Clinical Impact of CTLA4 and LAG3 Single-Nucleotide Polymorphisms in Multiple Myeloma Patients Treated With BCMA CAR T-Cell Therapy.

Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) is a highly effective treatment option for patients with relapsed refractory multiple myeloma (RRMM). However, reliable biomarkers predicting long-term treatment response remain elusive. Germline single-nucleotide polymorphisms (SNPs) in immune checkpoint regulators, including cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and lymphocyte activation gene 3 (LAG3) may affect CAR T-cell functionality and clinical efficacy. We conducted a retrospective analysis of 87 patients with RRMM treated with BCMA-directed CAR T-cells at a single academic center between May 2021 and September 2025, evaluating the impact of CTLA4 rs231775 and LAG3 rs870849 on relapse, progression-free survival (PFS), and overall survival (OS). The minor allele rs231775 of CTLA4 was present in 48%, while the minor allele of LAG3 rs870849 was observed in 87% of patients. Carriers of the CTLA4 rs231775 minor allele demonstrated lower relapse (40 vs. 53%) and mortality rates (31 vs. 44%) compared with major allele homozygotes, accompanied by significantly prolonged PFS and OS. Likewise, patients homozygous for the LAG3 rs870849 minor allele experienced reduced relapse (36 vs. 52%) and mortality rates (28 vs. 42%), significantly longer PFS, and a trend toward improved OS relative to carriers of the major allele. In conclusion, in our study, the minor alleles of CTLA4 rs231775 and LAG3 rs870849 were associated with superior clinical outcomes following BCMA-directed CAR T-cell therapy in RRMM patients. These findings suggest to further evaluate whether immune checkpoint SNPs could be biomarkers predicting response to BCMA-directed CAR T-cell therapy in MM which needs prospective studies and validation.