Background Relapsed/refractory multiple myeloma (RRMM) remains a clinical challenge despite therapeutic advances. CD38-directed chimeric antigen receptor T-cell (CAR-T) therapy, especially dual-target CD38/BCMA constructs, represents an emerging immunotherapeutic strategy. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of CD38-directed CAR-T in RRMM. Methods We systematically searched Medline, Embase, and Cochrane Library up to October 1, 2025. Eligible clinical trials investigating CD38-directed CAR-T (single-target or dual-target CD38/BCMA) for RRMM were included. Random-effects model was used to pool efficacy and safety outcomes of dual-target studies, while single-target CD38 data were summarized descriptively. Results A total of 4 studies involving 70 patients were included (3 dual-target CD38/BCMA studies, n=61; 1 single-target CD38 study, n=9). For dual-target CD38/BCMA CAR-T, the pooled overall response rate (ORR) was 89% (95% CI: 81%–97%), complete response/stringent complete response (CR/sCR) rate was 63% (95% CI: 44%–82%), and minimal residual disease (MRD)-negative rate was 67%. Mortality was 11%. The single-target CD38 CAR-T showed lower efficacy (ORR = 33%) and higher mortality (44%). Any-grade cytokine release syndrome (CRS) occurred in 83% of patients, with grade ≥3 CRS in 26%. Other adverse events included infections (23%), immune effector cell-associated neurotoxicity syndrome (ICANS, 13%), and kidney injury (13%). Conclusion Dual-target CD38/BCMA CAR-T demonstrates promising efficacy and manageable safety in RRMM. Evidence for single-target CD38 CAR-T remains limited and requires cautious interpretation. Further large-scale comparative studies are warranted to determine the optimal role of CD38-directed CAR-T in RRMM treatment sequencing.
Xu et al. (2026) studied this question.