Bispecific antibodies in multiple myeloma treatment: A journey in progress

Abstract

The incorporation of novel agents and monoclonal antibody-based therapies into the treatment of multiple myeloma (MM) has significantly improved long-term patient survival. However, the disease is still largely incurable, with high-risk patients suffering shorter survival times, partly due to weakened immune systems. Bispecific molecules, including bispecific antibodies (BisAbs) and bispecific T-cell engagers (BiTEs), encourage immune cells to lyse MM cells by simultaneously binding antigens on MM cells and immune effector cells, bringing those cells into close proximity. BisAbs that target B-cell maturation antigen (BCMA) and GPRC5D have shown impressive clinical activity, and the results of early-phase clinical trials targeting FcRH5 in patients with relapsed/refractory MM (RRMM) are also promising. Furthermore, the safety profile of these agents is favorable, including mainly low-grade cytokine release syndrome (CRS). These off-the-shelf bispecific molecules will likely become an essential part of the MM treatment paradigm. Here, we summarize and highlight various bispecific immunotherapies under development in MM treatment, as well as the utility of combining them with current standard-of-care treatments and new strategies. With the advancement of novel combination treatment approaches, these bispecific molecules may lead the way to a cure for MM.

Keywords: BCMA; CD38; FcRH5; GPRC5D; bispecific T-cell engager; bispecific antibody; immunotherapy; multiple myeloma.

Figure 1

Anti-myeloma activity of bispecific antibody (BiAb) and bispecific T-cell engager (BiTE) molecules in the bone marrow MM microenvironment. T-cell–redirecting BiAb and BiTE simultaneously bind to the myeloma-specific antigens on MM cells and CD3 on T cells. MM antigens include BCMA, CD38, CS1/SLAMF7, GPRC5D, and FcRH5, as indicated. Upon engagement, the immune synapse is formed, followed by the production and secretion of cytolytic molecules, i.e., perforin and granzymes, from T cells, resulting in MM cell lysis. This further induces T-cell activation, proliferation, and differentiation into various memory subsets. The BiAb/BiTE-mediated T-cell activation leads to increased levels of granzyme B, IFN-γ, IL2, IL6, IL8, IL10, and TNF-α. The BiAb/BiTE-mediated MM cell killing is negatively affected by cellular and molecular factors including bone marrow stromal cells (BMSC), osteoclast (OC), regulatory T cells (Treg), a proliferation-inducing ligand (APRIL), transforming growth factor-β (TGF-β), interleukin-6 (IL-6), soluble BCMA (sBCMA), and upregulation in PD-L1/PD1 axis. Conversely, upregulation in effector/target (E/T) ratio, CD8+ T cell, and differentiated T cells with central and stem-like memory subsets are associated with improved BiAb/BiTE-mediated MM cell lysis. Furthermore, the potency and durability of their ability to kill MM cells could be enhanced when combined with current standard-of-care therapies including daratumumab (DARA), elotuzumab (ELO), lenalidomide (LEN), or pomalidomide (POM). Moreover, soluble BCMA (sBCMA), constantly shed by gamma-secretase (GS), could antagonize optimal MM cell eradication by BCMA-targeting agents. The GS inhibitor (GSI) rapidly blocks the release of sBCMA and augments BCMA protein retention on the MM cell membrane, thereby MM cell targeting and killing are significantly improved. In a similar manner, the BiAbs or natural killer cell engagers (NKCEs) also target natural killer (NK) cell-related receptor antigens (i.e., CD16A, NKG2D, NKp30) to activate NK cells and augment their anti-MM activities. For example, the anti-CS1 Ab elotuzumab (ELO) enhances NK cell function via CS1 and NKG2D to kill MM cells. (Some elements of Figure 1 are created with BioRender.com).