T-Cell Redirecting Therapies in Multiple Myeloma: Pathogenesis and Management of Toxicities Beyond CRS and ICANS

Abstract

The introduction of chimeric antigen receptor T (CAR-T) cell and bispecific antibody (BsAb) therapies has revolutionized multiple myeloma (MM) treatment, offering exceptional efficacy, and culminating in recent regulatory approval. However, these therapies have brought unique toxicity challenges, manifesting not only with the well-established cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), but also with the emergence of other common and equally distinctive toxicities, including cytopenias, hypogammaglobulinemia, infections, and the rare but life-threatening immune effector cell-like lymphohistiocytosis syndrome (IEC-HS). These adverse events are characterized by unique mechanisms of action that differ from those of previous treatments for MM, thereby requiring specialized knowledge to optimize day-to-day management and ultimately maximize therapeutic benefits while ensuring patient safety. Additionally, the toxicity profiles of these T-cell engager therapies are becoming increasingly important in treatment decisions, with implications for patient selection and therapy sequencing. In this review, we provide a comprehensive overview of the current state-of-the-art regarding the incidence, etiopathogenetic mechanisms, and clinical manifestations of these increasingly less non-prototypical but still lesser-known side effects than CRS and ICANS, in order to offer clear and actionable insights into their effective management, while emphasizing critical points for future improvement, in view of the increasing number of MM patients who will benefit from the newly approved and upcoming immunotherapies.