The Phase 2 CARTITUDE-2 Trial: Updated Efficacy and Safety of Ciltacabtagene Autoleucel in Patients with Multiple Myeloma and 1-3 Prior Lines of Therapy (Cohort A) and with Early Relapse after First Line Treatment (Cohort B)
Authors: Hillengass Jens , Cohen Adam D. , Agha Mounzer E , Delforge Michel , Kerre Tessa , Roeloffzen Wilfried , Einsele Hermann , Goldschmidt Hartmut , Weisel Katja , Raab Marc S. , Scheid Christof , Anguille Sebastien , Sonneveld Pieter , Zweegman Sonja , Schecter Jordan M. , De Braganca Kevin C , Jackson Carolyn Chang , Vlummens Philip , Varsos Helen , Corsale Christina , Madduri Deepu , Yeh Tzu-min , Mistry Pankaj , Roccia Tito , Song Qingxuan , Akram Muhammad , Costa Filho Octavio , Geng Dong , Cohen Yael C. , Van De Donk Niels W.C.J. 
Published: December 2023

Introduction: CARTITUDE-2 (NCT04133636) is a phase 2, multicohort study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel), an anti-BCMA chimeric antigen receptor (CAR)-T cell therapy, in various populations of patients with multiple myeloma (MM). We previously reported 17-month median follow-up results from cohort A (1-3 prior lines of therapy [LOT] and lenalidomide [len]-refractory) and 18-month median follow-up results from cohort B (early relapse: ≤12 months after either autologous stem cell transplant [ASCT] or start of initial anti-myeloma treatment, if not transplanted). Cilta-cel is also under evaluation in patients with len-refractory MM after 1-3 LOT in the phase 3 CARTITUDE-4 study, which showed cilta-cel significantly prolonged progression-free survival (PFS) vs standard of care (HR, 0.26) at a median follow-up of 16 months. Here, we present updated efficacy and safety data from CARTITUDE-2 cohorts A and B, both with a median follow-up of ~29 months.

Methods: Patients in cohorts A and B, all naive to CAR-T and/or anti-BCMA therapies, received a single cilta-cel infusion (target dose 0.75×10 6 CAR+ viable T cells/kg) 5-7 days after lymphodepletion. In both cohorts, the primary endpoint was minimal residual disease (MRD)-negativity (10 -5 threshold, by next-generation sequencing or next-generation flow cytometry). Management strategies were implemented after the phase 1b/2 CARTITUDE-1 study to reduce risk of movement and neurocognitive treatment-emergent adverse events (MNTs).

Results: As of April 2023, 20 patients in cohort A had received cilta-cel (median follow-up, 29.9 months; 35% with high-risk cytogenetics; median 2 prior LOT; 95% refractory to last LOT; 40% triple-class refractory; 85% with prior ASCT). At the same data cut-off, 19 patients in cohort B hadreceived cilta-cel (median follow-up, 27.9 months; 16% with high-risk cytogenetics; 79% refractory to last LOT; 16% triple-class refractory; 79% with prior ASCT). All (100%) 17 MRD-evaluable patients in cohort A and 14 (93%) of 15 MRD-evaluable patients in cohort B achieved MRD negativity (10 -5 threshold). Eight (40%) of 20 patients in cohort A and 10 (53%) of 19 patients in cohort B sustained MRD negativity at 10 -5 for ≥6 months (Table 1). In the 20 patients in cohort A and 19 in cohort B, cilta-cel led to overall response rates of 95% (complete response or better [≥CR], 90%) and 100% (≥CR, 90%), respectively. Median PFS was not reached in either cohort, and 24-month PFS rates were 75% in cohort A and 73% in cohort B; respective 24-month overall survival rates were 75% and 84%. In cohort A, hematologic treatment-emergent adverse events (TEAEs) occurring between 17.1- and 29.9-month median follow-up included maximum grade (gr) 3/4 leukopenia in 1 patient (all gr,12 total; 60%), maximum gr 3/4 lymphopenia in 2 patients (all gr,16 total; 80%), and maximum gr 3/4 thrombocytopenia in 1 patient (all gr,16 total; 80%). In cohort B, no new patients reported hematologic TEAEs between 18.0- and 27.9-month median follow-up (Table 2). In cohort A, no new patients had CAR-T cell neurotoxicity, and no patients had a second primary malignancy (SPM). In cohort B, no new patients had MNTs, but other neurotoxicity (gr 2 sensory loss) occurred in 1 additional patient (all gr, 5 total; 26%) and resolved; and SPM (gr 4 choroid melanoma) occurred in 1 additional patient (all gr, 2 total; 11%). One new death (total 5) occurred in cohort A on day 666 due to progressive disease, and 1 new death (total 4) occurred in cohort B on day 749 due to cardiac arrest (not treatment related).

Conclusions: These longer-term follow-up data show that patients treated with cilta-cel in earlier LOT, both those with len-refractory MM after 1-3 LOT (cohort A) and those with early relapse (cohort B), experienced deep and durable responses. No new CAR-T-related safety signals, except for 1 additional CAR-T cell neurotoxicity in cohort B, were reported. Cohort A provides insight into potential longer-term survival outcomes that may be expected in the phase 3 CARTITUDE-4 trial, which enrolled the same patient population but has shorter follow-up thus far. The long-term cohort B data highlight the durable efficacy of cilta-cel in patients who had early relapse; this is a functionally high-risk population for whom standard risk factors, including a high-risk cytogenetic profile, may not predict risk of relapse and for whom there is significant unmet need.