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
1 other identifier
interventional
720
1 country
3
Brief Summary
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. 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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_3 multiple-myeloma
Started Jun 2026
Longer than P75 for phase_3 multiple-myeloma
3 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
May 28, 2026
CompletedFirst Posted
Study publicly available on registry
June 3, 2026
CompletedStudy Start
First participant enrolled
June 8, 2026
CompletedPrimary Completion
Last participant's last visit for primary outcome
October 1, 2033
ExpectedStudy Completion
Last participant's last visit for all outcomes
March 1, 2038
June 3, 2026
May 1, 2026
7.3 years
May 28, 2026
May 28, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (2)
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).
Assessed after Step 2 maintenance cycle 36 (cycle duration=4 weeks), at 144 weeks/36 months.
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.
Assessed 1-year after Step 2 consolidation randomization.
Secondary Outcomes (31)
1-Year MRD-Negative CR Rate [Cohort 1] (Step 3)
Assessed after Step 3 maintenance cycle 12 (cycle duration=4 weeks), at 48 weeks/12 months.
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)
Assessed day 1 every 3 cycles during Step 2 maintenance cycles 1-36 (cycle duration=4 weeks), up to 144 weeks/36 months.
EORTC QLQ-C30 RF Subscale Response [Cohort 1] (Step 3)
Assessed day 1 every 2 cycles during Step 3 maintenance cycles 1-12 (cycle duration=4 weeks), up to 48 weeks/12 months.
Median Progression-Free Survival (PFS) [Cohort 1] (Step 2)
Assessed day 1 of each cycle during Step 2 maintenance cycles 1-36 (cycle duration=4 weeks) on treatment, up to 144 weeks/36 months. In long-term follow-up, assessed every 3 months, up to 88 months after Step 2 maintenance registration.
Median Progression-Free Survival (PFS) [Cohort 1] (Step 3)
Assessed day 1 of each cycle during Step 3 maintenance cycle 1 and beyond (cycle duration=4 weeks) on treatment. In long-term follow-up, assessed every 3 months, up to 52 months after Step 3 registration.
- +26 more secondary outcomes
Study Arms (7)
Arm A (Induction and screening)
OTHERAll enrolled participants begin with Step 1 induction for 8 28-day cycles before end-of-induction cohort assignment. PBSC mobilization/collection is planned between Cycles 4-6 for participants without progression. End-of-induction MRD/response and risk status determine whether participants proceed to Cohort 1 or Cohort 2.
Arm B (Cohort 1 Maintenance Therapy Part 1)
OTHERParticipants 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.
Arm C: Cohort 1 Maintenance Therapy (Part 2), Single-Agent Iberdomide
OTHERAfter completion of Arm B, participants with MRD-negative CR status at Step 3 are assigned to Arm C and continue single-agent iberdomide until progression. Isatuximab is not administered in Arm C.
Arm D: Cohort 1 Maintenance Therapy (Part 2), Iberdomide + Isatuximab
OTHERAfter completion of Arm B, participants with MRD-positive or MRD-indeterminate disease, or \<VGPR at Step 3 evaluation (unless PD), continue iberdomide + isatuximab until progression.
Arm E: Cohort 2 Randomized Consolidation and Maintenance (HDM-ASCT Strategy)
ACTIVE COMPARATOREligible Cohort 2 participants are randomized to Arm E: 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.
Arm F: Cohort 2 Randomized Consolidation and Maintenance (Linvoseltamab Strategy)
EXPERIMENTALEligible 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.
Arm G: Cohort 2 Non-randomized 3-Drug Maintenance
OTHERParticipants in Cohort 2 who do not meet criteria for consolidation therapy may enter Arm G. 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.
Interventions
Supplied by Sanofi-Aventis (Sanofi); used in induction and maintenance/consolidation strategies in this protocol; administered subcutaneously in the maintenance tables provided; not administered in Arm C.
Supplied by Bristol Myers Squibb/Celgene (BMS); used across induction and maintenance phases; administered orally.
Commercial supply; used in induction and Arm G maintenance; administered subcutaneously in Arm G on Days 1 and 15 of each 28-day cycle.
Commercial supply; used in induction; may be administered intravenously or orally at investigator discretion; excluded from Arm G.
Commercial supply; used as conditioning therapy for Arm E before PBSC infusion/ASCT; administered intravenously.
Supplied by Regeneron; used in Arm F consolidation for 8 cycles before maintenance therapy.
Device: 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.
Eligibility Criteria
You may qualify if:
- 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)
- +10 more criteria
You may not qualify if:
- 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)
- +5 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Dana-Farber Cancer Institutelead
- Bristol-Myers Squibbcollaborator
- Celgene Corporationcollaborator
- Regeneron Pharmaceuticalscollaborator
- Sanoficollaborator
Study Sites (3)
Beth Israel Deaconess Medical Center (BIDMC)
Boston, Massachusetts, 02115, United States
Brigham and Women's Hospital
Boston, Massachusetts, 02115, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, 02115, United States
Related Publications (4)
Palumbo A, Bringhen S, Mateos MV, Larocca A, Facon T, Kumar SK, Offidani M, McCarthy P, Evangelista A, Lonial S, Zweegman S, Musto P, Terpos E, Belch A, Hajek R, Ludwig H, Stewart AK, Moreau P, Anderson K, Einsele H, Durie BG, Dimopoulos MA, Landgren O, San Miguel JF, Richardson P, Sonneveld P, Rajkumar SV. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015 Mar 26;125(13):2068-74. doi: 10.1182/blood-2014-12-615187. Epub 2015 Jan 27.
PMID: 25628469BACKGROUNDAvet-Loiseau H, Davies FE, Samur MK, Corre J, D'Agostino M, Kaiser MF, Raab MS, Weinhold N, Gutierrez NC, Paiva B, Neri P, Weisel K, Maura F, Walker BA, Bustoros M, Stewart AK, Usmani SZ, Hillengass J, Chng WJ, Keats JJ, Martinez-Lopez J, Sperling AS, Touzeau C, Zhan F, Raje NS, Cavo M, Bolli N, Ghobrial IM, Dhodapkar MV, Jagannath S, Spencer A, Parekh S, Bahlis NJ, Lonial S, Sonneveld P, Bergsagel L, Orlowski RZ, Morgan G, Mateos MV, Rajkumar SV, San Miguel JF, Anderson KC, Moreau P, Kumar S, Prosper F, Munshi NC. International Myeloma Society/International Myeloma Working Group Consensus Recommendations on the Definition of High-Risk Multiple Myeloma. J Clin Oncol. 2025 Aug 20;43(24):2739-2751. doi: 10.1200/JCO-24-01893. Epub 2025 Jun 9.
PMID: 40489728BACKGROUNDKumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, Munshi N, Lonial S, Blade J, Mateos MV, Dimopoulos M, Kastritis E, Boccadoro M, Orlowski R, Goldschmidt H, Spencer A, Hou J, Chng WJ, Usmani SZ, Zamagni E, Shimizu K, Jagannath S, Johnsen HE, Terpos E, Reiman A, Kyle RA, Sonneveld P, Richardson PG, McCarthy P, Ludwig H, Chen W, Cavo M, Harousseau JL, Lentzsch S, Hillengass J, Palumbo A, Orfao A, Rajkumar SV, Miguel JS, Avet-Loiseau H. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016 Aug;17(8):e328-e346. doi: 10.1016/S1470-2045(16)30206-6.
PMID: 27511158BACKGROUNDCocks K, Buchanan J. How scoring limits the usability of minimal important differences (MIDs) as responder definition (RD): an exemplary demonstration using EORTC QLQ-C30 subscales. Qual Life Res. 2023 May;32(5):1247-1253. doi: 10.1007/s11136-022-03181-4. Epub 2022 Jul 9.
PMID: 35809136BACKGROUND
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Clifton C. Mo, MD
Dana-Farber Cancer Institute
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Principal Investigator
Study Record Dates
First Submitted
May 28, 2026
First Posted
June 3, 2026
Study Start
June 8, 2026
Primary Completion (Estimated)
October 1, 2033
Study Completion (Estimated)
March 1, 2038
Last Updated
June 3, 2026
Record last verified: 2026-05
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP
- Time Frame
- Data can be shared no earlier than 1 year following the date of publication
- Access Criteria
- Contact the Belfer office for Dana -Farber Innovations (BODFI) at innovations@dfci.harvard.edu
The Harvard Cancer Consortium encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: \[contact information for Sponsor Investigator or designee\]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.