Bispecific Antibodies and T-Cell Engagers in Multiple Myeloma.

Abstract

Bispecific antibodies have reshaped the therapeutic landscape for relapsed/refractory multiple myeloma (RRMM), complementing proteasome inhibitors, IMiDs, and anti-CD38 antibodies and competing with BCMA-directed CAR-T cells. In this review, we discuss the structure, mechanisms of action, and clinical data for currently approved and emerging T-cell redirecting antibodies and discuss practical questions around sequencing with CAR-T therapy, toxicity mitigation, and resistance. Bispecific T-cell engagers have shown high response rates in early relapse, as well as multidrug-refractory disease and post-CAR-T relapse, but are limited by continuous dosing, infections, hypogammaglobulinemia, cytopenias, cytokine release syndrome (CRS), and neurologic toxicity. We review emerging concepts in resistance like T-cell exhaustion, antigen loss, soluble BCMA, and extramedullary disease and discuss strategies to enhance efficacy, including combinations with anti-CD38 antibodies and IMiDs. Bispecific antibodies have become indispensable in relapsed myeloma, and for patients who are ineligible for or relapse after CAR-T therapy. With multiple clinical trials and new molecules in development, rational sequencing and combination approaches will determine how far their promise translates into durable disease control.