OncoTrials - мониторинг клинических исследований

Описание

A prospective study in which hematological oncology patients who were vaccinated against RSV will undergo a blood test to assess their immune response to the vaccine. As part of the study, hematological oncology patients with CLL, lymphoma, acute leukemia, myelodysplastic syndrome, and multiple myeloma, who are being monitored at the Hematology Institute at Ichilov, will be offered a blood test to evaluate their immune response to the RSV vaccine (serology, neutralizing antibodies, and cellular response). In the study, a blood sample of up to 10 ml will be taken in a chemistry tube and blood bank on the day of vaccination and about one month after that. The serological test will be conducted in the hospital`s virology laboratory. The test result and its significance will be communicated to the patient by the treating hematologist in our clinic. In this group of patients, a follow-up will be conducted over a 12-month period (during routine clinic visits) to document the incidence of RSV infection and complications related to the vaccine.

Критерии включения

• * Patients aged 60 years and older
• * Patients diagnosed with multiple myeloma(MM) or lymphoma or CLL or myelodysplastic syndrome (MDS) or acute leukemia

Критерии исключения

• * Patients who have been previously vaccinated against RSV
• * Patients who have experienced a severe reaction to any vaccine in the past

Описание

This clinical trial evaluates the impact of preexisting and therapy-emergent germline and somatic variants on cytopenia in patients with multiple myeloma or CD19 positive lymphoproliferative disorder (LPD) following chimeric antigen receptor T-cell (CAR-T) therapy. The most common adverse event after CAR-T therapy is lower than normal blood cells (cytopenia) and up to one third of patients experience cytopenia that last longer than 30 days post-infusion. Germline and somatic variants are changes in genes found using cancer genomic tests. Cancer genetic/genomic testing is a series of tests that find specific changes in cancer cells or in blood deoxyribonucleic acid. Identifying gene mutations may help identify the risk of cytopenia in patients with multiple myeloma or CD19 positive LPD following CAR-T therapy.

Критерии включения

• * Age ≥ 18 years
• * Histologically or cytologically confirmed diagnosis of multiple myeloma (MM) as defined in International Myeloma Working Group (IMWG) criteria or a CD19+ lymphoproliferative disorder (LPD) as defined by 2016 World Health Organization (WHO) classification
• * Provide written informed consent
• * Willingness to provide mandatory bone marrow aspirate specimens for correlative research. All bone marrow aspirate samples are collected during a clinical procedure
• * Willingness to provide mandatory hair follicle specimens for correlative research
• * Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
• * Willingness to provide saliva and buccal samples for research

Критерии исключения

• * Ineligible for CAR-T therapy
• * Patients diagnosed with myeloid neoplasm before CAR-T therapy

Описание

This phase II trial studies how well mezigdomide/carfilzomib/dexamethasone (MeziKD) works in treating patients with multiple myeloma (MM) that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory) and have tumors from myeloma cells outside the bone marrow in the soft tissues or organs of the body (extramedullary disease /[EMD/]). Mezigdomide blocks important processes in myeloma cells and may lead to modulation of the immune system, including activation of T-lymphocytes, and downregulation of the activity of other proteins, some of which play key roles in the proliferation of certain cancer cell types. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Dexamethasone is a type of corticosteroid and is used to kill myeloma cells. It is used with other drugs to treat multiple myeloma. Giving MeziKD may kill more cancer cells in patients with relapsed/refractory multiple myeloma (RRMM) with EMD.

Критерии включения

• * Age ≥ 18 years of age
• * Have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
• * RRMM patients with one or more prior lines of therapy with at least one ES or PS lesion that is accessible to a biopsy. Accessibility will be assessed by the MM tumor board
• * Absolute neutrophil count: ≥ 1 x 10/^9/L
• * Platelets: ≥ 75 x 10/^9/L
• * Total bilirubin: ≤ 1.5 x upper limit of normal (ULN)
• * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase /[SGOT/])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase /[SGPT/]): ≤ 3 x ULN
• * Renal function: Estimated creatinine clearance ≥ 30 mL/min (Cockroft-Gault)
• * Adequate cardiac pump function with a left ventricular ejection fraction of ≥ 40%
• * Women of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry and for at least 28 days after the last dose of mezigdomide or 6 months after the last dose of carfilzomib. 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
• * Male patients (non-vasectomized) must agree to use contraception during the treatment period and for at least 28 days after the last dose of mezigdomide or 3 months after the last dose of carfilzomib and refrain from donating sperm during this period
• * 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

• * Participant has a history of anaphylaxis or hypersensitivity to thalidomide, lenalidomide, pomalidomide (including ≥ grade 3 rash during prior thalidomide, lenalidomide, or pomalidomide therapy), carfilzomib or dexamethasone, any cereblon E3 ligase modulators (CELMoD) agents, or the excipients contained in the formulations, or participant has any contraindications per local prescribing information
• * Administration of strong CYP3A modulators or proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole) within 2 weeks of starting study intervention
• * Participant is unable or unwilling to undergo protocol required thromboembolism prophylaxis
• * Patient has evidence of mucosal or internal bleeding and/or is platelet transfusion refractory
• * Any medical conditions that, in the investigator`s opinion, would impose excessive risk to the patient or would adversely affect his/her participation in this study
• * Known active infection requiring parenteral or oral anti-infective treatment within the past 14 days
• * Participant has a history of prior malignancy other than MM, except if the participant has been free of disease for ≥ 3 years or the participant had 1 of the following noninvasive malignancies treated with curative intent without known recurrence:
• * Basal or squamous cell carcinoma of the skin
• * Carcinoma in situ of the cervix or breast
• * Stage 1 bladder cancer
• * Incidental histological findings of localized prostate cancer such as tumor stage 1a or 1b (T1a or T1b) using the tumor, nodes, and metastasis (TNM) classification of malignant tumors OR prostate cancer that has been treated with curative intent
• * Other ongoing anti-myeloma therapy. Patients may be receiving concomitant therapy with bisphosphonates and low dose corticosteroids for symptom management and comorbid conditions. Doses of corticosteroid should be stable for at least 7 days prior to patient registration
• * Pregnant or breast-feeding females
• * Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse follow-up evaluation
• * Known active HIV or hepatitis B or C viral infection
• * Known history of HIV infection
• * Systemic amyloidosis or POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein /[M-protein/] and skin changes)
• * Prior peripheral stem cell transplant within 12 weeks of study enrollment
• * Radiotherapy within 14 days prior to cycle 1 day 1. However, if the radiation portal covered ≤ 5% of the bone marrow reserve, the patient may be enrolled irrespective of the end date of radiotherapy
• * Known intolerance to steroid therapy
• * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, severe cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• * Carfilzomib-refractory in the most recent line of therapy
• * Prior treatment with mezigdomide
• * Contraindication against conscious sedation
• * 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

Описание

This is a two-arm, open-label, randomized, single-site, pilot study testing the addition of CYT107 following autologous hematopoietic cell transplant (AHCT) in patients with multiple myeloma (MM). The hypothesis of this study is that recombinant human CYT107 can be safely administered after AHCT and will promote quantitative and qualitative T cell reconstitution, which will be associated with enhanced tumor cell clearance and reduced infectious complications. Patients will be randomized to either the intervention arm that will receive CYT107 + standard of care melphalan and AHCT or to the control arm that will receive standard of care melphalan and AHCT only.

Критерии включения

• * Histologically confirmed diagnosis of multiple myeloma.
• * Patient must be in first CR (including CR or sCR) or have PR or VGPR per IMWG criteria.
• * Patient must be candidate for melphalan and AHCT in the opinion of the treating physician.
• * At least 18 years of age.
• * ECOG performance status ≤ 2
• * Adequate bone marrow and organ function as defined below:
• * Total bilirubin ≤ 2 x IULN
• * AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN
• * Creatinine clearance ≥ 30 mL/min by Cockcroft-Gault
• * The effects of CYT107 on the developing human fetus are unknown. For this reason and also because many alkylating agents such as melphalan are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for one year post-transplant. Should a woman become pregnant or suspect she is pregnant, or a male suspect he has fathered a child during this time frame, s/he must inform the treating physician immediately.
• * Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Критерии исключения

• * High doses of corticosteroids (greater than 5 mg prednisone equivalent daily) within 2 weeks of Day -2.
• * A history of T-cell malignancy, plasma cell leukemia, or amyloidosis, or history of any other malignancy with the exceptions of in situ carcinomas, non-melanoma skin cancers, and malignancies for which all treatment was completed at least 2 years before Day -2 and the patient has no evidence of disease.
• * Currently receiving any other investigational agents.
• * A history of allergic reactions attributed to compounds of similar chemical or biologic composition to CYT107, melphalan, or other agents used in the study.
• * Azathioprine, methotrexate, and anti-tumor necrosis factor agents within 2 weeks of Day -2.
• * A history of congenital immunodeficiency syndrome or autoimmune disease. Patients with autoimmune disorders adequately controlled with medication (5 mg prednisone equivalent or less) are allowed.
• * A history of clinically-significant pulmonary disorders, such as severe asthma, severe COPD, restrictive lung disease, pulmonary embolism within 3 months prior to study enrollment, or active or prior interstitial lung disease/pneumonitis.
• * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
• * Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days of Day -2.
• * Patients without a backup autologous stem cell graft available.

Описание

Induction therapy approaches in recent years have evolved, now utilizing triple or quadruple drug regimens in the majority of patients. By combining anti-CD38 antibodies, proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and steroids, patients achieve longer remissions with their first- and second-line therapies but also become refractory to most or all three major drug classes earlier. For patients who are refractory to at least 3 of the commonly administered PIs and IMiDs, occurring after 2 lines of therapy in many, the median overall survival is only 5 months. Elderly, frail patients are not often candidates at this point for aggressive therapies like stem cell transplantation and CAR T-cell therapy thus necessitating effective yet tolerable treatments for elderly patients in early relapse (1-3 prior therapy). Talquetamab is a GPRC5DxCD3 bispecific antibody that redirects patients` T cells to myeloma cells which express GPRC5D. In the phase 1 MonumenTAL-1, heavily pretreated patients with a median of 6 prior lines of therapy attained a 70% response rate with 405 μg/kg of subcutaneous (SC) talquetamab. Importantly, subcutaneous talquetamab was found to be tolerable for the treated population, which included 28% of patients aged ≥70, with only three patients experiencing dose-limiting toxicities in the form of grade 3 rashes which responded to steroids. The anti-CD38 antibody daratumumab eliminates CD38-positive T and B regulatory cells, potentiates the activity of bispecific antibodies like talquetamab, and may improve its efficacy when used in combination. The aim of this study will be to assess the efficacy and safety of treating elderly patients with relapsed/refractory multiple myeloma with at least ≥2 prior lines of therapy with subcutaneous talquetamab. Patients who have progressive disease on talquetamab or who fail to respond after 3 cycles will have subcutaneous daratumumab added to their regimen.

Критерии включения

• * Documented multiple myeloma as defined by the criteria below:
• * Multiple myeloma diagnosis according to the IMWG diagnostic criteria
• * Measurable disease at screening as assessed by central laboratory, defined by at least 1 of the following:
• * Serum M-protein level ≥0.5 g/dL (central laboratory)
• * Urine M-protein level ≥200 mg/24 hours (central laboratory)
• * Light chain multiple myeloma without measurable M-protein in the serum or the urine: serum immunoglobulin free light chain ≥10 mg/dL or />100 mg/L (central laboratory) provided the serum free light chain ratio is abnormal (0.22 to 1.52 /[central laboratory/])
• NOTE: Local laboratory results of blood and urine M-protein measurements may be used to determine initial eligibility. Central laboratory results should still be obtained prior to the start of administration of study treatment in order to establish baseline values and confirm the results from the local laboratory.
• • Relapsed or refractory disease as defined below:
• * Relapsed disease is defined as an initial response to prior treatment, followed by confirmed progressive disease by IMWG criteria />60 days after cessation of treatment.
• * Refractory disease is defined as /<25% reduction in M-protein or confirmed progressive disease by IMWG criteria during previous treatment or ≤60 days after cessation of treatment. Received at least 1 prior line(s) of antimyeloma therapy including a minimum of 2 consecutive cycles
• NOTE: Participant must have undergone ≥1 complete cycle of treatment for each regimen, unless progressive disease was the best response to the regimen.
• NOTE: A single line of therapy may consist of 1 or more agents and may include induction, hematopoietic stem cell transplantation, and maintenance therapy. Radiotherapy, bisphosphonate, or a single short course of corticosteroids (no more than the equivalent of dexamethasone 40 mg/day for 4 days) would not be considered prior lines of therapy.
• * Subject must have received at least ≥2 prior line(s) of systemic antimyeloma therapy of treating physician`s discretion, including a PI and an IMID
• * Subjects who are anti-CD38 monoclonal antibody-naïve, exposed, or refractory will be allowed in Part 1; Only subjects who are anti-CD38 antibody-naïve or exposed will be allowed in Part 2, whereas subjects refractory to anti-CD38 monoclonal antibody will not be allowed in Part 2
• * Have clinical laboratory values meeting the following criteria during the Screening Phase: Hematology Hemoglobin: ≥7 g/dL (≥4.96 mmol/L; without transfusion support or erythropoietin use within 7 days before the laboratory test) Platelets: ≥50×109/L (without transfusion support or thrombopoietin receptor agonist within 7 days before the laboratory test) Absolute neutrophil count: ≥1.0×109/L (prior growth factor support is permitted but must be without support for 7 days for G-CSF or GM-CSF and for 14 days for pegylated GCSF before the laboratory test) Chemistry AST and ALT: ≤2.5×ULN eGFR: ≥30 mL/min based on Modified Diet in Renal Disease Formula calculation Total bilirubin: ≤2.0×ULN; except in participants with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤1.5×ULN is required) Serum calcium corrected for albumin: ≤14 mg/dL (≤3.5 mmol/L) or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L;)
• * Human immunodeficiency virus-positive participants are eligible if they meet all of the following:
• * No detectable viral load (ie, /<50 copies/mL) at screening
• * CD4+ count />300 cells/mm3 at screening
• * No acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 6 months of screening
• * Receiving HAART. Any changes in HAART due to resistance/progression should occur at least 3 months prior to screening. A change in HAART due to toxicity is allowed up to 4 weeks prior to screening.
• Note: HAART that could interfere with study treatment is excluded (consult the sponsor for a review of medications prior to enrollment) • A male participant must agree to wear a condom (with spermicidal foam/gel/film/cream/suppository) when engaging in any activity that allows for passage of ejaculate to another person during the study and for a minimum of 100 days after receiving the last dose of study treatment.
• NOTE: If the male participant is vasectomized, he still must wear a condom (with foam/gel/film/cream/suppository), but his female partner is not required to use contraception.
• * A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 100 days after receiving the last dose of study treatment.
• * Must be willing and able to adhere to the prohibitions and restrictions specified in this protocol (Section 2, including to not donate blood or blood components during the study and for 100 days after the last dose of study drug)
• * Sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study, and is willing to and able to participate in the study. Consent is to be obtained prior to the initiation of any study-related tests or procedures that are not part of standard-of-care for the subject`s disease.

Критерии исключения

• Any potential subject who meets any of the following criteria will be excluded from participating in the study:
• * Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study drug or its excipients (refer to the talquetamab and daratumumab Investigator`s Brochure and appropriate prescribing information).
• * Prior treatment with T-cell-engaging antibodies
• * Prior antitumor therapy as follows, prior to the first dose of study drug:
• o Any prior GPRC5D-directed therapy
• * Gene-modified adoptive cell therapy (eg, chimeric antigen receptor modified T cells, NK cells) within 3 months
• * Targeted therapy, epigenetic therapy, or treatment with an investigational drug or an invasive investigational medical device within 21 days or at least 5 half-lives, whichever is less.
• * Investigational vaccine other than SARS CoV-2 vaccine approved/ in use under emergency approval within 4 weeks o Live, attenuated vaccine within 4 weeks
• * Monoclonal antibody treatment for multiple myeloma within 21 days.
• * Cytotoxic therapy within 21 days.
• * Proteasome inhibitor therapy within 14 days. o Immunomodulatory agent therapy within 14 days. o Radiotherapy within 14 days or focal radiation within 7 days
• * Toxicities from previous anticancer therapies should have resolved to baseline levels or to Grade 1 or less except for alopecia or peripheral neuropathy.
• * Received a maximum cumulative dose of corticosteroids equivalent to ≥140 mg of prednisone within the 14-day period before the first dose of study drug.
• * Stem cell transplantation:
• * Previous allogenic stem cell transplant
• * Received an autologous stem cell transplant ≤12 weeks before the first dose of study drug
• * Known active CNS involvement or exhibits clinical signs of meningeal involvement of multiple myeloma. If either is suspected, negative whole brain MRI and lumbar cytology are required.
• * Plasma cell leukemia (/>20% circulating plasma cells and/or />2.0 x 109/L plasma cells by standard differential), Waldenström`s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein /[M-protein/], and skin changes), or primary amyloid light chain amyloidosis.
• * Myelodysplastic syndrome or active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than relapsed/refractory multiple myeloma. The only allowed exceptions are:
• o Non-muscle invasive bladder cancer treated within the last 24 months that is considered completely cured
• o Skin cancer (non-melanoma 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):
• - With a Gleason score of ≤6, treated within the last 24 months, or untreated and under surveillance
• * With a Gleason score of 3+4 that has been treated />6 months prior to full study screening and considered to have a very low risk of recurrence, or
• * History of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence
• * Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localized breast cancer and receiving antihormonal agents and considered to have a very low risk of recurrence
• * Other malignancy that is considered cured with minimal risk of recurrence.
• * Stroke or seizure within 6 months prior to signing ICF.
• * Any of the following:
• * Active Hepatitis B infection (ie, HBsAg or HBV-DNA positive). In the event the infection status is unclear, quantitative viral levels are necessary to determine the infection status see Section Hepatitis B Virus Testing 8.7.1.18.7.1 for further required assessments.
• * Active hepatitis C infection as measured by positive HCV-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 for at least 12 weeks following the completion of therapy, the participant is eligible for the study.
• * Any concurrent medical or psychiatric condition or 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, such as:
• * Uncontrolled diabetes o Acute diffuse infiltrative pulmonary disease
• * Evidence of active systemic viral, fungal, or bacterial infection, requiring systemic antimicrobial therapy within 7 days of start of study treatment
• * Active autoimmune disease requiring systemic immunosuppressive therapy within 6 months before start of study treatment.
• EXCEPTION: Participants with vitiligo, controlled type I diabetes, and prior autoimmune thyroiditis that is currently euthyroid based on clinical symptoms and laboratory testing are eligible regardless of when these conditions were diagnosed.
• * Disabling psychiatric conditions (e.g., alcohol or drug abuse), severe dementia, or altered mental status
• * Any other issue that would impair the ability of the participant to receive or tolerate the planned treatment at the investigational site, to understand informed consent or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments
• * History of non-compliance with recommended medical treatments • Plans to father a child while enrolled in this study or within 100 days after the last dose of study drug.
• • Presence of the following cardiac conditions:
• * New York Heart Association stage III or IV congestive heart failure
• * Myocardial infarction or coronary artery bypass graft ≤6 months prior to randomization
• * Uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities
• * History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration o History of severe non-ischemic cardiomyopathy • Major surgery 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.
• * NOTE: Participants with planned surgical procedures to be conducted under local anesthesia may participate. Kyphoplasty or vertebroplasty are not considered major surgery. If there is a question whether a procedure is considered a major surgery, the investigator must consult with the appropriate sponsor representative and resolve any issues before enrolling a participant in the study • Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) /<50% of predicted normal of DLCO /<50%).
• Note: FEV1 testing is required for participants suspected of having COPD and participants must be excluded if FEV1 /<50% of predicted normal.
• • Known moderate of persistent asthma within the past 2 years or currently has uncontrolled asthma of any classification.
• Note: Participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study.
• NOTE: Investigators should ensure that all study inclusion/exclusion criteria have been met at screening and prior to the first dose of study drug. If a subject`s clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study drug is given such that he or she no longer meets all eligibility criteria, supportive treatment may be administered according to local standards of care, if necessary, so that eligibility criteria may be met and laboratory test(s) may be repeated once, to determine if the subject qualifies for the study. If inclusion/exclusion criteria are not met after further evaluation, the subject should be excluded from participation in the study.

Описание

The goal of this clinical trial is to evaluate post-transplant immune reconstitution and lymphocyte recovery as well as the 3-year progression-free survival of patients with multiple myeloma in two treatment arms. One arm will receive Maintenance Vitamin D and the other arm will receive no maintenance Vitamin D prior to ASCT. Post ASCT arm 1 will have lenalidomide and maintenance VitD, and arm 2 will receive lenalidomide and no maintenance VitD. This clinical trial will also evaluate the overall response rate and survival for both treatment arms.

Критерии включения

• 1. Patients must be ≥ 18 years of age at time of registration to Step 1.
• 2. Patients must have history and physical exam within 28 days prior to registration.
• 3. Patients must have Zubrod/ECOG Performance Status ≤ 2.
• 4. Patients must have had a confirmed diagnosis of symptomatic MM (See Section 4.1) with measurable disease at the time of myeloma diagnosis that required systemic induction therapy prior to ASCT. Measurable disease is defined as measurable M protein in the serum (≥ 0.5g/dL) or urine (≥ 200 mg/24h) or serum free light chain assay (defined as ≥ 10 mg/dL /[≥ 100 mg/L/] on involved light chain) at the time of diagnosis. Patients with smoldering myeloma are not eligible until they have progressed to symptomatic myeloma.
• 5. Patients must be willing and able to take DVT prophylaxis (aspirin, low molecular weight heparin, warfarin, or equivalent oral anticoagulation) and comply with lenalidomide REMS program requirements.
• 6. Females of childbearing 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 registration. FCBP must agree to have a second pregnancy test within 24 hours prior to starting lenalidomide. Further, 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 lenalidomide. FCBP must also agree to ongoing pregnancy testing and must agree to not become pregnant for at least 3 months after the last dose of study treatment. A FCBP 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 (i.e., has had menses at any time during the preceding 24 consecutive months).Men must agree to use a latex condom during sexual contact with a FCBP, even if they have had a successful vasectomy, during the study treatment and for 3 months after the last dose of study treatment.
• 7. Patients must have evidence of adequate renal function, as defined by (1) creatinine clearance (CrCl) ≥ 10 mL/min., as measured by a 24-hour urine collection, or estimated by the Cockcroft and Gault formula. Values must be obtained within 28 days prior to registration. Estimated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female) 72 x creatinine (mg/dl)
• 8. Patients must have adequate hepatic function defined by the following within 28 days prior to registration: Total bilirubin ≤ 1.5 x IULN (institutional upper limit of the norm) and AST and ALT ≤ 3.0 x IULN
• 9. Patients must be acceptable for transplant per institutional guidelines:
• 10. Patient`s with human immunodeficiency virus (HIV) are eligible providing they are on effective antiretroviral therapy and have undetectable viral load at their most previous viral load test and within 6 months prior to registration.
• 11. Patients must be able to take and swallow oral medication (capsules) whole.
• 12. Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.

Критерии исключения

• 1. Any organ involvement by amyloidosis or evidence of amyloidosis related organ dysfunction.
• 2. Progressive disease at any time prior to registration.
• 3. Intolerance to the starting dose of lenalidomide (10 mg).
• 4. Prior allograft, prior organ transplant requiring immunosuppressive therapy, or have already received a previous autologous transplantation (e.g., requiring second ASCT at time of screening).
• 5. Prior malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years.
• 6. Received any investigational agents within 14 days prior to registration.
• 7. Seropositive for Hepatitis B
• 8. Seropositive for Hepatitis C
• 9. Hypercalcemia (serum calcium level /> 10.3 mg/dL) (institutional upper limit of the norm) at time of study entry.
• 10. Patients refractory to lenalidomide.
• 11. Patients that have received any investigational agents within 14 days prior to registration.
• 12. Any known impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). h known allergies to any of the study drugs.

Описание

The overall goal of the randomized control trial (RCT) will be to evaluate the efficacy of modifications to a web-based tool for patient decision-making regarding return of genomic results that will more closely focus on rare cancers. Participants will be given access to a web-based decision aid (or a standard control) that guides participants in making decisions about what type of genomic results they would like to receive from testing performed in the PE-CGS study (NCT06340646).

Критерии включения

• Eligibility Criteria:
• * Enrolled in the WU-PE-CGS study (IRB#202106129); that eligibility entails:
• * Diagnosis of cholangiocarcinoma
• * Diagnosis of multiple myeloma, must be African American
• * Diagnosis of colorectal cancer, must be African American and age 65 or older at time of diagnosis
• * At least 18 years old.
• * Able to understand an IRB-approved informed consent document and agree to participation
• * Have access to a personal computer, tablet or mobile device

Критерии исключения

Описание

This study is an open, single-arm, prospective, Phase I/II clinical study using "3+3" dose escalation and dose expansion to investigate the safety, maximum tolerated dose, in vivo pharmacokinetic profile, and preliminary efficacy of CAR-T cell injections for the treatment of relapsed/refractory malignant hematological neoplasms in subjects.

Критерии включения

• With their own consent and have signed an informed consent form, willing and able to comply with the planned visits, study treatment, laboratory tests and other experimental procedures; Patients with recurrent/refractory malignant hematologic tumors as determined by clinical diagnosis; Age 18 years and above, both male and female; Subjects with a physical status of 0/~2 on the Eastern Cooperative Oncology Group (ECOG) score; Expected survival />3 months from the date of informed consent; HGB ≥ 60g/L (transfusion is allowed); Liver and kidney function, cardiopulmonary function meet the following requirements: a) creatinine ≤1.5×ULN;b) Left ventricular ejection fraction ≥50%; c) Blood oxygen saturation />90%;d) Total bilirubin ≤ 1.5 × ULN; ALT and AST ≤ 2.5 × ULN; Subjects with pregnancy plans must agree to use contraception prior to enrollment in the study and after the study has lasted for six months; subjects should notify the investigator immediately if they become pregnant or suspect pregnancy.
• Subjects in the different cohorts will still be required to fulfill the following conditions:
• Lymphoma Cohort:
• B-cell lymphoma Diagnosis of CD19+ and/or CD20+ and/or CD22+ and/or BAFF+ B-cell lymphoma confirmed by pathology and histology; Inert B-cell lymphoma (CLL, FL, MZL, LPL, HCL); Aggressive B-cell lymphoma (DLBCL, BL, MCL).
• Meet the following criteria for relapsed or refractory B-cell lymphoma (meet 1 of the first 2 plus 3 below):
• Less than 50% tumor shrinkage or disease progression after 4 courses of standard regimen regulated chemotherapy; relapse after achieving CR after standard regimen chemotherapy; subjects must have received adequate prior therapy, including at least: Anti-CD20 monoclonal antibody; Anthracycline-containing combination chemotherapy. T-cell lymphoma
• Diagnosis of CD7+ refractory/relapsed T-lymphocyte lymphoma confirmed by pathology and histology, meeting any of the following criteria:
• Relapsed: Disease relapse determined after having previously received at least two standardized treatment regimens to achieve complete remission, or disease relapse after having undergone stem cell transplantation to achieve complete remission; Refractory: previous treatment with at least two regimens and failure to achieve complete remission after the last treatment, or failure to achieve remission or disease progression after stem cell transplantation.
• II Acute lymphoblastic leukemia cohort:
• Acute B-lymphoblastic leukemia Refractory/relapsed B-lymphoblastic leukemia diagnosed as CD19+ and/or CD20+ and/or CD22+ and/or BAFF+ confirmed by immunohistochemistry or flow cytometry.
• Refractory/relapsed B-lymphoblastic leukemia (meeting 1 of the following 4 criteria is sufficient):
• Relapse within 6 months of first remission; first refractory without achieving complete remission with 2 cycles of standard chemotherapy regimen; failure to achieve complete remission or relapse after first or multiple lines of salvage chemotherapy; those who are not suitable for HSCT, or who have abandoned HSCT due to medical constraints, or those who have relapsed after HSCT.
• Acute T-lymphoblastic leukemia
• Diagnosis of CD7+ refractory/relapsed T-ALL/LBL confirmed by immunohistochemistry or flow cytometry, meeting any of the following criteria:
• No CR after standard chemotherapy; CR after first treatment, but CR lasted less than 12 months; No CR after first or more remedial therapy; Relapse two or more times.
• III. multiple myeloma cohort:
• Positive expression of BCMA and/or CD19 and/or GPRC5D in myeloma cells by flow or immunohistochemistry; Patients with relapsed/refractory multiple myeloma who have received at least 1 prior therapy (including proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs)) or are resistant to proteasome inhibitors and/or immunomodulatory agents.
• IV. myeloid tumor cohort:
• Positive tumor cell antigen test results (CD7 and/or CD19 and/or CD47) confirmed by immunohistochemistry or flow cytometry; Diagnosis of myeloid tumors, including but not limited to AML and MDS, confirmed by pathology and the patient meets the following
• Relapse or refractory requirements:
• Relapse: reappearance of leukemic cells in the peripheral blood, or />5% of primitive cells found in the bone marrow, or extramedullary relapse after second-line or higher salvage therapy to achieve CR/CRi; Refractory: failure to achieve CR/CRi after at least 2 cycles of standard chemotherapy.

Критерии исключения

• a history of severe cardiac insufficiency with a left ventricular ejection fraction /<50%; A history of severe lung function-impairing disease; Combination of other malignant tumors in progressive stages; Combination of severe infections that cannot be effectively controlled; Combination of severe autoimmune disease or congenital immunodeficiency; Active hepatitis (Hepatitis B virus deoxyribonucleic acid /[HBV-DNA/] or Hepatitis C virus ribonucleic acid /[HCV-RNA/] test results above the lower limit of detection); Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS), or syphilis infection; History of severe allergy to biological products (including antibiotics); Allogeneic hematopoietic stem cell transplantation patients who still have acute graft-versus-host reaction (GvHD) one month after stopping immunosuppressive drugs; Presence of other serious physical or mental illnesses or abnormal laboratory tests that may increase the risk of participation in the study or interfere with the results of the study, as well as patients who, in the opinion of the investigator, are not suitable for participation in this study.

Описание

A phase II study of single agent elranatamab in patients with relapsed and/or refractory multiple myeloma (MM) who have previously received at least three classes of therapeutic agents and are refractory to the last line of treatment. The primary objective of this study is to improve the tolerability and safety of elranatamab in patients with relapsed and/or refractory multiple myeloma by evaluating an outpatient and intermittent dosing strategy.

Критерии включения

• 1. Relapsed and/or refractory MM defined as:
• 1. Documented evidence of progressive disease (PD) after achieving at least minimal response (MR) for ≥ 1 cycle during a previous MM treatment (i.e., relapsed MM).
• 2. Disease progression during or within 60 days from the end of the most recent MM treatment (i.e., refractory MM).
• 2. Measurable disease based on IMWG criteria, defined as at least one of the following, documented within 28 days before enrollment:
• 1. Serum M-protein ≥ 0.5 g/dl.
• 2. Urine M-protein excretion ≥ 200 mg/24 h.
• 3. Serum-free light chains (FLC) assay: Involved FLC level ≥ 10 mg/dl (≥ 100 mg/l) AND an abnormal serum-free light chain ratio (/< 0.26 or /> 1.65) only for patients without measurable serum or urine M protein.
• 3. Receipt of at least three prior classes of drugs either in separate regimens or as combinations.
• The three classes are defined as:
• An immunomodulatory drug (lenalidomide or pomalidomide), a proteasome inhibitor (bortezomib, ixazomib, carfilzomib), and an anti-CD38 drug (daratumumab or isatuximab).
• 4. At least 18 years of age.
• 5. Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2.

Критерии исключения

• Medical conditions
• 1. Active plasma cell leukemia (either 20% of peripheral white blood cells or /> 2.0 × 109/L circulating plasma cells by standard differential).
• 2. Amyloidosis.
• 3. POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder, Skin Changes).
• 4. Monoclonal gammopathy of unknown significance or smoldering multiple myeloma.
• 5. Solitary plasmacytoma.
• 6. Stem cell transplant within 12 weeks prior to enrollment or active graft versus host disease.
• 7. History of prior treatment with a BCMA targeting agent.
• Laboratory Parameters
• 8. Laboratory results within 28 days as per below prior to enrollment:
• * Absolute neutrophil count (ANC) ≤ 1.0 x 109 /L) (use of growth factor is permitted if completed at least 7 days prior to enrollment).
• * Platelet count ≤ 25 x 109 /L (transfusion support permitted if completed at least 7 days prior to enrollment).
• * Hemoglobin ≤ 8.0 g/dL (transfusion support permitted if completed at least 7 days prior to enrollment, concurrent erythropoietin stimulating agents allowed).
• * Serum AST and ALT /> 2.5 x upper limit of normal (ULN).
• * Creatinine clearance /< 30 mL/min (according to the Cockcroft Gault formula, by 24-hour urine collection for creatinine clearance, or according to local institutional standard method).
• * Total bilirubin /> 2.0 x ULN (≥ 3.0 unless known to have Gilbert`s disease).
• Support Requirement
• 9. As this protocol requires outpatient administration, the patient will be excluded if they cannot agree to the following for the first 9 days post-first dose of drug administration:
• 1. Staying within 60 minutes of travel distance to their trial-based hospital.
• 2. Must have a caregiver/support person who will stay with the patient.
• 3. Patient and/or their caregiver/support person agree to monitor and record oral temperature q8 hours.
• 4. Patients must agree that if they have an oral temperature of (≥38°C), they must report to the study team within 1 hour and can come to the hospital for admission within 2 hours.
• Other co-morbidities
• 10. Impaired cardiovascular function or clinically significant cardiovascular diseases, defined as any of the following within 6 months before enrollment:
• * Acute myocardial infarction or acute coronary syndromes (eg, unstable angina, coronary artery bypass graft, coronary angioplasty or stenting, symptomatic pericardial effusion).
• * Clinically significant cardiac arrhythmias (eg, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia).
• * Thromboembolic or cerebrovascular events (eg, transient ischemic attack, cerebrovascular accident, deep vein thrombosis /[unless associated with a central venous access complication/], or pulmonary embolism).
• * Prolonged QT syndrome (or triplicate average QTcF />470 msec at screening).
• 11. Ongoing Grade ≥2 peripheral sensory or motor neuropathy.
• 12. History of Guillain-Barre Syndrome (GBS) or GBS variants, or history of any Grade ≥3 peripheral motor polyneuropathy.
• 13. Unresolved acute effects of any prior therapy for MM in the last three months to either baseline severity or NCI CTCAE ≤Grade 1.
• 14. Active HBV, HCV, SARS-CoV2, HIV, or any active, uncontrolled bacterial, fungal, or viral infection.
• 15. Any other active malignancy within 2 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ.
• 16. Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions (including lab abnormalities), or surgical (major surgery within 14 days prior to enrollment) that could interfere with the patient`s safety, obtaining informed consent or compliance to the study procedures.
• 17. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to elranatamab or any of the components of the study treatment.
• Concomitant Medications
• 18. Treatment with a chemotherapeutic or anti-MM drug within the last 28 days or 5 half-lives (whichever is shorter) prior to enrollment or are currently enrolled in another interventional clinical study.
• 19. Receipt of any other therapy to treat cancer (including radiation, biologics, cellular therapies, and/or steroids at doses /> 20 mg dexamethasone or equivalent) within 14 days prior to the enrollment.
• 20. Receipt of any live vaccine within 30 days prior to enrollment or expected need of live vaccination during study participation. (Administration of locally approved non-live vaccine can be done as per local guidelines during the screening and/or treatment period including the COVID-19 mRNA vaccine. Elranatamab should be administered ± 7 days from the SARS-CoV-2 vaccine administration).
• Pregnancy and Contraception
• 21. Pregnancy or lactating female or inability of female patients of childbearing potential (FCBP) to meet contraception requirements (see Section 5.1.3.).
• Informed Consent
• 22. Inability to provide signed, informed consent.

Описание

This phase of the protocol (protocol part B), seeks to evaluate the new formulation in healthy normal volunteers to confirm the new formulation provides comparable human dosimetry to which was seen and published in protocol part A. Additionally, the new formulation will be studied utilizing an expanded patient population to include patients with confirmed diagnosis of multiple myeloma (MM), low-grade lymphoma, or MM and lymphoma patients who are status post bone marrow transplant (BMT) with negative imaging and suspected recurrence.

Критерии включения

• Healthy Volunteer:
• * Adult 18 years of age or older
• * Able to give informed consent.
• * Able to comprehend and willing to follow instructions for study procedures as called for by the protocol
• * Capable of lying still and supine within the PET/CT scanner for up to 75 minutes.
• * No illicit drug use or other inhaled drug use (including pharmacologic agents and illicit drugs) within the past year per self-reporting mechanisms.
• * No history of claustrophobia or other condition that has previously or would interfere with completion of protocol specified imaging sessions.
• * Not currently pregnant or nursing: Subject must be surgically sterile (has had a documented bilateral oophorectomy and/or documented hysterectomy), post-menopausal (cessation of menses for more than 1 year), non-lactating, or of childbearing potential for whom a urine pregnancy test (with the test performed within the 24 hour period immediately prior to administration of 64Cu-LLP2A) is negative.
• Inclusion Criteria Hematological Malignancy:
• * Clinical or pathologically defined MM or lymphoma including both newly diagnosed, relapsed or refractory disease:
• * Multiple Myeloma defined in accordance with the International Myeloma Working Group criteria
• * Low-grade lymphoma, including the following subtypes: follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia
• * Adult 18 years of age or older and able to provide informed consent
• * Capable of lying still and supine within the PET/CT scanner for up to 75 minutes.
• * No history of claustrophobia or other condition that has previously or would interfere with completion of protocol specified imaging sessions
• * Not currently pregnant or nursing: Subject must be surgically sterile (has had a documented bilateral oophorectomy and/or documented hysterectomy), post-menopausal (cessation of menses for more than 1 year), non-lactating, or of childbearing potential for whom a urine pregnancy test (with the test performed within the 24 hour period immediately prior to administration of 64Cu-LLP2A) is negative
• * Patients participating in imaging or therapeutic trials with investigational agents are eligible to participate

Критерии исключения

Описание

This phase I trial tests the safety and side effects of SX-682 in combination with standard of care treatment carfilzomib, daratumumab-hyaluronidase, and dexamethasone 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). SX-682 works by blocking certain sites on cells that suppress the ability of the immune system to destroy tumor cells. Blocking those specific sites allows other cells of the immune system to become "free" to kill tumor cells. Carfilzomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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 tumor cells, including myeloma cells. Daratumumab may block CD38 and help the immune system kill tumor cells, while hyaluronidase helps to deliver daratumumab to CD38-expressing tumor cells through a subcutaneous injection. Dexamethasone is in a class of medications called corticosteroids. It is known to kill myeloma cells and is also used to reduce inflammation and lower the body`s immune response to monoclonal antibodies like dratumumab and help lessen its side effects. Giving SX-682 in combination with carfilzomib, daratumumab-hyaluronidase and dexamethasone may be safe and tolerable in treating patients with relapsed or refractory multiple myeloma

Критерии включения

• * Confirmed relapsed/ refractory multiple myeloma
• * Measurable disease including at least one of the following criteria:
• * Serum M-protein ≥ 0.5 g/dL
• * Urine M-protein ≥ 200 mg/24h
• * Serum free light chain assay: involved free light chain (FLC) level greater or equal to 100 mg/L provided serum free light chain ratio is abnormal
• * Bone marrow plasma cells ≥ 10% total bone marrow cells
• * ≥ 1 prior line of therapy
• * Planned treatment with a carfilzomib/daratumumab/dexamethasone regimen
• * Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• * Absolute neutrophil count: ≥ 3 x 10/^9/L
• * Platelets: ≥ 75 x 10/^9/L
• * Hemoglobin: ≥ 7 g/dL
• * Total bilirubin: ≤ 1.5 x upper limit of normal (ULN): ≤ 3.0 x ULN for Gilbert`s syndrome
• * Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase /[SGOT/]) / alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase /[SGPT/]): ≤ 3 x ULN
• * Renal Function: Estimated creatinine clearance ≥ 45 mL/min (Cockroft-Gault)
• * Left ventricular ejection fraction of at least 50%
• * Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry and for 6 months following the last dose of the investigational drug. 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
• * 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

• * Patients with non-secretory myeloma, systemic light chain amyloidosis or, plasmacytoma
• * Intolerance to SX-682 or any other of the treatment components
• * Refractory to prior carfilzomib (i.e. relapse or progression on or within 60 days after completion of treatment)
• * Refractory to prior daratumumab (i.e. relapse or progression on or within 60 days after completion of treatment)
• * Concomitant medication(s) known to be (a) a strong inhibitor or inducer of CYP3A4, or (b) QT prolonging as defined in the drug`s approved label, with the exception of drugs that are considered absolutely essential for the care of the subject or if the investigator believes that beginning therapy with such medication is vital to an individual subject`s care while on study, and in either case, there is no alternative medication
• * Electrocardiogram (ECG) demonstrating a corrected QT (QTc) interval /> 470 msec or patients with congenital long QT syndrome
• * Coronary artery bypass, angioplasty, vascular stent, myocardial infarction, angina or congestive heart failure in the last 6 months
• * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, class III or IV heart failure (New York Heart Association functional classification system) or psychiatric illness/social situations that would limit compliance with study requirements
• * History of hepatitis B, C or HIV
• * Known active bacillus tuberculosis infection
• * Pregnant or nursing 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

Описание

This study evaluates immune responses after CAR-T therapy to find out if CAR-T therapy reduces the effectiveness of the vaccines (vaccine immunity) against diseases such as measles, mumps and rubella, among others in patients with multiple myeloma and non-Hodgkin lymphoma.

Критерии включения

• * /* Willingness to provide written informed consent before any study-specific procedures or activities are performed
• * Age ≥ 18 years of age, at the time of consent
• * Documented, histologically or cytologically confirmed diagnosis of multiple myeloma (MM), diffuse large B cell lymphoma (DLBCL),follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL), or primary mediastinal B cell lymphoma (PMBL). All number of prior lines of therapy are allowed
• * History of prior vaccination against common VPD
• * Approved by managing physician for CAR-T therapy, with preparative conditioning planned within the next 90 days
• * Approved by managing physician for revaccination against Streptococcus pneumoniae or tetanus

Критерии исключения

• * /* Ongoing use of immunosuppressive agents or plans for immunosuppressive therapy that would interfere with interpretation of study endpoints
• * Uncontrolled, intercurrent illness including, but not limited to, systemic infection, symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements or make the study procedures unadvisable

Описание

This single-arm, open-label study aims to determine the efficacy and safety of low-dose, limited-duration teclistamab as a consolidation scheme in newly diagnosed multiple myeloma (NDMM) patients.

Критерии включения

• * ≥18 years of age.
• * Newly diagnosed multiple myeloma.
• * Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 0 or 1.
• * Women of childbearing potential must have a negative serum pregnancy test prior to starting treatment and agree to use a highly effective method of contraception, such as a hormonal method that inhibits ovulation, an intrauterine device, or a vasectomy partner.
• * Males: agree to use a highly effective contraceptive method, such as a male condom or vasectomy.

Критерии исключения

• * History of previous treatment for MM.
• * Active central nervous system (CNS) involvement or clinical signs of meningeal involvement of multiple myeloma.
• * Plasma cell leukemia, Waldenström`s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes) or AL amyloidosis.
• * Severe active infection secondary to viruses, bacteria or fungi.
• * Pulmonary disease requiring supplemental oxygen.
• * History of allogeneic or autologous hematopoietic cell transplantation.
• * Vaccination with live attenuated virus in the 4 weeks prior to teclistamab administration.
• * Major surgery during the 2 weeks prior to the first dose or absence of complete recovery from surgery.
• * Presence of other concomitant malignancy.
• * Hepatitis B and C virus infection or human immunodeficiency virus (HIV) infection.
• * Cerebrovascular events or seizures in the last 6 months.
• * Congestive heart failure class III-IV according to NYHA (New York Heart Association Stage).
• * Acute myocardial infarction or history of coronary revascularization surgery in the last 6 months.
• * Women of childbearing age: active pregnancy prior to the first administration of treatment.

Описание

This phase I/II trial tests the safety, side effects, and best dose of iberdomide and how well it works in combination with daratumumab, elotuzumab, and dexamethasone in treating patients with multiple myeloma that has come back after a period of improvement (relapsed). Immunotherapy with iberdomide, may induce changes in body`s immune system and may interfere with the ability of tumor cells to grow and spread. 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. Elotuzumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. 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. Giving iberdomide in combination with daratumumab, elotuzumab, and dexamethasone may be safe, tolerable and/or effective in patients with relapsed multiple myeloma.

Критерии включения

• * Age ≥ 18 years at the time of signing the informed consent form (ICF).
• * Diagnosis of relapsed multiple myeloma with ≤ 3 prior lines of therapy including treatment with proteasome inhibitors (i.e., ixazomib, carfilzomib, bortezomib), immunomodulatory imide drugs (i.e., lenalidomide, pomalidomide), and anti-CD38 drugs (i.e., daratumumab, isatuximab). Patients are required to have received a proteasome inhibitor, immunomodulatory imide drug, or combination of the two drug classes during first-line treatment.
• * Note: Prior treatment with iberdomide is not allowed. Patients should not be refractory simultaneously to all other drugs in the combination.
• * Measurable disease.
• * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2.
• * Hemoglobin ≥ 8.0 g/dL (obtained ≤14 days prior to registration).
• * Absolute neutrophil count (ANC) ≥ 1000/m/^3 (obtained ≤14 days prior to registration).
• * Platelet count ≥ 50,000/mm/^3. Note: It is not permissible to transfuse subjects to achieve minimum platelet counts (obtained ≤14 days prior to registration).
• * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (≤ 3 x ULN for patients with Gilbert`s syndrome) (obtained ≤14 days prior to registration).
• * Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 2 x ULN and alkaline phosphatase ≤ 1.5 x ULN (obtained ≤14 days prior to registration).
• * Calculated creatinine clearance ≥ 30 ml/min using the Cockcroft-Gault (obtained ≤14 days prior to registration).
• * Negative pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only. Note: A person of childbearing potential (PCBP) is a person who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) and must:
• * Have 2 negative pregnancy tests prior to starting study treatment and must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact.
• AND
• * 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 two forms of contraception: one highly effective, and one additional effective (barrier) measure of contraception without interruption 28 days prior to starting investigational product, during the study treatment, and for at least 28 days after the last dose of iberdomide, 90 days after the last dose of daratumumab, 7 months after last dose of elotuzumab whichever is longer.
• * NOTE: Non-childbearing potential is defined as follows (by other than medical reasons):
• * ≥ 45 years of age and has not had menses for /> 24 months.
• * 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.
• * Willingness to follow Pregnancy Prevention Program requirements:
• * Persons of childbearing potential must agree to 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 7 months after the last dose of study intervention. These patients must also agree not to donate eggs (ova, oocytes) for the purpose of reproduction during this period.
• * Persons able to father a child must agree that during the treatment intervention period and for 6 months after the last dose of study treatment (to allow for clearance of any altered sperm), the participant will:
• * Refrain from donating sperm while on study treatment, during dose interruptions and for at least 6 months following last dose of study treatment, 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 such as a male condom (even if they have undergone successful vasectomy), and when having sexual intercourse with a person of childbearing potential who is not currently pregnant his partner will use an additional highly effective contraceptive method with a failure rate of /< 1% per year.
• * Provide written informed consent.
• * Willingness to provide mandatory bone marrow specimens for correlative research.
• * Willing and able to adhere to the study visit schedule and other protocol requirements. Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• * Willing to refrain from donating blood while on study treatment, during dose interruptions and for at least 28 days following the last dose of study treatment.

Критерии исключения

• * Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:
• * Pregnant persons
• * Nursing persons
• * Men or women of childbearing potential who are unwilling to employ adequate contraception.
• * Receiving any other concurrent chemotherapy, or any ancillary therapy considered investigational.
• * Note: Bisphosphonates are supportive care rather than therapy and are thus allowed while on protocol treatment.
• * Known to be human immunodeficiency virus (HIV) positive known or suspected active hepatitis C infection or seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen /[HBsAg/]) at registration or ≤ 3 months prior to registration.
• * Note: Participants with resolved hepatitis B infection (i.e., subjects 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 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.
• * Evidence of cardiovascular disease risk, as defined by any of the following:
• * Evidence of current clinically significant uncontrolled arrhythmias, including clinically significant electrocardiogram (ECG) abnormalities such as 2nd degree (Mobitz 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 ≤ three (3) months prior to registration.
• * Class III or IV heart failure as defined by the New York Heart Association functional classification system /[NYHA, 1994/]
• * Uncontrolled hypertension
• * History of life-threatening ventricular arrhythmias.
• * Known moderate or severe persistent asthma, or currently has uncontrolled asthma of any classification.
• * Unable or unwilling to undergo protocol required thromboembolism prophylaxis.
• * Has taken a strong inhibitor or inducer of CYP3A4/5 including grapefruit, St. John`s Wort or related products ≤ 14 days prior to registration.
• * Known allergy to any of the study medications, their analogues or excipients in the various formulations.
• * Major surgery ≤ 14 days prior to registration.
• * Has been treated with an investigational agent (i.e., an agent not commercially available) ≤ 28 days or 5 half-lives (whichever is longer) prior to registration.
• * Any serious medical or psychiatric illness that could, in the investigator`s opinion, potentially interfere with the completion of treatment according to this protocol.
• * Any co-morbidity which would interfere with patient`s ability to participate in trial, e.g. uncontrolled infection, uncompensated heart or lung disease.
• * History of anaphylaxis or hypersensitivity to thalidomide, lenalidomide, or pomalidomide.
• * Peripheral neuropathy grade ≥ 2.
• * Severe acute respiratory syndrome coronavirus 2 infection ≤ 14 days prior to registration for mild or asymptomatic infections OR ≤ 28 days prior to registration for severe/critical illness.
• * Gastrointestinal disease that may significantly alter the absorption of iberdomide.
• * Received a live vaccine ≤ 90 days prior to registration.
• * Prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years with the exception of the following noninvasive malignancies:
• * Basal cell carcinoma of the skin
• * Squamous cell carcinoma of the skin in situ (stage 0)
• * Carcinoma in situ of the cervix
• * Carcinoma in situ of the breast
• * Incidental histologic finding of prostate cancer (T1a or T1b using the TNM /[tumor, nodes, metastasis/] clinical staging system) or prostate cancer that is curative.
• * Received hydroxychloroquine, quinacrine, chloroquine, methotrexate, leflunomide, sulfasalazine, mycophenolate mofetil, mycophenolic acid ≤ 28 days prior to registration.
• * Received daily nonsteroidal anti-inflammatory drugs (NSAIDs) ≤ 14 days prior to registration. Note: Allowed if dose has been stable for at least 14 days.
• * Received immunomodulating or immunosuppressive therapy as follows:
• * Etanercept ≤ 28 days prior to registration
• * Belimumab ≤ 12 weeks prior to registration
• * B-cell depleting or modulating agents (such as rituximab or anti-CD22 therapy) ≤ 365 days prior to registration.

Описание

This study aims to evaluate the efficacy and safety of post-transplant consolidation therapy with the KPD regimen (carfilzomib, pomalidomide, and dexamethasone) versus no consolidation, followed by maintenance therapy, in patients with transplant-eligible newly diagnosed multiple myeloma (TE-NDMM). The primary goal is to compare minimal residual disease (MRD) negativity rates and overall treatment outcomes between the two groups.

Критерии включения

• * Age ≥18 years.
• * Newly diagnosed MM eligible for transplantation.
• * Received upfront triplet or quadraplet induction regimen.
• * Received upfront ASCT after induction.
• * ECOG score /< 2.
• * Adequate Organ Function Reserve:
• 1. Alanine aminotransferase (ALT) / Aspartate aminotransferase (AST) ≤ 2.5 × UNL (upper limit of normal);
• 2. Serum total bilirubin ≤ 1.5 × UNL. If the patient has congenitally high bilirubin, direct bilirubin must be ≤ 1.5 × UNL;
• 3. Left ventricular ejection fraction (LVEF) ≥ 50% as diagnosed by echocardiography, with no clinically significant electrocardiogram (ECG) abnormalities;
• 4. Basal oxygen saturation /> 95% in room air;
• * Women of childbearing age agree to use effective contraceptive measures during the period of using the study drug and within 3 months after the last administration of the study drug; and to use highly effective contraceptive measures for at least 1 year thereafter. Male participants with fertile partners must agree to use effective barrier contraception during the period of using the study drug and within 3 months after the last administration of the study drug;
• * The participant is willing and able to comply with the study procedures and voluntarily signs the written informed consent form.

Критерии исключения

• * Patients with primary plasma cell leukemia or POEMs syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes);
• * Patients diagnosed with primary amyloidosis, Waldenström`s macroglobulinemia, monoclonal gammopathy of undetermined significance, or smoldering multiple myeloma;
• * Patients with severe mental disorders, altered mental status, or a history of central nervous system (CNS) diseases such as epileptic seizures, cerebral vascular ischemia/ hemorrhage, dementia, cerebellar diseases, or any autoimmune diseases involving the CNS;
• * Patients with a history of the following genetic diseases: Fanconi anemia, Shwachman-Diamond syndrome, Costello syndrome, or any other known bone marrow failure syndrome;
• * Patients who underwent a diagnosis or treatment for another malignancy within 1 year prior to randomization, or had a previous diagnosis of another malignancy with evidence of residual disease (excluding patients with any type of non-melanoma skin cancer or completely resected carcinoma in situ);
• * Patients with active infectious diseases, known human immunodeficiency virus (HIV) positivity, or active hepatitis B or C infection;
• * Patients known to be allergic to any of the study drugs, their analogs, or any excipients of the study drugs in various formulations;
• * Patients with concurrent or suspected central nervous system infiltration;
• * Patients with drug use, medical, psychological, or social conditions that may interfere with the participant`s ability to participate in the study or the assessment of study outcomes;
• * Pregnant or lactating women;
• * Any other conditions deemed by the investigator as unsuitable for enrollment.

Описание

This is a single-arm, open-label study to evaluate the efficacy and safety of BCMA CAR-T in dynamic high-risk patients with multiple myeloma

Критерии включения

• 1. Be informed and voluntarily sign the Informed Consent Form (ICF).
• 2. Age between 18 and 75 years (inclusive).
• 3. Have measurable disease meeting at least one of the following criteria: Serum M-protein ≥1 g/dL (/>10 g/L) as detected by serum protein electrophoresis (SPEP), or quantifiable IgA or IgD levels for IgA or IgD-type myeloma; Urine M-protein ≥200 mg/24 hours; In cases where serum and urine M-protein do not meet the above thresholds, an abnormal free light chain (FLC) ratio (normal range: 0.26 to 1.65) and involved serum FLC ≥100 mg/L.
• 4. Have received only one line of standard anti-myeloma therapy, including: Induction therapy with at least one proteasome inhibitor, one immunomodulatory agent, and corticosteroids; Sequential autologous hematopoietic stem cell transplantation or consolidation therapy; Maintenance therapy based on either a proteasome inhibitor or an immunomodulatory agent.
• 5. Meet at least one of the following dynamic high-risk criteria: Early relapse: Disease progression or relapse within 18 months of starting first-line therapy, including progression or relapse within 12 months post-autologous hematopoietic stem cell transplantation; Primary refractory disease: Failure to achieve at least minimal response (MR) after four cycles of induction therapy; Relapse with new genetic abnormalities: Gain(1q), del(17p), or TP53 mutation.
• 6. Confirmed expression of the BCMA target antigen on MM cells by flow cytometry or bone marrow immunohistochemistry.

Критерии исключения

• 1. Primary plasma cell leukemia.
• 2. Concurrent amyloidosis.
• 3. Involvement of the central nervous system (CNS).
• 4. Previous treatment with BCMA-targeted therapy or CAR-T cell therapy.
• 5. Disease progression or relapse within 3 months of autologous hematopoietic stem cell transplantation.

Описание

The goal of this observational study is to learn about antithrombotic regimens in Multiple myeloma patients. The main question it aims to answer is the efficacy of different types of thromboprophylaxis (antiplatelet agents, heparins, oral anticoagulants) in preventing venous thromboembolism (VTE).

Критерии включения

• 1. Age equal to or greater than 18 years of age.
• 2. New diagnosis of symptomatic MM according to the CRAB or the SLIM criteria of the International Myeloma Working Group
• 3. First active treatment for MM started after recruitment in the study
• 4. Signed informed consent

Критерии исключения

• 1. Patients having had thrombosis within 6 months before diagnosis of MM
• 2. Patients with need of combined antithrombotic regimens (i.e. VKA or DOAC or LMWK and one or two antiplatelet drugs)
• 3. Ongoing first active treatment for MM initiated before the starting of the study.

Описание

The primary purpose of this study is to assess the efficacy (overall response rate) of subcutaneous (SC) via on body delivery system (SC-OBDS) isatuximab in combination with weekly carfilzomib and dexamethasone (Kd) in adult participants with RRMM having received 1 to 3 prior lines of therapy.

Критерии включения

• * Participants must have a documented diagnosis of MM.
• * Participants with measurable disease defined as at least one of the following:
• * Serum M-protein ≥0.5 g/dL measured using serum protein immunoelectrophoresis and/or
• * Urine M-protein ≥200 mg/24 hours measured using urine protein immunoelectrophoresis and/or
• * Serum free light chain (FLC) assay: Involved FLC assay ≥10 mg/dL (≥100 mg/L) and an abnormal serum FLC ratio (/<0.26 or />1.65).
• * Participants with relapsed and/or refractory MM with at least 1 prior line of therapy and no more than 3 prior lines of therapy.
• * Contraceptive use by /[men and women/] should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• * Male participants agree to practice true abstinence or agree to use contraception while receiving study treatment, during dose interruptions and at least 5 months following study treatment discontinuation, even if has undergone a successful vasectomy.
• * A female participant is eligible to participate if she is not pregnant, not breastfeeding, and either is not a female of childbearing potential (FCBP XE " FCBP " //f Abbreviation //t "female of childbearing potential" ) or agrees to practice complete abstinence or use contraception.
• * Capable of giving signed informed consent.

Критерии исключения

• Participants are excluded from the study if any of the following criteria apply:
• * Primary refractory MM defined as participants who have never achieved at least a minimal response (MR) with any treatment during the disease course.
• * Participants with prior anti-CD38 treatment if: a) administered /< 6 months before first isatuximab administration or, b) intolerant to the anti-CD38 previously received.
• * Participants who are refractory to carfilzomib.
• * Known history of allergy to captisol (a cyclodextrin derivative used to solubilize carfilzomib), prior hypersensitivity to sucrose, histidine (as base and hydrochloride salt), polysorbate 80, or any of the components (active substance or excipient) of study treatment that are not amenable to premedication with steroids, or intolerance to arginine and Poloxamer 188 that would prohibit further treatment with these agents.
• * Participants with contraindication to dexamethasone and/or to carfilzomib.
• * Any anti-myeloma drug treatment within 14 days before the first isatuximab administration, including dexamethasone.
• * Prior allogenic HSC transplant with active graft versus host disease (GvHD XE " GvHD " //f Abbreviation //t "graft versus host disease" ) (GvHD any grade and/or being under immunosuppressive treatment within the last 2 months).
• * Any major procedure within 14 days before the first isatuximab administration: plasmapheresis, major surgery (kyphoplasty is not considered a major procedure), radiotherapy.
• * Vaccination with a live vaccine within 4 weeks before the first isatuximab administration. Seasonal flu vaccines that do not contain live virus are permitted.
• * Participant not suitable for participation, whatever the reason, as judged by the Investigator, including medical or clinical conditions, or participants potentially at risk of noncompliance to study procedures.
• The above information is not intended to contain all considerations relevant to the potential participation in a clinical trial.

Описание

The goal of this open label, phase two, prospective, non-randomized, sponsor-initiated explorative trial is to test self-administration of subcutaneous Elranatamab in the patients` homes in patients with relapsed multiple myeloma exposed to at least one proteasome inhibitor, one IMID and one anti CD-38 antibody. The main question/[s/]it aims to answer are:

* To evaluate the safety of self-administration of Elranatamab in the patients` own homes using registrations of occurrence of CRS, Immune effector cell-associated neurotoxicity syndrome (ICANS) and infections.
* To evaluate the feasibility of self-administration of Elranatamab in the patients´ own homes by registration of discarded doses, planned doses administered at home and doses diverted from the patients` homes to the outpatient clinic.
* To elucidate the perspectives of patients and their caregivers of self-administration of Elranatamab at home by interviewing both parties at end of treatment (EOT).
* To elucidate the perspectives of involved healthcare professionals in a focus group interview at end of study (EOS).
* To clarify time spent on self-administration at home compared to administration at the outpatient clinic by registering time consumption for patients, caregivers and healthcare professionals.
* To evaluate the patients` QoL during self-administration using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) together with the Functional Assessment of Cancer Therapy-Cognitive (FACT Cognitive).
* To clarify if self-administration in the patients` homes leads to additional unplanned contacts with the healthcare system as a whole by weekly registration of any unplanned contacts.
* To determine financial costs of self-administration at home compared to administration at the outpatient clinic from the perspectives of patients, caregivers and the healthcare system by collecting data on lost earnings, transport costs and salary costs.
* To evaluate the feasibility of the use of an electronic registration of side effects prior to treatment by comparing electronic patient reported outcome (PRO) data to registrations performed by nurses in the outpatient clinic during telephone consultations.

Participants will be asked to

* register time spend
* answer PRO-questionnaires
* weekly register any unplanned contact to the heathcare system
* be interviewed

Критерии включения

• * ≥ 18 years of age at the time of signing the informed consent form.
• * Relapsed MM according to the IMWG criteria.
• * Measurable disease defined as: M-protein quantities ≥ 0.5 g/dL by serum protein electrophoresis (sPEP) or ≥ 200 mg/24-hour urine collection by urine protein electrophoresis (uPEP) and/or Serum free light chain (FLC) levels /> 100 mg/L (10 mg/dL) involved light chain and an abnormal kappa/lambda (κ/λ) ratio in patients without measurable disease in the serum or urine.
• * Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0, 1 or 2.
• * Previously exposed to at least one proteasome inhibitor, one IMID and one anti CD-38 antibody.
• * Documented disease progression during or after last anti-myeloma regimen.
• * Possibility of being observed by a capable caregiver during self-administration.
• * ANC ≥1.0 x 109/L (G-CSF allowed).
• * Platelets ≥25 x 109/L.
• * 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 3 months following the last dose of study treatment.

Критерии исключения

• * Any significant medical condition, laboratory abnormality or psychiatric illness that would prevent the subject from participating in the study.
• * Prior history of ICANS.
• * Prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years with the exception of the following non-invasive malignancies:
• * Basal cell carcinoma of the skin
• * Squamous cell carcinoma of the skin
• * Carcinoma in situ of the cervix
• * Carcinoma in situ of the breast
• * Incidental histologic finding of prostate cancer (T1a or T1b using the TNM /[tumor, nodes and metastasis/] clinical staging system) or prostate cancer that is curative
• * Plasma cell leukemia, Waldenstrom`s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes) or clinically significant Amyloidosis.
• * Female who is pregnant, breastfeeding or who intends to become pregnant during the participation in the study.
• * Positivity for human immunodeficiency virus (HIV), chronic or active hepatitis B or active hepatitis A or C.
• * Resident on an unbridged island.
• * Not being able to register PRO-data electronically.

Описание

The goal of this observational study is to study the effectiveness and complications of novel immunotherapies used in the treatment of multiple myeloma in routine care in Norway. The aim is to close knowledge gaps, generate evidence for future clinical trials and contribute to future consensus on how to monitor for adverse events, and what mitigation strategies should be implemented, so that we can increase patient survival and quality-of-life.

Критерии включения

• * Participants age ≥ 18 years
• * Prior diagnosis of one of the following
• * Multiple myeloma as defined according to IMWG criteria
• * Primary plasma cell leukemia as defined according to IMWG consensus definition
• * AL-amyloidosis as defined according to IMWG criteria
• * Planned treatment with one of the following outside clinical trials (list to be amended based on approvals within the EU):
• * Teclistamab (Tecvayli)
• * Elranatamab (Elrexfio)
• * Talquetamab (Talvey)
• * Idecabtagene vicleucel (ide-cel/Abecma)
• * Ciltacabtagene autoleucel (cilta-cel/Carvykti)

Критерии исключения

• * None

Описание

Multiple myeloma is the second most common haematological cancer. Recent innovations have made it possible for relapsed/refractory patients to benefit from the innovative immunotherapy of bispecific antibodies. These antibodies stimulate the immune system to attack tumour cells. The treatment involves an escalating dose of three subcutaneous injections every 2 to 4 days for a total of about 10 days, followed by a weekly treatment phase.

The University Hospital of Toulouse was the first centre in France to offer outpatient dose escalation for this innovative treatment. This form of treatment depends on clinical and logistical feasibility. Where appropriate, patients are treated in a conventional unit. An analysis carried out at Toulouse University Hospital suggests a response to treatment, with no increased risk of complications in the outpatient setting. Patients` quality of life may also be unaffected. In addition, given the increasing demand for care in a context of finite resources, the economic evaluation of healthcare initiatives is becoming essential if we are to maintain a high-quality healthcare system that is accessible to all.

Критерии включения

• * Relapsed and/or refractory multiple myeloma
• * Treated with teclistamab, elranatamab ou talquetamab
• * More than 18 years old
• * Having received the information from the study and not having objected to participate
• * Day hospital care in case of clinical feasibility (good general condition, no rapid progression or major tumor burden, no current infection) and logistics (accommodated less than 30 minutes from the IUCT Oncopole for 48 hours after each dose escalation) or in conventional hospitalization at the IUCT Oncopole

Критерии исключения

• * Illiterate subjects or those with a language barrier

Описание

The goal of this study is to assess the efficacy of induction treatment with daratumumab-hyaluronidase (dara SC) with cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) for four cycles in patients with newly diagnosed multiple myeloma who have new onset renal failure. This study will also investigate the difference responses in African American (AA) patients versus non-African American patients.

The primary questions this study aims to answer are:

1. To evaluate the very good partial response rate (VGPR) after 4 cycles of Dara-CyBord.
2. To evaluate the renal response rate (RRR) after 4 cycles of Dara-CyBord.

Критерии включения

• 1. Patients must have had a confirmed new diagnosis of MM following revised IMWG criteria.
• 2. Patients must have Zubrod/ECOG Performance Status ≤ 2.
• 3. Patients must have renal insufficiency. Renal insufficiency is defined as eCrCl /< 60 mL/min (using Cockcroft-Gault Equation for Cr Cl) and/or necessitating dialysis
• 4. must not have known allergies to any of the study drugs. Must have adequate organ function.
• 5. International normalized ratio (INR) and prothrombin time (PT) ≤1.5 × ULN. Activated partial thromboplastin time (aPTT) ≤1.5 × ULN.

Критерии исключения

• * 1. Known seropositive for: human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C.
• 2. Known Chronic obstructive pulmonary disease (COPD). 3. Known Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification.
• 4. Known Clinically significant heart disease is defined as: myocardial infarction within 6 months before enrollment, or unstable or uncontrolled disease/condition related to or affection cardiac function.
• 5. Women who are pregnant, breastfeeding, or planning to become pregnant while enrolled in this study.
• 6. Patients with grade 3 or 4 peripheral neuropathy 7. Patients with other active malignancies that require concurrent treatment 8. Known CNS involvement or plasma cell leukemia, or AL amyloidosis 9. Participants with active infection requiring systemic therapy 10. Has known substance abuse disorders that would interfere with cooperation with the requirements of the study.

Описание

The purpose of this study is to identify multiple myeloma in the precancerous MGUS stage in order to reduce the risk of delayed diagnosis of multiple myeloma, decrease morbidity related to multiple myeloma at progression, and improve long term outcomes.

Критерии включения

• SCREENING Inclusion Criteria:
• * Self-identify as Black and/or African American
• * Age 30 years or older at the time of consent
• * Capable and willing to provide informed consent. NOTE: HIPAA (Health Insurance Portability and Accountability Act) authorization for the release of personal health information may be included in the informed consent or obtained separately
• * Reside in Charlotte, NC, or the surrounding area, based on self-report
• SCREENING Exclusion Criteria:
• * Self-reported history of MGUS, SMM, MM, AL amyloidosis, plasma cell leukemia, solitary plasmacytoma, Waldenstrom Macroglobulinemia, and POEMS.
• LONGITUDINAL Inclusion Criteria:
• * Test positive for monoclonal gammopathy during screening portion of the study
• * Consent to the longitudinal portion of the study
• LONGITUDINAL Exclusion Criteria:
• * The participant previously underwent diagnostic work up as part of CHAAMP Internal Pilot that did not result in a diagnosis of MGUS, Smoldering Multiple Myeloma or other non-plasma cell disorder.

Критерии исключения

Описание

The goal of this observational study is to improve the treatment of hematological patients with secondary immunodeficiency (SID) by developing a patient-reported outcome (PRO) instrument to detect clinically diagnosed infections. The study focuses on adults diagnosed with chronic lymphocytic leukemia (CLL) or multiple myeloma (MM) who are at increased risk of infections due to SID.

The main questions it aims to answer are:

1. Can a newly developed PRO screening tool for infection-related symptoms reliably detect infections in patients with SID?
2. How does the health-related quality of life change over the treatment course

Participants will:

* Complete daily electronic PRO questionnaires (ePRO) to monitor infection-related symptoms
* Complete ePRO health-related quality of life questionnaires every 1.5 months
* Participate in study visits every three months to ensure documentation of clinical data

Критерии включения

• * Adult patient (/>=18 years of age)
• * Access to an internet device (e.g., personal computer or tablet to use a web-based platform, or smartphone where the study app can be installed - all common iOS and Android systems)
• * German-speaking
• * Diagnosis of multiple myeloma or chronic lymphocytic leukemia
• * Secondary immunodeficiency (defined as: recurrent infections, infections requiring inpatient treatment, hypogammaglobulinemia, neutropenia and/or lymphopenia on differential blood cell counts, deficit in lymphocyte subsets as assessed by flow cytometry)

Критерии исключения

Описание

This is a single center, single arm, open-label, dose-escalation clinical study to observe the safety, tolerability, preliminary efficacy, pharmacokinetics, pharmacodynamics of ESO-T01 injection for treating 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 immunohistochemistry;
• 3. Previously treated with at least 2 lines of anti-MM therapy, with at least 1 complete treatment cycle for each line, and disease progression within 12 months after the most recent anti-myeloma treatment, or being refractory to both immunomodulatory drugs and proteasome inhibitors, along 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 evaluates the efficacy of elranatamab alone in patients with relapsed and/or refractory Multiple myeloma who has previously received 1 to 3 combinations of treatment.

Критерии включения

• 1. Provision of signed and dated informed consent form
• 2. Stated willingness to comply with all study procedures and availability for the duration of the study
• 3. Prior diagnosis of relapsed/refractory MM and have received 1 to 3 prior lines of therapy as defined by the IMWG criteria (Rajkumar et al., 2014) including anti-CD38 monoclonal antibody, proteosome inhibitor (PI), and immunomodulatory drug (IMiD), and BCMA-directed chimeric antigen receptor T-cell (CAR T-cell) therapy
• 1. Refractory is defined as having disease progression while on therapy or within 60 days of last dose in any line, regardless of response.
• 2. If participant has not received BCMA-directed CAR T-cell therapy, must be ineligible for CAR T-cell therapy or deferred such treatment by participant
• 4. Aged greater or equal to 18 years
• 5. Measurable disease as defined by any of the following:
• 1. Serum M-protein level ≥ 0.5 g/dL by serum protein electrophoresis (SPEP), or
• 2. Urine M-protein ≥ 200mg/24 hours by urine protein electrophoresis (UPEP), or
• 3. Involved serum free light chain ≥ 10 mg/dL (≥100mg/L) AND an abnormal serum free light chain ratio in patients without measurable disease in the serum or urine
• 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• 7. Adequate hematological function defined as
• 1. Absolute neutrophil count (ANC) ≥1,000/mm3 (G-CSF not permitted for at least 1 week prior to the first dose of elranatamab)
• 2. Hemoglobin ≥8.0 g/dL (transfusion support is permitted if completed at least 1 week prior to planned start of dosing)
• 3. Platelet count ≥75,000/mm3 or ≥50,000/mm3 if />50% involvement with plasma cells in the screening bone marrow (transfusion support is permitted if completed at least 1 week prior to planned start of dosing)
• 8. Adequate renal function with estimated creatinine clearance (CrCl) ≥30 mL/min as calculated using Cockcroft-Gault equation.
• 9. Adequate liver function defined as
• 1. Aspartate and alanine aminotransferase (AST and ALT) ≤2.5 x upper limit of normal (ULN); ≤5.0 x ULN if there is liver involvement by the tumor.
• 2. Alkaline phosphatase ≤2.5 x ULN (≤5 x ULN in case of bone metastasis).
• 3. Total bilirubin ≤2.0 mg/dL, except in patients with Gilbert Syndrome who must have a total bilirubin less than 3.0 mg/dL.
• 10. Able to receive outpatient treatment of elranatamab by meeting the following criteria:
• 1. Lives within 30minutes from the site of medication administration
• 2. Reliable caregiver present, who is able to watch participant continuously for at least until 48 hours after administration of first full treatment dose
• 3. No history of grade 3-4 CRS or grade 3-4 ICANS from other immune effector cell or bispecific antibody therapies
• 11. Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade ≤1
• 12. Serum pregnancy test (for females of childbearing potential) negative at screening.
• a. Female patients of non-childbearing potential must meet at least 1 of the following criteria: i. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed with a serum follicle stimulating hormone (FSH) level confirming the postmenopausal state.
• ii. Have undergone a documented hysterectomy and/or bilateral oophorectomy. iii. Have medically confirmed ovarian failure. b. All other female patients (including female patients with tubal ligations) are considered to be of childbearing potential.
• 13. Agreement to adhere to Lifestyle Considerations (see section 5.3 and Appendix 2) throughout study duration

Критерии исключения

• 1. Subjects with smoldering multiple myeloma, IgM multiple myeloma, Waldenstrom`s macroglobulinemia, amyloidosis, POEMS syndrome, and primary and secondary plasma cell leukemia, defined as circulating plasma cells ≥ 5%
• 2. Extramedullary relapse who does not meet criteria for measurable disease as above
• 3. Active malignancy other than Multiple Myeloma requiring treatment in the past 3 years, with the exception of successfully treated non-metastatic squamous or basal skin carcinoma
• 4. Known CNS involvement by multiple myeloma
• 5. Active, uncontrolled autoimmune disorders
• 6. Active uncontrolled infection. Active infections must be resolved and/or controlled at least 14 days prior to enrollment.
• 7. Radiation therapy within 2 weeks prior to study entry (bone lesions requiring radiation may be treated with limited /[ie, ≤25% of bone marrow in field/] radiation therapy during this period).
• 8. Last systemic treatment within 2 weeks or 5 half lives, whichever is shorter. Subjects can receive a maximum of 160mg of dexamethasone or equivalent during screening, but at least 7 days prior to start of therapy.
• 9. Last radiation treatment to multiple sites within 2 weeks and single site within 1 week
• 10. History of autologous stem cell transplant within 100 days prior to study enrollment.
• 11. History of allogeneic transplant within 1 year prior to study enrollment or active graft versus host disease.
• 12. On immunosuppressive therapy for concurrent comorbid conditions
• 13. Other major uncontrolled medical comorbidities that may put patients at risk of serious adverse event with treatment with study medication.
• 14. Clinically significant, uncontrolled cardiac disease
• 15. Grade ≥2 peripheral sensory or motor neuropathy
• 16. History of Guillan-Barre syndrome
• 17. Other surgical (including major surgery within 14 days prior to enrollment) or psychiatric conditions including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator`s judgment, make the participant inappropriate for the study.
• 18. Previous administration with an investigational drug within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer).
• 19. Pregnancy or lactation
• 20. Known or suspected hypersensitivity to the study intervention or any of its excipients.

Описание

This study if for people who have been diagnosed with multiple myeloma and their doctors are recommending radiation to help treat it. Typically, radiation consists of 2-3 weeks of external beam radiation therapy. Doctors leading this study would like to see if a shorter radiation course (i.e., hypofractionation) for pelvic radiation is safe for multiple myeloma. Because participants in this study will receive a shortened radiation course, each daily treatment dose that is delivered would be slightly higher than normal. This higher daily dose would be delivered because the study team would like to see if higher doses of radiation are as safe given over a shorter number of days compared to 2-3 weeks. The purpose of this study is to make sure that hypofractionation is safe and effective for individuals with multiple myeloma.

Критерии включения

• - For entry into the study, the following criteria must be met prior to dosing on Day 1. No exceptions will be granted. Eligibility criteria for this study have been carefully considered to ensure the safety of the study participants and that the results of the study can be used. It is imperative that participants fully meet all eligibility criteria.
• 1. Signed Written Informed Consent
• * Participants must be able to give self-consent and then sign and date an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written informed consent in accordance with local regulatory and institutional guidelines. This consent must be obtained before the performance of any protocol-related procedures that are not considered part of normal participant care.
• * Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study.
• 2. Type of Participant and Disease Characteristics
• 1. General inclusion criteria:
• * Men or women ≥ 18 years of age.
• * Have clinically confirmed relapsed/refractory Multiple Myeloma with up to 5 osseous lesions that can be treated with radiation therapy (SINS score ≤ 13 or Mirels` score ≤ 9) iii) Have undergone appropriate standard of care treatment options (in the opinion of the treating investigator).
• iv) Participants must have measurable disease as defined by RECIST Version 1.1, including at least one tumor lesion that meets criteria for radiation.
• 1. . 0.25 cc to 65 cc of viable tumor approximately 5 cm in maximal dimension. Tumors larger than 65 cc can be partially treated but the whole tumor should receive at least the minimal prescribed dose confirmed by the study team.
• v) Participants must have an Eastern Cooperative Oncology Group performance status that is greater than or equal to 2 vi) Adequate organ function, as defined by lab values that will be confirmed by the study doctor.
• 3. Age and Reproductive Status
• * Participants must be males and females ≥ 18 years of age at the time of informed consent.
• * Participants who are women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 72 hours prior to the start of study.
• c) Participants who are women must not be breastfeeding. d) Participants who are women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) and up to 5 months post last dose of study drug(s).
• e) Participants who are women of childbearing potential who are continuously not heterosexually active are exempted from contraceptive requirements but still must undergo pregnancy testing as described in this section.
• f) Participants who are males and who are sexually active with women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) and up to 7 months post last dose of study drug(s). In addition, male participants must be willing to refrain from sperm donation during this time.
• g) Participants who are azoospermic males are exempt from contraceptive requirements.
• Investigators shall counsel women of childbearing potential , and male participants who are sexually active with women of childbearing potential , on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise on the use of highly effective methods of contraception, which have a failure rate of /< 1% when used consistently and correctly.

Критерии исключения

• 1. Target Population
• • Participants must not have SINS (spinal instability neoplastic score) less than 13 or Mirels` score less than 9 prior to starting radiation treatment
• • Participants must not receive any concurrent anti-myeloma or systemic therapy of any form.
• • Participants who have not recovered (i.e. greater than grade 1 or at baseline) from adverse events due to a previously administered agent will be excluded. Participants may receive concurrent steroids.
• i) Note: subjects with greater than grade 2 neuropathy are an exception to this criterion and may qualify for the study.
• ii) Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• iii) Note: subjects with any grade alopecia are an exception to this criterion and may qualify for the study • Participants must not have had prior radiation therapy (defined as less than 10 percent of prior prescription dose) to the area planning to be treated with radiation.
• • Participants who have had prior cytotoxic chemotherapy must not receive that therapy within 2 weeks of the initiation of radiation
• • Participants who have had prior anti-cancer monoclonal antibody (mAb) or other small molecules must not receive that therapy within 7 days of the initiation of radiation
• • Participants must not have a known additional malignancy that could confuse analysis of on-study treatment. Inclusion of all study participants with more than one malignancy must be discussed and approved by the PI.
• * Participants must not have a known history of non-infectious pneumonitis that required steroids for treatment.
• * Participants must not have evidence of interstitial lung disease.
• * Participants must not have a current seizure disorder.
• * Participants must not have a history or current evidence of any condition, therapy or laboratory abnormality that might confound the results of the trial, interfere with the subject`s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
• * If known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C is detected then patient is not eligible for treatment of liver lesions
• * Participants must not have had uncontrolled or significant cardiovascular disease including, but not limited to, any of the following:
• * Myocardial infarction or stroke/transient ischemic attack within the past 6 months
• * Uncontrolled angina within the past 3 months
• * Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes)
• * History of other clinically significant heart disease (e.g. cardiomyopathy, congestive heart failure with New York Heart Association functional classification III to IV, pericarditis, significant pericardial effusion, or myocarditis)
• * Cardiovascular disease-related requirement for daily supplemental oxygen therapy.
• * Participants may not concomitantly use statins while on study. However, a patient using statins for over 3 months prior to study drug administration and in stable status without creatine kinase (CK) rise may be permitted to enroll.
• * Participants may not have current or history of clinically significant muscle disorders (e.g. myositis), recent unresolved muscle injury, or any condition known to elevate serum creatine kinase (CK) levels.
• * Participants must not be prisoners or be involuntarily incarcerated.
• * Participants must not be compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.
• Eligibility criteria for this study have been carefully considered to ensure the safety of the study participants and that the results of the study can be used. It is imperative that participants fully meet all eligibility criteria.

Описание

The purpose of this study is to learn about the impact that the services and programs provided by the Leukemia and Lymphoma Society have among patients with blood cancer, such as access to care, quality of life, and financial burden.

Критерии включения

• * Be currently receiving primary or relapse treatment for a diagnosis of leukemia, lymphoma, myeloma, myelodysplastic syndromes (MDS), or myeloproliferative neoplasms (MPN)
• * Report experiencing at least one unmet need addressed by the LLS Program (i.e., medical care including second opinions, travel for care, clinical trial access, financial and insurance needs, supportive programs, disease and treatment education)
• * Not be currently participating in any LLS programs or services
• * Be willing to be followed for 6 months
• * Speak English or Spanish

Критерии исключения

• * Are not receiving primary or relapse treatment for a diagnosis of leukemia, lymphoma, myeloma, myelodysplastic syndromes (MDS), or myeloproliferative neoplasms (MPN)
• * Are not experiencing unmet needs addressed by the LLS Program (i.e., medical care including second opinions, travel for care, clinical trial access, financial and insurance needs, supportive programs, disease and treatment education)
• * Are currently participating in any LLS programs or services
• * Are not willing to be followed for 6 months
• * Do not speak English or Spanish.

Описание

The aim of the study is to assess the efficacy and safety of BCD-248 as a therapy for relapsing and/or refractory multiple myeloma.

Критерии включения

• 1. Signed informed consent form.
• 2. Age ≥18 years.
• 3. Documented diagnosis of multiple myeloma according to the IMWG criteria.
• 4. Measurable disease at screening.
• 5. Subjects who received at least 2 lines of therapy for multiple myeloma, including a proteasome inhibitor, an immunomodulatory drug, anti-CD38 therapy.
• 6. Documented progression according to the IMWG criteria during or after the last line of therapy.
• 7. Evidence of at least a partial response according to the IMWG criteria to at least 1 previous line of therapy.
• 8. ECOG score 0-2.

Критерии исключения

• 1. Subjects who were previously treated with anti-BCMA or anti-CD3 drugs.
• 2. Use of any investigational medicinal products or medical devices within 30 days or 5 half-lives (whichever is longer) prior to the expected start of the study therapy or planned use of investigational medicinal products or medical devices during participation in this study, except for the use described in this Protocol.
• 3. Autologous hematopoietic stem cell transplantation within 12 weeks prior to the expected start of the study therapy or a history of allogenic stem cell transplantation, regardless of when it was performed.
• 4. Planned hematopoietic stem cell transplantation before disease progression during this study.
• 5. A history of other malignancies within 5 years before screening, excluding squamous and basal cell skin cancers, carcinoma in situ of the cervix or breast, or other malignancies, which, in the opinion of the Investigator, have been adequately treated and have a minimal risk of recurrence within 5 years.
• 6. Concomitant diseases and/or conditions that significantly increase the risk of AEs during the study:
• * Stable angina pectoris, functional class III-IV.
• * Unstable angina and/or myocardial infarction within less than 6 months before the expected start of the study therapy.
• * Chronic heart failure, NYHA class III-IV;
• * Clinically significant (in the Investigator`s opinion) cardiac arrhythmia and conduction disorders that do not respond to the maximum possible antiarrhythmic therapy (therapy should be stable for 4 weeks before the expected start of the study therapy);
• * Moderate to severe asthma, grade III-IV chronic obstructive pulmonary disease, a history of angioedema, severe respiratory failure;
• * Active autoimmune diseases (subjects with type 1 diabetes mellitus and hypothyroidism requiring only hormone replacement therapy, as well as with skin diseases (vitiligo, alopecia, or psoriasis) that do not require systemic therapy are eligible);
• * Any infection within 14 days prior to the expected start of the study therapy, requiring systemic etiotropic therapy or which, in the opinion of the Investigator, may increase the risk of infectious complications;
• * Any other concomitant disease or condition, which, in the Investigator`s opinion, significantly increases the risk of AEs in the study.
• 7. Subjects with amyloidosis.
• 8. Clinical signs of meningeal involvement of multiple myeloma.
• 9. HIV infection, active HBV infection, hepatitis C.
• 10. Major surgery within less than 14 days prior to the expected start of the study therapy, incomplete recovery from surgery, or planned surgery during participation in the study.
• 11. Pregnancy or breastfeeding, as well as intention to become pregnant or father a child during the study period and within 180 days after receiving the last dose of the IP.

Описание

The purpose of this study is to compare the efficacy and safety of BMS-986393 versus standard regimens in adult participants with Relapsed or Refractory and Lanalidomide-refractory Multiple Myeloma.

Критерии включения

• * Participants must have relapsed or refractory multiple myeloma (RRMM).
• * Participants must have received at least 1 but no greater than 3 prior multiple myeloma (MM) regimens which may include a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody, and be refractory to lenalidomide (LEN) (progression on or within 60 days of completing LEN therapy).
• * Participants must have a documented diagnosis of MM as per International Myeloma Working Group Criteria.
• * Participants must have measurable disease during screening.
• * Participants must have adequate organ function.
• * Participants must have an Eastern Cooperative Oncology group performance status 0 or 1.

Критерии исключения

• * Participants must not have known active or history of central nervous system (CNS) involvement of Multiple Myeloma (MM).
• * Participants must not have solitary plasmacytomas or non-secretory myeloma without other evidence of measurable disease.
• * Participants must not need urgent treatment due to rapidly progressing MM.
• * Other protocol-defined Inclusion/Exclusion criteria apply.

Описание

This is a prospective, non-inferiority study comparing VRD±D followed by BCMA CAR-T cell therapy versus VRD±D followed by autologous hematopoietic stem cell transplantation in the treatment of newly diagnosed multiple myeloma patients.

Критерии включения

• 1. Be informed and voluntarily sign the Informed Consent Form (ICF).
• 2. Age between 18 and 70 years (inclusive).
• 3. Have measurable disease meeting at least one of the following criteria: Serum M-protein ≥1 g/dL (/>10 g/L) as detected by serum protein electrophoresis (SPEP), or quantifiable IgA or IgD levels for IgA or IgD-type myeloma; Urine M-protein ≥200 mg/24 hours; In cases where serum and urine M-protein do not meet the above thresholds, an abnormal free light chain (FLC) ratio (normal range: 0.26 to 1.65) and involved serum FLC ≥100 mg/L.
• 4. Confirmed expression of the BCMA target antigen on MM cells by flow cytometry or bone marrow immunohistochemistry.
• 5. Assessed by the investigator as transplant-eligible.

Критерии исключения

• 1. Primary plasma cell leukemia.
• 2. Concurrent amyloidosis.
• 3. Involvement of the central nervous system (CNS).
• 4. Previous treatment with BCMA-targeted therapy or CAR-T cell therapy.

Описание

This is a prospective, single-arm, multicenter, open-label study to evaluate the efficacy and safety of aponermin-based bridging therapy prior to CAR-T infusion in relapsed/refractory multiple myeloma patients with extramedullary disease.

Критерии включения

• 1. Be informed and voluntarily sign the Informed Consent Form (ICF).
• 2. Age ≥18 years.
• 3. Confirmed diagnosis of Multiple Myeloma(MM) (IMWG consensus guidelines)
• 4. Subjects with diagnosed relapsed or refractory extramedullary multiple myeloma according to IMWG criteria and have had at least 1 prior lines of therapy. Extramedullary disease (EMD) is defined as soft-tissue plasmacytomas NOT arising from skeletal lesions. The maximum diameter of extramedullary lesions should ≥2cm detected by physical exam and confirmed (when required) by Weight Bearing CT/MRI/PET-CT and/or biopsy.
• 5. ECOG score is ≤ 2
• 6. No active infections.
• 7. Negative for HBV-DNA, HCV-RNA, and HIV.
• 8. Liver function meeting the following criteria: Total bilirubin /<1.5 × ULN (patients with Gilbert`s syndrome must have total bilirubin /<3 × ULN), ALT and AST /<3 × ULN.
• 9. Renal function meeting the following criteria: Creatinine clearance ≥30mL/min (calculated using the Cockcroft-Gault formula).
• 10. Blood tests conducted within 7 days before screening must meet the following standards: WBC count ≥1.0×10⁹/L, Hemoglobin ≥70g/L, Platelet count ≥75×10⁹/L or ≥50×10⁹/L (if ≥50% plasma cells are present in bone marrow); Or as determined appropriate by the investigator.
• 11. Patients receiving hematopoietic growth factors (e.g., erythropoietin, granulocyte colony-stimulating factor /[G-CSF/], granulocyte-macrophage colony-stimulating factor /[GM-CSF/], and platelet-stimulating factors such as thrombopoietin /[TPO/] or interleukin-11) must stop such treatments at least 2 weeks prior to screening.
• 12. Non-pregnant female patients must confirm pregnancy negativity at screening (via β-hCG serum test or urine pregnancy test).
• 13. Male patients, female patients of childbearing potential, and their partners must agree to use effective contraception during the treatment period and for at least 3 months after CAR-T cell infusion.
• 14. Male patients must agree not to donate sperm, starting from the initial screening period until 90 days after the last dose.
• 15. Patients must agree to comply with study procedures and follow-up visits.

Критерии исключения

• 1. Plasma cell leukemia or solitary plasmacytoma.
• 2. Prior exposure to both BCMA- and GPRC5D-targeted therapies (patients who have received only one of these targeted therapies are eligible for enrollment).
• 3. Evidence of primary or secondary resistance to elotuzumab, carfilzomib, or thalidomide.
• 4. Pregnant or breastfeeding women, or women with pregnancy plans within the next six months.
• 5. Infectious diseases (e.g., HIV, active tuberculosis, etc.).
• 6. Active hepatitis B or hepatitis C infection.
• 7. Abnormal vital signs or inability to cooperate with examinations.
• 8. Mental or psychological disorders preventing compliance with treatment or treatment evaluation.
• 9. Severe allergic constitution or severe allergic history, particularly to aponermin, carfilzomib, thalidomide, dexamethasone or other effective components or excipients of related drugs.
• 10. Significant dysfunction of major organs, such as the heart, lungs, or brain.
• 9) Patients with severe autoimmune diseases. 11) Any other reasons deemed unsuitable for participation in this study as determined by the investigator.

Описание

This study is researching an experimental drug called REGN7945 in combination with another experimental drug called linvoseltamab, (also known as REGN5458) (each individually called a "study drug" or "study drugs" when combined).

This study is the first time REGN7945 will be tested in humans. Linvoseltamab has previously been studied by itself (without other cancer drugs) in participants who had advanced multiple myeloma that returned and needed to be treated again after several other therapies had failed.

The aim of the study is to see how safe, tolerable, and effective REGN7945 is when given in combination with linvoseltamab, compared with linvoseltamab alone.

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

* What side effects may happen from taking the study drug(s)
* How many people treated with REGN7945 and linvoseltamab compared to linvoseltamab alone have improvement of their multiple myeloma and by how much
* How long people benefit from receiving REGN7945 in combination with linvoseltamab compared with linvoseltamab alone
* How much study drug(s) is in the blood at different times
* Whether the body makes antibodies against the study drugs(s) (which could make the study drug(s) less effective or could lead to side effects)
* If there is any change in pain and cancer-related symptoms, how well people are able to function, and their quality of life when taking the study drug(s)

Критерии включения

• 1. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 as described in the protocol
• 2. Received at least 3 lines of therapy including exposure to at least 1 anti-CD38 antibody, 1 immunomodulatory imide drug (IMiD), and 1 proteasome inhibitor (PI) and have demonstrated disease progression on or after the last therapy, as defined in the protocol. Prior treatment with other BCMA directed immunotherapies, including BCMA CAR-T cells and BCMA antibody-drug conjugates (Phase 1 and 2), and with BCMA x CD3 bispecific antibodies (Phase 1 only), is allowed
• 3. Participants must have the measurable disease for response assessment as described in the protocol
• 4. Adequate hematologic, hepatic, and renal function as described in the protocol

Критерии исключения

• 1. Diagnosis of plasma cell leukemia, primary systemic light-chain amyloidosis (including myeloma associated amyloidosis), Waldenström macroglobulinemia (lymphoplasmacytic lymphoma), or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
• 2. Treatment with any systemic anti-cancer therapy within 5 half-lives or within 28 days before first administration of study drug, whichever is shorter
• 3. History of allogeneic stem cell transplantation within 6 months, or autologous stem cell transplantation within 12 weeks of the start of study treatment
• 4. Treatment with systemic corticosteroid treatment with more than 10 mg per day of prednisone or steroid equivalent within 72 hours of start of study drug
• 5. Participants who have known central nervous system (CNS) involvement with MM or known or suspected progressive multifocal leukoencephalopathy (PML), history of a neurocognitive condition or CNS disorder, or history of seizure within 12 months prior to study enrollment
• 6. Live or live attenuated vaccination within 28 days before first study drug administration with a vector that has replicative potential
• 7. Has received a COVID-19 vaccination within 1 week of planned start of study medication as described in the protocol
• 8. Myelodysplastic syndrome or another malignancy in the past 3 years, except for nonmelanoma skin cancer, in situ carcinoma, thyroid cancer, or low-risk early stage prostate adenocarcinoma, as described in the protocol
• 9. Significant cardiovascular disease as described in the protocol
• 10. Uncontrolled infection with HIV, Hep B or Hep C infection, or other uncontrolled infection, such as CMV, as described in the protocol
• 11. Known hypersensitivity to both allopurinol and rasburicase
• Note: Other protocol-defined Inclusion/ Exclusion Criteria apply

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; clinical relapse: a. New bone lesions or soft tissue plasmacytomas (excluding osteoporotic fractures); b. Confirmed increase (≥ 50% increase in SPD of measurable lesions with an absolute value of ≥ 1 cm) in pre-existing plasmacytomas or bone lesions.
• 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

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

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
• * Known 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

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

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 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 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 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 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.