Real‑world comparison of CAR‑T therapy versus bispecific antibodies in Relapsed/Refractory multiple myeloma

Abstract Introduction Chimeric-antigen-receptor T-cell (CAR-T) drugs include idecabtagene vicleucel and ciltacabtagene autoleucel while GPRC5D/BCMA-directed bispecific antibodies include talquetamab, teclistamab and elranatamab, both of these classes of drugs have transformed the treatment of relapsed/refractory multiple myeloma (RRMM). However, direct comparative effectiveness data among them still remain limited; therefore, we evaluated survival, response and toxicity of these classes from a federated electronic-health-record cohort. Methods Adults aged 18 years or more with RRMM receiving CAR-T or a bispecific antibody between 25 Oct 2021 and 1 Jan 2025 were identified in the US Collaborative Network (70 health-care organisations) of TriNetX database. Propensity-score matching balanced demographics, comorbidities and prior therapy, yielding two well-matched cohorts with 696 patients each. Outcomes were assessed from day +1 to +730. The primary endpoints were all-cause mortality and multiple-myeloma (MM) remission. Key secondary endpoints included cytokine-release syndrome (CRS), immune-effector-cell neurotoxicity (ICANS), grade ≥3 neutropenia/lymphopenia, sepsis, pneumonia, thrombocytopenia, hepatotoxicity and acute-kidney injury. Risk ratios (RR) and hazard ratios (HR), along with two-sided p values, were derived from TriNetX statistics. Results The median follow-up time period was recorded as 274 days for the CAR-T cohort, while it was 278 days for bispecifics cohort. Follow-up data was available for all of the patients (100%). Mortality was recorded in 12.9% (90 out of a total of 696) with CAR-T, as compared to 23.7 % (165 out of 696) with bispecifics (RR 0.55; HR 0.515, 95 % CI 0.40-0.67; log-rank p < 0.001). Moreover, MM-remission was noted in 58.2% of patients that received CAR-T therapy, as compared to 37.6% in bispecifics receiving patients (RR 1.55; HR 1.914, 95% CI 1.64-2.24; p < 0.001). CRS occurred in 47.7% versus 21.4% (RR 2.22, p < 0.001); ICANS in 13.6% versus 10.0 % (RR 1.37, p = 0.05). Furthermore, grade ≥3 neutropenia and lymphopenia were more frequently seen with CAR-T rather than bispecifics (neutropenia 57.3 % vs 31.5 %, RR 1.82; lymphopenia 8.2 % vs 3.0 %, RR 2.71, respectively). Notably, severe infections were less common in CAR-T cohort with sepsis 7.8% vs 17.1% (RR 0.45) and pneumonia 13.9% vs 25.4% (RR 0.55), both having log rank p < 0.001. However, thrombocytopenia (40.5% vs 30.6%, RR 1.32) and CRS-related re-hospitalisation were higher after CAR-T therapy. Cases of hepatotoxicity were virtually non-existent in both cohorts (0 % vs 1.4 %). Additionally, acute kidney injury was rarer in the CAR-T cohort, as compared to the bispecific cohort (21.3% vs 28.6%, RR 0.74; p = 0.002). Finally, the safety profile of both drug classes were more or less similar beyond the cytopenias and CRS. Conclusions This large, propensity-matched real-world cohort study showed that CAR-T therapy confers significantly higher remission and survival rates compared to the bispecific antibodies. However, this comes at the cost of more CRS, myelosuppression, and rehospitalization for CAR-T therapy, while bispecific antibodies carry a greater burden of severe respiratory and septic complications. These risk–benefit profiles demonstrate the need to choose drugs by personalising it for the patients for example CAR-T may be preferred for fit patients who can tolerate acute immune toxicities, whereas bispecifics remain a valuable option when cytopenia risk is significant.