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.
Highlights
Multiple myeloma (MM) is the second most common hematological malignancy and is responsible for 2.1% of all cancer deaths in the U.S, as of 2020 [1]
This includes IgG-like BsAbs consisting of fragment antigen-binding (Fab) domains connected to a fragment-crystallizable (Fc) region, and bispecific T cell engagers (BiTEs) consisting of two scFv units fused with a short flexible linker (Figure 1) [14,18,19,26,30]
A proliferation-inducing ligand (APRIL) [51]. This interaction results in downstream signals to TNF-R-associated factor 1 (TRAF-1), TRAF-2, and TRAF-3, inducing activation of NF-κB, ETS-like transcription factor 1 (Elk-1), c-jun N-terminal kinase (JNK), and p38 [52]
Summary
Multiple myeloma (MM) is the second most common hematological malignancy and is responsible for 2.1% of all cancer deaths in the U.S, as of 2020 [1]. The incorporation of CD38-targeting antibodies into both first-line and relapse regimens has substantially improved the progression-free survival (PFS) and overall survival (OS) of both newly diagnosed and relapsed/refractory (R/R) MM patients [7,8,9,10,11] These novel drugs have significantly improved the outcome of MM, the majority of patients will eventually develop multi-drug-resistant disease, which is associated with very poor survival [12,13]. In the last few years, novel immunotherapeutic formats were developed and evaluated in heavily pre-treated patients This has recently led to new approvals for this subset of patients, including the BCMA-targeting chimeric antigen receptor (CAR) T cell product ide-cel (Abecma) and the antibody-drug conjugate belantamab mafodotin (Blenrep), a BCMA-targeting mAb conjugated to the cytotoxic agent monomethyl auristatin-F [4,15,16,17]. The future direction of BsAbs as an MM treatment will be addressed
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