Targeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy

Abstract

The approval of the first two monoclonal antibodies targeting CD38 (daratumumab) and SLAMF7 (elotuzumab) in late 2015 for treating relapsed and refractory multiple myeloma (RRMM) was a critical advance for immunotherapies for multiple myeloma (MM). Importantly, the outcome of patients continues to improve with the incorporation of this new class of agents with current MM therapies. However, both antigens are also expressed on other normal tissues including hematopoietic lineages and immune effector cells, which may limit their long-term clinical use. B cell maturation antigen (BCMA), a transmembrane glycoprotein in the tumor necrosis factor receptor superfamily 17 (TNFRSF17), is expressed at significantly higher levels in all patient MM cells but not on other normal tissues except normal plasma cells. Importantly, it is an antigen targeted by chimeric antigen receptor (CAR) T-cells, which have already shown significant clinical activities in patients with RRMM who have undergone at least three prior treatments, including a proteasome inhibitor and an immunomodulatory agent. Moreover, the first anti-BCMA antibody–drug conjugate also has achieved significant clinical responses in patients who failed at least three prior lines of therapy, including an anti-CD38 antibody, a proteasome inhibitor, and an immunomodulatory agent. Both BCMA targeting immunotherapies were granted breakthrough status for patients with RRMM by FDA in Nov 2017. Other promising BCMA-based immunotherapeutic macromolecules including bispecific T-cell engagers, bispecific molecules, bispecific or trispecific antibodies, as well as improved forms of next generation CAR T cells, also demonstrate high anti-MM activity in preclinical and even early clinical studies. Here, we focus on the biology of this promising MM target antigen and then highlight preclinical and clinical data of current BCMA-targeted immunotherapies with various mechanisms of action. These crucial studies will enhance selective anti-MM response, transform the treatment paradigm, and extend disease-free survival in MM.

Revealing the impact of recurrent and rare structural variants in multiple myeloma

“…High-confidence driver genes supported by both overexpression and an amplification peak: CCND1 , CCND2 , MYC , NSD2 ( WHSC1) , P2RY2/FCHSD2 , FOXO3 , MAP3K14 , CD40 , LTBR , TNFRSF17 , PRKCD , SEC62 / SAMD7 , SOX30 and GLI3 ( Figure 5A ). Of particular interest, TNFRSF17 was involved by SVs in 5 % of patients (n = 38) and encodes B-Cell Maturation Antigen (BCMA), a therapeutic target of chimeric antigen receptor T-cells (CAR-T) and monoclonal antibodies ( Figure 4B ) 41 . We also confirmed previous reports that virtually all SVs involving MYC resulted in its overexpression, including deletions and inversions, which acted by repositioning MYC next to the super-enhancers of NSMCE2 , roughly 2 Mb upstream 42 .…”

CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

“…protein belongs to the tumor necrosis factor receptor (TNFR) superfamily, along with B-cell activation factor receptor (BAFF-R) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) (8). By binding to their ligands a proliferation-inducing ligand (APRIL) and BAFF, they regulate B cell proliferation, survival and differentiation into plasma cells (8).…”

“…protein belongs to the tumor necrosis factor receptor (TNFR) superfamily, along with B-cell activation factor receptor (BAFF-R) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) (8). By binding to their ligands a proliferation-inducing ligand (APRIL) and BAFF, they regulate B cell proliferation, survival and differentiation into plasma cells (8). Recent studies have shown that membrane-bound BCMA (mBCMA) is cleaved on the cell surface by the gamma-secretase complex to a soluble form of BCMA (sBCMA) that includes the extracellular domain and a small part of the transmembrane domain (9).…”

“…BCMA is currently being evaluated in numerous clinical trials as an immunotherapy target in multiple myeloma (8). BCMA-targeted immunotherapy agents have shown improved responses in relapsed and refractory patients (10,11).…”

The genomic features associated with high-risk multiple myeloma

“…Identifying these patients at presentation, when their therapy can be modified from the “one size fits all” approach, could result in them being included in clinical trials designed to address their poor prognosis. This is becoming increasingly important as a number of new therapeutic strategies have recently become available, including chimeric antigen receptor (CAR)-T cell therapies and bi-specific antibodies, which while they are currently being evaluated for relapse refractory disease could be effective for this high risk NDMM segment [1]. …”