Salomon Manier 1, Mario Boccadoro2, Jesús San-Miguel3, Kenshi Suzuki4, Amrita Krishnan5, Niels van de Donk6, Gordon Cook7, Andrzej Jakubowiak8, Deepu Madduri9, Salma Afifi9, An-Sofie Stevens10, Jordan M Schecter9, William Deraedt10, Steven Kuppens10, Pankaj Mistry11, Lida Pacaud12, Annemiek Broijl13, Francesca Gay2, Roberto Mina2, Leo Rasche14, Philippe Moreau15, María-Victoria Mateos16, Hermann Einsele14, Pieter Sonneveld13Lille University, CHU Lille, Lille, France, 2University of Turin, Turin, Italy, 3University of Navarra, Pamplona, Spain, 4Japanese Red Cross Medical Center, Tokyo, Japan, 5City of Hope Comprehensive Cancer Center, Duarte, United States, 6Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands, 7Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom, 8University of Chicago, Chicago, United States, 9Janssen Research & Development, Raritan, United States, 10Janssen Research & Development, Beerse, Belgium, 11Janssen Research & Development, High Wycombe, United Kingdom, 12Legend Biotech USA, Piscataway, United States, 13Erasmus MC Cancer Institute, Rotterdam, Netherlands, 14University Hospital of Würzburg, Würzburg, Germany, 15Clinical Hematology, University Hospital Hotel-Dieu, Nantes, France, 16University Hospital of Salamanca/IBSAL/CIC, Salamanca, Spain

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

Methods: Patients aged ≥18 years with NDMM (based on International Myeloma Working Group criteria), measurable disease at screening, and high-dose therapy and ASCT as part of their intended initial treatment plan are eligible. Exclusion criteria include patients with any prior therapy for multiple myeloma or smoldering myeloma (except for a short course of corticosteroids). After providing informed consent, patients are randomized 1:1 into two treatment arms. Target recruitment is 750 patients. In the cilta-cel arm, patients will undergo apheresis prior to receiving 6 cycles of DVRd induction therapy. Patients will then receive lymphodepletion with intravenous cyclophosphamide (300 mg/m2) and fludarabine (30 mg/m2) daily for 3 days, followed by a single infusion of cilta-cel at a target dose of 0.75×106 CAR+ viable T cells/kg 5–7 days later. After cilta-cel infusion, patients will receive lenalidomide post CAR-T therapy for 2 years (or longer, per investigator discretion). Patients in the control arm will receive 4 cycles of DVRd induction therapy, followed by ASCT and 2 cycles of DVRd consolidation. After consolidation, patients will receive lenalidomide maintenance therapy for 2 years (or longer, per investigator discretion). The dual primary endpoints are progression-free survival (PFS) and minimal residual disease (MRD)-negative CR sustained for ≥12 months. MRD status is assessed by next-generation sequencing at a sensitivity of at least 10-5. Secondary endpoints include the following: 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 conducted.

Results: Patient enrollment opened in September 2022. The anticipated primary completion is in June 2026.

Conclusions: The EMagine/CARTITUDE-6 study will assess the efficacy and safety of a cellular therapy approach with cilta-cel versus standard of care ASCT in patients with NDMM who are eligible for transplant.

Clinical Trial Registry: NCT05257083

Disclosure: Manier-Consultancy: Abbvie, Adaptive Biotechnology, Amgen, Celgene/BMS, GlaxoSmithKline, Janssen, Novartis, Oncopeptide, Pfizer, Regeneron, Roche, Sanofi, Takeda; Honorarium: none.

Boccadoro-Honoraria/Research funding/Advisory: Amgen, Celgene, Sanofi, Novartis, Janssen, BMS, AbbVie, GlaxoSmithKline, Mundipharma.

San-Miguel-Consultancy/Advisory: Abbvie, Amgen, BMS, Celgene, GSK, Haemalogix, Janssen-Cilag, Karyopharm, MSD, Novartis, Takeda, Regeneron, Roche, Sanofi, SecuraBio.

Suzuki-Honoraria/Research funding/Consultancy: Amgen, Takeda, BMS, ONO, Novartis, Sanofi, AbbVie, Janssen.

Krishnan-Research funding/Consultancy/Speakers’ Bureau/Equity Holder: Janssen, Adaptive Biotechnologies, Sanofi, Pfizer, Regeneron, Takeda, BMS, Sutco.

Donk-Research funding/Advisory: Amgen, Servier, Cellectis, Takeda, Adaptive Biotechnologies, Celgene, BMS, Novartis, Roche, Bayer, Janssen.

Cook-Consultancy/Research funding/Speakers Bureau: Takeda, BMS, Amgen, Roche, Janssen, Sanofi, Karyopharm, Pfizer.

Jakubowiak-Consultancy/Honoraria/Advisory: Janssen.

Madduri-Consultancy/Research funding/Employment: Janssen, BMS, Takeda, GSK, Kinevant, Legend, Sanofi, Celgene, Amgen, Allogene, Celgene.

Afifi, Stevens, Kuppens, Mistry-Employment: Janssen.

Schecter, Deraedt-Employment: Janssen and holder of stock options in a privately-held company.

Pacaud-Employment: Legend Biotech USA.

Broijl-Advisory/honoraria/Other: Janssen, Sanofi, Amgen, BMS.

Gay-Honoraria/Advisory: Amgen, Celgene, Janssen, Takeda, BMS, AbbVie, GlaxoSmithKline, Roche, Adaptive Biotechnologies, Oncopeptides, Bluebird bio, Pfizer.

Mina-Consultancy/Honoraria/Advisory: Janssen, Celgene, Takeda, Amgen, BMS, Sanofi.

Rasche-Honoraria/Advisory: GSK, Janssen, Pfizer, Amgen, BMS, Sanofi.

Moreau-Honoraria: AbbVie, Janssen, Celgene, Amgen, Sanofi.

Mateos-Advisory: Janssen, Celgene, Takeda, Amgen, GSK, AbbVie, Pfizer, Regeneron, Roche, Sanofi, Oncopeptides, Seagen.

Einsele-Consultancy/Honoraria/Advisory/Other: Travel Grants, Research-funding: BMS/Celgene, Janssen, Amgen, Takeda, Sanofi, GSK, Novartis.

Sonneveld-Advisory/Research funding: Amgen, Janssen, Celgene, Pfizer, Karyopharm, BMS.

27 - Multiple Myeloma