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.
Highlights
Multiple myeloma (MM), the second most common hematologic malignancy in the United States, accounts for 1% of malignancies and 10% of hematologic cancers [1]
MEDI2228 was characterized by weak binding capacity to recombinant monomeric human B cell maturation antigen (BCMA), but strong binding to membrane-bound BCMA
It kills an average of 95% of tumor cells in the presence of soluble form BCMA (sBCMA) at levels up to 720 ng/mL, without impact on IC50
Summary
Multiple myeloma (MM), the second most common hematologic malignancy in the United States, accounts for 1% of malignancies and 10% of hematologic cancers [1]. Both BCMA ligands APRIL and BAFF, to a lesser extent, are critical BM factors supporting growth and survival of malignant PCs in MM [31, 62] The levels of both ligands are significantly increased in serum samples of MM patients vs normal controls [31, 71]. GSK2857916, the first therapeutic anti-BCMA antibody–drug conjugates (ADCs) with multiple mechanisms of action against MM cells, used alone and with MM-protecting BM components, rapidly eliminates MM cells in two murine models and significantly prolongs survival of mice [42] These promising data further support clinical development of BCMA-targeted immunotherapies in MM.
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