Search

This study estimated the comparative efficacy of ciltacabtagene autoleucel (cilta-cel; CARTITUDE-1), a chimeric antigen receptor (CAR)-T-cell therapy, versus 3 non-CAR-T therapies (belantamab mafodotin [DREAMM-2], selinexor plus dexamethasone [STORM Part 2], and melphalan flufenamide plus dexamethasone [HORIZON]), each with distinct mechanisms of action, for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were triple-class exposed to an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody.Pairwise matching-adjusted indirect treatment comparisons (MAICs) were conducted using patient-level data for cilta-cel from CARTITUDE-1 and summary level data for each comparator (2.5 mg/kg cohort in DREAMM-2, modified intention-to-treat population in STORM Part 2, and triple-class refractory patients in HORIZON). Treated patients from CARTITUDE-1 who satisfied the eligibility of the comparator trial were included. MAICs adjusted for imbalances in important prognostic factors between CARTITUDE-1 and the comparator populations. Comparative efficacy of cilta-cel versus each therapy was estimated for overall response rate, complete response or better rate, progression-free survival, and overall survival.After adjustment, patients treated with cilta-cel demonstrated at least a 3.1-fold and at least a 10.3-fold increase in the likelihood of achieving an overall response or complete response or better, respectively, at least a 74% reduction in the risk of disease progression or death, and at least a 47% reduction in the risk of death. These results were statistically significant.Cilta-cel showed improved efficacy over each comparator for all outcomes, demonstrating its potential as an efficacious treatment for patients with triple-class exposed RRMM.

Background Ciltacabtagene autoleucel (cilta-cel) is a CAR-T cell therapy with two B-cell maturation antigen–targeting single-domain antibodies. The phase 1b/2 CARTITUDE-1 study is evaluating cilta-cel in patients (pts) with RRMM. Here we report updated results from a longer median duration of follow-up of 18 months (mos). Methods Eligible pts had MM, received ≥3 prior regimens (or were double refractory to a proteasome inhibitor and immunomodulatory drug), and received anti-CD38 antibody. A single cilta-cel infusion (target dose: 0.75×106 CAR+ viable T cells/kg; range, 0.5–1.0×106) was given 5–7 days (d) after lymphodepletion with 300 mg/m2 cyclophosphamide and 30 mg/m2 fludarabine daily for 3 d. Primary objectives were to assess cilta-cel safety, confirm the recommended phase 2 dose (phase 1b), and evaluate efficacy (phase 2). Cytokine release syndrome (CRS) was graded by Lee et al (Blood 2014) and neurotoxicity by Common Terminology Criteria for Adverse Events (CTCAE), v5.0 in phase 1b. CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded by American Society for Transplantation and Cellular Therapy (ASTCT) criteria in phase 2. Here, Lee et al and CTCAE v5.0 were mapped to ASTCT for CRS and ICANS, respectively. Results As of Feb 11, 2021, 97 pts (median of 6 prior lines) received cilta-cel. Overall response rate was 97.9% (95% CI, 92.7–99.7), with 80.4% achieving stringent complete response (sCR) and 94.8% achieving ≥very good partial response. Median time to first response was 1 mo (range, 0.9–10.7), and median time to ≥CR was 2.6 mos (range, 0.9–15.2). Median duration of response was 21.8 mos (95% CI, 21.8–NE). Of 61 pts evaluable for minimal residual disease (MRD), 91.8% were MRD negative at 10-5. 18-month progression-free survival (PFS) and overall survival rates (95% CI) were 66% (54.9–75.0) and 80.9% (71.4–87.6), respectively. Median PFS was 22.8 mos (95% CI, 22.8–NE) for all pts, and not reached for pts with sCR. Grade 3/4 hematologic adverse events (AEs) ≥20% included neutropenia (95%), anemia (68%), leukopenia (61%), thrombocytopenia (60%), and lymphopenia (50%). CRS occurred in 95% of pts (4% grade 3/4); median time to onset was 7 d (range, 1–12), and median duration was 4 d (range, 1–14, except 1 pt with 97 d duration). CRS resolved in all but one with grade 5 CRS/haemophagocytic lymphohistiocytosis. CAR-T cell neurotoxicity occurred in 21% of pts (grade ≥3, 10%). 21 deaths occurred during the study after cilta-cel infusion: none within the first 30 d, 2 within 100 d, and 19 after 100 d. Ten deaths were due to disease progression, 6 were treatment-related, and 5 were due to AEs unrelated to treatment. Conclusions At a median follow-up of 18 mos, a single infusion of cilta-cel yielded early, deep, and durable responses in heavily pretreated pts with RRMM, with manageable safety. Cilta-cel is being investigated in other MM populations in earlier lines of therapy and in outpatient settings.

Context Cilta-cel, a CAR-T cell therapy containing 2 BCMA-targeting single domain antibodies designed to confer high avidity binding, is being evaluated in the CARTITUDE-1 phase 1b/2 study. Objectives Provide updated results with a longer duration (median 12.4 months) of follow-up. Patients or Other Participants Patients had RRMM, measurable disease, ≥3 prior regimens (or double refractory to proteasome inhibitor and immunomodulatory drug) and received anti-CD38. Interventions A single cilta-cel infusion at the targeted dose of 0.75×106 (0.5–1.0×106) CAR+ viable T cells/kg was infused after cyclophosphamide/fludarabine lymphodepletion. Main Outcomes Measures The primary objectives were characterization of cilta-cel safety and confirmation of recommended phase 2 dose (phase 1b) and evaluation of efficacy (phase 2). Cytokine release syndrome (CRS) was graded by Lee 2014 and neurotoxicity by CTCAE in phase 1b; both were graded by ASTCT criteria in phase 2. Lee 2014 and CTCAE grading were mapped to ASTCT criteria for CRS and ICANS, respectively. Response was assessed per IMWG criteria. Results At 12.4-month median follow-up, 97 patients (median of 6 prior lines) received cilta-cel. Overall response rate was 97% (95% CI, 91–99), and 67% had stringent complete response (sCR). Median time to first response was 1 month (range, 1–9), median time to ≥CR was 2 months (range, 1–15), and median duration of response was not reached. Of 57 minimal residual disease (MRD)-evaluable patients, 93% were MRD-negative at 10–5. The 12-month progression-free survival (PFS) and overall survival rates (95% CI) were 77% (66–84) and 89% (80–94), respectively; median PFS was not reached. Grade 3/4 hematologic AEs included neutropenia (95%), anemia (68%), leukopenia (61%), thrombocytopenia (60%), and lymphopenia (50%). CRS occurred in 95% of patients (4% grade 3/4), with median time to onset of 7 days (range, 1–12). CAR-T cell neurotoxicity occurred in 21% patients (10% grade ≥3). Fourteen deaths occurred during the study: 0 ≤30 days, 2 ≤100 days, and 12 >100 days post-infusion, of which 5 were from disease progression and 4 from treatment-related AEs. Conclusions A single cilta-cel dose yielded early, deep, and durable responses with manageable safety in heavily pre-treated patients with RRMM. Acknowledgement The study was funded by Janssen Research & Development, LLC and Legend Biotech, Inc.