Novel Quadruplets and the Age of Immunotherapies in the Treatment of Newly Diagnosed Multiple Myeloma

Abstract

Multiple myeloma (MM) is the second most common hematologic cancer, with an estimated worldwide incidence of over 175 000 newly diagnosed patients annually and over 130 000 patients living with the disease in the US. 1 Although there is not yet an established curative therapy, the past couple of decades have been heralded by the development of novel therapeutics translating into patients with myeloma living longer. This is especially highlighted by the US Food and Drug Administration (FDA) approvals of the first monoclonal antibody-based immunotherapies-the recent most exciting drugs have been those interrogating the immune system, either in vivo or ex vivo. Where historically patients derived only modest clinical benefit from traditional cytotoxic chemotherapies-fraught with significant toxicity-modern novel immunotherapies have not only significantly improved efficacy but have increased tolerability and quality of life for patients in this new era of MM.The current novel immunotherapies for MM showing great promise are of many types, but broadly speaking are of 4 classes. In the first class, naked monoclonal antibodies (eg, elotuzumab and daratumumab) target specific MMassociated tumor antigens (eg, SLAMF7 and CD38, respectively). Binding of the antibody, in turn, activates complementdependent cytotoxicity, antibody-dependent cellular cytotoxicity mediated by natural killer cells, and/or antibodydependent cellular phagocytosis mediated by macrophages leading to MM cell death. 2 In the second class of drugs, antibody-drug conjugates, the antibody targeting the myelomaspecific antigen is attached to a payload, which on binding to the MM cell is internalized (eg, belantamab mafodotin). The third and fourth classes of drugs, chimeric antigen receptor T-cell (CAR-T) therapies and bispecific T-cell engaging antibody (BiSAb) therapies, harness the powerful cytotoxic effects of T cells.Arguably, one of the most important developments in the field of MM for 2021-2022 has been the approval of the first and second B-cell maturation antigen (BCMA)-directed CAR-T therapies. CAR-T therapy involves the adoptive transfer of engineered autologous MM antigen-specific T cells that have been expanded in the laboratory. 3 Idecabtagene vicleucel and ciltacabtagene autoleucel were approved based on an overall response rate of 73% and 97%, a complete response rate of 33% and 67%, and a minimal residual disease (MRD) negativity rate of 26% and 34%, respectively, in highly refractory patient populations. 4,5 Bispecific T-cell engaging antibodies create an immunologic synapse between endogenous T cells and MM cells through their respective target antigens (eg, CD3 and

Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone for the Treatment of High-Risk Newly Diagnosed Multiple Myeloma

“…30 As we and others have shown that high rates of MRD negativity and sustained MRD negativity are achieved with extensive quadruplet treatment approaches, it is time to re-evaluate the role of high-dose melphalan, especially considering recent findings of significantly increased mutational burden and detrimental long-term effects of genomic damage. [32][33][34][35] In the near future, consequent implementation of T-cell engaging strategies in frontline treatment with CAR-T cell application replacing high-dose melphalan or use of bispecific antibodies in maintenance strategies will allow further treatment optimization and are expected to achieve unprecedented high MRD negativity and sustained MRD negativity rates. standard-of-care arm was ethically not justifiable.…”

CD38‐Specific Gallium‐68 Labeled Peptide Radiotracer Enables Pharmacodynamic Monitoring in Multiple Myeloma with PET

“…[ 9 ] However, there are efforts underway to reduce toxicity by tailoring or tapering treatment in patients who have little or no detectable measurable residual disease (MRD). [ 10 ] As a result, accurate detection of small amounts of disease will become increasingly important for this growing patient population. Also, efforts are underway to increase CD38 expression on MM cells by treatment with agents such as all‐trans retinoic acid (ATRA) to take advantage of the excellent anti‐CD38 therapeutic options available.…”