Bispecific Antibodies for the Management of Relapsed/Refractory Multiple Myeloma

Simple Summary Bispecific antibodies (BsAbs) provide a new mode of targeting multiple myeloma (MM) plasma cells (PCs), basing their action on the activation and redirection of the T-cell compartment against neoplastic cells. Two BCMA-targeting (teclistamab and elranatamab) plus one GPRC5D-targeting (talquetamab) BsAbs are available for the management of heavily pretreated patients with relapsed/refractory (RR) MM. Novel strategies to augment potency, reduce toxicity, and improve management are under investigation. This review summarizes the clinical applications of BsAbs and discusses the current challenges of the treatment and opportunities for optimization.Abstract Bispecific antibodies (BsAbs) are artificially engineered antibodies that can bind simultaneously to the CD3 subunit within the T-cell receptor complex and an antigen on tumor cells, leading to T-cell activation and tumor cell killing. BsAbs against BCMA or GPRC5D have shown impressive clinical activity in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), with some agents having already received regulatory approval after the third (by the European Medicines Agency, EMA) or fourth (by the Food and Drug Administration, FDA) line of therapy; the results of early-phase clinical trials targeting FcRH5 are also promising. Overall, BsAbs as monotherapy correlated with an ORR that exceeded 60%, with a high CR rate ranging between 25% and 50% and a median PFS of around 1 year among patients with a median of 4-6 prior lines of therapy. The main toxicities include cytokine release syndrome, cytopenias, hypogammaglobulinemia, and infections; on-target off-tumor adverse events involving the skin, mucosa, hair, and nails may also occur with anti-GPRC5D BsAbs. Active research to increase their efficacy and improve their tolerance is still in progress, including combination therapies and application in earlier treatment lines and the development of novel agents. A better understanding of the mechanisms of resistance is a challenge and could lead to more personalized approaches.