Teclistamab Associated Cytokine Release Syndrome and Immune Effector Cell Associated Neurotoxicity Syndrome: Pooled Analysis of Real-World Studies Combined with Analysis of the Faers Database

Background: Teclistamab is a bispecific antibody that attaches to both CD3 receptor complex on T-cells and BCMA on myeloma cells leading to lysis of myeloma cells via T-cell activation. It was approved by FDA in 2022 after a landmark study showed efficacy in relapsed or refractory multiple myeloma. The same study reported high incidence of Cytokine Release Syndrome (CRS, 72.1%) and a relatively low incidence of Immune effector Cell Associated Neurotoxicity Syndrome (ICANS, 3%). Given limited real-world data reflecting diverse populations, we did a pooled analysis of all the real-world studies available in the current literature and a review of the FAERS database to provide a comprehensive report on these potentially serious immune mediated side effects.

Methods: Reports of incidence of CRS and ICANS were extracted from the published literature on real-world safety data of Teclistamab available through the MEDLINE database up to July 2024. Random-effects meta-analytic model was used to estimate the weighted proportion of all included studies. Heterogeneity between the studies was evaluated using the heterogeneity index (I²) and P-value. Additionally, a retrospective pharmacovigilance study was conducted using the FDA Adverse Events Reporting System database to further investigate the association of CRS and ICANS with Teclistamab reported by healthcare personnel during post-marketing surveillance. Reporting odds ratio was calculated with 95% confidence interval and disproportionality signal analysis used to measure strength of association.

Results: A total of 19 studies involving 1,032 patients were analyzed to investigate CRS associated with Teclistamab (n=554 of 1032), while 14 studies with 775 patients were examined for ICANS related to Teclistamab use (n=72 of 775). Pooled analysis revealed a significant proportion of CRS among patients treated with Teclistamab (0.51; 95% CI: 0.44-0.58), with substantial heterogeneity between studies (I² = 80.2%; p < 0.01). Similarly, the proportion of ICANS associated with Teclistamab use was significant (0.08; 95% CI: 0.05-0.11), with moderate heterogeneity (I² = 41.3%; p < 0.01). Within the FAERS database, there were 1322 cases of physician-reported side effects from Teclistamab. Of these, 1135 cases had serious outcomes, and death was reported in 330 cases. CRS was the most common side effect, followed by ICANS. There were 180 cases of CRS, 50 cases of ICANS, and 47 cases where both CRS and ICANS occurred together. Of these, death was reported in a total of 51 cases (18 cases of CRS, 13 cases of ICANS, and 20 cases with concurrent CRS and ICANS). Disproportionality signal analysis showed strong strength of association of both CRS (ROR 101.5; 95% CI 87.8-117.2; p<0.01) and ICANS (ROR 108.3; 95% CI 87.7-133.7; p<0.01) with Teclistamab.

Conclusions: To our knowledge, the current study provides the most comprehensive real-world data on CRS and ICANS associated with Teclistamab use. The pooled analysis indicates a lower proportion of CRS and slightly higher proportion of ICANS cases associated with Teclistamab compared to the MajesTEC 1 study. Most of the cases of CRS and ICANS in the current study were Grade 1/2 in severity. This suggests that Teclistamab may offer a safer alternative to CAR T-cell therapies that continue to demonstrate higher rates of CRS and ICANS in pooled analysis of real-world studies. Although 18% of all cases of Teclistamab-associated CRS and ICANS in the FAERS database reported death, the specific cause of death cannot be definitively attributed to CRS or ICANS. Further studies are needed to validate these findings.

No relevant conflicts of interest to declare.