontinuing lenalidomide, even if they have undergone a successful vasectomy. Male patients taking lenalidomide must abstain from donating blood, semen, or sperm during study participation and for at least 4 weeks after discontinuation from lenalidomide.
• * Patients who are randomized to receive lenalidomide need to register into the mandatory Risk Evaluation and Mitigation Strategies (REMS) program and be willing and able to comply with the requirements of REMS.
• * Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Критерии исключения

• * Patients who are in urgent need for MM therapy (such as in the setting of acute kidney injury, or high disease burden concerning for impending organ failure) may begin study treatment immediately after receiving one cycle of bortezomib combination (e.g. bortezomib-dexamethasone or cyclophosphamide-bortezomib-dexamethasone) or one course of pulse dose dexamethasone 20-40mg once daily for four days. No washout period is required.
• * Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities /> grade 1) with the exception of alopecia.
• * Patients who are receiving any other investigational agents.
• * History of allergic reactions attributed to compounds of similar chemical or biologic composition to selinexor (KPT-330) or other agents used in study.
• * Concomitant medications: Supportive care therapies such as bone directed therapies (zoledronic acid, denosumab), intravenous immunoglobulin therapy (IVIG) and anti-viral agents are allowed and recommended as per standard of care (SOC). Strong CYP3A4 inhibitors and strong CYP3A4 inducers are prohibited, due to their respective increase or decrease in bortezomib exposure. If strong CYP3A4 inhibitors cannot be avoided, then patients will be monitored for signs of bortezomib toxicity and a dose reduction of bortezomib will be considered.
• * Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous.
• * Pregnant women are excluded because this study involves an investigational drug that may cause genotoxic, teratogenic, and mutagenic effects on the developing fetus and newborn and drugs that have known genotoxic, teratogenic, or abortifacient effect.
• * Because there is potential risk for adverse events in nursing infants secondary to treatment of the mother with the drugs used in this study, breastfeeding is not allowed during treatment for all drugs and for 2 months after last dose of bortezomib and 1 week after the last dose of selinexor.

Описание

This phase II trial investigates the effect of belantamab mafodotin and lenalidomide on minimal residual disease negative rates in patients with multiple myeloma with minimal residual disease positive after stem cell transplant. Belantamab mafodotin is a monoclonal antibody, called belantamab, linked to a chemotherapy drug, called mafodotin. Belantamab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as B-cell maturation antigen (BCMA) receptors, and delivers mafodotin to kill them. Lenalidomide may help block the formation of growths that may become cancer, and is used as a standard of care treatment for multiple myeloma. Giving belantamab mafodotin and lenalidomide may help to maintain minimal residual disease negativity in patients with multiple myeloma.

Критерии включения

• * Age />= 18 years of age at time of consent
• * Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• * Histologically or cytologically confirmed diagnosis of multiple myeloma (MM) as defined according to International Myeloma Working Group (IMWG), 2016 criteria, and
• * Patient is considered transplant eligible, and
• * Is not MRD negative complete response (CR) after high dose chemotherapy
• * Absolute neutrophil count (ANC) />= 1.5 X 10/^9/L (within 14 days of first dose of study treatment)
• * Hemoglobin />= 8.0 g/dL (within 14 days of first dose of study treatment)
• * Platelets />= 75 X 10/^9/L (within 14 days of first dose of study treatment)
• * Total bilirubin =/< 1.5 X upper limit of normal (ULN) (isolated bilirubin />= 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin /< 35%) (within 14 days of first dose of study treatment)
• * Alanine aminotransferase (ALT) =/< 2.5 X ULN or /< 5 times ULN if documented liver infiltration (within 14 days of first dose of study treatment)
• * Estimated glomerular filtration rate (eGFR) />= 30 mL/min/ 1.73 m/^2 (within 14 days of first dose of study treatment)
• * Spot urine (albumin/creatinine ratios (spot urine) /< 500 mg/g (56 mg/mmol) OR urine dipstick Negative/trace (if />= 1+ only eligible if confirmed =/< 500 mg/g (56 mg/mmol) by albumin/creatinine ratio (spot urine from first void) (within 14 days of first dose of study treatment)
• * A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
• * Not a woman of childbearing potential (WOCBP) OR
• * A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 4 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period
• * Female participants of childbearing potential are to have a negative serum pregnancy test within 24 hours before the first dose of study intervention
• * A male participant must agree to use an adequate method of contraception (as described below) during the treatment period and for at least 6 months after the last dose of study treatment to allow for clearance of any altered sperm, along with the following:
• * Refrain from donating sperm PLUS either:
• * Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent. OR
• * Must agree to use contraception/barrier
• * All prior treatment-related toxicities (defined by National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0) must be =/< grade 1 at the time of enrolment except for alopecia
• * Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

Критерии исключения

• * Evidence of active bleeding requiring intervention within the last four weeks prior to first dose of study treatment
• * Current corneal epithelial disease except mild changes in corneal epithelium
• * Any major surgery within the last four weeks of first dose of study treatment
• * Use of contact lenses while participating in this study
• * Participant must not have had plasmapheresis within 7 days prior to first dose of study treatment
• * Presence of active renal condition (infection, requirement for dialysis or any other condition that could affect patient`s safety). Patients with isolated proteinuria resulting from MM are eligible
• * Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions (including lab abnormalities) that could interfere with patient`s safety or compliance to the study procedures
• * Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. Note: Stable chronic liver disease (including Gilbert`s syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if patient otherwise meets entry criteria
• * Malignancies other than disease under study, unless the second malignancy has been medically stable for at least 2 years and, in the opinion of the principal investigators, will not affect the evaluation of the effects of clinical trial treatments on the currently targeted malignancy. Participants with curatively treated non-melanoma skin cancer may be enrolled without a 2-year restriction
• * Evidence of cardiovascular risk including any of the following:
• * Evidence of current clinically significant uncontrolled arrhythmias, including clinically significant electrocardiography (EKG) abnormalities such as 2nd degree (type II) or 3rd degree atrioventricular (AV) block.
• * History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within two months of first dose.
• * Class III or IV heart failure as defined by the New York Heart Association functional classification system.
• * Uncontrolled hypertension
• * Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to belantamab mafodotin or lenalidomide
• * Active infection requiring antibiotic, antiviral, or antifungal treatment
• * Known human immunodeficiency virus (HIV) infection
• * Presence of hepatitis B surface antigen (HBsAg), at or within 3 months of registration Note: If Hepatitis B core antibody (HBcAb) present, see additional monitoring recommendations
• * Positive hepatitis C antibody test result or positive hepatitis C ribonucleic acid (RNA) test result at or within 3 months prior registration. Note: Patients with positive hepatitis C antibody due to prior resolved disease can be eligible, only if a confirmatory negative hepatitis C RNA test is obtained.
• * Note: Hepatitis RNA testing is optional and patients with negative hepatitis C antibody test are not required to also undergo hepatitis C RNA testing
• * Best corrected visual acuity in the worst seeing eye worse than 20/100 (Snellen equivalent). Participants with vision worse than 20/100 due to a treatable condition (e.g., cataract) may be considered on an individual case basis within 6 months before registration
• * Use of an investigational drug within 14 days of first dose of study treatment or five half-lives, whichever is shorter, preceding the first dose of study drug. Prior treatment with a monoclonal antibody within 30 days of first dose of study treatment
• * Previously progressed on treatment with belantamab mafodotin
• * Pregnant or lactating female participants
• * Unwilling or unable to follow protocol requirements
• * Any condition which in the investigator`s opinion deems the participant an unsuitable candidate to receive study drug