B-Cell Maturation Antigen (BCMA) As a Target for New Drug Development in Relapsed and/or Refractory Multiple Myeloma

Abstract

<jats:p>During the past two decades there has been a major shift in the choice of agents to treat multiple myeloma, whether newly diagnosed or in the relapsed/refractory stage. The introduction of new drug classes, such as proteasome inhibitors, immunomodulators, and anti-CD38 and anti-SLAMF7 monoclonal antibodies, coupled with autologous stem cell transplantation, have approximately doubled the disease’s five-year survival rate. However, this positive news is tempered by the realization that these measures are not curative and patients eventually relapse and/or become resistant to the drug’s effects. Thus, there is a need to discover newer myeloma-driving molecular markers and develop innovative drugs designed to precisely regulate the actions of such putative targets. B cell maturation antigen (BCMA), which is found almost exclusively on the surfaces of malignant plasma cells to the exclusion of other cell types, including their normal counterparts, has emerged as a specific target of interest in this regard. Immunotherapeutic agents have been at the forefront of research designed to block BCMA activity. These agents encompass monoclonal antibodies, such as the drug conjugate belantamab mafodotin; bispecific T-cell engager strategies exemplified by AMG 420; and chimeric antigen receptor (CAR) T-cell therapeutics that include idecabtagene vicleucel (bb2121) and JNJ-68284528.</jats:p>

The role of belantamab mafodotin for patients with relapsed and/or refractory multiple myeloma

“…8 B-cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand), who are members of the TNF family that serves as ligands for BCMA, have also been associated with the proliferation of MM cells in the bone marrow. 8,13 Thus far, trials targeting BAFF and APRIL as part of the BAFF/APRIL/BCMA axis have been rather disappointing, and thus, BCMA has become a target of interest. 13 BCMA also has minimal expression in naïve B cells and non-hematopoietic cells, which is of particular importance from a therapeutic perspective.…”

“…8,13 Thus far, trials targeting BAFF and APRIL as part of the BAFF/APRIL/BCMA axis have been rather disappointing, and thus, BCMA has become a target of interest. 13 BCMA also has minimal expression in naïve B cells and non-hematopoietic cells, which is of particular importance from a therapeutic perspective. [8][9][10][11][12] In addition to its uses therapeutically, BCMA is also of interest as a biomarker in MM.…”

“…For example, soluble BCMA (sBCMA) levels are increased in MM patients and have been found to correlate with the tumor burden and survival, and could potentially be useful for monitoring response during MM treatment. 8,10,13 Moreover, sBCMA has a half-life of 24-26 hours, so changes in sBCMA levels may reflect changes in disease status faster than changes in paraprotein levels. 8,9 However, further investigation is needed into these uses of sBCMA in measuring response to therapy.…”

“…8 In general, ADCs can improve the efficacy of a naked mAb by combining a tumor antigen-specific mAb with a toxic payload that becomes internalized upon binding of the ADC to the tumor cell, ultimately resulting in cell death. 6,8,[12][13][14][15] For example, belamaf is a first-in-class ADC that uses a protease-resistant linker to combine an afucosylated humanized IgG1 anti-BCMA mAb with monomethyl auristatin F (MMAF), which is an inhibitor of tubulin polymerization. 6,8,[10][11][12][13][14][15] Preclinical studies demonstrated encouraging anti-MM activity of belamaf through several mechanisms of action including direct apoptosis through the ADC mechanism, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and immunogenic cell death.…”

Novel Approaches to Improve Myeloma Cell Killing by Monoclonal Antibodies

“…Other studies with Belantamab Mafodotin either as single-agent or in combination with other drugs are currently ongoing. Moreover, many others anti-BCMA mAbs drug conjugate are in clinical development [ 96 ].…”