Efficacy and safety of the BCMA-directed CAR-T CELL therapy, ciltacabtagene autoleucel, in patients with progressive multiple myeloma after 1-3 prior lines of therapy: Initial results from cartitude-2
Authors: M. Agha, A. Cohen, D. Madduri, Y. Cohen, M. Delforge, J. Hillengass, H. Goldschmidt, K. Weisel, M. S. Raab, C. Scheid, J. Schecter, K. De Braganca, H. Varsos, L. Wang, M. Vogel, M. Carrasco-Alfonso, M. Akram, X. Wu, T. Nesheiwat, H. Einsele
Journal: HemaSphere (2021)

Background: Ciltacabtagene autoleucel (Cilta-cel) is a chimeric antigen receptor T (CAR-T) cell therapy expressing two B-cell maturation antigen (BCMA)-targeting, single-domain antibodies designed to confer avidity. CARTITUDE-2 (NCT04133636) is a multicohort, phase 2 study evaluating cilta-cel safety and efficacy in various clinical settings for patients with multiple myeloma (MM) and exploring suitability of outpatient administration. Aims: We report initial results from Cohort A of CARTITUDE-2. Methods: All patients provided informed consent. Patients from Cohort A had progressive MM after 1-3 prior lines of therapy (LOT), including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), were lenalidomide refractory, and had no prior exposure to BCMA-targeting agents. A single cilta-cel infusion (target dose: 0.75×106 CAR+ viable T cells/kg) was given 5-7 days after initiating lymphodepletion (cyclophosphamide [300 mg/m2] and fludarabine [30 mg/m2] daily for 3 days). The primary objective was minimal residual disease (MRD) 10-5 negativity. Secondary outcomes were response rates per International Myeloma Working Group criteria and safety (adverse events [AEs] were graded per Common Terminology Criteria for Adverse Events;cytokine release syndrome [CRS] and immune effector cell?associated neurotoxicity syndrome [ICANS] were graded per American Society for Transplantation and Cellular Therapy). Results: At the data cutoff of Feb 2021 (median follow-up of 5.8 months;range: 2.5-9.8), 20 patients (65% male;median age 60 years [range: 38-75]) had received cilta-cel;one patient was treated in an outpatient setting. Patients received a median of 2 prior LOT (range: 1-3);12 patients received <3 prior LOT and 8 received 3 prior LOT. All patients were exposed to PI, IMiD, and dexamethasone, 95% to alkylating agents, and 65% to daratumumab. The majority (95%) were refractory to their last LOT, and 40% were triple refractory. The overall response rate was 95% (95% CI: 75-100) with 75% (95% CI: 51-91) achieving ≥complete response, and 85% (95% CI: 62-97) achieving ≥very good partial response. Median time to first response was 1.0 month (range: 0.7-3.3), and median time to best response was 1.9 months (range: 0.9-5.1). The median duration of response was not reached. All patients (n=4) with MRD-evaluable samples at 10-5 at the time of data cutoff were MRDnegative. Hematologic AEs (in ≥20% of patients) were neutropenia (95%;grade 3/4: 90%), thrombocytopenia (80%;grade 3/4: 35%), anemia (65%;grade 3/4: 40%), lymphopenia (60%;grade 3/4: 55%), and leukopenia (55%;all grade 3/4). CRS occurred in 85% of patients;10% were grade 3/4. The median time to CRS onset was 7 days (range: 5-9), with a median duration of 3.5 days (range: 2-11). CAR-T cell neurotoxicity occurred in 20% of patients (all grade 1/2). Three patients had ICANS (1 was grade 1;2 were grade 2) with median time to onset of 8 days (range: 7-11) and median duration of 2 days (range: 1-2). One patient had grade 2 facial paralysis with time to onset of 29 days and duration of 51 days. One death occurred due to COVID-19, which was assessed as treatment-related by investigator. The safety profile was manageable in the patient treated in an outpatient setting. Summary/Conclusion: A single cilta-cel infusion at the recommended phase 2 dose led to early and deep responses with manageable safety in patients with MM who had received 1-3 prior LOT. Updated efficacy and safety findings will inform suitability of outpatient treatment in this and other cohorts of CARTITUDE-2 as well as the CARTITUDE-4 study.