DVRd Followed By Ciltacabtagene Autoleucel Versus DVRd Followed By ASCT in Patients with Newly Diagnosed Multiple Myeloma Who Are Transplant Eligible: A Randomized Phase 3 Study (EMagine/CARTITUDE-6)

Background: For patients with newly diagnosed multiple myeloma (NDMM) who are transplant eligible, daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd) is recommended by the National Comprehensive Cancer Network guidelines as induction therapy followed by autologous stem cell transplant (ASCT), consolidation, and maintenance therapy. Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor (CAR)-T cell therapy with 2 B-cell maturation antigen (BCMA)–targeting single-domain antibodies. In the phase 1b/2 CARTITUDE-1 study, a single infusion of cilta-cel resulted in deep and durable responses with a manageable safety profile in heavily pretreated patients with relapsed/refractory MM. At a median follow-up of 27.7 months, the overall response rate (ORR) was 98%, 83% of patients achieved stringent complete response (CR), and median duration of response was not reached. The randomized, open-label, global, multicenter, phase 3 EMagine/CARTITUDE-6 study (EMN28/68284528MMY3005; NCT05257083) aims to compare the efficacy of DVRd followed by cilta-cel and lenalidomide versus DVRd followed by ASCT, DVRd, and lenalidomide.

Study Design and Methods: Eligible patients are aged ≥18 years with NDMM per International Myeloma Working Group diagnostic criteria, have measurable disease at screening, and have high-dose therapy and ASCT as part of their intended initial treatment plan. Exclusion criteria are patients who have received any prior therapy for MM or smoldering myeloma (except a short course of corticosteroids). After giving informed consent, patients are randomized 1:1 into 2 treatment arms (target recruitment: N=750). In the cilta-cel arm, patients will undergo apheresis before receiving 6 cycles of DVRd induction. After induction, patients will receive lymphodepletion (intravenous cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² daily for 3 days), followed by a single cilta-cel infusion (target dose 0.75×10⁶ CAR+ viable T cells/kg) 5–7 days later. After the cilta-cel infusion, patients will receive lenalidomide post CAR-T therapy for 2 years (or longer, at investigator discretion). In the control arm, patients will receive 4 cycles of DVRd induction, followed by ASCT and 2 cycles of DVRd consolidation. Patients will then receive lenalidomide maintenance for 2 years (or longer at investigator discretion). The dual primary endpoints are progression-free survival (PFS) and minimal residual disease (MRD)-negative CR sustained for ≥12 months, with MRD status determined by next-generation sequencing at a sensitivity of at least 10^-5. Secondary endpoints include ORR, ≥CR rate, overall MRD-negative CR rate, time to subsequent therapy, PFS on next-line therapy, overall survival, adverse events, pharmacokinetic/pharmacodynamic markers, and changes in health-related quality of life. Exploratory correlative biomarker analyses will also be performed. Enrollment opens in September 2022, with anticipated primary completion in June 2026. This study will investigate the efficacy and safety of a cellular therapy approach with cilta-cel versus standard of care ASCT in patients with NDMM who are transplant eligible.

Figure: EMagine/CARTITUDE-6 Study Design