Comprehensive assessment of adverse event profiles associated with bispecific T cell engagers in multiple myeloma.
Authors: Golmohammadi Mobina , Albayyadhi Maram , Moradi Azam , Dima Danai , Sholehrasa Hossein , Xu Xuan , Mazzoni Sandra Ann , Raza Shahzad , Jaberi-Douraki Majid 
Published: June 2024

e19527

Background: Multiple myeloma (MM) is a hematologic malignancy caused by the uncontrolled proliferation of malignant plasma cells. Bispecific T Cell engagers (BiTEs) are a novel class of drugs currently assessed in the setting of relapsed/refractory MM. BiTEs are designed to target specific antigenic epitopes on the surface of plasma cells and CD3 on T cells. The plasma cell targets include B cell maturation antigen (BCMA), G protein coupled receptor, class C, group 5, member D (GPRC5D) and Fc receptor homolog 5 (FcRH5). Methods: We conducted a comprehensive review of the available literature including abstracts and full publications using PubMed/Scopus through Dec 31, 2023. We found 23 studies which include BCMA agents: teclistamab (Tec), elranatamab, linvoseltamab, pavurutamab, and alnuctamab; and non-BCMA targets including: GPRC5D, talquetamab (Tal) and FcRH5, cevostamab, as well as combination therapies including a BiTE, specifically Tec+Tal and Tal+daratumumab (Tal+D). A pooled analysis based on the Welch's test was then performed on all BiTEs to compare the safety profile of each agent. t-distributed stochastic neighbor embedding (t-SNE) was also applied to cluster 23 BiTEs based on their AEs. Results: We found a cohort of 1899 patients with MM across 23 studies. 1094 individuals underwent treatment involving BCMAs. 677 were subjected to non-BCMA anti-agents. 65 participants received Tec + Tal and 63 patients received Tal+D. The median follow-up duration for both BCMA BiTE and non-BCMA BiTE groups extended to 9 and 14 months. When analyzing hematological AEs of any grade, neutropenia and anemia affected 44% of patients and lymphopenia 40%. Respiratory infections manifested in 44%. CRS (Cytokine Release Syndrome) was reported in 64%. Dysgeusia was reported in only non-BCMA at 53%. Grade 3+ AEs were as follows: neutropenia at 40%, infections at 18%, CRS at 2%, anemia at 28%, and lymphopenia at 45%. Upon conducting a comprehensive pooled analysis, subtle disparities emerged between BCMA and non-BCMA BiTEs. More instances of CRS and CRS with Tocilizumab occurred with BCMA BiTEs vs non-BCMA BiTes, P < 0.024. Friedman's findings emphasized substantial distinctions between BCMA and non-BCMA agents for both overall and severe G3+ AEs (p < 0.0001). t-SNE was applied to examine the clustering patterns among agents across all grades and grades 3+ AEs. The findings revealed that agents with all grades and grades 3+ showed similar clustering patterns except for one agent. Conclusions: The use of BiTEs in MM has demonstrated remarkable efficacy; however, these have been linked to a unique AE profile. Our results showed that non-BCMA were associated with less hematotoxicity (combined G3+ AEs and hypogammaglobulinemia), whereas BCMA BiTEs were associated with less CRS rates. This is important information for treatment selection and mitigation strategy development aiming to optimize patient outcomes.