T cell redirecting bispecific antibodies for multiple myeloma: emerging therapeutic strategies in a changing treatment landscape

Abstract

In recent years, the treatment landscape of multiple myeloma has continued to evolve with the introduction of novel immunotherapies. This progress has translated to improved overall survival for patients, but an unmet need remains in the heavily pretreated and high-risk subsets of patients. Emerging immunotherapies in the form of CAR-T cell therapies have been approved for multiple myeloma. However, CAR-T cell therapy has logistical limitations and there is a need for immunotherapies that are readily available, safe, and effective in RRMM. Currently, pending approval, there are many "off the shelf" bispecific antibodies being developed that target BCMA, GPRC5D, FcRH5 and other cell surface proteins. Preliminary efficacy data has suggested that these bispecific antibody therapies have similar response rates (∼50-80%) in heavily pretreated patients. Similarly, to CAR-T cell therapy, cytokine release syndrome and immune effector cell associated neurotoxicity syndrome are adverse events of key interest and incidence range from ∼40 to 90% and 3 to 20%, respectively. In this review, we highlight the various bispecific immunotherapies under development in the treatment of multiple myeloma with a focus on the data from clinical phase I and II studies.

Keywords: BiTE therapies; CAR-T; Multiple myeloma; bispecific antibodies; immunotherapy.

Figure 1:

Various Therapeutic Mechanisms. A) Antibody drug conjugate (ADC) has a variable region to bind target on tumor cell. Once internalized, ADC is broken down in lysosome, releases cytotoxic payload and leads to tumor cell death. B) Bispecific Antibody (BSAb) has specificity for tumor antigen and another target (CD3 in this example which leads to release of granzymes and perforins and tumor cell death). Antibodies may be engineered to bind monovalently or bivalently to target. Also, Fc domain may be silenced or may be intact leading to ADCC. Trispecific antibodies incorporate variations of this design to target a third antigen aimed at evading resistance, improving half-life or adding a function. C) Monoclonal antibody (MAb) can recognize target on tumor cell and lead to ADCC, ADCP, CDC, and target specific modulation. D) Bispecific T-cell Engagers (BiTE) consist of a linker and two set of heavy/light variable domains target to tumor antigen and T-cell target such as CD3. When engaged, the T cell releases granzymes and perforins that lead to tumor cell death. Figure 1 Created with BioRender.com.