Mechanisms of resistance to bispecific T cell engagers in multiple myeloma and their clinical implications

Bispecific T cell engagers (TCE) are revolutionizing patient care in multiple myeloma (MM). These monoclonal antibodies, that redirect T cells against cancer cells, are now approved for the treatment of triple-class exposed relapsed refractory multiple myeloma (RRMM). They are currently tested in earlier lines of the disease, including in first line. Yet, primary resistance occurs in about one third of RRMM patients, and most responders eventually develop acquired resistance. Understanding the mechanisms of resistance to bispecific TCE is thus essential to improve immunotherapies in MM. Here, we review recent studies investigating the clinical and molecular determinants of resistance to bispecific TCE. Resistance can arise from tumor-intrinsic or tumor-extrinsic mechanisms. Tumor-intrinsic resistance involves various alterations leading to the loss of the target antigen such as chromosome deletions, point mutations or epigenetic silencing. Loss of MHC class I, preventing MHC class I:TCR co-stimulatory signaling, was also reported. Tumor-extrinsic resistance involves abundant exhausted T cell clones and several factors generating an immunosuppressive microenvironment. Importantly, some resistance mechanisms impair response to one TCE while preserving the efficacy of others. We next discuss the clinical implications of these findings. Monitoring the status of target antigens in tumor cells and their immune environment will be key to select the most appropriate TCE for each patient, and to design combination and sequencing strategies for immunotherapy in multiple myeloma.-