Background: BCMA-directed CAR-T therapies and bispecific antibodies (BsAbs) have transformed the treatment landscape for relapsed/refractory multiple myeloma (RRMM), yet the optimal sequencing of these therapies remains unclear. Limited access to CAR-T – especially across Europe – and the lack of direct comparative data hinder clinical decision-making. To address this, we conducted a large, real-world, multicenter European study using propensity-weighted analysis to compare the efficacy, safety, and accessibility of CAR-T versus BsAb therapy in RRMM.

Methods: We retrospectively analyzed 640 patients with RRMM treated with either a BCMA-directed CAR-T product (n=399; including idecabtagene vicleucel [ide-cel], ciltacabtagene autoleucel [cilta-cel], and academic CAR-T construct [ARI]) or a BsAb (n=241; including teclistamab, talquetamab, and elranatamab). Among BsAb-treated patients, 200 had no access to CAR-T due to regulatory, logistical, or economic barriers. Inverse probability of treatment weighting (IPTW) was used to adjust for baseline differences in key prognostic covariates: extramedullary disease (EMD), high-risk cytogenetics, International Staging System (ISS), ECOG performance status, penta-refractoriness, and age. The co-primary endpoints were overall response rate (ORR) and progression-free survival (PFS), assessed by Kaplan-Meier analysis and IPTW-adjusted Cox proportional hazards regression. Safety endpoints were immune effector cell associated neurotoxicity (ICANS), cytokine release syndrome (CRS), and non-relapse mortality (NRM).

Results: Patients treated with BsAb were generally older (median age 66 vs. 64 years) and exhibited a higher burden of adverse clinical features compared to those receiving CAR-T therapy. Specifically, high-risk cytogenetics (74% vs. 55%), extramedullary disease (EMD, 32% vs. 25%), and ECOG performance status ≥2 (35% vs. 17%) were more prevalent in the BsAb cohort. The ORR was significantly higher among CAR-T recipients (p<0.001), with complete response rates reaching 58% in the CAR-T group versus 15% in BsAb-treated patients. Among CAR-T products, cilta-cel achieved the highest complete response rate (69%), followed by academic CAR-T (ARI, 60%) and ide-cel (48%). In contrast, BsAbs showed markedly lower CR rates: elranatamab (22%), teclistamab (17%), and talquetamab (9%).

At a median follow-up of 12 months, PFS consistently favored CAR-T over BsAb treatment. Unadjusted 12-month PFS was 66% in the CAR-T group compared to 47% for BsAbs. This benefit was maintained across subgroups stratified by EMD status: among EMD-negative patients, 12-month PFS was 70% (CAR-T) vs. 54% (BsAb), and for EMD-positive patients, 52% vs. 32%, respectively. Product-level analysis highlighted cilta-cel with the highest PFS at 86%, followed by ARI (69%) and ide-cel (52%). Among BsAbs, teclistamab and elranatamab showed comparable PFS rates of 44% and 46%. In IPTW-adjusted Cox regression, BsAb therapy remained significantly associated with shorter PFS (HR 1.54; 95% CI: 1.13-2.10; p=0.006). EMD (HR 2.03; 95% CI: 1.43-2.87; p<0.001) and ECOG ≥2 (HR range: 2.08-2.66; p<0.02) were identified as strong independent predictors of inferior PFS, while age and high-risk cytogenetics showed attenuated effects after adjustment.

Safety profiles differed notably between modalities. BsAbs were generally better tolerated, with lower incidences of CRS and ICANS compared to cilta-cel and ide-cel. ARI showed similarly low toxicity to BsAbs. However, NRM varied significantly across agents (p=0.005): NRM was 5% for ide-cel, 6% for both cilta-cel and ARI, but higher in BsAb recipients – 12% for teclistamab, 11% for talquetamab, and notably 20% for elranatamab

Conclusion: This is the first large-scale, real-world comparative analysis of BCMA-targeted CAR-T versus BsAb therapies in RRMM across European countries, adjusted for both access disparities and baseline prognostic factors. Cilta-cel and ARI demonstrated superior PFS compared to BsAbs, while ide-cel performed comparably to BsAb therapies. In settings where access to commercial CAR-Ts is limited or absent, academic CAR-T approaches must match the efficacy of cilta-cel to offer a meaningful advantage over readily available off-the-shelf BsAbs. These data underscore the importance of both innovation and equitable access in determining treatment sequencing strategies in RRMM.

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2025
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