MagnetisMM-6 part 2: A phase 3, open-label, randomized study of elranatamab in combination with daratumumab and lenalidomide vs daratumumab, lenalidomide, and dexamethasone in transplant-ineligible or -deferred patients with newly diagnosed multiple myeloma

Abstract Background MagnetisMM-6 (NCT05623020) is an open-label, 2-arm, randomized, phase 3 study to evaluate the efficacy and safety of elranatamab in combination with daratumumab and lenalidomide (EDR) versus daratumumab, lenalidomide, and dexamethasone (DRd) in patients with transplant-ineligible (TI) or transplant-deferred (TD) newly diagnosed multiple myeloma (NDMM). The move to evaluate T-cell redirection therapies upfront is supported by their deep responses in relapsed/refractory settings and the potential benefit of an intact immune system earlier in the course of disease. The recommended phase 3 dose was selected from Part 1 of the study based on the early and promising efficacy and manageable safety profile of EDR in patients with relapsed/refractory MM (RRMM) and TI NDMM (Quach et al J Clin Oncol 2025;43[16 suppl]:7504). Methods For Part 2, key inclusion criteria are age ≥18 years with TI (defined by age or comorbidities impacting the possibility of transplant) or TD (defined as patients who are clinically transplant-eligible but who do not intend to receive transplant as the first line of therapy) NDMM per IMWG criteria; ECOG performance status ≤2; and adequate hepatic, renal, and bone marrow function. Part 2 will enroll approximately 870 patients. Eligible patients will be randomized 1:1 to receive EDR or DRd and will be stratified by R-ISS disease stage (I/II vs III), region (North America vs Europe vs rest of the world), and age/transplant eligibility (TD vs TI <75 years old vs TI ≥75 years old). Patients in the EDR arm will receive subcutaneous (SC) elranatamab as a step-up dose regimen of 12 mg on day (D) 1, 32 mg on D4, and 76 mg on D8, followed by elranatamab 76 mg SC every 4 weeks (Q4W) starting on D1, cycle (C) 1; daratumumab 1800 mg SC weekly (D1, D8, D15, D22 in C1-C2), every 2 weeks (D1, D15 in C3-C6), and Q4W (D1 in C7+); and oral lenalidomide 25 mg daily on D1-D21 in 28-day cycles. In the EDR arm, daratumumab will be discontinued at the end of 12 cycles if complete response or better (≥CR) is already achieved, or at the time ≥CR is achieved if it occurs after C12. Patients in the DRd arm will receive SC daratumumab and oral lenalidomide as detailed above plus dexamethasone 40 mg (20 mg if age >75 years or BMI <18.5) orally on D1, D8, D15, and D22. All patients will receive treatment until disease progression, withdrawal of consent, lost to follow-up, unacceptable toxicity, or study termination. The dual primary endpoints for Part 2 are minimal residual disease (MRD) negativity rate (10-5) at 12 months after randomization and progression-free survival (PFS) per IMWG criteria. The key secondary endpoint is overall survival; other secondary endpoints include, overall and sustained MRD negativity rate, duration of MRD negativity, objective response rate, complete response rate, time to response, duration of response and complete response, PFS by investigator, PFS2 (time to second objective disease progression by investigator), pharmacokinetics, immunogenicity, and health-related quality of life (HRQOL) measures. Biomarker data, healthcare resource utilization data, and additional HRQOL measures will be collected as part of exploratory endpoints. Results N/A Conclusions N/A