Bispecific Antibodies in Multiple Myeloma: Present and Future

Abstract

Despite many recent advances in therapy, there is still no plateau in overall survival curves in multiple myeloma. Bispecific antibodies are a novel immunotherapeutic approach designed to bind antigens on malignant plasma cells and cytotoxic immune effector cells. Early-phase clinical trials targeting B-cell maturation antigen (BCMA), GPRC5D, and FcRH5 have demonstrated a favorable safety profile, with mainly low-grade cytokine release syndrome, cytopenias, and infections. Although dose escalation is ongoing in several studies, early efficacy data show response rates in the most active dose cohorts between 61% and 83% with many deep responses; however, durability remains to be established. Further clinical trial data are eagerly anticipated.

Significance: Overall survival of triple-class refractory multiple myeloma remains poor. Bispecific antibodies are a novel immunotherapeutic modality with a favorable safety profile and impressive preliminary efficacy in heavily treated patients. Although more data are needed, bispecifics will likely become an integral part of the multiple myeloma treatment paradigm in the near future. Studies in earlier lines of therapy and in combination with other active anti-multiple myeloma agents will help further define the role of bispecifics in multiple myeloma.

Figure 1.

Bispecific and trispecific antibody structure. Bispecific antibodies. A, Bispecific T-cell and NK-cell engagers bring immune effector cells in proximity to specific antigen-expressing myeloma cells to promote direct cell-mediated cytotoxicity. The Fc portion provides stability and a longer half-life in the circulation, allowing for intermittent rather than continuous dosing. B, Bispecific compounds lacking an Fc portion have a very short half-life and require continuous infusions. These are only representative schematics; there is significant variability in antibody structure across compounds, leading to differing pharmacokinetic and pharmacodynamic profiles. C, Trispecific antibody targeting an immune effector cell and two distinct myeloma antigens. D, Trispecific antibody with costimulation of the immune effector cell to enhance cytotoxicity.

Figure 2.

Bispecific and trispecific antibody targets in multiple myeloma. Filling color denotes functional class of the target antigen; filling intensity denotes stage of translational development: clinical (darker) or preclinical (lighter). NY-ESO-1 antigen is presented by MHC class I, which requires therapeutic antibody to recognize NY-ESO-1 in complex with patient-specific MHC-I allele. PD-1 has been targeted in combination with bispecific antibodies but is not itself a direct target of bispecifics.