Current State of the Art and Prospects of T Cell-Redirecting Bispecific Antibodies in Multiple Myeloma

Abstract

Multiple myeloma (MM) patients eventually develop multi-drug-resistant disease with poor survival. Hence, the development of novel treatment strategies is of great importance. Recently, different classes of immunotherapeutic agents have shown great promise in heavily pre-treated MM, including T cell-redirecting bispecific antibodies (BsAbs). These BsAbs simultaneously interact with CD3 on effector T cells and a tumor-associated antigen on MM cells, resulting in redirection of T cells to MM cells. This leads to the formation of an immunologic synapse, the release of granzymes/perforins, and subsequent tumor cell lysis. Several ongoing phase 1 studies show substantial activity and a favorable toxicity profile with BCMA-, GPRC5D-, or FcRH5-targeting BsAbs in heavily pre-treated MM patients. Resistance mechanisms against BsAbs include tumor-related features, T cell characteristics, and impact of components of the immunosuppressive tumor microenvironment. Various clinical trials are currently evaluating combination therapy with a BsAb and another agent, such as a CD38-targeting antibody or an immunomodulatory drug (e.g., pomalidomide), to further improve response depth and duration. Additionally, the combination of two BsAbs, simultaneously targeting two different antigens to prevent antigen escape, is being explored in clinical studies. The evaluation of BsAbs in earlier lines of therapy, including newly diagnosed MM, is warranted, based on the efficacy of BsAbs in advanced MM.

Multiple Myeloma in the Era of Novel Agents and Stem Cell Therapies

“…BsAbs are novel immunotherapeutic approaches that are designed to bind antigens on malignant plasma cells and cytotoxic effector cells, such as T-cells and natural killer cells [67,68]. The use of BsAbs early in clinical trials has shown a favorable safety profile and impressive preliminary efficacy in heavily pretreated patients with MM with response rates ranging between 61% and 83% [67][68][69]. However, CRS and neurotoxicity have been reported and resistance mechanisms were found to be related to the following: tumor-related features, T-cell characteristics, and impact of components of the immune suppressive tumor microenvironment [66,69].…”

“…Various clinical trials are currently evaluating combining BsAbs with other agents, such as CD38 monoclonal antibodies, and immunomodulatory agents such as pomalidomide to further improve the duration and depth of responses [69]. Together with CAR T-cells, BsAbs represent a new dimension in precision medicine in MM [68].…”

Gaps and opportunities in the treatment of relapsed-refractory multiple myeloma: Consensus recommendations of the NCI Multiple Myeloma Steering Committee

“…Results from the phase 1/2 study of teclistamab in triple-class exposed, relapsed disease (N = 150) showed promising outcomes, with an ORR of 62% and 9-month PFS of 58.5% [57,58]. GPRC5D is an orphan G protein-coupled receptor expressed at significantly higher levels on myeloma cells compared with normal plasma cells targeted by the talquetamab bispecific antibody, which has shown promise in early studies [59]. Fc receptor-homolog 5 (FcRH5) is a type I membrane protein expressed on B cells and plasma cells, and is found on myeloma cells with near 100% prevalence.…”

Siltuximab as a primary treatment for cytokine release syndrome in a patient receiving a bispecific antibody in a clinical trial setting

“…Cytokine release syndrome (CRS) is a known side effect of immunotherapy, including chimeric antigen receptor (CAR)-T cell therapy, T cell redirecting bispecific antibodies, and bispecific T cell engagers. 1,2 CRS can be mild to life-threatening and requires careful monitoring and management. 2 The anti-interleukin (IL)-6 receptor antibody tocilizumab is approved in the US and other regions to treat severe or life-threatening CRS induced by CAR-T cell therapy.…”