Anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma with extramedullary disease: Comparative outcomes and evolving strategies

Abstract

Abstract BACKGROUND/OBJECTIVE: Extramedullary disease (EMD) in relapsed/refractory multiple myeloma (RRMM) has aggressive biology, immune evasion, and poor survival. While anti-B-Cell Maturation Antigen Chimeric Antigen Receptor T-cell (Anti BCMA CAR T-cell) therapy has transformed RRMM outcomes, there's limited efficacy in EMD. This systematic review aims to synthesize clinical outcomes, toxicities, and biological insights from recent trials of anti-BCMA CAR T-cell therapy in EMD patients, highlighting trends in response rates, progression-free survival (PFS), and emerging dual-targeted strategies. METHODS A PRISMA-2020–guided systematic search of PubMed, Embase, Web of Science, and Cochrane from inception to 1 July 2025 was conducted. Eligible studies enrolled adults with relapsed/refractory myeloma and described outcomes for patients with baseline extramedullary disease (EMD) treated with an anti-BCMA CAR-T product. Two reviewers independently screened records, extracted study-level data (CAR construct, objective response rate [ORR], progression-free survival [PFS], overall survival [OS], grade ≥3 CRS/ICANS), and assessed risk of bias with ROBINS-I (observational) or JBI checklists (case-series). Discrepancies were resolved with consensus. Prespecified endpoints were ORR and median or landmark PFS in EMD. OS and severe toxicities were taken as secondary. Due to heterogeneity in constructs and reporting, the findings were synthesised qualitatively, with exploratory random-effects pooling when at least three studies reported a common metric. Seven studies met the inclusion criteria, comprising five early-phase trials and two large real-world registries. RESULTS We included seven prospective or real-world series published between 2021 and 2025. More than 160 relapsed/refractory multiple-myeloma patients with baseline extramedullary disease (EMD) showed that anti-BCMA CAR-T therapy yields high initial responses, but limited durability was observed in this subgroup. In the three foundational single-target BCMA studies (Deng, Que, Li), overall response rates (ORR) were comparable between EMD and non-EMD cohorts, yet survival diverged sharply—Deng et al. documented 360-day declines in both PFS and OS, Que et al. reported median PFS 121 days versus 361 days and OS 248 versus 1,024 days, and Li et al. noted worse long-term efficacy in EM-E patients, who also exhibited higher interleukin-6 levels and severe CRS. Commercial ide-cabtagene vicleucel data reinforced this pattern, which was seen in the French FENIX registry (n = 213; 23 % EMD), which demonstrated median PFS 6.2 versus 14.8 months, while a North-American multi-centre cohort showed day-90 ORR 52 % versus 82 % and median PFS 5.3 versus 11.1 months, establishing EMD as an independent adverse factor. Antigen-broadening approaches appeared to have improved the outcomes: dual BCMA + CD19 CAR-T (Qi) achieved a 64.5 % ORR, 5-month PFS, and 9.7-month OS in extra-osseous EMD, albeit with 22.6 % grade ≥3 local toxicities linked to systemic CRS, whereas a bispecific BCMA/GPRC5D construct (Yao) reached 100 % ORR (44.4 % CR), 63 % 1-year PFS, and 60 % OS with only grade 1–2 CRS and no ICANS. Across studies, EMD correlated with higher-grade CRS/ICANS, elevated IL-6, and an exhausted CD8⁺ tumour micro-environment, underscoring distinct biology and the need for consolidation or next-generation cellular strategies. CONCLUSION Extramedullary disease (EMD) in relapsed/refractory multiple myeloma (RRMM) remains a high-risk subset with inferior survival despite comparable initial responses to anti-BCMA CAR T-cell therapy. Across seven studies, EMD consistently emerged as an independent adverse prognostic factor, marked by elevated IL-6, CD8⁺ T-cell exhaustion, and increased inflammatory toxicities. While single-target BCMA constructs show limited durability, emerging dual-targeted constructs – such as BCMA+CD19 and bispecific BCMA/GPRC5D – show promising efficacy and tolerability. This shows us that antigen broadening may help overcome resistance. These findings underscore the need for biologically informed CAR T-cell designs, consolidation strategies, and EMD-specific trials to optimize outcomes in high-risk groups.