OncoTrials - мониторинг клинических исследований

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 ≥ 60mL/min.

Критерии исключения

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

Описание

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

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

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

Критерии включения

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any study-related procedures not part of normal medical care are performed, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.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

Критерии исключения

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

Описание

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

Критерии включения

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

Критерии исключения

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

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 which must include a second or third generation immunomodulator, proteosome inhibitor (PI), and anti CD38 monoclonal antibody (mAb) administered with the same or different line.
• AND
• * Must be either relapsed or refractory to the above therapies, or are intolerant to them, based up on the Investigator`s judgment.
• * 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 which must include a second or third generation immunomodulator, PI, anti-CD38 mAb, and anti-B Cell Maturation Antigen (anti-BCMA) agent. AND
• * Must be either relapsed or refractory to the above therapies, or are intolerant to them, based up on the Investigator`s judgment.
• * 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.
• * 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

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

Критерии включения

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

Критерии исключения

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

Описание

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

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

Критерии включения

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

Критерии исключения

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

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

The purpose of this study is to evaluate whether a novel decision support tool called PRIME (Preference Reporting to Improve Management and Experience), which combines values-elicitation with tailored feedback to patients and providers, improves patient-reported values-concordance of initial treatment decisions compared to usual care.

Критерии включения

• In order to participate in this study a subject must meet all of the eligibility criteria outlined below.
• 1. Written or verbal informed consent obtained to participate in the study and HIPAA authorization for the release of personal health information.
• 2. Subjects are willing and able to comply with study procedures based on the judgment of the investigator.
• 3. Age ≥ 60 years at the time of consent.
• 4. New patient to either the hematologic malignancies clinic or the bone marrow transplant/cellular therapy clinic.

Критерии исключения

• All subjects meeting any of the exclusion criteria listed below at baseline will be excluded from study participation:
• 1. Dementia, altered mental status, or psychiatric condition that would prohibit the understanding or rendering of informed consent or participation in the intervention.

Описание

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

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

Критерии включения

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

Критерии исключения

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

This clinical trial tests the effectiveness of a home-based mindfulness physical activity program with remote monitoring combined with structured telephone-based health coaching to decrease fatigue and improve quality of life in older patients with multiple myeloma (MM). Studies have shown that MM patients have the highest symptom burden among all blood cancers, with older patients experiencing more symptoms and problems, such as fatigue and decreased quality of life, compared to younger patients. There is some data to support that physical activity may have beneficial effects on fatigue, physical function, and quality of life in older cancer patients. Studies have also shown that older patients prefer activities that are gentle, holistic, and home-based. Mindfulness-based interventions have been shown to have positive effects on sleep, depression, anxiety and cancer-related fatigue. Health coaching is a patient centered behavioral change intervention that is delivered by various healthcare professionals and involves goal-setting, self-discovery, and accountability. Health coaching interventions have been shown to increase physical activity levels and improve quality of life. A home-based mindfulness physical activity program with remote monitoring combined with structured telephone-based health coaching may decrease fatigue and improve the quality of life in older patients with MM.

Критерии включения

• * Diagnosed with MM and has received treatment with />= 1 prior lines of treatment, and currently on maintenance treatment with a proteasome inhibitor and/or immunomodulatory agent, and/or anti-C38 antibody
• * The ability to read and respond to questions in English
• * Age ≥ 65 years
• * Moderate or higher fatigue ( /> 4) on a scale of 0-10 based on fatigue rating to question: - Rate your average fatigue over the last week, where 0 is no fatigue and 10 is extreme fatigue
• * Have wi-fi connection, as the program requires wi-fi to operate

Критерии исключения

• * Does not meet listed inclusion criteria

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

The purpose of this study is to evaluate the real-world characteristics and outcomes of participants with smoldering multiple myeloma (SMM) overall and by high-risk and non-high-risk SMM according to (AQUILA study criteria /[NCT03301220/], Mayo 20-2-20 and international myeloma working group (IMWG) 2020 risk classification models), and to evaluate the risk of progressing of SMM to multiple myeloma (MM) and outcomes in participants after progressing to MM.

Критерии включения

• * Have a documented diagnosis of smoldering multiple myeloma (SMM). SMM is defined as: (a) Clonal bone marrow plasma cells (BMPCs) greater than or equal to (/>=) 10 percent (%) and/or serum M-protein />= 3 grams per deciliter (g/dL) and/or urine M-protein />= 500 milligram per 24 hours (mg/24hrs). (b) Absence of 60 % plasma cells, involved/uninvolved free light chain (FLC) ratio />= 100 and involved FLC />= 10, and magnetic resonance imaging (MRI) lesions- calcium elevation, renal insufficiency, anemia, and bone lesions (SLiM-CRAB) criteria
• * Informed consent obtained prior to retrospective data collection in accordance with local requirements, either an informed consent form (ICF) indicating that the participants signed a consent for data collection for this research and agrees to have their data collected and analyzed, with source data verification (SDV), or the country does accept the ICF waiver for such type of studies
• * Data recorded in participants` medical charts from date of SMM diagnosis and at least one year after should be available in the participant`s medical chart at the participating site. However, data from any participants who died within the first year or after the first year after the SMM diagnosis is eligible

Критерии исключения

• * Therapy for multiple myeloma (MM) initiated within 90 days of SMM diagnosis
• * Date of SMM diagnosis is missing
• * Have an MM-defining event at the stage of SMM diagnosis
• * Participants who received an investigational treatment for SMM are not eligible. However, participants that received an investigational treatment only after evolution to MM (not during SMM observational period) are eligible

Описание

Objective 1: To test whether treatment with plasma exchange improves renal recovery in patients with light chain cast nephropathy Objective 2: To compare renal outcomes among patients treated with plasma exchange versus daratumumab-based regimens versus non-daratumumab based-regimens.

Критерии включения

• for Plasma Exchange-Treated Patients:
• 1. Adult (≥18 years old)
• 2. Either a new diagnosis of multiple myeloma confirmed by bone marrow plasmayctosis />10% or acute relapse of multiple myeloma
• 3. Light chain cast nephropathy, with involved light chain />500 mg/L
• 4. Acute kidney injury, defined as ≥1.5-fold rise in SCr from baseline (as defined in study outcomes) or the need for renal replacement therapy (RRT).
• 5. Treated with at least 1 round of plasma exchange within 30 days of diagnosis of cast nephropathy
• 6. Treated with plasma exchange in 2010 or later
• Inclusion Criteria for Control Patients:
• 1. Adult (≥18 years old)
• 2. Either a new diagnosis of multiple myeloma confirmed by bone marrow plasmayctosis />10% or acute relapse of multiple myeloma
• 3. Light chain cast nephropathy, with involved light chain />500 mg/L
• 4. Acute kidney injury, defined as ≥1.5-fold rise in SCr from baseline or the need for renal replacement therapy (RRT)

Критерии исключения

• for Both Plasma Exchange-Treated Patients and Control Patients:
• 1. Patients with end stage kidney disease
• 2. Patients with amyloidosis or monoclonal immunoglobulin deposition disease
• 3. Patients with chronic lymphocytic leukemia, plasma cell leukemia, or Waldenstrom`s
• 4. Moribund condition (e.g., patients who died within 48 hours of initiation of plasma exchange)
• 5. Active urinary tract obstruction on renal imaging
• 6. Patients with significant albuminuria (≥2+ on urinary dipstick or />10% fraction on UPEP)
• 7. Patients with other biopsy-proven causes of AKI (non-cast nephropathy lesions)
• 8. Patients who did not receive clone-directed therapy for myeloma
• 9. Patients who received plasma exchange />30 days from the time of diagnosis of cast nephropathy

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

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

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

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

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

Критерии включения

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

Критерии исключения

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

Описание

This is Phase 2, open-label, multicentre, non-randomised study evaluating participants with newly diagnosed MM eligible for high-dose therapy. The goal of the study is to determine if consolidation with T-cell redirectors - Talquetamab and Teclistamab in sequence will improve the response depth: increase MRD negative CR rate.

Критерии включения

• 1. Participant must have documented MM satisfying the IMWG criteria.
• 2. Newly diagnosed patients eligible for high dose therapy and ASCT.
• 3. ECOG performance status score ≤2.
• 4. HIV-positive participants are eligible if they meet all of the following
• 1. No detectable viral load (ie, /<50 copies/mL) at screening
• 2. CD4+ count />300 cells/mm3 at screening
• 3. No AIDS-defining opportunistic infection within 6 months of screening
• 4. 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.
• 5. Must sign an ICF indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.
• 6. Willing and able to adhere to the lifestyle restrictions specified in this protocol.
• 7. A female participant of childbearing potential must have a negative highly sensitive serum (β hCG) pregnancy test at screening
• 8. A female participant must be
• 1. Not of childbearing potential or
• 2. Of childbearing potential and practicing true abstinence; or have a sole partner who is vasectomized; or practicing 2 effective methods of contraception
• 9. A female participant must agree not to donate eggs or freeze for future use during the study and for 6 months after receiving the last dose of study treatment.
• 10. A male participant must wear a condom when engaging any sexual 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.
• 11. 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.
• 12. Have clinical laboratory values meeting the following criteria
• 1. Hemoglobin ≥8 g/dL
• 2. Platelets ≥75×109/L
• 3. ANC ≥1.0×109/L
• 4. AST and ALT ≤2.5×ULN
• 5. eGFR ≥30 mL/min
• 6. Total bilirubin /<1.5×ULN

Критерии исключения

• 1. Waldenström`s macroglobulinemia, POEMS syndrome, or primary amyloid light chain amyloidosis.
• 2. Known active CNS involvement or exhibits clinical signs of meningeal involvement of MM. If either is suspected, negative whole brain MRI and lumbar cytology are required.
• 3. Peripheral neuropathy or neuropathic pain Grade 2 or higher
• 4. Excluded for any of the following:
• 1. Any ongoing myelodysplastic syndrome or B cell malignancy (other than MM).
• 2. Any history of malignancy, other than MM, which is considered at high risk of recurrence requiring systemic therapy.
• 3. Any active malignancy (ie, progressing or requiring treatment change in the last 24 months) other than MM. The only allowed exceptions are malignancies treated within the last 24 months that are considered cured:
• 1. Non-muscle invasive bladder cancer (solitary Ta-PUN-LMP or low grade, /<3 cm, no CIS).
• 2. Non-melanoma skin cancers treated with curative therapy or localized melanoma treated with curative surgical resection alone.
• 3. Non-invasive cervical cancer.
• 4. Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ or history of localized breast cancer (anti-hormonal therapy is permitted).
• 5. Localized prostate cancer (M0, N0) with a Gleason Score ≤7a, treated locally only (RP/RT/focal treatment).
• 6. Other malignancy that is considered cured with minimal risk of recurrence in consultation with the sponsor`s medical monitor.
• 5. Stroke within 6 months prior to signing ICF.
• 6. Presence of the following cardiac conditions:
• 1. New York Heart Association stage III or IV congestive heart failure (see Appendix )
• 2. Myocardial infarction or coronary artery bypass graft ≤6 months prior to enrollment, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina)
• 3. Uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities
• 4. History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration
• 5. History of severe non-ischemic cardiomyopathy
• 7. 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:
• 1. Uncontrolled diabetes
• 2. Evidence of active systemic viral, fungal, or bacterial infection, requiring systemic antimicrobial therapy
• 3. History of autoimmune disease with the exception of vitiligo, type I diabetes, and prior autoimmune thyroiditis that is currently euthyroid based on clinical symptoms and laboratory testing
• 4. Gastrointestinal disease that may significantly alter the absorption of oral drugs
• 5. Disabling psychiatric conditions (eg, alcohol or drug abuse), severe dementia, or altered mental status
• 8. 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 (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments
• 9. Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study drug or its excipients
• 10. Any of the following:
• 1. Hepatitis B infection (ie, HBsAg or HBV-DNA positive).
• 2. Active hepatitis C infection as measured by positive HCV-RNA testing.
• 11. Prior or current systemic therapy or stem cell transplantation for any plasma cell dyscrasia, with the exception of emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment.
• 12. 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.
• 13. Contraindications to the use of Dara-VRd per SmPC.
• 14. Prior or concurrent exposure to any of the following, in the specified time frame prior to first dose of study treatment:
• 1. Investigational vaccine other than SARS-CoV-2 vaccine approved/in use under emergency approval within 4 weeks. Non-live or non-replicating vaccines authorized for emergency use (eg, COVID-19) by local health authorities are allowed.
• 2. Live, attenuated vaccine within 4 weeks
• 3. Monoclonal antibody therapy within 21 days (not used for the treatment of MM)
• 4. Received a strong CYP3A4 inducer within 5 half-lives prior to start of administration of study treatment
• 15. Participant is pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of study treatment.
• 16. Participant plans to father a child while enrolled in this study or within 100 days after the last dose of study treatment.

Описание

The purpose of this study is to evaluate the effects of the addition of SG301 injection to pomalidomide and dexamethasone in subjects with relapsed or refractory multiple myeloma.

Критерии включения

• 1. Understand and voluntarily sign the informed consent form (ICF).
• 2. Males and females aged 18-75 years (inclusive)
• 3. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2
• 4. Expected survival time of ≥3 months.
• 5. Subjects had a documented diagnosis of multiple myeloma with evidence of measurable disease.
• 6. Subjects had received at least 1 prior lines of anti-myeloma therapy, which must include lenalidomide and a proteasome inhibitor (bortezomib, carfilzomib or ixazomib) given alone or in combination.
• 7. Subjects must have documented evidence of PD on or after the last regimen.
• 8. Adequate function of vital organs
• 9. Women of childbearing potential (WOCBP) must agree to follow instructions for methods of contraception for 4 weeks before the start of study treatment, for the duration of study treatment, and for 6 months after cessation of SG301 or 4 weeks after cessation of pomalidomide, whichever is longer. WOCBP must have 2 negative serum or urine pregnancy tests, one 10-14 days prior to start of study treatment and one 24 hours prior to the start of study treatment.

Критерии исключения

• 1. Primary refractory multiple myeloma defined as participants who had never achieved at least a minimal response (MR) with any treatment during the disease course.
• 2. Bone independent extramedullary disease at screening.
• 3. Subjects who are primary refractory to a prior CD38 monoclonal antibody therapy.
• 4. Previous exposure to pomalidomide.
• 5. Subject has received chemotherapy or small molecule antitumor therapy within 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is shorter, before the first dose of study treatment;
• 6. Subject has received tumor biotherapy within 4 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is shorter, before the first dose of study treatment;
• 7. Subject has received investigational agents within 4 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is shorter (but not less than 14 days), before the first dose of study treatment;
• 8. Active hepatitis B, or C.
• 9. Known HIV infection.
• 10. Known active tuberculosis or positive treponema pallidum antibodies.
• 11. Subjects with clinical significant organ dysfunction that does not meet the study needs.
• 12. Previous allogenic stem cell transplant or autologous stem cell transplantation (ASCT) before the first dose of study treatment.
• 13. Known allergy to any component of the investigational medicinal product.
• 14. Any concurrent medical or psychiatric condition or disease (eg, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) 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.

Описание

Multiple myeloma is a hematologic malignancy that can cause anemia, renal failure, bone disease, and hypercalcemia. Today, myeloma is considered a chronic disease and most patients will receive ongoing biological treatments. As a result, this disease causes a number of symptoms related to the disease itself or its treatment, which include, among others, weakness and fatigue, bone or nerve pain, depression and anxiety, gastrointestinal symptoms, impairment of sexual function, etc. These symptoms cause significant damage to quality-of-life which is similar in patients who receive different treatment lines. As a result, the FDA emphasized quality-of-life as a key outcome for the approval of new drugs for the disease.

The conventional therapeutic approach to the various symptoms is based on supportive care guidelines including pharmacological and non-pharmacological treatment of pain, gastrointestinal symptoms, psychological components, etc. These treatments involve side effects and usually refer to individual symptoms.

Complementary and integrative medicine includes treatments of touch, movement, mind-body, acupuncture, nutrition and nutritional supplements. Many studies have shown the effectiveness of these treatments on various symptoms in cancer patients including pain, depression and anxiety, fatigue and weakness, gastrointestinal symptoms, etc. In myeloma patients, the effect of diet and nutritional supplements was mainly examined, but there is also little information on the effectiveness of mind-body treatments on symptoms of anxiety and depression, as well as acupuncture on neuropathy or on symptoms experienced by myeloma patients around autologous bone marrow transplantation.

In recent years, a wide variety of new drugs have entered the market that cause side effects that were unknown until now and little is known about the effect of complementary medicine treatments on symptoms and quality-of-life of myeloma patients since the development of these drugs.

In this study we will examine the effect of complementary and integrative medicine treatments (including acupuncture, touch, movement, mind-body) on the quality-of-life and symptoms that characterize myeloma patients during treatment with different lines of therapy, including new drugs.

Patients with a diagnosis of multiple myeloma who meet the study/'s inclusion criteria will be divided into the intervention group (complementary medicine treatments) and the control group (no treatments) according to their preferences. All the patients of the intervention group and the patients of the control group who agree will be asked to fill out quality-of-life questionnaires validated and translated into Hebrew, Arabic and Russian before the start of the treatment. The questionnaires include European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) which is a general quality-of-life questionnaire for cancer patients, with the addition of MY20 which is an addition of 20 specific questions for patients with multiple myeloma, the Edmonton Symptom Assessment System (ESAS) questionnaire which examines the severity of 10 common symptoms in patients with malignant disease, and the EuroQol-5 Dimension (EQ-5D) questionnaire which examines quality-of-life in cancer patients and is used as a primary outcome in many clinical studies. The same questionnaires will be sent again 1-2 weeks after the end of the treatments in the intervention group and 6-8 weeks after recruitment in the control group. Socio-demographic and medical data will also be collected from the patients and their medical records.

Критерии включения

• * Age over 18
• * Diagnosis of multiple myeloma
• * Possibility to answer questionnaires once a month in Hebrew, Arabic or Russian
• * Signing an informed consent form

Критерии исключения

• * Age under 18 years
• * In patients who will receive acupuncture: platelet level below 20x10/^9/L
• * In patients who will receive reflexology: deep vein thrombosis in the leg
• * Hemodynamic instability
• * Psychiatric disorder impairing competence

Описание

This is a single-center, open-label, single-arm study to evaluate the safety and efficacy of bispecific BCMA-GPRC5D CAR-T cells in patients with relapsed or refractory multiple myeloma who received three or more lines of therapy.

Критерии включения

• 1. The patient or his/her guardian understands and voluntarily signs the informed consent, and is expected to complete the follow-up examination and treatment of the study procedure;
• 2. Age 18-75 years old, gender unlimited;
• 3. Diagnosed as Multiple Myeloma (MM) according to the international standard for multiple myeloma (IMWG);
• 4. The presence of measurable disease at screening meets one of the following criteria:Serum M-protein ≥ 1.0 g/dL or Urine M-protein ≥ 200 mg/24h or diagnosed as Light-chain MM without measurable disease in serum and urine; Serum free light chain ≥ 10 mg/dL with an abnormal κ/λ ratio;
• 5. Patients must relapse or be refractory after three or more lines of therapy, which at least include: one Proteasome Inhibitor (PI), one Immunomodulatory Drug (IMiD), and one anti-CD38 monoclonal antibody;
• 6. diagnosed as relapsed/refractory disease or primary refractory disease;
• 7. The last treatment is ineffective, or the disease progresses within 60 days after the end of the last therapy;
• 8. The patient has recovered from the toxicity of the prior treatment, i.e., CTCAE toxicity grade /< 2 (unless the abnormality is related to the tumor or is stable as judged by the investigator and has little impact on safety or efficacy);
• 9. ECOG score 1-2 points and the expected survival period ≥ 3 months;
• 10. Liver, kidney and cardiopulmonary functions meet the following requirements:
• 1. Total bilirubin ≤ 1.5×ULN, alanine aminotransferase (ALT) ≤ 3 × ULN and aspartate aminotransferase (AST) ≤ 3 × ULN;
• 2. Serum creatinine ≤ 1.5×ULN, or creatinine clearance ≥ 60 mL/min;
• 3. Hemoglobin (Hb) ≥ 50 g/L without prior blood transfusion within 7 days;
• 4. Baseline peripheral oxygen saturation /> 92%;
• 5. Corrected serum calcium ≤ 12.5 mg/dL (≤ 3.1 mmol/L) or free (ionized, ionic) calcium ≤ 6.5 mg/dL (≤ 1.6 mmol/L);
• 6. Left ventricular ejection fraction (LVEF) /> 45%, without confirmed pericardiac effusion and abnormal electrocardiography with clinical significance;
• 7. Without clinically significant pleural effusion;
• 11. Venous access could be established; without contraindications of apheresis.

Критерии исключения

• 1. Have been diagnosed with or treated for aggressive malignancies other than multiple myeloma;
• 2. Prior antitumor therapy (prior to blood collection for CAR-T preparation) : targeted therapy, epigenetic therapy, or investigational drug therapy within 14 days or at least 5 half-lives, whichever is shorter;
• 3. It is suspected that MM has involved the central nervous system or meninges and has been confirmed by MRI or CT, or there are other active central nervous system diseases;
• 4. Patients with Fahrenheit macroglobulinemia, POEMS syndrome, or primary AL, amyloidosis;
• 5. Subjects with positive HBsAg or HBcAb positive and peripheral blood HBV DNA titer is higher than the lower limit of detection of the research institution; HCV antibody positive; HIV antibody positive; CMV DNA titer is higher than the lower limit of detection of the research institution; EBV DNA titer is higher than the lower limit of detection of the research institution;
• 6. Patients have a severe allergic history;
• 7. Any unstable systemic disease: including but not limited to unstable angina, cerebrovascular accident or transient cerebral ischemia (within 6 months before screening), myocardial infarction (within 6 months before screening), congestive heart failure /[New York Heart Association (NYHA) classification ≥ grade III/];
• 8. Systemic diseases judged by researchers to be unstable: including but not limited to severe liver, kidney or metabolic diseases requiring drug treatment;
• 9. Patients with acute/chronic graft-versus-host disease (GVHD) or requiring immunosuppressive therapy for GVHD within 6 months prior to screening;
• 10. Active autoimmune or inflammatory diseases of the nervous system;
• 11. Patients develop oncology emergencies and need to be treated before screening or infusion;
• 12. Uncontrolled infections that need antibiotics treatment;
• 13. Exposure to hematopoietic growth factor of cells within 1-2 weeks before apheresis;
• 14. Exposure to Corticosteriods or immunosuppressive agents within 2 weeks before apheresis;
• 15. Patients receive a major surgical operation within 4 weeks before lymphodepletion or do not recover completely before the enrollment; or plan to receive a major surgical operation during the study period;
• 16. Live attenuated vaccine within 4 weeks before screening;
• 17. Persons with serious mental illness;
• 18. Alcoholics or persons with a history of drug abuse;
• 19. Pregnant or Lactating Women; Patients and his or her spouse have a fertility plan within two years after CAR-T cell infusion;
• 20. Any unsuitable to participate in this trial judged by the investigator.

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

This study aims to provide a basis for further clinical development of YKST02. YKST02 is a study medicine that targets multiple myeloma and activates the human body to fight against this disease.

Критерии включения

• 1. Participants or their legally acceptable representative must sign an ICF indicating that the participants understand the purpose of, and procedures required for the study and are willing to participate in the study.
• 2. Diagnosis of multiple myeloma according to the IMWG criteria.
• 3. Receipt of at least two prior classes of drugs either in separate regimens or as combinations. The three classes are defined as: An immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 drug.
• 4. Measurable disease at screening, as defined by at least 1 of the following:
• 1. Serum M-protein ≥0.5 g/dL;
• 2. Urinary M-protein excretion ≥200 mg/24 hours;
• 3. Abnormal serum free light chain (FLC) ratio ( /<0.26 or />1.65) and serum immunoglobulin FLC≥10 mg/dL.
• 5. Eastern Cooperative Oncology Group Performance Status (ECOG) of 0-1.
• 6. An estimated survival time of more than 12 weeks.
• 7. Recovery to Grade 0-1 (Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0) from adverse events related to prior therapy except alopecia.
• 8. Adequate hematological and organ function.
• 9. Female participants of childbearing potential must have a negative serum pregnancy test at screening. Female patients who are sexually active must use highly effective methods of contraception throughout the study and for 3 months following the last dose of study treatment.
• 10. Male participants must agree to use reliable methods of contraception (barrier methods or sexual abstinence) and avoid sperm donation throughout the study period and until 3 months after the last dose.

Критерии исключения

• 1. Plasma cell leukemia (/>2.0×10/^9/L plasma cells by standard differential), Waldenstrom`s Macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or primary light-chain amyloidosis.
• 2. History of antitumor therapy as follows, before the first dose of study drug:
• 1. Targeted therapy with small molecule drug within 2 weeks or 5 half-lives, whichever is longer;
• 2. Targeted therapy with macromolecular drug or Immunomodulatory agent therapy within 2 weeks;
• 3. Chemotherapy within 2 weeks;
• 4. Treatment with an investigational drug within 2 weeks or 5 half-lives, whichever is shorter;
• 5. Radical/extensive radiotherapy within 4 weeks, or local palliative radiotherapy within 2 weeks, or acute toxicity induced by previous radiotherapy have not recovered to grade ≤1;
• 6. Autologous stem cell transplantation within 12 weeks;
• 7. History of organ transplant, or allogeneic stem cell transplantation within 6 months;
• 8. Prior treatment with any B cell maturation antigen (BCMA) targeted therapy;
• 9. Prior treatment with any BCMA targeted chimeric antigen receptor modified /[CAR/]-T cells therapy.
• 3. Any active acute graft-versus-host disease (GvHD), grade 2-4 (according to Glucksberg criteria) or active chronic GvHD requiring systemic treatment within 2 weeks.
• 4. Prior myelodysplastic syndrome or malignancy within 5 years, except for localized malignancies that have been adequately treated or free of the disease for ≥ 5 years, e.g., basal cell carcinoma of the skin, squamous cell carcinoma of the skin, non-muscle invasive bladder cancer, localized prostate cancer, carcinoma in situ of the cervix, carcinoma in situ of the breast.
• 5. Active central nervous system (CNS) involvement or exhibition of clinical signs of meningeal involvement of multiple myeloma, or other evidence of uncontrolled metastases to the CNS or meninges, judged by the investigator.
• 6. (a) History of or current relevant CNS pathology as epilepsy, seizure, paresis, aphasia, apoplexia, severe brain injuries, cerebellar disease, organic brain syndrome, psychosis; (b) Evidence for presence of inflammatory lesions and/or vasculitis on cerebral MRI.
• 7. History or evidence of cardiovascular disease, including:
• 1. Acute coronary syndromes (eg, myocardial infarction, unstable angina) within 6 months prior to enrollment;
• 2. Coronary angioplasty or stenting within 6 months prior to enrollment;
• 3. Clinically significant unstable arrhythmias (eg, atrial fibrillation), however, atrial fibrillation has been controlled for over 30 days prior to the first dose of YKST02 were allowed;
• 4. New York Heart Association (NYHA) stage III or higher congestive heart failure within 6 months prior to enrollment; Cardiac valve morphological abnormalities recorded by ECHO (≥ grade 2), note that grade 1 cardiac valve morphological abnormalities (such as mild regurgitation/stenosis) were allowed, but participants with moderate valve thickening were excluded;
• 5. Left ventricular ejection fraction (LVEF) below lower limit of the study center, or LVEF/<50% if there is no lower limit at the study center;
• 6. The Fridericia-corrected QT interval (QTcF) ≥ 470 msec (female) or ≥ 450 msec (male)；
• 7. Implantable defibrillator;
• 8. Clinically uncontrollable hypertension (i.e., SBP≥160 mm Hg and/or DBP≥100 mm Hg).
• 8. Known allergy to monoclonal antibody drugs or exogenous immunoglobulin.
• 9. Any major organ surgery or significant trauma within 4 weeks prior to the first dose of YKST02, or those requiring elective surgeries during the study, and all AEs associated with surgery or significant trauma have not recovered before the first dose of the YKST02.
• 10. Regular dose of systemic corticosteroids during 4 weeks prior to initiation of study drug, or anticipated need of corticosteroids exceeding prednisone 20 mg/day or equivalent during the trial, or any other systemic immunosuppressive therapy within 4 weeks prior to study entry.
• 11. Virological tests: Hepatitis B virus surface antigen (HBsAg) positive and/or hepatitis B core antibody (HBcAb) positive, and hepatitis B virus (HBV) deoxyribonucleic acid (DNA) quantitative />ULN of the testing institution; Hepatitis C antibody (HCV-Ab) positive and hepatitis C virus-RNA (HCV-RNA) quantitative /> ULN of the testing institution; Anti-human immunodeficiency virus (Anti-HIV) positive. Participants will be excluded from the study if any of the above criteria is met.
• 12. Uncontrolled active infections requiring oral or intravenous systemic therapy, except for local treatment.
• 13. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage (once a month or more frequently).
• 14. Pregnant or lactating women.
• 15. Known mental disorder that may affect study compliance or poor compliance.
• 16. Receipt of any live attenuated vaccines or live virus vaccine within 4 weeks prior to the first dose of study treatment.
• 17. Other serious systemic diseases or laboratory abnormalities or other reasons that the investigator believes are not appropriate for participating the study.

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

This will be a 2 year study to evaluate and improve cancer sequencing as applied to the characterization of tumor molecular make-up and the identification of novel therapeutics (n=100). Participants who will undergo tumor biopsy for management of multiple myeloma (MM) will self-refer to the study or be referred by their treating physician. Participants will initially meet with a clinician to review study consents and provide medical, medication, and family history information. After informed consent, biospecimen samples from peripheral blood, cheek swab, and tumor samples from bone marrow (aspirate and biopsy), peripheral blood, or any mass/fluid containing tumor cells will be obtained (from procedures indicated as part of their standard oncology care) for cancer sequencing (CS) (whole exome sequencing of germline and tumor genomes, RNA sequencing of tumor transcriptome, single cell, and CyTOF analysis). CS data will be interpreted via somatic variation identification, network modeling, and cancer transcriptome profiling to facilitate mapping activity levels of genes to networks and for identifying genes activated or dysregulated in cancer cells. Sequencing and analysis will be performed at the Genomics Core Facility at the Icahn School of Medicine at Mount Sinai. In instances where internal sequencing capabilities do not allow for certain types of analysis, de-identified samples or data may be sent out to third parties for additional analysis. The study will be using GenPath, a division of BioReference® Health, LLC for this project which is a CLIA certified lab. All genetic tests will be performed in a CLIA certified lab and all tests will be FDA or NYS approved. The RNA Sequencing test will receive NYS Department of Health (Wadsworth Center) approval before results are provided to physicians and patients. Samples will be de-identified and processed by the Mount Sinai Human Immune Monitoring Core (HIMC) before being sent to an external CLIA-certified lab for sequencing and analysis. Interpretation will be performed by a multidisciplinary team that includes genomicists, pathologists, and clinicians familiar with the particular cancer diagnosed in the participant. Once results are available, they will be shared with the participant and treating physician during a follow-up results session and any findings obtained explained. This study is not intended to implement findings, only to report them.

Критерии включения

• * Patients must be 18 years of age at the time of registration.
• * Participant must have an established diagnosis of relapsed Multiple Myeloma based on IMWG criteria, be willing to participate, and able to consent
• * Participant must have a treating physician who agrees to participate in the study
• * Participant will be undergoing a bone marrow biopsy or tumor biopsy as part of their standard of care.
• * Patients must be willing to participate in this study and able to sign informed consent.
• * Participants are not participating in any interventional clinical trial using systemic therapy directed towards control of MM.

Критерии исключения

• * Known diagnosis of AL amyloidosis, Waldenstrom Macroglobulinemia, POEMS, or Castleman´s disease.
• * Diagnosis of cancer other than myeloma or skin cancer (squamous cell or basal cell) that is ongoing or treated within the last 2 years.
• * Tumor sample inadequate or unavailable for analysis (e.g., due to insufficient number of tumor cells).
• * Patient will not be receiving systemic MM-directed chemotherapy/immunotherapy in the following 2 months from the time tumor biopsy is performed.

Описание

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

The study is split into 2 parts:

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

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

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

Критерии включения

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

Критерии исключения

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

Описание

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

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

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

Критерии включения

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

Критерии исключения

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

Описание

To learn if giving elranatamab before and after an autologous stem cell transplant (ASTC) can help to control newly diagnosed, high-risk MM. An ASTC is a type of transplant in which a person`s own stem cells are collected, preserved, and returned to them.

Критерии включения

• 1. Transplant eligible patients with newly diagnosed multiple myeloma (NDMM).
• 2. High-risk multiple myeloma/*
• 3. Participants with disease response ≥ PR to induction therapy
• 4. Age ≥ 18 and ≤ 75. Non-English-speaking participants are eligible.
• 5. Karnofsky performance status ≥70 (Appendix A).
• 6. Adequate liver function (total bilirubin ≤1.5X ULN; ALT ≤2.5 X ULN)
• 7. Estimated creatinine clearance ≥40 mL/min. Creatinine clearance may be calculated using Cockcroft-Gault, estimated glomerular filtration rate (Modification of Diet in Renal Disease /[MDRD/]), or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula). /*
• 8. Participant agrees to not donate blood while taking lenalidomide and for 28 days after stopping lenalidomide.
• 9. Participant agrees to enroll in the lenalidomide REMS program.
• 10. Women of child-bearing potential (WOCPB) must abstain from heterosexual intercourse or agree to use a contraceptive method that is highly effective (with a failure rate of /<1% per year), preferably with low user dependency (as described in Appendix B), plus one additional effective method at least 28 days before starting therapy, during the intervention period, at least 28 days after the last dose of lenalidomide and at least 4 months after the last dose of elranatamab, and agrees not to donate eggs (ova, oocytes) for reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relation to the first dose of the study intervention. A WOCBP must have a negative highly sensitive serum pregnancy test (as required by local regulations) within 10-14 days and also within 24 hours before the first dose of the study intervention.
• Non Nonchildbearing potential is defined as follows (by other than medical reasons):
• * ≥ 45 years of age and has not had menses for />1 year.
• * Participants who have been amenorrhoeic for /<2 years without a 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.
• 11. Male participant agrees to contraceptive use that should be consistent with institutional guidelines regarding the methods of contraception for those participating in clinical studies.
• * Male participants are eligible to participate if they agree to the following during the intervention period and for 1 (for lenalidomide) to 4 (for elranatamab) months after the last dose of study treatment to allow for clearance of any altered sperm: - Refrain from donating sperm during treatment (including dose interruptions) and for 4 weeks after their last dose of lenalidomide and 4 months after the last dose of elranatamab.
• 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 in Appendix B. /*Definition of high-risk and ultra-high-risk MM15:
• * High-risk MM:
• o Presence of a high-risk chromosomal abnormality (HRCA) including: 17p13 deletion; t(4;14); t(14;16); t(14;20); Gain or amplification 1q by FISH.
• * Ultra-high-risk MM
• * Presence of ≥2 HRCA.
• Exclusion Criteria:
• • History of allergic reactions attributed to compounds of similar chemical or biologic composition to elranatamab or other agents used in study.
• • Drug interactions (Prohibited unless considered medically necessary):
• a. At projected clinical doses, TMDD (target mediated drug disposition) of elranatamab is expected. If concomitant medication alters target expression, it can potentially impact the PK of elranatamab. Drugs like anti-thymocyte globulin (ATG) can deplete T-cells and can potentially impact the PK of drugs targeting CD3. b. Elranatamab has been shown to increase T-cell activation and induce cytokine production (including IL-2, IL-6, IL-10, TNF-alpha and IFN-gamma). Cytokines have been shown to modulate expression of CYP enzymes and transporters, therefore, elranatamab can potentially affect CYP enzyme and transporter expression levels, and consequently modulate the clearance of concomitant medications that are substrates for these enzymes or transporters. When administering elranatamab, it is important to exercise caution with concomitant medications, especially those that are sensitive substrates of the cytochrome P450 (CYP) enzyme system and have a narrow therapeutic index. Increased exposure of CYP substrates is more likely to occur after the first dose of elranatamab on Day 1 and up to 14 days after the 32 mg dose on Day 4 and during and after CRS. Examples of such medications include cyclosporine. During this critical window, it`s imperative to closely monitor the toxicity or concentrations of these concomitant drugs. If necessary, dose adjustments for these co-administered drugs should be considered to ensure patient safety. c. Cytochrome P450 (CYP) enzyme system is responsible for the metabolism of a vast number of drugs. Below are examples of drugs metabolized by specific CYP enzymes that could be impacted if elranatamab alters the activity or expression of these enzymes. Exercise caution when using these drugs: i. CYP2C9 substrates:
• <!-- -->
• 1. - Warfarin
• 2. - Phenytoin
• 3. - Celecoxib
• 4. - Losartan ii. CYP3A4 substrates:
• <!-- -->
• 1. - Statins: simvastatin, atorvastatin, lovastatin
• 2. - Calcineurin inhibitors: cyclosporine, tacrolimus
• 3. - Antiretroviral drugs: ritonavir, saquinavir, nelfinavir
• 4. - Benzodiazepines: diazepam, alprazolam
• 5. - Calcium channel blockers: nifedipine, verapamil, diltiazem
• 6. - Macrolide antibiotics: erythromycin, clarithromycin iii. CYP2D6 substrates:
• <!-- -->
• 1. - Antipsychotics: aripiprazole, risperidone, haloperidol
• 2. - Tricyclic antidepressants: amitriptyline, nortriptyline, imipramine
• 3. - Beta-blockers: metoprolol, propranolol, carvedilol
• 4. - Codeine
• 5. - Tamoxifen iv. CYP1A2 substrates:
• 1. - Theophylline 2. - Fluvoxamine 3. - Clozapine v. CYP2C19 substrates:
• 1. - Omeprazole
• 2. - Citalopram
• 3. - Diazepam d. For participants on digoxin, monitor digoxin plasma levels periodically with the concomitant use of lenalidomide. Refer to lenalidomide USPI for additional information.
• • History of progressive disease at any time before starting maintenance.
• • Participants with non-secretory MM (no measurable disease on electrophoresis and immunofixation). Participants with a measurable disease on PET scan or bone marrow will be eligible.
• • Participants with Waldenströms macroglobulinemia.
• • Participants with POEMS syndrome.
• • Participants with smoldering MM (IMWG criteria)
• • Participants with plasma cell leukemia.
• • Participants with standard-risk MM.
• • Participants with relapsed and/or refractory MM.
• • Participant must not have presence of active renal condition (infection, requirement for dialysis or any other condition that could affect participant`s safety). Participants with isolated proteinuria resulting from MM are eligible, provided they fulfil inclusion criteria.
• • Participant must not have current unstable liver or biliary disease defined by the presence of ascites, encephalopathy, coagulopathy, esophageal or gastric varices, persistent jaundice, or cirrhosis. Note: Stable non-cirrhotic chronic liver disease (including Gilbert`s syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if otherwise meets entry criteria.
• • Uncontrolled and active pulmonary disease.
• • Participant must not have used an investigational drug or approved systemic anti-myeloma therapy (including systemic steroids) within 14 days or five half-lives, whichever is shorter, preceding the first dose of study drug.
• • Participant must not have any evidence of active mucosal or internal bleeding.
• • Participant must not have an uncontrolled infection.
• • Participant must not have evidence of cardiovascular risk, including any of the following:
• * Evidence of current clinically significant uncontrolled arrhythmias, including clinically significant 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 within three (3) months of screening.
• * Class III or IV heart failure as defined by the New York Heart Association functional classification system.16
• * Uncontrolled hypertension (blood pressure that remains above goal despite the concurrent use of three antihypertensive drug classes). • Participant must not have known HIV infection. • Participant must not have active Hepatitis B and/or C infection. • Participant must not have invasive malignancies other than disease under study, unless the second malignancy has been medically stable for at least 2 years and, in the opinion of the principal investigators, will not affect the evaluation of the effects of clinical trial treatments on the currently targeted malignancy. Participants with curatively treated non-melanoma skin cancer may be enrolled without a 2-year restriction. • Participants must not be pregnant or lactating. • Patients with cognitive impairments and/or any serious unstable pre-existing medical condition or psychiatric disorder that can interfere with safety or with obtaining informed consent or compliance with study procedures.

Критерии исключения

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

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

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

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

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

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

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

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

Критерии включения

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

Критерии исключения

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

Описание

Despite the consequent use of Tocilizumab together with conventional antipyretics at early/first signs of emerging CRS, CRS (and eventually the subsequent development of ICANS) remain a major concern for patients.

This study aims to identify safety and efficacy of prophylactic Tocilizumab treatment. In particular, to explore whether prophylactic Tocilizumab treatment can decrease the incidence and severity of CRS (and subsequent eventual neurotoxicity) following CAR-T-treatment.

Критерии включения

• * Patients planned to receive commercial CAR-T treatment for all registered indications comprising lymphomas, leukemias or myeloma at a single academic center (Bern Inselspital)
• * With written informed consent
• * Considered by the investigator to be clinically fit for this treatment
• * Patients aged ≥18 years

Критерии исключения

• * Previous Tocilizumab treatment within 3 months prior to CAR-T infusion
• * Patients with treatment with an investigational compound within 8 weeks prior to CAR-T infusion
• * Women who are pregnant or breast feeding, or women intending to become pregnant during the study period; or participants lacking safe contraception, defined as: Female participants of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the investigator in individual cases during study treatment and for a total of 12 months; Female participants who are surgically sterilised / hysterectomised or post-menopausal for longer than 2 years are not considered as being of child bearing potential.
• * Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant
• * Previous enrolment into the current study
• * Enrolment of the investigator, his/her family members, employees and other dependent persons

Описание

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

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

Критерии включения

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

Критерии исключения

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

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

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

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

Критерии включения

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

Критерии исключения

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

Описание

The purpose of this study is to compare the pharmacokinetics (processes by which drugs are absorbed, distributed in the body, and excreted) between teclistamab made from the current commercial manufacturing process (pre-change) and the new manufacturing process (post-change).

Критерии включения

• * Documented diagnosis of multiple myeloma as defined by the criteria below: (a) Multiple myeloma diagnosis according to International Myeloma Working Group (IMWG) diagnostic criteria (b) Measurable disease at screening as defined by any of the following: (1) Serum M-protein level greater than or equal to (/>=) 0.5 grams per deciliter (g/dL) (central laboratory); or (2) Urine M-protein level />=200 milligrams (mg)/24 hours (central laboratory); or (3) Serum immunoglobulin free light chain />=10 milligrams per deciliter (mg/dL) (central laboratory) and abnormal serum immunoglobulin kappa lambda free light chain ratio
• * Received 1 to 3 prior lines of antimyeloma therapy, including a minimum of 2 consecutive cycles each of a protease inhibitor (PI), lenalidomide, and an anti-cluster of differentiation 38 (CD38) monoclonal antibody (or minimum of 6 doses if anti CD38 monoclonal antibody was only part of a maintenance regimen) in any prior line
• * Documented evidence of progressive disease or failure to achieve a response to last line of therapy based on investigator`s determination of response by IMWG criteria
• * Have an eastern cooperative oncology group (ECOG) performance status score of 0 to 2
• * A female participant of childbearing potential must have a negative highly sensitive serum pregnancy test at screening and within 24 hours of the start of study treatment and must agree to further serum or urine pregnancy tests during the study

Критерии исключения

• * Received any bispecific antibody and/or chimeric antigen receptor T cell (CAR-T) cell therapy
• * Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study drug or its excipients
• * Received a live, attenuated vaccine within 4 weeks before the first dose of study drug. Non-live or non-replicating vaccines authorized for emergency use by local health authorities are allowed
• * Central nervous system involvement or clinical signs of meningeal involvement of multiple myeloma. If either is suspected, negative whole brain magnetic resonance imaging (MRI) and lumbar cytology may be required
• * Participant had major surgery or had significant traumatic injury within 2 weeks prior to randomization, 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

Описание

This is an open-label, multicenter phase 1 clinical trial to evaluate the safety and tolerability, efficacy, and pharmacokinetics of SIM0500 in adult participants with Relapsed or Refractory Multiple Myeloma(RRMM). The trial is consisted of two parts, Part 1 (dose escalation) and Part 2 (dose optimization). In both parts, SIM0500 will be administered until disease progression, intolerable toxicity, withdraw of consent or end of trial.

Критерии включения

• 1. Voluntary participation and signature of informed consent form.
• 2. ≥18 years of age.
• 3. Have documented diagnosis of relapsed or refractory multiple myeloma according to Criteria for Response to Multiple Myeloma Treatment(IMWG)diagnostic criteria who have failed all established standard of care.
• 4. Life expectancy ≥12 weeks.
• 5. Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.
• 6. Adequate hematologic, hepatic, and renal function.

Критерии исключения

• 1. Toxicities from previous anticancer therapies should have resolved to baseline levels or to Grade 1 or less except for alopecia or peripheral neuropathy.
• 2. Active hepatitis B (HBsAg positive and HBV DNA ≥ 1×104 copies/mL or ≥ 2,000 international unit /[IU/]/mL) or hepatitis C (HCV antibody positive and HCV RNA ≥ ULN) infection; participant with HBsAg positive or detective HBV-DNA at screening should receive antiviral treatment as per local practice during the trial.
• 3. Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).
• 4. Participant is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial.
• 5. Active known or suspected autoimmune disease. Participants with vitiligo, residual hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment or conditions not expected to recur in the absence of an external trigger, type 1 diabetes mellitus (blood glucose can be controlled by insulin therapy) can be included.
• 6. Current or previous other malignancy within 3 years of study entry, except basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix or breast.
• 7. Known active central nervous system (CNS) involvement or exhibits clinical signs of meningeal involvement of multiple myeloma.
• 8. Participants with known active infection within 14 days prior to the first SIM0500.

Описание

This trial is a single-arm, single-center, open-label clinical trial to evaluate the safety, efficacy, and metabolism kinetics of CT071 in patients with high-risk newly diagnosed multiple myeloma.

Критерии включения

• Participants must meet all of the following criteria to be enrolled:
• 1.Volunteer to participate in the clinical trial; the participants themselves fully understand and are informed of this study, and sign the informed consent form and are willing to follow and able to complete all trial procedures;
• 2.Age ≥ 18 years, male or female;
• 3.Participants must have newly diagnosed with multiple myeloma according to International Myeloma Working Group diagnostic criteria 2014 ;
• 4.Measurable disease based on at least one of the following parameters (International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma 2016); the values for these parameters obtained up to 60 days prior to signing the Informed Consent Form including the results at the time of diagnosis may be used.
• 1. Serum M-protein ≥ 1.0 g/dL;
• 2. Urine M-protein ≥ 200 mg/24 hr;
• 3. Serum free light chain (FLC): involved FLC level ≥ 10 mg/dL (100 mg/L) provided serum FLC ratio is abnormal.
• 5.Known to have the following high risk factors, i.e. At least one of the following conditions is met:
• 1)Meet any one or more of the cytogenetic criteria: del (17p); t (4; 14); t (14; 16); t (14; 20); 1q21 amplification ≥ 4 copies; 2)R-ISS stage 3; R2-ISS stages 3 and 4; 3)Presence of soft tissue extramedullary plasmacytoma 4)2%-5% in peripheral plasma cells;
• 6.Eastern Cooperative Oncology Group (ECOG) score 0-2;
• 7.Participants should meet the following test results (repeat tests are allowed):
• 1)Hematology: Absolute neutrophil (ANC) count ≥ 1.0 × 109/L; Platelet (PLT) ≥ 50 × 109/L; Hemoglobin (Hb) ≥ 7.5 g/dL; 2)Blood chemistry: Endogenous creatinine clearance ≥ 40 mL/min (see Appendix 1 using the Cockcroft-Gault formula); Alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN), aspartate aminotransferase (AST) ≤ 2.5 × ULN, total bilirubin ≤ 1.5 × ULN; 3)International normalized ratio (INR), or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN.
• 8.Venous access required for collection can be established and there is no contraindication for cell collection.
• 9.Females of childbearing potential (WOCBP) must have a negative serum pregnancy test at screening and must be willing to use effective and reliable contraception for at least 12 months after CT071 infusion.
• 10.A male participant, if sexually active with a female of childbearing potential, is willing to use a highly effective and reliable method of contraception for 1 year after receiving trial treatment. All male participants absolutely refrain from donating sperm during the trial and for 1 year after receiving trial treatment.
• Exclusion Criteria:
• Participants were not enrolled in the trial if they met any of the following criteria:
• 1. Patients with non-secretory MM.
• 2. Prior treatment for MM other than up to 2 cycles of (bortezomib, lenalidomide, dexamethasone) for induction, including but not limited to cytotoxic therapy, proteasome inhibitors, immunomodulators, targeted therapy, radiotherapy (patients are eligible for this trial if the radiation field covers ≤ 5% bone marrow reserve regardless of the end date of radiotherapy), epigenetic therapy, etc.
• 3. Pregnant or lactating females.
• 4. Patients with severe mental disorders or altered mental status, history of central nervous system disease, such as epilepsy, intracranial hemorrhage, paralysis, aphasia, stroke, severe brain injury, dementia, Parkinson`s disease, cerebellar disease, memory impairment, spinal cord compression, psychiatric disease or any disease involving the central nervous system, or suspected central nervous system (CNS) metastasis, or any autoimmune disease involving the CNS, with or suspected CNS infiltration.
• 5. Participants had other malignancies, including the following that were considered to have been successfully treated: non-metastatic basal cell or squamous cell skin cancer, non-metastatic prostate cancer, carcinoma in situ of the breast or cervix, and non-muscle invasive bladder cancer.
• 6. Active autoimmune disease that results in end organ damage or requires systemic immunosuppressive/systemic disease modifying drugs, including but not limited to Crohn`s disease, rheumatoid arthritis, systemic lupus erythematosus and other patients requiring long-term immunosuppressive therapy.
• 7. Have any uncontrolled active infection (defined as exhibiting persistent signs or symptoms associated with infection that do not improve despite appropriate anti-infective therapy), or other serious active viral, bacterial, or uncontrolled systemic fungal infection. I
• 8. Positive test results for biomarkers of any of the following pathogenic microorganisms: human immunodeficiency virus (HIV) antibody, Treponema pallidum antibody (TPPA), hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HBsAg) (core antigen /[HBcAb/] positive must have DNA copies below the lower limit of normal).
• 9. Vaccination with live attenuated vaccine or mRNA vaccine within 8 weeks and inactivated vaccine within 4 weeks prior to screening.
• 10. Patients who are allergic or intolerant to lymphodpletion drugs, tocilizumab, or allergic to the ingredients of CT071 cell infusion preparation (DMSO); Or previous history of other severe allergies, such as anaphylactic shock.
• 11. Clinically significant cardiac abnormalities, including but not limited to:
• 1)Uncontrolled congestive heart failure (New York Heart Association Class III or IV heart failure, see Appendix 3); 2)Myocardial infarction, coronary artery bypass grafting or unstable angina within 6 months prior to apheresis; 3)History of clinically significant uncontrolled cardiac arrhythmias such as ventricular arrhythmias; 4)History of severe non-ischemic cardiomyopathy; 5)Left ventricular ejection fraction (LVEF) /< 50%, diagnosed by echocardiography, without clinically significant ECG abnormalities; 6)Other heart disease that, in the opinion of the investigator, may jeopardize the health of the participant when participating in this clinical trial.
• 12.Participants with known or suspected chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) /< 50% of the predicted normal value of spirometry, or other lung disease that, in the judgment of the investigator, significantly affects lung function or affects the safety of the participant, such as asthma, interstitial lung disease, diffuse lung disease, pulmonary infection, pulmonary embolism, etc.
• 13.No need for supplemental oxygen for maintenance and oxygen saturation /< 92% in room air.
• 14.Participant has a history of stroke or seizure within 6 months prior to the screening period.
• 15.Has had major surgery before screening, or is planned to undergo major surgery after the trial treatment (excluding cataract and other surgery under local anesthesia). The investigator must discuss with the sponsor to determine whether a surgery is major surgery before enrolling the participant in the trial.
• 16.The participant has not recovered to Common Terminology Criteria for Adverse Events (CTCAE) v5.0 ≤ Grade 1 from toxicities attributable to previous treatments, except for alopecia, peripheral neuropathy, and other events that, in the judgment of the investigator, are unlikely to result in lymphodepletion or cumulative toxicities of CT071 treatment; 17.Other conditions considered inappropriate for participation in this clinical trial by the investigator.

Критерии исключения

Описание

Multiple myeloma (MM) is a cancer of the blood`s plasma cells. The cancer is typically found in the bones and bone marrow (the spongy tissue inside of the bones) and can cause bone pain, fractures, infections, weaker bones, and kidney failure. Treatments are available, but MM can come back (relapsed) or may not get better (refractory) with treatment. This is a study to determine the safety and pharmacokinetics of ABBV-383 in adult participants with relapsed/refractory (R/R) MM.

ABBV-383 is an investigational drug being developed for the treatment of R/R MM. This study is broken into 3 Arms: Arm A with 2 parts and Arm B as an expansion. Participants will receive ABBV-383 as a subcutaneous (SC) injection and intravenous (IV) infusion in Arm A and SC injections of ABBV-383 in Arm B. Around 55 adult participants with relapsed/refractory multiple myeloma will be enrolled at approximately 25 sites across the world

In Arm A participants will receive one of two doses of ABBV-383 as an SC injection and (IV) infusions, during the 151 week study duration. In Arm B, participants will receive the selected dose from Arm A as SC injections, during the 151 week study duration.

There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and questionnaires.

Критерии включения

• * Eastern Cooperative Oncology Group (ECOG) performance of /<= 2.
• * Participants with relapsed or refractory multiple myeloma who have received 3-5 prior lines of therapies and with prior triple class exposure including a proteasome inhibitor, anti-CD38 monoclonal antibody and an immunomodulatory drug.
• * Must be naïve to treatment with ABBV-383.

Критерии исключения

• - Received B-cell maturation antigen (BCMA)xCD3 bispecific antibody.

Описание

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

Критерии включения

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

Критерии исключения

Описание

This is a Phase I dose-escalation study to evaluate the safety, tolerability and preliminary efficacy of an autologous BCMA-targeting RNA-engineered CAR T-cell therapy in patients with Relapsed/Refractory Multiple Myeloma. The cell product is referred to as Descartes-15

Критерии включения

• * Patients must be 18 years of age or older at the time of enrollment.
• * Patients must be diagnosed with active and measurable relapsed/refractory multiple myeloma.
• * Patients must have failed at least 3 prior lines of therapy which must have included an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 drug or biologic. Failure of treatment and measurable myeloma disease are defined as per 2016 IMWG criteria.
• * Patients must have clinical performance status of ECOG 0-2.
• * Patients must have adequate vital organ function as defined by:
• * Hemoglobin ≥8 g/dL
• * Absolute neutrophil count /> 1000/ mm3
• * Platelets /> 50,000/mm3
• * ALT/AST levels lower than 3-fold of normal
• * Creatinine clearance ≥45 mL/min/1.73 m2
• * Normal cardiac and pulmonary function
• * No thromboembolic events in the past 3 months
• * No heparin allergy or active infection

Критерии исключения

• * Patients who have any active and uncontrolled infection.
• * Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine or systemic steroids above 40 mg/day prednisone equivalent).
• * Patients who have active central nervous system disease.

Описание

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

Критерии включения

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

Критерии исключения

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

Описание

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

Критерии включения

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

Критерии исключения

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