Bispecific antibodies in the treatment of multiple myeloma

Abstract

The treatment paradigm in myeloma is constantly changing. Upfront use of monoclonal antibodies like daratumumab along with proteasome inhibitors (PI)s, and immune modulators (IMiD)s have significantly improved survival and outcomes, but also cause unique challenges at the time of relapse. Engaging immune T cells for tumour cell kill with chimeric antigenic T-cell (CAR T-cell) therapy and bispecific antibodies have become important therapeutic options in relapsed multiple myeloma. Bispecific antibodies are dual antigen targeting constructs that engage the T cells to plasma cells through various target antigens like B-cell membrane antigen (BCMA), G-protein-coupled receptor family C group 5 member D (GPRC5D), and Fc receptor-homolog 5 (FcRH5). These agents have proven to induce deep and durable responses in heavily pre-treated myeloma patients with a predictable safety profile and the ease of off-the-shelf availability. Significant research is ongoing to overcome resistance mechanisms like T cell exhaustion, target antigen mutation or loss and high disease burden. Various trials are also studying these agents as first line options in the newly diagnosed setting. These agents play an important role in the relapsed setting, and efforts are underway to optimize their sequencing in the myeloma treatment algorithm.

Fig. 1. Bispecific antibodies and their tumour specific antigenic targets on myeloma cells.

This figure depicts the various myeloma cell target antigens that have been studied preclinically or clinically, along with the BsAbs constructs used and their associated effector cell antigen targets.

Fig. 2. Resistance mechanisms and strategies to mitigate them.

Resistance mechanisms to BsAbs are varied and include tumour-intrinsic features, T-cell fitness and exhaustion, and interaction with bone marrow stromal cells. This figure shows the impact of various targeted interventions to mitigate currently understood resistance mechanisms.