Next-Generation Therapies for Multiple Myeloma

Abstract

Recent therapeutic advances have significantly improved the outcome for patients with multiple myeloma (MM). The backbone of successful standard therapy is the combination of Ikaros degraders, glucocorticoids, and proteasome inhibitors that interfere with the integrity of myeloma-specific superenhancers by directly or indirectly targeting enhancer-bound transcription factors and coactivators that control expression of MM dependency genes. T cell engagers and chimeric antigen receptor T cells redirect patients' own T cells onto defined tumor antigens to kill MM cells. They have induced complete remissions even in end-stage patients. Unfortunately, responses to both conventional therapy and immunotherapy are not durable, and tumor heterogeneity, antigen loss, and lack of T cell fitness lead to therapy resistance and relapse. Novel approaches are under development to target myeloma-specific vulnerabilities, as is the design of multimodality immunological approaches, including and beyond T cells, that simultaneously recognize multiple epitopes to prevent antigen escape and tumor relapse.

Keywords: CAR T cell; EP300; T cell engagers; bispecific antibody; chimeric antigen receptor; multiple myeloma; superenhancers.

Figure 1

Timeline of introduction and FDA approval of drugs for the treatment of MM. Drugs are colored on the basis of the six main classes to which they belong. Drugs colored in black have relatively unique mechanisms of action and more limited use. For two of these (panobinostat and belantamab mafodotin), FDA approval was withdrawn in 2022. Abbreviations: ACTH, adrenocorticotropic hormone; ADC, antibody drug conjugate; BCMA, B cell maturation antigen; CAR, chimeric antigen receptor; cilta-cel, ciltacabtagene autoleucel; ide-cel, idecabtagene vicleucel; FcRH5, Fc receptor homolog 5; FDA, US Food and Drug Administration; GPRC5D, G protein–coupled receptor, class C group 5 member D; HDACi, histone deacetylase inhibitor; mAb, monoclonal antibody; MM, multiple myeloma.

Figure 2

Myeloma cell biology and therapeutic clinical targets. Myeloma is the malignant counterpart of a terminally differentiated bone marrow plasma cell that secretes a large amount of monoclonal antibody. This puts the endoplasmic reticulum under continuous stress, further aggravated by PIs, creating a unique vulnerability. PIs also prevent NFκB activation by inhibiting processing of the inactive NFκB2 P100 to its active form, P52. NFκB is a key survival factor for MM cells, at least in part by promoting the transcription of prosurvival protein BCLX_L and BCL2, the latter being a direct target of venetoclax. NFκB, with IKZF1 and other transcription factors, also plays a central role in maintaining the activity of myeloma superenhancers that drive the expression of MYC and IRF4, key MM dependencies. Transcription factors bind to superenhancers and recruit EP300 to deposit the H3K27 acetyl marks that, once read by BRD4, allow the recruitment of RNAPII and transcription elongation. Several classes of drugs impair superenhancer function: PIs and glucocorticoids directly or indirectly target NFκB, while Ikaros degraders and ION251 induce degradation of IRF4 and IKZF1, respectively; BET, HDAC, and EP300 inhibitors target these coactivators. NFκB expression is dependent on the binding of BAFF and APRIL to their receptor BCMA, although constitutive activation of NFκB occurs in 20% of patients with MM. Because of its restricted expression in plasma cells, BCMA is an ideal target for antibody drug conjugate, bispecific antibodies, and CAR T cells. Other cell surface receptor targets in MM are CD38 and SLAMF7, which are targeted by monoclonal antibodies, and GPRC5D and FcRH5, which are targeted by bispecific antibodies. Selinexor inhibits the nuclear export of tumor suppressor genes. Abbreviations: BCMA, B cell maturation antigen; CAR, chimeric antigen receptor; FcRH5, Fc receptor homolog 5; GPRC5D, G protein–coupled receptor, class C group 5 member D; GR, glucocorticoid receptor; HDAC, histone deacetylase; MM, multiple myeloma; PI, proteasome inhibitor; RNAPII, RNA polymerase II. Figure adapted from images created with BioRender.com.

Figure 3

Mechanisms of action and new approaches for CAR T cell and T cell engager therapies to treat MM. Current cell therapy for MM involves engineering autologous T cells to express a CAR that recognizes specific antigens on the surface of tumor cells (depicted in the box), resulting in (①) immunological synapse formation, (②) T cell activation via intracellular CAR signaling domains, and (③) tumor cell killing. All CAR T cells approved to treat MM target BCMA. Numerous strategies are being evaluated to improve the clinical efficacy of CAR T cell therapy for MM (left). Current T cell engagers, also called bispecific antibodies, for treating MM utilize antibody-like molecules designed to simultaneously bind a tumor antigen (depicted in the box) and the T cell surface protein CD3, part of the common T cell receptor complex. The physical binding of CD3 on T cells leads to immunological synapse formation, T cell activation, and tumor cell killing. Numerous strategies are being evaluated to improve the clinical efficacy of T cell engager therapy for MM (right). Abbreviations: allo, allogeneic; BCMA, B cell maturation antigen; CAR, chimeric surface receptor; FcRH5, Fc receptor homolog 5; GPRC5D, G protein–coupled receptor, class C group 5 member D; MM, multiple myeloma; NK, natural killer cell; TCR, T cell receptor; sBCMA, soluble BCMA. Figure adapted from images created with BioRender.com.