Comparative disproportionality analysis of cytokine release syndrome associated with FDA-approved bispecific T-cell engagers in relapsed/refractory multiple myeloma

Abstract Introduction:Bispecific T-cell engagers (BiTEs) are an important immunotherapeutic option for patients with relapsed/refractory multiple myeloma (RRMM). However, cytokine release syndrome (CRS) remains a key immune-mediated adverse event associated with these agents. Comparative real-world safety data across individual BiTE therapies are limited. We performed a disproportionality analysis using the FDA Adverse Event Reporting System (FAERS) to evaluate and compare the strength of CRS safety signals for all FDA-approved BiTEs in RRMM. Methods:We extracted individual retrospective case safety reports from the FAERS database for three BiTE therapies—teclistamab, talquetamab, and elranatamab—used in individuals with “plasma cell myeloma” as the disease indicator. Disproportionality analysis was performed using reporting odds ratio (ROR), proportional reporting ratio (PRR), and Bayesian information component (IC). The comparator group included all other therapies used in multiple myeloma. RORs with 95% confidence intervals (CI) were calculated to assess statistical significance. A signal was considered significant if the lower bound of the 95% confidence interval (CI) of ROR exceeded 1, PRR ≥2 with chi-square ≥4, or IC025 (lower 95% CI of IC) >0. Data collection, refining and processing was done using Microsoft Excel and Stata. Results:All three BiTEs showed statistically significant disproportionality signals for CRS. Teclistamab had the strongest association, with an ROR of 8.59 (95% CI: 7.42–9.95), a PRR of 7.16, and an IC of 2.59. Talquetamab demonstrated an ROR of 6.93 (95% CI: 5.30–9.04), a PRR of 5.91, and an IC of 2.50. Elranatamab showed the lowest CRS signal among the three, with an ROR of 6.15 (95% CI: 4.77–7.93), a PRR of 5.35, and an IC of 2.36. Conclusion:CRS is a consistent and significant adverse event across all FDA-approved BiTE therapies for RRMM. Among these agents, teclistamab demonstrated the highest disproportionality signal for CRS, whereas elranatamab exhibited the lowest. These differences may reflect variations in cytokine activation profiles or administration protocols and could help guide treatment decisions and CRS mitigation strategies in clinical practice. Further prospective studies are needed to confirm these findings.