D2 - Isa-Iber-VD Induction, Followed by Risk & Response Adapted Consolidation & Maintenance, in Transplant-Eligible NDMM

Phase 3Not Yet RecruitingNCT07624513

Dana-Farber Cancer Institute720 enrolled

Overview

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.

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. It is expected that about 720 people will take part in this research study. Sanofi Pharmaceuticals, is supporting this research study by providing isatuximab, Celgene, a subsidiary of Bristol-Myers Squibb, is providing, iberdomide, and Regeneron is providing linvoseltamab. Study drugs are free of charge and all sponsors are providing some funding for the study.

Interventions

IsatuximabDRUG

Supplied 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.

IberdomideDRUG

Supplied by Bristol Myers Squibb/Celgene (BMS); used across induction and maintenance phases; administered orally.

Bortezomib (B)DRUG

Commercial supply; used in induction and Arm G maintenance; administered subcutaneously in Arm G on Days 1 and 15 of each 28-day cycle.

DexamethasoneDRUG

Commercial supply; used in induction; may be administered intravenously or orally at investigator discretion; excluded from Arm G.

MelphalanDRUG

Commercial supply; used as conditioning therapy for Arm E before PBSC infusion/ASCT; administered intravenously.

LinvoseltamabDRUG

Supplied by Regeneron; used in Arm F consolidation for 8 cycles before maintenance therapy.

On Body Delivery System (OBDS)DEVICE

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

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: * 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. Exclusion Criteria: * 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

Outcomes

Primary Outcomes

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).

Time frame: 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.

Time frame: Assessed 1-year after Step 2 consolidation randomization.

Secondary Outcomes

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.

Time frame: 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)

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.

Time frame: 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)

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.

Time frame: 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)

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.

Time frame: 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)

PFS based on Kaplan-Meier method is defined as the time from maintenance Step 3 registration until the earlier of 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 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.

Time frame: 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.

Best Response [Cohort 1] (Step 2)

Frequency of best response over Step 2 maintenance including stringent complete response(sCR), CR, very good partial response (VGPR), partial response (PR), minimal response (MR), stable disease (SD) or progressive disease (PD) per IMWG-URC.

Time frame: Assessed at day 1 of each cycle over 36 cycles of Step 2 maintenance treatment (cycle duration=4 weeks), up to 144 weeks/36 months.

Best Response [Cohort 1] (Step 3)

Frequency of best response over Step 3 maintenance including sCR, CR, VGPR, PR, MR, SD or PD per IMWG-URC.

Time frame: Assessed day 1 of every cycle of Step 3 maintenance treatment and in long term follow-up every 3 months, up to approximately 52 months.

Serious Adverse Events (SAE) Rate [Cohort 1] (Step 2)

SAE rate is defined as the proportion of participants who experience any untoward medical occurrence at any dose that results in death, is life-threatening (i.e., the patient was at risk of death at the time of the event, not hypothetically), requires inpatient hospitalization or prolongation of existing hospitalization (excluding planned hospitalizations), results in persistent or significant disability or incapacity (defined as substantial disruption of normal life functions), is a congenital anomaly or birth defect, or is considered a medically important event.

Time frame: Assessed continuously over 36 cycles of Step 2 maintenance treatment (cycle duration=4 weeks), up to 144 weeks/36 months + 30 days.

SAE Rate [Cohort 1] (Step 3)

Time frame: Assessed continuously over Step 2 maintenance treatment (cycle duration=4 weeks), up to approximately 52 months + 30 days.

Grade 3 or Higher Non-Hematologic (NH) Treatment-Related Adverse Event (TRAE) Rate [Cohort 1] (Step 2)

Grade 3 or higher NH TRAE rate is defined as the proportion of participants who experience a grade 3 or higher NH AE based on CTCAEv5 with a treatment attribution of possible, probable or definite over Step 2 maintenance therapy.

Time frame: Assessed continuously over 36 cycles of Step 2 maintenance treatment (cycle duration=4 weeks), up to 144 weeks/36 months + 30 days.

1-Year Grade 3 or Higher Hematologic TRAE Rate [Cohort 1] (Step 3)

Grade 3 or higher hematologic TRAE rate is defined as the proportion of participants who experience a grade 3 or higher hematologic AE based on CTCAEv5 with a treatment attribution of possible, probable or definite over Step 3 maintenance therapy.

Time frame: Assessed continuously over 36 cycles of Step 2 maintenance treatment (cycle duration=4 weeks), up to 144 weeks/36 months + 30 days.

Grade 3 or Higher TRAE Rate [Cohort 1] (Step 2)

Grade 3 or higher TRAE rate is defined as the proportion of participants who experience a grade 3 or higher hematologic or non-hematologic adverse event based on CTCAEv5 with a treatment attribution of possible, probable or definite over maintenance therapy.

Time frame: Assessed continuously over 36 cycles of Step 2 maintenance treatment (cycle duration=4 weeks), up to 144 weeks/36 months + 30 days.

1-Year Grade 3 or Higher Non-Hematologic (NH) Treatment-Related Adverse Event (TRAE) Rate [Cohort 1] (Step 3)

Time frame: Assessed continuously over 12 cycles of Step 3 maintenance (cycle duration=4 weeks), up to 1 year + 30 days.

1-Year Grade 3 or Higher Hematologic TRAE Rate [Cohort 1] (Step 3)

Time frame: Assessed continuously over 12 cycles of Step 3 maintenance (cycle duration=4 weeks), up to 1 year + 30 days.

1-Year Grade 3 or Higher TRAE Rate [Cohort 1] (Step 3)

Grade 3 or higher hematologic TRAE rate is defined as the proportion of participants who experience a grade 3 or higher NH or hematologic AE based on CTCAEv5 with a treatment attribution of possible, probable or definite over Step 3 maintenance therapy.

Time frame: Assessed continuously over 12 cycles of Step 3 maintenance (cycle duration=4 weeks), up to 1 year + 30 days.

1-Year EORTC QLQ-C30 RF Subscale Response [Cohort 2] (Step 2)

Time frame: Assessed day 1 every 2 cycles or every 2 months on Step 2 treatment, up to 1 year.

Median PFS [Cohort 2] (Step 2)

PFS based on Kaplan-Meier method is defined as the time from Step 2 randomization until the earlier of 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 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.

Time frame: Assessed day 1 of each cycle or every month during Step 2 treatment. In long-term follow-up, assessed every 3 months, up to 88 months after Step 2 randomization.

Maintenance Best Response [Cohort 2] (Step 2)

Frequency of best response over Step 2 maintenance including sCR, CR, VGPR, PR, MR, SD or PD per IMWG-URC.

Time frame: Assessed at day 1 of each cycle over Step 2 maintenance treatment (cycle duration=4 weeks), up to 80 months.

1-Year Best Response [Cohort 2] (Step 2)

Frequency of best response over Step 2 consolidation and maintenance treatment up, to 1-year, including sCR, CR, VGPR, PR, MR, SD or PD per IMWG-URC.

Time frame: Assessed at day 1 of each cycle or every month over Step 2 treatment, up to 1 year.

Consolidation Best Response [Cohort 2] (Step 2)

Frequency of best response over Step 2 consolidation treatment up including sCR, CR, VGPR, PR, MR, SD or PD per IMWG-URC.

Time frame: Assessed day 1 over 8 cycles of Step 2 consolidation (cycle duration=4 weeks), up to 32 weeks/8 months; or from start of high-dose melphalan (HDM) day -2, though day 0 peripheral blood stem cell (PBSC) infusion up to maintenance start prior to day 110.

Maintenance SAE Rate [Cohort 2] (Step 2)

Time frame: Assessed continuously over Step 2 maintenance treatment, up to 80 months + 30 days.

Consolidation SAE Rate [Cohort 2] (Step 2)

Time frame: Assessed continuously over 8 Step 2 consolidation cycles (4 weeks each), up to 32 weeks/8 months +30 days; or from high-dose melphalan (HDM) day -2 through day 0 PBSC infusion to maintenance start before day 110 +30 days.

Maintenance Grade 3 or Higher NH TRAE Rate [Cohort 2] (Step 2)

Time frame: Assessed continuously over Step 2 maintenance treatment, up to 80 months + 30 days.

1-Year Grade 3 or Higher NH TRAE Rate [Cohort 2] (Step 2)

Time frame: Assessed continuously over Step 2 consolidation and maintenance treatment, up to 1-year + 30 days.

Maintenance Grade 3 or Higher Hematologic TRAE Rate [Cohort 2] (Step 2)

Time frame: Assessed continuously over Step 2 maintenance treatment, up to 80 months + 30 days.

1-Year Grade 3 or Higher Hematologic TRAE Rate [Cohort 2] (Step 2)

Time frame: Assessed continuously over Step 2 consolidation and maintenance treatment, up to 1-year + 30 days.

Maintenance Grade 3 or Higher TRAE Rate [Cohort 2] (Step 2)

Grade 3 or higher TRAE rate is defined as the proportion of participants who experience a grade 3 or higher hematologic or NH AE based on CTCAEv5 with a treatment attribution of possible, probable or definite over Step 2 maintenance therapy.

Time frame: Assessed continuously over Step 2 maintenance treatment, up to 80 months + 30 days.

1-Year Grade 3 or Higher TRAE Rate [Cohort 2] (Step 2)

Time frame: Assessed continuously over Step 2 consolidation and maintenance treatment, up to 1-year + 30 days.

Consolidation Grade 3 or Higher NH TRAE Rate [Cohort 2] (Step 2)

Consolidation Grade 3 or Higher Hematologic TRAE Rate [Cohort 2] (Step 2)

Consolidation Grade 3 or Higher TRAE Rate [Cohort 2] (Step 2)

D2 - Isa-Iber-VD Induction, Followed by Risk & Response Adapted Consolidation & Maintenance, in Transplant-Eligible NDMM

Overview

Conditions

Interventions

Eligibility

Locations (3)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts