Bispecific Antibodies in Multiple Myeloma: Opportunities to Enhance Efficacy and Improve Safety

Simple Summary Multiple myeloma, a cancer of the bone marrow, is the commonest cancer of adults in the Western World. Therapies have advanced dramatically in recent years, equating to improved survival and quality of life for patients, but those with resistant disease still have less favourable outcomes. Bispecific antibodies represent a new treatment option for patients with myeloma. These antibodies activate the patient's own T-cells to kill their tumour cells and have shown impressive results in relapsed refractory myeloma. In this review, we consider ways to improve the activity of these new therapies, as well as to reduce the risk of serious side effects. Bispecific antibodies are immune treatments. Given that the immune system is defective in myeloma, we discuss combining bispecific antibodies with other treatments to improve T-cell function in these patients. We also consider how to reduce the risk of cytokine release syndrome, an important side effect of these therapies. Multiple myeloma (MM) is the second most common haematological neoplasm of adults in the Western world. Overall survival has doubled since the advent of proteosome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies. However, patients with adverse cytogenetics or high-risk disease as determined by the Revised International Staging System (R-ISS) continue to have poorer outcomes, and triple-refractory patients have a median survival of less than 1 year. Bispecific antibodies (BsAbs) commonly bind to a tumour epitope along with CD3 on T-cells, leading to T-cell activation and tumour cell killing. These treatments show great promise in MM patients, with the first agent, teclistamab, receiving regulatory approval in 2022. Their potential utility is hampered by the immunosuppressive tumour microenvironment (TME), a hallmark of MM, which may limit efficacy, and by undesirable adverse events, including cytokine release syndrome (CRS) and infections, some of which may be fatal. In this review, we first consider the means of enhancing the efficacy of BsAbs in MM. These include combining BsAbs with other drugs that ameliorate the effect of the immunosuppressive TME, improving target availability, the use of BsAbs directed against multiple target antigens, and the optimal time in the treatment pathway to employ BsAbs. We then discuss methods to improve safety, focusing on reducing infection rates associated with treatment-induced hypogammaglobulinaemia, and decreasing the frequency and severity of CRS. BsAbs offer a highly-active therapeutic option in MM. Improving the efficacy and safety profiles of these agents may enable more patients to benefit from these novel therapies and improve outcomes for patients with high-risk disease.

Automated summary

Multiple myeloma (MM) is the most common cancer in adults in the Western world. Bispecific antibodies are a promising new treatment option that activate the patient's own T-cells to kill tumor cells. However, the immunosuppressive tumor microenvironment and adverse effects pose challenges to the efficacy and safety of these therapies. Improving the activity and reducing the risk of side effects are important areas of focus.