Bortezomib, Lenalidomide and Dexamethasone (VRd) Followed By Ciltacabtagene Autoleucel Versus Vrd Followed By Lenalidomide and Dexamethasone (Rd) Maintenance in Patients with Newly Diagnosed Multiple Myeloma Not Intended for Transplant: A Randomized, Phase 3 Study (CARTITUDE-5)

Introduction: For transplant-eligible patients (pts) with newly diagnosed multiple myeloma (NDMM), autologous stem cell transplant (ASCT) is the standard of care treatment (tx). However, ASCT, which includes a standard melphalan conditioning regimen that is associated with systemic toxicity, is not always feasible due to various reasons including advanced age, co-morbidities, and pt frailty. ASCT-eligible pts may also opt to defer the procedure as initial therapy. For pts with NDMM who are ineligible or unwilling to pursue ASCT, the VRd regimen is an effective tx option; however, pts continue to have inferior outcomes, and there is a need for more effective tx strategies, including ones with a curative intent. Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T cell (CAR-T) 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 in heavily pretreated patients with relapsed/refractory multiple myeloma with a manageable safety profile (Berdeja, Lancet, 2021). At a median follow-up of 18 months (mo), the overall response rate was 98% (80% with stringent complete response), and the 18-mo overall survival (OS) rate was 81%.

Objective: The randomized phase 3 CARTITUDE-5 study (NCT04923893) will compare the efficacy of VRd induction followed by cilta-cel versus VRd induction followed by Rd maintenance in pts with NDMM for whom ASCT is not planned as initial therapy.

Methods: Eligible pts (target recruitment: N=650) are ≥18 years of age with documented MM diagnosis per International Myeloma Working Group criteria, measurable disease at screening, and Eastern Cooperative Oncology Group performance status ≤1. Pts are eligible 1) if they are not candidates for high-dose chemotherapy with ASCT due to advanced age or comorbidities that are likely to have a negative impact on tolerability of this procedure or 2) if they choose to defer high-dose chemotherapy with ASCT as initial treatment. Pts with a frailty index ≥2 based on the Myeloma Geriatric Assessment Score, prior CAR-T or BCMA-targeting therapy, or any prior therapy for MM or smoldering myeloma (with the exception of a short course of steroids or one cycle of VRd) will be excluded. All enrolled pts will receive five to six 21-day (d) cycles of the VRd regimen (one cycle allowed prior to screening): 1.3 mg/m ² subcutaneous bortezomib on d 1, 4, 8 and 11; 25 mg oral lenalidomide on d 1-14; and 20 mg oral dexamethasone on d 1, 2, 4, 5, 8, 9, 11, and 12. Pts without disease progression will then be randomized 1:1 to the cilta-cel arm or Rd maintenance (control) arm (Figure). In the cilta-cel arm, pts will undergo apheresis and receive two more 21-d cycles of VRd as bridging therapy; pts will then be administered cilta-cel (target dose: 0.75×10 ⁶ CAR+ viable T cells/kg) 5-7 d after lymphodepletion chemotherapy (intravenous cyclophosphamide 300 mg/m ² and fludarabine 30 mg/m ² daily for 3 d) followed by a tx-free observation phase. In the control arm, pts will receive two additional 21-d cycles of VRd followed by Rd maintenance in 28-d cycles (25 mg oral lenalidomide on d 1-21 and 40 mg oral dexamethasone on d 1, 8, 15, and 22) until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS). Secondary endpoints include sustained minimal residual disease (MRD)-negative complete response (CR), as assessed by next-generation sequencing; MRD-negative CR rate at 9 mo; overall MRD-negative CR rate; OS; proportion of pts who achieve ≥CR; time to subsequent anti-myeloma therapy; PFS on next-line therapy (PFS2); incidence and severity of adverse events; pharmacokinetic and pharmacodynamic markers; and changes in health-related quality of life. Results from this study will provide insights into the efficacy and safety of VRd followed by cilta-cel in pts with NDMM. Additionally, VRd tx followed by a single infusion of cilta-cel vs continuous tx with Rd until disease progression may offer pts the benefit of a tx-free period.

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