Pooled Analysis on Bispecific Antibody-Related Toxicities in Multiple Myeloma
Authors: Golmohammadi Mobina , Dima Danai , Albayyadhi Maram , Moradi Azam , Raza Shahzad , Jaberi-Douraki Majid 
Published: December 2023

Background: Multiple myeloma (MM) is a hematologic malignancy caused by the uncontrolled proliferation of malignant plasma cells in the bone marrow. Bispecific antibodies (BsAbs) are a new novel class of drugs currently assessed in the setting of relapsed/refractory MM (RRMM), with impressive outcomes. BsAbs are designed to direct against specific antigenic epitopes on the surface of malignant plasma cells, with two main categories: B-cell maturation antigen (BCMA) or other (non-BCMA) antigens which include G-protein coupled receptor family C group 5 member D (GPRC5D) and Fc Receptor-Like 5 (FcRH5).
Methods: We conducted a pooled analysis of the available literature on BsAbs reported in the form of abstract or full peer-reviewed publications, published until June 2023, using PubMed, Scopus, Google Scholar and Embase databases. BsAbs were classified into two groups: BCMA and non-BCMA-directed agents. Studies on BsAbs used in combination with other plasma-cell directed agents, and studies reporting outcomes of patients who had prior exposure of other BsAbs were excluded. BsAb included in our study were the following: Teclistamab, Elranatamab, REGN-5458, AMG420, AMG701, CC-93269, TNB-383B, Linvoseltamab, Talquetamab, and Cevostamab. We collected safety data including cytokine release syndrome (CRS), neurotoxicity, infections rates and hematologic toxicities. We used T-test statistics to determine significance (p-value&lt;0.05) and comparisons between the BCMA and non-BCMA groups.
Results: A total of 1926 patients with RRMM treated with BsAbs were included in this analysis. Among them, 1288 (66.7%) received a BCMA-directed BsAbs, while 638 (33.1%) received a non-BCMA-directed bsAb. Patient baseline characteristics including prior lines of therapy (LOT), and refractoriness status were comparable between the two groups. The median age of the entire cohort was 63 years and had a median of 5 prior LOT. Median follow-up duration was 5.35 and 5.6 months for the patients treated with BCMA agents and non-BCMA agents, respectively. CRS was reported in 59.6% of all patients, infections in 50%, neutropenia in 41.86%, anemia in 37.32%, and lymphopenia in 36.41%. For grade 3-4 adverse events (AEs), the percentages were as follows: CRS 22.9%, infections 21.46%, neutropenia 38.12%, and anemia 25.37%. Non-BCMA-targeting BsAbs showed no significant difference in all grade and type hematologic toxicities (neutropenia, anemia, lymphopenia, leukopenia, and thrombocytopenia combined) compared to BCMA-targeting BsAbs (p=0.57). However, a significant difference was observed when comparing BCMA-targeting to non-BCMA-targeting BsAbs in terms of combined grade 3-4 hematologic toxicity (p=0.0002). In addition, the group of patients who received BCMA-targeting BsAbs had significantly worse hypogammaglobulinemia compared to patients treated with non-BCMA BsAbs (p=0.006). The overall CRS rate (all grades) was significantly higher in non-BCMA BsAbs (p&lt;0.0001), however, both groups experienced similar grade 3-4 CRS rates. Neurotoxicity rates were also similar between the two groups (p=0.067).
Conclusion: The use of BsAbs in MM has demonstrated remarkable efficacy; however, these have been linked to a unique adverse event profile. Our results showed that non-BCMA bsAb were associated less hematotoxicity (combined grade 3-4 events and hypogammaglobulinemia), whereas BCMA bsAb were associated with less CRS rates. This is important information for treatment selection and mitigation strategy development aiming to optimize patient outcomes.