Frontiers in Multiple Myeloma Cell Therapy - Approaching a Cure? A Comprehensive Meta-Analysis of anti-BCMA CAR-T Cell Therapies

Abstract

Multiple myeloma is a B cell hematological cancer that remains incurable despite recent novel immunotherapy approaches that have drastically improved survival outcomes. Patients inevitably become resistant to drug treatment and relapse, demanding more effective therapies that use innovative mechanisms to evade tumor resistance. In recent years, chimeric antigen receptor-modified T (CAR-T) cell therapy has demonstrated unprecedented success in multiple myeloma, specifically by the targeting of the B cell maturation antigen (BCMA). Nevertheless, many limitations currently restrict the long-term therapeutic efficacy of BCMA CAR-T cells in multiple myeloma and thus several innovative approaches are being developed to mitigate these issues. Given the rapidly evolving nature of this field, no meta-analysis has evaluated the current state of BCMA CAR-T cell therapy. Therefore, I undertook a meta-analysis of clinical trials for BCMA CAR-T cells in multiple myeloma specifically to evaluate the impact of novel strategies on efficacy and safety. 39 clinical trials were assessed and subgrouped into seven categories based on the presence of additional modalities to the CAR construct or alterations in the manufacturing process. This meta-analysis demonstrated an aggregated overall response rate of 88% (95% CI: 84 - 91) and cytokine release syndrome rate of 10% (95% CI: 7 - 15), confirming the remarkable outcomes and tolerable safety profiles previously reported. Subgroup meta-analyses identified the use of combinations of CAR-T cells, bispecific CAR-T cells, or CAR-T cells with reduced immunogenicity to be associated with greater clinical responses. The inclusion of BCMA expression as a requirement for trial enrollment was significantly associated with improved clinical responses. Furthermore, all strategies demonstrated comparable or significantly reduced rates of cytokine release syndrome, suggesting that new approaches can be added to CAR-T cells without compromising their safety profiles. This study represents the largest BCMA CAR-T cell therapy meta-analysis to date, and establishes associations between novel CAR constructs and manufacturing protocols that have not yet been reported. The results of this study provide clinicians and researchers with insight into the current state of BCMA CAR-T cells and may aid in establishing how best to optimize CAR-T cell constructions for maximal clinical efficacy in the future.