Abstract B106: NASH as a Silent Threat: Impaired Survival in Relapsed/Refractory Myeloma Patients Treated with Teclistamab

Abstract Introduction Teclistamab is a bispecific BCMA-directed CD3 T-cell engager approved for the treatment of adult patients with relapsed/refractory multiple myeloma (RRMM) after ≥4 prior lines of therapy. By simultaneously binding to CD3 on T cells and BCMA on myeloma cells, it facilitates T-cell activation and tumor cell lysis independent of T-cell receptor specificity or MHC class I expression. Teclistamab is associated with hepatotoxicity, including rare cases of fatal hepatic failure. Clinical trials report elevations in AST in 34% of patients (Grade 3/4 in 1.2%), ALT in 28% (Grade 3/4 in 1.8%), and total bilirubin in 6% (Grade 3/4 in 0.6%). Liver injury may occur independently or alongside cytokine release syndrome (CRS) with risk of viral reactivation. In this study, we investigated five-year mortality outcomes among patients with RRMM receiving Teclistamab, comparing those with underlying nonalcoholic steatohepatitis (NASH) to those without, to assess the impact of hepatic comorbidity on long-term survival. Methods We performed a retrospective cohort study using de-identified data from TriNetX, a global research network comprising over 172 million patient records. Adults with RRMM treated with Teclistamab were stratified by presence of NASH (N=14) versus no documented NASH (N=957). The primary outcome was five-year mortality; secondary analysis assessed liver enzyme trends within three months post-treatment. Propensity score matching was used to balance baseline characteristics, including age, sex, ethnicity, and comorbidities. Results Five-year survival was significantly lower in the NASH cohort (32.5%) compared to non-NASH patients (58.8%, p < 0.009). Within three months of Teclistamab initiation, the NASH group showed increases in ALT (34 to 62 U/L), AST (28 to 32 U/L), total bilirubin (0.67 to 1.93 mg/dL), and direct bilirubin (0.42 to 1.4 mg/dL). In the non-NASH group, changes were minimal: ALT (9 to 13 U/L), AST (10 to 11 U/L), total bilirubin (0.41 to 0.5 mg/dL), and direct bilirubin (0.3 to 0.32 mg/dL). Discussion Our findings suggest that NASH may be a significant risk factor for reduced survival in Teclistamab-treated RRMM patients. Teclistamab-induced hepatotoxicity is primarily immune-mediated, rather than due to direct hepatic metabolism. This immune-mediated hepatotoxicity, exacerbated by CRS and cytokine surges (i.e, IL-6, TNF-α, IFN-γ), may impose an added burden in patients with compromised hepatic reserve. The finding is consistent with clinical trials such as MajesTEC-1, where CRS occurred in over 70% of patients and was temporally associated with elevations in AST, ALT, and bilirubin. Although most liver enzyme abnormalities were reversible and not dose-dependent, at least one fatal case of hepatic failure was reported. These findings underscore the role of immune effector mechanisms in liver toxicity and highlight the importance of careful monitoring in patients with preexisting hepatic vulnerability, such asNASH Citation Format: Allen Seylani, Kayvon Sanjasaz, Assal Sadighian. NASH as a Silent Threat: Impaired Survival in Relapsed/Refractory Myeloma Patients Treated with Teclistamab [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B106.