Keeping Myeloma in Check: The Past, Present and Future of Immunotherapy in Multiple Myeloma

Abstract

Multiple myeloma is an incurable disease of malignant plasma cells and an ideal target for modern immune therapy. The unique plasma cell biology maintained in multiple myeloma, coupled with its hematological nature and unique bone marrow microenvironment, provide an opportunity to design specifically targeted immunotherapies that selectively kill transformed cells with limited on-target off-tumor effects. Broadly defined, immune therapy is the utilization of the immune system and immune agents to treat a disease. In the context of multiple myeloma, immune therapy can be subdivided into four main categories: immune modulatory imide drugs, targeted antibodies, adoptive cell transfer therapies, and vaccines. In recent years, advances in all four of these categories have led to improved therapies with enhanced antitumor activity and specificity. In IMiDs, modified chemical structures have been developed that improve drug potency while reducing dose limiting side effects. Targeted antibody therapies have resulted from the development of new selectively expressed targets as well as the development of antibody drug conjugates and bispecific antibodies. Adoptive cell therapies, particularly CAR-T therapies, have been enhanced through improvements in the manufacturing process, as well as through the development of CAR constructs that enhance CAR-T activation and provide protection from a suppressive immune microenvironment. This review will first cover in-class breakthrough therapies for each of these categories, as well as therapies currently utilized in the clinic. Additionally, this review will explore up and coming therapeutics in the preclinical and clinical trial stage.

Therapeutics to harness the immune microenvironment in multiple myeloma

“…The second humanized monoclonal FDA-approved for MM is elotuzumab (Bristol-Myers Squibb), which binds the signaling lymphocytic activation molecule family 7 (SLAMF7, CD319, cell-surface glycoprotein CD2 subset 1/CS1), on the MM cell surface [ 67 ] . SLAMF7 is also modestly expressed on NK cells and certain T cells [ 68 , 69 ] . In combination with lenalidomide and dexamethasone, elotuzumab enhances progression-free survival (PFS) in RRMM.…”

“…Isatuximab (Sanofi/Genzyme) targets a specific epitope on the transmembrane glycoprotein CD38, different from that targeted by daratumumab, and inhibits CD38 hydrolase activity [ 68 - 75 ] . CD38 regulates migration and receptor-mediated adhesion by binding to CD31 or hyaluronic acid.…”

T cells isolated from G-CSF-treated multiple myeloma patients are suitable for the generation of BCMA-directed CAR-T cells

“…Presently, most developed CAR-T cells are autologous therapies that are made by transducing a CAR molecule into endogenous T cells derived from the patient that is destined to receive the treatment. 8 For MM, current clinical trials for anti-BCMA CAR-T cells have recruited patients who have relapsed multiple times in response to several therapeutic agents, including the three main families of drugs for this disease; proteasome inhibitors (bortezomib and carfilzomib), immunomodulatory drugs (lenalidomide and pomalidomide), and anti-CD38 monoclonal antibodies. 9 However, at this stage in the disease, T cell abnormalities are promoted by cytokines secreted by malignant plasma cells and suppressive immune cells as well as other thus far uncharacterized mechanisms.…”

Daratumumab for the Treatment of Multiple Myeloma: A Review of Clinical Applicability and Operational Considerations

“…1 Although still an incurable malignancy, recent decades have witnessed rapid improvements in treatment, from cytotoxic chemotherapy to more targeted and immunologic therapies. 2 Among the several recently approved novel therapeutics, monoclonal antibodies (MoAbs) have been shown to be particularly useful and their incorporation into MM care has generated excitement and focus among both patients and clinicians. 3 Among the MoAbs for MM, daratumumab began first-in-human trials in 2008 and was approved by the US Food and Drug Administration (FDA) in November of 2015 as monotherapy in the relapsed/refractory setting.…”