Management of Bispecific Antibody Toxicities: A Focus on Multiple Myeloma

Bispecific antibodies (BsAb) are a class of T-cell-redirecting therapies used in a variety of advanced malignancies. BsAb can be associated with clinically significant toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infections. CRS occurs in up to two thirds of patients and can be associated with ICANS in rare cases. CRS is best treated with tocilizumab, while glucocorticoids are effective in treating both. BsAb-associated CRS and ICANS are mostly low-grade and are confined to the step-up and first full doses. However, the risk of infection persists throughout BsAb therapy and is the leading cause of nonrelapse mortality, particularly with B-cell maturation antigen (BCMA)-targeting BsAbs, due to profound B-cell and plasma cell depletion, resulting in near-universal hypogammaglobulinemia. Infection risk is also increased due to cytopenias, neutropenia and lymphopenia, occurring during the first 6 months of BsAb therapy. Current infection prophylaxis guidelines recommend universal herpes simplex virus, varicella zoster virus, and Pneumocystis jirovecii pneumonia prophylaxis, with primary intravenous immunoglobulin prophylaxis strongly recommended for BCMA-targeting BsAbs. A few other acute toxicities associated with BsAbs include infusion-related reactions generally noted very early (<6 hours) from start of the infusion, and tumor flare reactions usually occurring during the first BsAb cycle. A few important toxicities have been noted with bispecific constructs targeting GPRC5D, including alternation of taste, unintentional weight loss, rash, and nonrash skin and nail toxicities significantly affecting patient's quality of life. A few late but rare complications include progressive multifocal leukoencephalopathy and second primary malignancies, which require continued vigilance. As the use and number of BsAb continues to grow, the knowledge of the characteristics, timing, and management of BsAb toxicities is essential to current clinical practice.