Comprehensive assessment of adverse event profiles associated with bispecific antibodies in multiple myeloma

Abstract

Background: Multiple myeloma (MM) represents a hematological malignancy characterized by the uncontrolled proliferation of malignant plasma cells within the bone marrow. Ongoing research endeavors are focused on investigating the potential of Bispecific T Cell engagers (BiTEs) as a therapeutic approach for relapsed/refractory MM, demonstrating promising preliminary results. Methods: We conducted a comprehensive review of the available biomedical literature, including abstracts and full publications, using PubMed, Scopus, and Nature databases until the beginning of 2023. BiTEs were classified into two groups: B-cell maturation antigen (BCMA) and nonBCMA targeting BiTEs, which included GPRC5D, and GPRC5D×BCMA. Our study included 23 different trials. Data about the frequencies of various adverse events (AEs) including hematological and non-BCMA hematological were collected. A pooled analysis based on Welch's t-test was then performed on all BiTEs to compare the safety profile of each agent from BCMA and non-BCMA. For clustering, we used t-distributed stochastic neighbor embedding (t-SNE). Results: In this research, we looked at various studies involving a total of 1,899 patients with MM across twenty-three trials. Among them, 1,094 patients received treatment with BCMA inhibitors, while 677 patients were treated with non-BCMA inhibitors. Additionally, 65 patients were treated with a combination of Teclistamab and Talquetamab (Tec_Tal), and 63 patients received a combination of Talquetamab and Daratumumab (Tec_Dar). The median follow-up for all groups was 12.6 months. In terms of all-grade hematological AEs, neutropenia was observed in 43.87% of patients, anemia was observed in 43.96%, infections occurred in 44.05%, CRS was reported in 64.16%, and lymphopenia was observed in 40.33%. For grade 3/4 AEs, the percentages were as follows: neutropenia 40.03%, infections 18.18%, CRS 1.84%, anemia 28.48%, and lymphopenia 45.09%. 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 grade 3/4 AEs (p<0.0001). t-SNE was applied to examine the clustering patterns among agents across all grades and grade 3/4 AEs. The findings revealed that agents with all grades and grade 3/4 showed similar clustering patterns except for two agents. Conclusion: The use of BiTEs in MM has demonstrated efficacy; however, these have been linked to a unique AE profile. Our results showed that non-BCMA were associated with less hematotoxicity (combined grade 3/4 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.