Monospecific and Bispecific Chimeric Antigen Receptor (CAR) T-cell Therapy in Multiple Myeloma: A Systematic Review,...

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment for relapsed/refractory multiple myeloma (RRMM). However, comparative effectiveness across CAR products, target antigens, and patient subgroups remains incompletely characterized. Particularly, with the emergence of G protein-coupled receptor family C group 5 member D (GPRC5D)-directed, bispecific, and dual-target strategies, efficacy in patients who have relapsed/refractory disease after anti-B cell maturation antigen (BCMA) therapy has not been studied in detail. We systematically searched 5 electronic databases from January 1, 2010 to December 5, 2025. Eligible studies reported clinical outcomes of CAR T-cell therapy in MM. Primary efficacy endpoints included overall response (ORR) and complete response (CR) rate. Safety endpoints included hematologic and immunologic toxicities. Random-effects meta-analyses were performed using R, with prespecified subgroup and meta-regression analyses according to demographic, disease and treatment-related factors such as antigen target, CAR construct, prior treatment burden, extramedullary disease and high-risk cytogenetics. Of 52 reports of 44 cohorts (2 frontline and 42 relapsed/refractory cohorts) including 1833 patients were analyzed. Across all CAR T-cell platforms, the pooled ORR was 88% (95% confidence interval [CI]: 83 to 91) and CR rate was 55% (95% CI: 47 to 62). For autologous BCMA-directed CAR T-cell therapy, ORR was 89% (95% CI: 82 to 93) and CR rate was 57% (95% CI: 47 to 66), whereas allogeneic BCMA CAR-T had a lower ORR of 58% (95% CI: 1 to 100) and CR rate of 21% (95% CI: 6 to 51). Bispecific and dual-target strategies demonstrated encouraging activity with BCMA/CD19-directed CAR T-cells achieving an ORR of 92% (95% CI: 89 to 95) and CR rate of 64% (95% CI: 16 to 94), while BCMA/CD38-directed CAR T-cells achieved an ORR of 88% (95% CI: 82 to 93) and CR rate of 61% (95% CI: 22 to 90). For GPRC5D-directed CAR T-cell therapy, ORR was 89% (95% CI: 84 to 92) and CR rate was 50% (95% CI: 32 to 69). Among BCMA-relapsed/refractory patients, subsequent GPRC5D-directed CAR T-cell therapy achieved an ORR of 82% (95% CI: 66 to 91) and CR rate of 35%. MRD negativity was observed in 78% (95% CI: 68 to 86) of evaluable patients overall. Subgroup analyses demonstrated significantly lower ORR and CR in cohorts with higher extramedullary disease. Grade ≥3 hematologic toxicities were frequent: neutropenia occurred in 83% (95% CI: 76 to 89), leukopenia in 73% (95% CI: 59 to 83), anemia in 46% (95% CI: 38 to 54), and thrombocytopenia in 48% (95% CI: 41 to 56). Grade ≥3 cytokine release syndrome occurred in 8% (95% CI: 6 to 11), while grade ≥3 immune effector cell-associated neurotoxicity syndrome occurred in 3% (95% CI: 2 to 5). CAR T-cell therapy produces high response rates, substantial depth of remission, and frequent MRD negativity in multiple myeloma, including heavily pretreated RRMM. Antigen switching strategies after anti-BCMA failure with GPRC5D-directed strategies appear promising. Bispecific and dual-target CAR T-cell strategies appear especially promising, with high response rates and deep remissions. Extramedullary disease and high prior treatment burden remain important poor prognostic factors. However, these findings remain largely derived from early-phase, single-arm studies, and prospective comparative trials are needed to further guide optimal choice of CAR-T and long-term efficacy.