Discussion
neurotoxicity, B-cell lymphoma, CRS
EVENTS, B-CELL LYMPHOMA
Patients with RRMM with triple-class exposure have poor outcomes and a high unmet need for new therapiesCRS and neurotoxicity are common events with CAR T cell treatments. In CRB-401, there were relatively few grade 3 CRS events (Based upon the totality of the efficacy and safety results during the dose escalation phase, the safety monitoring committee supported the recommended phase 2 dose range of 150–450 × 10One observation from the CRB-401 study was that the median OS (34.2 months) was much longer than the median PFS (8.9 months). There are several possible explanations for this difference, including that CAR T therapy in most patients provides a prolonged period without any antimyeloma therapy, which may allow better tolerance of subsequent therapies postrelapse and outcomes. Recent real-world data on outcomes postrelapse following anti-BCMA CAR T therapy support this possible explanationRelative to the first reported data from CRB-401 (ref. Key correlates of long-term response to ide-cel included more naive, less-differentiated T cells and fewer senescent cells in the PBMC manufacturing starting material. Recent exposure to select antimyeloma therapies such as HSCT, IMiDs and alkylators likely had an impact on the PBMC features associated with long-term response, with IMiD exposure being associated with generally favorable responses and HSCT/alkylators associated with less favorable responses. The finding that durable response is correlated with more highly functional DP CAR T cells is consistent with findings reported in CD19 CAR T cell studiesThe current analyses of the CRB-401 study had a few potential limitations. First, because this was a phase 1 study, differences in survival endpoints such as PFS and OS in patients treated with ide-cel could not be fully elucidated because these endpoints were exploratory. Despite this limitation, prior studies of CAR T cell therapies also reported large differences in PFS and OS similar to those observed in the CRB-401 trial of axicabtagene ciloleucel in patients with refractory large B-cell lymphoma (for example, PFS, 5.8 months; OS, not reached with a median follow-up of 15.4 months, with an estimated 24-month OS of 50.5% (refs. Overall, the long-term results from CRB-401 continue to demonstrate the safety and tolerability of ide-cel. Further, deep and durable long-term responses were observed with ide-cel in heavily pretreated patients with RRMM, with a favorable clinical benefit-risk profile at target dose levels ≥150 × 10