Determination 2 - Isatuximab, Iberdomide, Bortezomib and Dexamethasone Induction, Followed by Risk- and Response-Adapted Consolidation and Maintenance Therapy, in Transplant-Eligible Patients With Newly Diagnosed Multiple Myeloma (NDMM)
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 720
- 试验地点
- 3
研究概览
简要总结
The purpose of the study is to determine the best treatment approach based on the risk profile of the cancer cells and on how the disease responds to treatment. This is a randomized research study evaluating treatment for transplant-eligible participants with newly diagnosed multiple myeloma (NDMM). Induction therapy in this study includes the drugs isatuximab, iberdomide, bortezomib, and dexamethasone. After induction therapy, participants will receive consolidation and maintenance therapy that is adapted based on their risk profile and response to treatment.
The research study procedures include: screening for eligibility, study visits, blood and bone marrow tests, disease assessments, treatment with study drugs, and follow-up visits.
It is expected that about 720 participants will take part in this study.
详细描述
This is a Phase III, open-label, multicenter randomized research study designed to evaluate different treatment strategies for people with multiple myeloma. The study will look at how often participants achieve MRD (measurable residual disease)-negative status after maintenance therapy, compare different consolidation approaches, and assess long-term outcomes. Participants who are eligible will be assigned to study groups based on their cytogenetic risk and how their disease responds to induction therapy.
All participants will first receive induction treatment with isatuximab, iberdomide, bortezomib, and dexamethasone for 8 cycles. After induction, participants with standard-risk disease who are MRD-negative will continue to maintenance treatment with isatuximab and iberdomide for up to 36 cycles. After that, depending on their MRD status, they may continue on iberdomide alone or remain on the combination treatment. Participants with high-risk cytogenetics and those who remain MRD-positive after completion of induction will be randomized to receive either high-dose melphalan followed by autologous stem cell transplant or eight cycles of linvoseltamab consolidation, followed by maintenance isatuximab and iberdomide until progression of disease. Participants who are deemed medically ineligible for HDM-ASCT (after enrollment but before randomization) and those with indeterminate MRD status after induction may receive maintenance treatment with isatuximab, iberdomide, and bortezomib in lieu of randomization. The study also includes biomarker testing and participant-reported outcome assessments.
The research study procedures include screening for eligibility, clinic visits, blood tests, urine tests, computed tomography (CT) scans, bone marrow sample collection and biobanking, MRD testing, stem cell collection, skeletal survey or positive emission tomography (PET) scans, and electrocardiograms.
The study drugs include melphalan, bortezomib, isatuximab, and dexamethasone, which are approved by the FDA for the initial treatment of multiple myeloma. Linvoseltamab is approved by the FDA for multiple myeloma that has returned after at least four prior lines of treatment. Iberdomide is approved by the FDA for multiple myeloma that has returned after at least one prior line of treatment.
The study also includes an injector device, referred to as the On Body Delivery System (OBDS), also called Isatuximab subcutaneous Wearable Injection System. OBDS is a sterile, single-use, disposable, elastomeric, user-filled medical device, which includes an on-body delivery device designed for subcutaneous delivery of a defined volume of drug product and an integrated drug product syringe transfer base.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •N- NDMM based on IMWG criteria with clonal bone marrow plasma cells ≥10% or biopsy proven bony or extramedullary disease/plasmacytoma (EMD) with any one or more CRAB-features or myeloma defining events (Rajkumar, 2024) (See Appendix E)
- •- Age 18 - 75 years. (Patients aged 71-75 years who are deemed transplant-eligible by investigator may be enrolled after discussion with and approval from the Sponsor - Investigator)
- •- Eligible for HDM-ASCT, at time of registration per investigator's assessment, and willing to defer HDM-ASCT if in Cohort 1 or be randomized to HDM-ASCT vs. linvoseltamab if in Cohort 2 (Cohort assignment may not be known until after induction therapy)
- •- Bone marrow analysis with cytogenetic risk status established by fluorescence in situ hybridization (FISH) and NGS with TP53 by PlasmaSEQ at screening and positive identification of B-cell Clonality (ID) conducted by Adaptive Biotechnologies clonoSEQ® assay
- •Qualified archival BMA may be submitted to Adaptive Biotechnologies clonoSEQ® assay.
- •Results from a previously performed clonoSEQ® assay as standard of care may be acceptable if they meet the requirement of B-cell clonality ID.
- •Previously performed BMA for FISH is acceptable if it can establish cytogenetic risk per Section 5.4.2 along with NGS for TP53 by PlasmaSEQ.
- •Results must be within 1 year of screening and be representative of current NDMM. Results older than one year must be approved by the Sponsor-Investigator.
- •Measurable disease defined by at least one of the following:
- •Serum protein electrophoresis (SPEP): Serum M protein ≥0.5 mg/dL
- •Urine protein electrophoresis (UPEP): Urine M protein ≥200 mg/24 hours
- •Serum free light chain (FLC) assay: involved FLC ≥10 mg/dL (≥100 mg/L) and abnormal serum FLC ratio (<0.26 or >1.65)
- •Screening laboratory evaluations meeting the following parameters:
- •Absolute neutrophil count (ANC) ≥1,000 cells/dL (1.0 × 10^9/L). Growth factor support is not permitted within 10 days [14 days for pegfilgrastim], prior to registration
- •Platelet count ≥ 75,000 cells/dL (75 x 109/L) without transfusions required during the 14 days prior to registration
- •Total Bilirubin ≤ 2 X upper limit of normal (ULN) (except patients with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
- •Aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) (SGPT) ≤ 3.0 x ULN
- •Calculated creatinine clearance ≥30 mL/min (See Appendix B)
- •Hemoglobin ≥ 8.0 g/dl (red blood cell [RBC] transfusions are permitted)
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (see Appendix A)
- •Ability and willingness to complete HRQoL and PRO-CTCAE® assessments
- •Must be able to take antithrombotic prophylaxis
- •Sexually active IOCBP agree to use protocol-specified contraceptive methods, at least 28 days prior to starting study drug, while taking study drug, including interruptions in study drugs, and for at least 28 days after the last dose of iberdomide, 5 months after isatuximab, 6 months after linvoseltamab and bortezomib, or males (including those who have had a vasectomy), sexually active with IOCBP, agree to use protocol specified contraceptive methods while taking study drug, including interruptions in study drug and for at least 28 days after the last dose of iberdomide, 5 months after isatuximab, 6 months after linvoseltamab and bortezomib according the PPP (See Appendix G)
- •All patients (male and female with or without childbearing potential) agree to counseling according to the PPP and to abstain from donating blood products for at least 28 days after the last dose of iberdomide and semen or sperm while taking study drug and for at least 28 days after the last dose of iberdomide according to the PPP (See Appendix G) and for 3 months after the last dose of isatuximab, 6 months after the last dose of linvoseltamab and bortezomib
- •Both men and women of all races and ethnic groups are eligible for this trial.
排除标准
- •Prior therapy for MM. Patients may have received:
- •Corticosteroids for management of MM not exceeding the equivalent of 160 mg of dexamethasone in a 2-week period and without change in dosing requirements within 7 days prior to registration
- •Focal palliative radiation for the management of bone pain ≥ 7 days prior to registration
- •Treatment for smoldering multiple myeloma (SMM) if the prior treatment was not an anti-CD38 or anti-BCMA-based therapy:
- •Patients with a prior history of serious allergic reactions associated with thalidomide, lenalidomide, or pomalidomide should not receive iberdomide as they could be at higher risk of hypersensitivity
- •Resolution of symptoms of prior treatment to ≤ grade 1or baseline
- •Known intolerance to steroid therapy
- •Central nervous system (CNS) involvement of MM
- •History of progressive multifocal leukoencephalopathy (PML), known or suspected PML, or history of a neurocognitive condition, CNS movement disorder, history of seizure within 12 months prior to enrollment
- •Peripheral neuropathy grade ≥3, or grade 2 with pain on clinical exam during screening period
- •Prior history of malignancies, other than MM, will be excluded unless the participant has been free of the disease for ≥ 3 years, except for the following non-invasive malignancies: basal or squamous cell skin carcinoma, carcinoma in situ of the cervix, carcinoma in situ of the breast, incidental histological findings of prostate cancer (T1a or T1b using the TNM clinical staging system), or prostate cancer that is curative
- •Any medical or psychiatric illness that in the investigator's opinion would impose excessive risk or would adversely affect patient participation
- •Concurrent uncontrolled cardiovascular conditions (uncontrolled hypertension [HTN], uncontrolled arrhythmias, congestive heart failure [CHF], unstable angina, grade 3 thromboembolic event or myocardial infarction in the past 6 months)
- •Concurrent symptomatic amyloidosis or plasma cell leukemia
- •POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes)
- •Pregnant or breast feeding female or female who intends to become pregnant during the study
- •Seropositive for human immunodeficiency virus (HIV-1), chronic or active hepatitis B (defined as positive hepatitis B surface antigen [HepBSAg] or Hepatitis B core antibody [HepBcore Ab]) or hepatitis C (Hep C Ab), or acute hepatitis A; if any history of exposure to hepatitis B or C, then PCR should be negative
- •History of tuberculosis or systemic fungal disease
- •Concurrent active infection requiring therapeutic treatment
- •Lack of clonal identification by Adaptive Biotechnologies clonoSEQ® test
研究组 & 干预措施
Arm A (Induction and screening)
All enrolled participants begin with Step 1 induction that consists of eight 28-day cycles before end-of-induction cohort assignment. Peripheral Blood Stem Cells (PBSC) mobilization/collection is planned after completion of 4-6 cycles of induction for participants without disease progression. End-of-induction MRD/response and cytogenetic risk status determine whether participants proceed to post-induction Cohort 1 or Cohort 2.
干预措施: Iberdomide (Drug)
Arm B (Cohort 1 Maintenance Therapy Part 1)
Participants assigned to Cohort 1 enter Arm B and receive isatuximab + iberdomide maintenance for 36 cycles. Maintenance should begin within 28 days of the last induction cycle.
干预措施: On Body Delivery System (OBDS) (Device)
Arm D: Cohort 1 Maintenance Therapy (Part 2), Iberdomide + Isatuximab
After completion of Arm B, participants with MRD-positive or MRD-indeterminate disease, or <VGPR (very good partial response) at Step 3 evaluation [unless Progressive Disease (PD)], continue iberdomide + isatuximab until progression.
干预措施: On Body Delivery System (OBDS) (Device)
Arm G: Cohort 2 Non-randomized 3-Drug Maintenance
Participants in Cohort 2 who do not meet criteria for consolidation therapy may enter Arm G. Standard Risk (SR) MRD-indeterminate participants may also enter Arm G or, with Sponsor-Investigator approval, may be randomized in Cohort 2. Arm G is a 3-drug maintenance regimen continued in 28-day cycles until progression. The protocol explicitly states that dexamethasone is excluded from Arm G.
干预措施: Isatuximab (Drug)
Arm G: Cohort 2 Non-randomized 3-Drug Maintenance
Participants in Cohort 2 who do not meet criteria for consolidation therapy may enter Arm G. Standard Risk (SR) MRD-indeterminate participants may also enter Arm G or, with Sponsor-Investigator approval, may be randomized in Cohort 2. Arm G is a 3-drug maintenance regimen continued in 28-day cycles until progression. The protocol explicitly states that dexamethasone is excluded from Arm G.
干预措施: On Body Delivery System (OBDS) (Device)
Arm E: Cohort 2 Randomized Consolidation and Maintenance (HDM-ASCT) Strategy
Eligible Cohort 2 participants are randomized to Arm E: High-Dose Melphalan followed by Autologous Stem Cell Transplantation (HDM-ASCT) consolidation followed by isatuximab + iberdomide maintenance until progression. The protocol identifies Arm E as the control arm and describes HDM-ASCT-based therapy as the SOC comparator for Cohort 2. Consolidation should begin preferably within 30 days, and no later than 42 days, after induction completion. Maintenance begins 60-110 days after PBSC infusion.
干预措施: On Body Delivery System (OBDS) (Device)
Arm E: Cohort 2 Randomized Consolidation and Maintenance (HDM-ASCT) Strategy
Eligible Cohort 2 participants are randomized to Arm E: High-Dose Melphalan followed by Autologous Stem Cell Transplantation (HDM-ASCT) consolidation followed by isatuximab + iberdomide maintenance until progression. The protocol identifies Arm E as the control arm and describes HDM-ASCT-based therapy as the SOC comparator for Cohort 2. Consolidation should begin preferably within 30 days, and no later than 42 days, after induction completion. Maintenance begins 60-110 days after PBSC infusion.
干预措施: Melphalan (Drug)
Arm E: Cohort 2 Randomized Consolidation and Maintenance (HDM-ASCT) Strategy
Eligible Cohort 2 participants are randomized to Arm E: High-Dose Melphalan followed by Autologous Stem Cell Transplantation (HDM-ASCT) consolidation followed by isatuximab + iberdomide maintenance until progression. The protocol identifies Arm E as the control arm and describes HDM-ASCT-based therapy as the SOC comparator for Cohort 2. Consolidation should begin preferably within 30 days, and no later than 42 days, after induction completion. Maintenance begins 60-110 days after PBSC infusion.
干预措施: Isatuximab (Drug)
Arm E: Cohort 2 Randomized Consolidation and Maintenance (HDM-ASCT) Strategy
Eligible Cohort 2 participants are randomized to Arm E: High-Dose Melphalan followed by Autologous Stem Cell Transplantation (HDM-ASCT) consolidation followed by isatuximab + iberdomide maintenance until progression. The protocol identifies Arm E as the control arm and describes HDM-ASCT-based therapy as the SOC comparator for Cohort 2. Consolidation should begin preferably within 30 days, and no later than 42 days, after induction completion. Maintenance begins 60-110 days after PBSC infusion.
干预措施: Iberdomide (Drug)
Arm A (Induction and screening)
All enrolled participants begin with Step 1 induction that consists of eight 28-day cycles before end-of-induction cohort assignment. Peripheral Blood Stem Cells (PBSC) mobilization/collection is planned after completion of 4-6 cycles of induction for participants without disease progression. End-of-induction MRD/response and cytogenetic risk status determine whether participants proceed to post-induction Cohort 1 or Cohort 2.
干预措施: Isatuximab (Drug)
Arm A (Induction and screening)
All enrolled participants begin with Step 1 induction that consists of eight 28-day cycles before end-of-induction cohort assignment. Peripheral Blood Stem Cells (PBSC) mobilization/collection is planned after completion of 4-6 cycles of induction for participants without disease progression. End-of-induction MRD/response and cytogenetic risk status determine whether participants proceed to post-induction Cohort 1 or Cohort 2.
干预措施: On Body Delivery System (OBDS) (Device)
Arm B (Cohort 1 Maintenance Therapy Part 1)
Participants assigned to Cohort 1 enter Arm B and receive isatuximab + iberdomide maintenance for 36 cycles. Maintenance should begin within 28 days of the last induction cycle.
干预措施: Isatuximab (Drug)
Arm F: Cohort 2 Randomized Consolidation and Maintenance (Linvoseltamab Strategy)
Eligible Cohort 2 participants are randomized to Arm F: linvoseltamab consolidation for 8 cycles followed by isatuximab + iberdomide maintenance until progression. The protocol explicitly identifies Arm F as the experimental arm and hypothesizes superior efficacy versus Arm E. Maintenance should begin within 2-4 weeks after the last linvoseltamab dose.
干预措施: Iberdomide (Drug)
Arm F: Cohort 2 Randomized Consolidation and Maintenance (Linvoseltamab Strategy)
Eligible Cohort 2 participants are randomized to Arm F: linvoseltamab consolidation for 8 cycles followed by isatuximab + iberdomide maintenance until progression. The protocol explicitly identifies Arm F as the experimental arm and hypothesizes superior efficacy versus Arm E. Maintenance should begin within 2-4 weeks after the last linvoseltamab dose.
干预措施: On Body Delivery System (OBDS) (Device)
Arm F: Cohort 2 Randomized Consolidation and Maintenance (Linvoseltamab Strategy)
Eligible Cohort 2 participants are randomized to Arm F: linvoseltamab consolidation for 8 cycles followed by isatuximab + iberdomide maintenance until progression. The protocol explicitly identifies Arm F as the experimental arm and hypothesizes superior efficacy versus Arm E. Maintenance should begin within 2-4 weeks after the last linvoseltamab dose.
干预措施: Linvoseltamab (Drug)
Arm G: Cohort 2 Non-randomized 3-Drug Maintenance
Participants in Cohort 2 who do not meet criteria for consolidation therapy may enter Arm G. Standard Risk (SR) MRD-indeterminate participants may also enter Arm G or, with Sponsor-Investigator approval, may be randomized in Cohort 2. Arm G is a 3-drug maintenance regimen continued in 28-day cycles until progression. The protocol explicitly states that dexamethasone is excluded from Arm G.
干预措施: Bortezomib (B) (Drug)
Arm C: Cohort 1 Maintenance Therapy (Part 2), Single-Agent Iberdomide
After completion of Arm B, participants with MRD-negative Complete Response (CR) status at Step 3 are assigned to Arm C and continue single-agent iberdomide until progression. Isatuximab is not administered in Arm C.
干预措施: Iberdomide (Drug)
Arm B (Cohort 1 Maintenance Therapy Part 1)
Participants assigned to Cohort 1 enter Arm B and receive isatuximab + iberdomide maintenance for 36 cycles. Maintenance should begin within 28 days of the last induction cycle.
干预措施: Iberdomide (Drug)
Arm G: Cohort 2 Non-randomized 3-Drug Maintenance
Participants in Cohort 2 who do not meet criteria for consolidation therapy may enter Arm G. Standard Risk (SR) MRD-indeterminate participants may also enter Arm G or, with Sponsor-Investigator approval, may be randomized in Cohort 2. Arm G is a 3-drug maintenance regimen continued in 28-day cycles until progression. The protocol explicitly states that dexamethasone is excluded from Arm G.
干预措施: Iberdomide (Drug)
Arm A (Induction and screening)
All enrolled participants begin with Step 1 induction that consists of eight 28-day cycles before end-of-induction cohort assignment. Peripheral Blood Stem Cells (PBSC) mobilization/collection is planned after completion of 4-6 cycles of induction for participants without disease progression. End-of-induction MRD/response and cytogenetic risk status determine whether participants proceed to post-induction Cohort 1 or Cohort 2.
干预措施: Dexamethasone (Drug)
Arm F: Cohort 2 Randomized Consolidation and Maintenance (Linvoseltamab Strategy)
Eligible Cohort 2 participants are randomized to Arm F: linvoseltamab consolidation for 8 cycles followed by isatuximab + iberdomide maintenance until progression. The protocol explicitly identifies Arm F as the experimental arm and hypothesizes superior efficacy versus Arm E. Maintenance should begin within 2-4 weeks after the last linvoseltamab dose.
干预措施: Isatuximab (Drug)
Arm D: Cohort 1 Maintenance Therapy (Part 2), Iberdomide + Isatuximab
After completion of Arm B, participants with MRD-positive or MRD-indeterminate disease, or <VGPR (very good partial response) at Step 3 evaluation [unless Progressive Disease (PD)], continue iberdomide + isatuximab until progression.
干预措施: Isatuximab (Drug)
Arm D: Cohort 1 Maintenance Therapy (Part 2), Iberdomide + Isatuximab
After completion of Arm B, participants with MRD-positive or MRD-indeterminate disease, or <VGPR (very good partial response) at Step 3 evaluation [unless Progressive Disease (PD)], continue iberdomide + isatuximab until progression.
干预措施: Iberdomide (Drug)
Arm A (Induction and screening)
All enrolled participants begin with Step 1 induction that consists of eight 28-day cycles before end-of-induction cohort assignment. Peripheral Blood Stem Cells (PBSC) mobilization/collection is planned after completion of 4-6 cycles of induction for participants without disease progression. End-of-induction MRD/response and cytogenetic risk status determine whether participants proceed to post-induction Cohort 1 or Cohort 2.
干预措施: Bortezomib (B) (Drug)
研究者
Clifton Mo, MD
Principal Investigator
Dana-Farber Cancer Institute