Idecabtagene Vicleucel, a BCMA-Targeted CAR T-Cell Therapy, in Patients with RRMM

The KarMMa trial is a pivotal phase 2 study of idecabtagene vicleucel (ide-cel; bb2121), a B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory multiple myeloma (RRMM) who had exposure to at least 3 prior regimens, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody, and were refractory to their last regimen per the International Myeloma Working Group. The aim of the study was to assess the efficacy and safety of idecabtagene vicleucel in patients with RRMM with a primary end point of overall response rate (ORR). Complete response (CR), duration of response (DOR), minimal residual disease (MRD), and progression-free survival (PFS) were assessed as secondary end points, as well as pharmacokinetics. Exploratory end points included immunogenicity, BCMA expression and loss, cytokines, and T-cell immunophenotype.

The study included 128 patients who received idecabtagene vicleucel infusion (150 x 106 CAR+ T-cells, n = 4; 300 x 106 CAR+ T-cells, n = 70; 450 x 106 CAR+ T-cells, n = 54) following lymphodepletion with cyclophosphamide 300 mg/m2 plus fludarabine 30 mg/m2 for 3 days. Approximately 88% of patients required bridging therapy during CAR T-cell manufacturing. The median age of included patients was 61 years. Patients received 3 to 16 prior regimens, with an average of 6, and 86% were triple refractory. More than half of patients had high tumor burden, 39% had extramedullary disease, and 35% had high-risk cytogenetics. The ORR was 50% in patients receiving 150 x 106 CAR+ T-cells, 69% in patients receiving 300 x 106 CAR+ T-cells, and 82% in patients receiving 450 x 106 CAR+ T-cells, with an ORR of 73% in the total population. The response was rapid with time to first response occurring within 1 month. The median follow-up was 13.3 months. A clinically meaningful OR was observed across all subgroups. CR rates ranged from 25% to 39% across the 3 doses, with an average of 33% and a median time of 2.8 months. Among those with CR, 79% tested negative for MRD and 21% were not evaluable. The median DOR was 10.7 months, with increases as the dose increased, and a DOR of 19 months in those achieving a CR. The median PFS was 8.8 months, increasing as dose increased. In patients achieving CR, the PFS was 20 months. Approximately 78% of patients were event-free at 12 months, but survival data are immature with 66% of patients censored overall.

The overall exposure (AUC0-28d) and peak serum concentration (Cmax) increased with dose. The median peak CAR+ T-cell expansion occurred at 11 days and was higher in responders. Greater expansion was associated with longer PFS. CAR+ T-cells demonstrated durable persistence and were able to be detected in 59% of patients at 6 months and 36% of patients at 12 months.

Cytopenia occurred in 91% of patients and infection in 69%. Overall, cytokine release syndrome occurred in 84% of patients with only 5 (9%) patients experiencing grade 3, 1 grade 4, and 1 grade 5. In addition to the death due to cytokine release syndrome, 4 additional deaths were recorded within 8 weeks of idecabtagene vicleucel infusion, which were due to multiple myeloma progression (2), bronchopulmonary aspergillosis (1), and gastrointestinal hemorrhage (1). Approximately 18% of patients experienced neurotoxicity, 3% of which were grade 3, with no grade 4 or 5 neurotoxicity events.

Overall, idecabtagene vicleucel demonstrated frequent, deep, and durable responses in highly refractory RRMM patients with a tolerable safety profile.

Reference

Abstract and Presentation S209. EHA 2020. June 12, 2020. Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T cell therapy, in patients with relapsed and refractory multiple myeloma: initial KarMMa results.

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