The B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T-cell therapy BMS-986354 demonstrated great safety and activity in patients with relapsed or refractory (R/R) multiple myeloma (MM), according to phase I data published in Leukemia.
BMS-986354 has the same target — BCMA — as other approved CAR T-cell products available for patients with R/R MM. However, it is manufactured using a newly developed process known as “NEX-T”, which aims “to optimize phenotypic attributes, shorten manufacture time, and yield myeloma control with favorable safety profile.”
“As a result, you end up with a product that can induce deep and durable responses despite a much smaller number of cells,” said study researcher Luciano J. Costa, MD, PhD, director of the multiple myeloma program at the University of Alabama at Birmingham. “Moreover, the cells are of a different profile with a higher proportion of central memory cells and a lower proportion of effector cells. These characteristics are associated with greater persistence and potentially longer disease control.”
Eligible study participants had to have confirmed progression during or within 12 months of their last therapy or had no response and confirmed progression within the prior six months to their most recent therapy. All had received a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 monoclonal antibody, and prior autologous hematopoietic cell transplantation.
Sixty-five patients received CAR T-cell therapy with BMS-986354. During the dose-escalation portion of the study, patients received 20 (n=7), 40 (n=24), or 80 (n=11) x 106 CAR+ T cells. During dose expansion, 23 patients were treated at the recommended phase II dose of 40 x 106 CAR+ T cells.
Objective responses occurred in 95% of patients, with almost half (46%) achieving complete response (CR). Of those patients who achieved partial response or CR, the median duration of response was 11.3 months.
“While we can’t directly compare the results with those of other CAR-T products, we found both efficacy and safety to be encouraging,” Dr. Costa said. “There was one episode of high-grade cytokine release syndrome (CRS) and one episode of high-grade neurotoxicity. No patient developed late-onset neurotoxicity or movement disorders.”
Overall, 82% of patients experienced CRS, but only 2% were grade 3 or worse. Neurotoxicity occurred in 8% of patients, with only 2% grade 3 or worse. About one-third (32%) of patients had infection, 5% of which were grade 3 or worse. No deaths from infection occurred. About three-quarters of patients experienced cytopenias, but prolonged neutropenia was rare, occurring in 8% of patients.
“While this product was safe and had a high rate of responses, the median progression-free survival was 12.3 months, short of what our field expects to advance CAR T-cell therapy,” Dr. Costa said. “Lessons learned from this platform and from this trial are being deployed in novel investigational products exploring further improvements in manufacturing and multitargeting.”
The researchers compared phenotype characterization of BMS-986354 with another BCMA-targeting CAR T-cell therapy, orvacabtagene autoleucel. BMS-986354 cells showed a higher proportion of T central memory cells (CCR7 + CD45RA-, 83% vs. 53%), were less differentiated, and had enhanced potency and proliferative capacity.
Dr. Costa said the results are limited by the fact that this is a first-in-human dose-finding trial with a sample size that is relatively small and heterogeneous.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Ravi G, Richard S, Kumar S, et al. Phase 1 clinical trial of B-cell maturation antigen (BCMA) NEX-T® chimeric antigen receptor (CAR) T cell therapy CC-98633/BMS-986354 in participants with triple-class exposed multiple myeloma [published online ahead of print, 2025 Feb. 5]. Leukemia. doi: 10.1038/s41375-025-02518-5.
