Current Novel Targeted Therapeutic Strategies in Multiple Myeloma

Abstract

Multiple myeloma (MM) is a hematologic malignancy caused by the clonal expansion of immunoglobulin-producing plasma cells in the bone marrow and/or extramedullary sites. Common manifestations of MM include anemia, renal dysfunction, infection, bone pain, hypercalcemia, and fatigue. Despite numerous recent advancements in the MM treatment paradigm, current therapies demonstrate limited long-term effectiveness and eventual disease relapse remains exceedingly common. Myeloma cells often develop drug resistance through clonal evolution and alterations of cellular signaling pathways. Therefore, continued research of new targets in MM is crucial to circumvent cumulative drug resistance, overcome treatment-limiting toxicities, and improve outcomes in this incurable disease. This article provides a comprehensive overview of the landscape of novel treatments and emerging therapies for MM grouped by molecular target. Molecular targets outlined include BCMA, GPRC5D, FcRH5, CD38, SLAMF7, BCL-2, kinesin spindle protein, protein disulfide isomerase 1, peptidylprolyl isomerase A, Sec61 translocon, and cyclin-dependent kinase 6. Immunomodulatory drugs, NK cell therapy, and proteolysis-targeting chimera are described as well.

Keywords: immunotherapy; multiple myeloma; targeted therapy.

Figure 1

Novel therapies in multiple myeloma and their mechanisms of action. Created with BioRender.com, accessed on 3 June 2024. Abbreviations: IMiD, immunomodulatory drug; CELMoD, cereblon E3 ligase modulator; Th1, Type 1 T helper; NK, natural killer; CAR, chimeric antigen receptor; BCMA, B cell maturation antigen; GPRC5D, G protein–coupled receptor, class C, group 5, member D; IFNγ, interferon γ; TFNα, tumor necrosis factor α; Bcl-2, B cell lymphoma-2; CD18, cluster of differentiation 18; CD38, cluster of differentiation 38, CD3, cluster of differentiation 3; SLAMF7, signaling lymphocyte activation molecular family 7; FcRH5, Fc receptor-homolog 5.