A phase 1 clinical trial evaluating BMS-986354, a novel B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy, has demonstrated promising efficacy and safety in patients with relapsed/refractory multiple myeloma (RRMM).
The multicenter study enrolled 77 patients across 10 institutions, with 65 patients receiving the therapy across three dose levels: 20, 40, and 80 x 106 CAR+ T cells. The patient population was heavily pretreated, with a median of 5 prior treatment regimens, and 91% were triple-class refractory.
Remarkable Clinical Responses
The therapy showed impressive clinical activity with an overall response rate of 95% (95% CI: 87%-99%) across all dose levels. Complete or stringent complete responses were achieved in 46% of patients. At the recommended phase 2 dose of 40 x 106 cells, 94% of patients achieved at least a partial response, with 38% reaching complete response.
Responses proved durable, with a median duration of response of 11.3 months for all responders and 15.1 months for those achieving complete response. The median progression-free survival was 12.3 months across all dose levels.
Enhanced Safety Profile
BMS-986354 demonstrated a manageable safety profile. While cytokine release syndrome (CRS) occurred in 82% of patients, it was predominantly low-grade, with only one patient experiencing grade 4 CRS. Neurotoxicity was observed in just 8% of patients, with most cases being grade 1.
The therapy's safety profile compares favorably to existing BCMA CAR T-cell treatments, with notably lower rates of severe CRS and neurotoxicity. No treatment-related deaths were reported.
Innovation in Manufacturing
The NEX-T® manufacturing process used for BMS-986354 represents a significant advancement over conventional methods. Despite using the same CAR construct as its predecessor (orva-cel), BMS-986354 achieved similar clinical outcomes at approximately one-tenth the dose, demonstrating enhanced potency and proliferative capacity.
The manufacturing process produced CAR T-cells with superior phenotypic characteristics, including a higher proportion of central memory T cells (83% vs. 53% in CD4+ cells) compared to conventional manufacturing. This improved memory phenotype may contribute to better long-term disease control.
Manufacturing Efficiency
The median time from apheresis to product availability was 30 days, with a total "vein-to-vein" time of 45 days, demonstrating efficient manufacturing capabilities. The process showed robust reliability with minimal manufacturing failures.
Future Implications
While BMS-986354 is not currently being further developed, the study validates the potential of the NEX-T® manufacturing process for future CAR T-cell therapies. The ability to achieve powerful anti-tumor responses with lower cell doses while maintaining a favorable safety profile represents a promising direction for cellular therapy development.
