Idecabtagene Vicleucel (ide-cel, bb2121) in Relapsed and Refractory Multiple Myeloma: Analyses of High-Risk Subgroups in the KarMMa Study

Background: Outcomes remain poor in patients with high-risk relapsed and refractory multiple myeloma (RRMM) receiving conventional treatments, including immunomodulatory drugs (IMiD agents), proteasome inhibitors (PIs), and anti-CD38 antibodies. The pivotal phase 2 KarMMa study (NCT03361748) demonstrated deep and durable responses with idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, in triple-class exposed patients with RRMM. The overall response rate (ORR), complete response (CR) rate, median duration of response (DOR), and median progression-free survival (PFS) were 73%, 33%, 10.7 months, and 8.8 months, respectively, across the target dose levels of 150−450 × 10⁶ CAR+ T cells, and 82%, 39%, 11.3 months, and 12.1 months at the highest target dose of 450 × 10⁶ CAR+ T cells (Munshi et al. J Clin Oncol. 2020;38[suppl, abstr]:8503). The most frequent all-grade adverse events were cytopenias (97%) and cytokine release syndrome (84%). Here we report safety and efficacy from the KarMMa study in patient subgroups that are historically difficult to treat.

Methods: Patients in KarMMa had received ≥3 prior regimens, including an IMiD agent, a PI, and an anti-CD38 antibody, and were refractory to their last regimen per International Myeloma Working Group (IMWG) criteria. After lymphodepletion with cyclophosphamide (300 mg/m²/day) and fludarabine (30 mg/m²/day) for 3 days followed by 2 days of rest, patients received target doses of 150, 300, or 450 × 10⁶ CAR+ T cells. We performed subgroup analyses in patients stratified by high-risk characteristics, including those with extramedullary disease, high-risk cytogenetics [del(17p), t(4;14), and t(14;16)], high tumor burden (defined as ≥50% bone marrow plasma cells), receipt of bridging therapy, disease stage III at baseline (per the revised International Staging System [R-ISS]), and >1 prior regimen per year. The primary endpoint was ORR. Additional endpoints included CR rate (key secondary), DOR, PFS, and safety. ORR and CR were assessed per IMWG criteria; DOR and PFS were analyzed via Kaplan-Meier methods.

Results: Among all 128 ide-cel treated patients, 39% had extramedullary disease, 35% had high-risk cytogenetics, 51% had high tumor burden, 88% received bridging therapy, 16% had R-ISS disease stage III, and 47% had received >1 prior antimyeloma regimen per year. The ORR and CR rate were ≥65% and ≥20%, respectively, across all high-risk subgroups examined except patients with R-ISS disease stage III (Table). Notably, the presence of extramedullary disease and baseline tumor burden did not substantially affect ORR (70% with and 76% without extramedullary disease; 71% with and 77% without high tumor burden). CR rates were 24% in patients with and 39% in patients without extramedullary disease, and 29% in patients with and 37% in patients without high tumor burden. The median DOR was ≥9.1 months and the median PFS was ≥7.5 months in all subgroups examined except in patients with R-ISS stage III (Table). In the subgroups (baseline tumor burden and bridging therapy) analyzed for safety, no new safety signals were identified.

Conclusions: These results demonstrate the benefit of ide-cel in historically difficult-to-treat patient subsets. Deep and durable responses were observed in most subgroups, even in those with the highest risk, including patients with more aggressive disease features (extramedullary disease, high-risk cytogenetics, and high tumor burden), and those who received bridging therapy or multiple prior regiments per year. These results further support the favorable benefit-risk profile of ide-cel and suggest that ide-cel represents a promising treatment option for patients with RRMM, including those with high-risk disease.