Immunotherapy in myeloma: how far have we come?

Abstract

The treatment of multiple myeloma (MM) has evolved substantially over the past decades, leading to a significantly improved outcome of MM patients. The introduction of high-dose therapy, especially, and autologous stem cell transplantation, as well as the development of new drugs, such as immunomodulatory drugs (IMiDs) and proteasome inhibitors have contributed to the improvement in survival. However, eventually most MM patients relapse, which indicates that there is a need for new agents and novel treatment strategies. Importantly, the long-term survival in a subset of MM patients after allogeneic stem cell transplantation illustrates the potential of immunotherapy in MM, but allogeneic stem cell transplantation is also associated with a high rate of treatment-related mortality. Recently, a better insight into several immune-evasion mechanisms, which contribute to tumor progression, has resulted in the development of active and well-tolerated novel forms of immunotherapy. These immunotherapeutic agents can be used as monotherapy, or, even more successfully, in combination with other established anti-MM agents to further improve depth and duration of response by preventing the outgrowth of resistant clones. This review will discuss the mechanisms used by MM cells to evade the immune system, and also provide an overview of currently approved immunotherapeutic drugs, such as IMiDs (e.g. lenalidomide and pomalidomide) and monoclonal antibodies that target cell surface antigens present on the MM cell (e.g. elotuzumab and daratumumab), as well as novel immunotherapies (e.g. chimeric antigen receptor T-cells, bispecific antibodies and checkpoint inhibitors) currently in clinical development in MM.

Keywords: CAR-T cells; IMiDs; bispecific antibodies; checkpoint inhibitors; immunotherapy; monoclonal antibodies; multiple myeloma.

Figure 1.

Schematic overview of immunotherapeutic options in multiple myeloma. Ab: antibody; allo-SCT: allogeneic stem cell transplantation; CAR T-cells: chimeric antigen receptor T-cells; DLI: donor lymphocyte infusion; IMiDs: immunomodulatory drugs; NK: natural killer; PD-1: programmed death receptor 1; PD-L1: programmed death ligand 1; SLAMF7: signaling lymphocytic activation molecule family 7.

Figure 2.

Schematic overview of mHag presentation on recipient cells leading to activation of donor T-cells. Genetic polymorphisms leading to differences in amino acids can give rise to differential presentation of mHags on cells of the recipient (right), whereas cells of the donor present no antigen or a different antigen. mHag: minor histocompatibility antigen; MHC: major histocompatibility complex; SNP: single nucleotide polymorphism; TCR: T-cell receptor.

Figure 3.

The ubiquitin E3-ligase complex CRL4^CRBN causing ubiquitination of IKZF1 and IKZF3 after IMiD binding, leading to their proteasomal degradation and subsequent immunomodulatory and MM cytotoxic effects. CRBN: Cereblon; CUL4: cullin 4A; DDB1: damage-specific DNA binding protein; IKZF: Ikaros family zinc finger protein; IL-2: interleukin 2; IRF4: interferon regulatory factor 4; MM: multiple myeloma; ROC1: RIN G finger protein 1; TNF: tumor necrosis factor.