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.
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
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
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
Parallel
Isatuximab
DrugSupplied by Sanofi-Aventis (Sanofi); used in induction and maintenance/consolidation strategies in this protocol; administered subcutaneously (SC) in the maintenance tables provided; not administered in Arm C.
Iberdomide
DrugSupplied by Bristol Myers Squibb/Celgene (BMS); used across induction and maintenance phases; administered orally.
Bortezomib (B)
DrugCommercial supply; used in induction and Arm G maintenance; administered subcutaneously in Arm G on Days 1 and 15 of each 28-day cycle.
Dexamethasone
DrugCommercial supply; used in induction; may be administered intravenously or orally at investigator discretion; excluded from Arm G.
Melphalan
DrugCommercial supply; used as conditioning therapy for Arm E before PBSC infusion/ASCT; administered intravenously.
Linvoseltamab
DrugSupplied by Regeneron; used in Arm F consolidation for 8 cycles before maintenance therapy.
On Body Delivery System (OBDS)
DeviceDevice: On Body Delivery System (OBDS) - Sanofi-Aventis device used with isatuximab administration; abdominal/periumbilical single-site application with post-dose needle retraction and lock-out.
7
Treatment groupsSee each treatment group below.
3-Year Sustained Minimal Residual Disease (sMRD)-negative Complete Response (CR) Rate [Cohort 1] (Step 2)
sMRD-negative CR rate is defined as the proportion of participants who sustain MRD negativity at a minimum 10\^-5 sensitivity assessed by next-generation sequencing (NGS) during the time of confirmed CR or better response per the International Myeloma Working Group Uniform Response Criteria (IMWG-URC).
1-Year MRD-Negative CR Rate [Cohort 2] (Step 2)
MRD-negative CR rate is defined as the proportion of participants who achieve MRD negativity at a minimum 10\^-5 sensitivity assessed by NGS during the time of confirmed CR or better response per IMWG-URC.
1-Year MRD-Negative CR Rate [Cohort 1] (Step 3)
MRD-negative CR rate is defined as the proportion of participants who sustain MRD negativity or convert to MRD negativity at a minimum 10\^-5 sensitivity assessed by NGS during the time of confirmed CR or better response per IMWG-URC.
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Role Functioning (RF) Subscale Response [Cohort 1] (Step 2)
EORTC QLQ-C30 RF subscale response is defined as an increase of ≥15 points in the RF score from Step 2 baseline, based on established guidelines. The RF subscale consists of 2 items scored on a 4-point Likert scale ("Not at all" to "Very much"). Raw scores are reverse scored and linearly transformed to a 0-100 scale then averaged, with higher scores indicating better functioning. Number of responses over Step 2 maintenance treatment is summed by participant.
EORTC QLQ-C30 RF Subscale Response [Cohort 1] (Step 3)
EORTC QLQ-C30 RF subscale response is defined as an increase of ≥15 points in the RF score from Step 3 baseline, based on established guidelines. The RF subscale consists of 2 items scored on a 4-point Likert scale ("Not at all" to "Very much"). Raw scores are reverse scored and linearly transformed to a 0-100 scale then averaged, with higher scores indicating better functioning. Number of responses over Step 3 maintenance treatment is summed by participant.
Median Progression-Free Survival (PFS) [Cohort 1] (Step 2)
PFS based on Kaplan-Meier method is defined as the time from maintenance Step 2 registration until the earlier of disease progression (PD) per IMWG-URC or death due to any cause (events). Deaths occurring beyond 6 months from the date last known progression-free are not counted as events and instead censored at the date of last disease evaluation. Patients who start Non-Protocol Therapy (NPT) prior to PD are censored at the date of NPT. Patients alive who did not experience PD or start NPT are censored at the date of last disease evaluation.
Click on the lead sponsor to view all of their trials.
Dana-Farber Cancer Institute
Lead sponsor
Sanofi
Collaborator
Bristol-Myers Squibb
Collaborator
Celgene Corporation
Collaborator
Regeneron Pharmaceuticals
Collaborator
