Risk of Infections Associated with the Use of Bispecific Antibodies in Multiple Myeloma: A Pooled Analysis

INTRODUCTION The use of bispecific antibodies in the treatment of relapsed/refractory multiple myeloma (MM) is showing early promising overall response rates in heavily pre-treated patients. Bispecific antibodies can target B cell maturation antigen (BCMA), or non-BCMA antigens including GPRC5D and FcRH5. Infectious complications related to the use of bispecific antibodies are not well described. Here we aimed to explore the frequencies, characteristics, and outcomes of infections during treatment with bispecific antibodies. METHODS All bispecific antibodies used in MM with reported data either in an abstract format or full publication were included. We included the most recent reported results for each included trial. The data cut-off point was July, 2022. We collected data on frequencies of neutropenia, lymphopenia, infections, cytokine release syndrome (CRS), and death related to infection. Pooled analysis of infectious complications was performed using R statistical software version 4.0.5 (R Project for Statistical Computing) RESULTS Ten trials were included in our analysis. A total of 790 MM patients were treated with a bispecific antibody in the studied period (73% of patients treated with an agent targeting BCMA). Pooled median follow up was short at 4.9 months. Treatment related adverse events (AEs) were reported in 100% of included studies. AEs of interest reported in all included studies included all grade neutropenia in 35% (n=279), all grade infections in 44% (n=351), all grade CRS in 64% (n=509). Pooled estimates using reported specific AEs that included grade III/IV neutropenia in 37%, grade III/IV infections in 26%, grade III/IV CRS in 1.5%, all grades pneumonia in 12%, grade III/IV pneumonia in 13%, all grade COVID-19 in 15% and grade III/IV COVID-19 in 11%. Non-BCMA targeted bispecific antibodies were associated with lower grade III/IV neutropenia (45.6% vs. 24.4%) and lower grade III/IV infections (27.5% vs. 16.9%) when compared to BCMA-targeted bispecific antibodies. Other significant infections included cytomegalovirus infection/re-activation in 4% of reported trials. Other infections included central line associated blood stream infections (CLABSI), urinary tract infection, adenovirus infection, pneumocystis jiroveci pneumonia and progressive multifocal leukoencephalopathy. Hypogammaglobulinemia was reported in 48.5%, while death was reported in 53 patients of which 18 were reported to be secondary to infections. Infections leading to death included COVID-19, streptococcus pneumonia, influenza, aspergillosis, hepatitis and pneumonia due to adenovirus, and sepsis due to unidentified organism. CONCLUSIONS Bispecific antibodies are associated with infectious complications that maybe related to underlying MM, previous therapies and/or their mechanism of action. Certain precautions should be used when using bispecific antibodies to mitigate the risk and/or identify and treat infections promptly. Guidelines should consider implementation of prophylactic measures and/or baseline testing while bispecific antibodies are being studied in clinical trials and when they are approved for clinical use.