Immunotherapy of multiple myeloma

Abstract

Multiple myeloma (MM), a bone marrow-resident hematological malignancy of plasma cells, has remained largely incurable despite dramatic improvements in patient outcomes in the era of myeloma-targeted and immunomodulatory agents. It has recently become clear that T cells from MM patients are able to recognize and eliminate myeloma, although this is subverted in the majority of patients who eventually succumb to progressive disease. T cell exhaustion and a suppressive bone marrow microenvironment have been implicated in disease progression, and once these are established, immunotherapy appears largely ineffective. Autologous stem cell transplantation (ASCT) is a standard of care in eligible patients and results in immune effects beyond cytoreduction, including lymphodepletion, T cell priming via immunogenic cell death, and inflammation; all occur within the context of a disrupted bone marrow microenvironment. Recent studies suggest that ASCT reestablishes immune equilibrium and thus represents a logical platform in which to intervene to prevent immune escape. New immunotherapies based on checkpoint inhibition targeting the immune receptor TIGIT and the deletion of suppressive myeloid populations appear attractive, particularly after ASCT. Finally, the immunologically favorable environment created after ASCT may also represent an opportunity for approaches utilizing bispecific antibodies or chimeric antigen receptor T cells.

Figure 1. Potential immunoediting in multiple myeloma.

Cancer immunoediting involves three sequential phases: elimination, equilibrium, and escape (15). Elimination is mediated by collaboration of the adaptive and the innate immunity to eradicate malignant cells prior to the onset of clinical presentation. However, if elimination is incomplete and rare myeloma cell variants enter dormancy, equilibrium is established. After autologous stem cell transplantation (ASCT), equilibrium is mediated by effector T cells and is IFN-γ–dependent. Escape is associated with the accumulation of genetic mutations, resistance to immune effectors, CD8⁺ T cell exhaustion, and changes in the microenvironment. Regulatory T cells (Tregs), suppressive dendritic cells (DCs), T helper 17 (Th17) cells, tumor-associated macrophages, and myeloid-derived suppressor cells (MDSCs) all encourage escape and inhibit CD8⁺ T cell function. ASCT appears to restore a period of immune equilibrium but is usually followed by further escape and disease progression.

Figure 2. Immunotherapies for myeloma.

Immunotherapies for myeloma target the tumor itself, suppressive myeloid populations, and/or immune cells. CD38-targeted mAbs target CD38-expressing myeloma cells and suppressive myeloid cells by antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP), which also facilitates immune cell activation. Autologous stem cell transplantation (ASCT) disrupts the tumor microenvironment (TME), directly eliminates myeloma cells, and promotes T cell–mediated antimyeloma responses. Chimeric antigen receptor T cells (CAR T) and oncolytic viruses directly promote lysis of myeloma cells. Immune checkpoint inhibitors and cancer vaccination approaches directly enhance T and NK cell–mediated antimyeloma responses. Immunomodulatory imide drugs (IMiDs) directly inhibit myeloma cell growth, reduce angiogenesis, and promote immune cell activation.

Figure 3. Induction of a favorable immunological environment after ASCT.

Active myeloma is associated with an immunosuppressive bone marrow (BM) microenvironment that is characterized by an expansion of suppressive dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), CSF-1R–expressing macrophages, regulatory T cells (Tregs), and exhausted CD8⁺ T cells. T cell exhaustion occurs in response to chronic antigen exposure and IL-10 derived from suppressive DCs. Furthermore, myeloma cell growth is supported by IL-17A from Th17 cells and paracrine IL-6 production. After ASCT, a lymphodepleted and inflammatory environment is created that promotes myeloma-specific memory T cell expansion and the priming of naive T cells by functional dendritic cells. Myeloma-specific CD8⁺ effector T cells (Teff) mediate IFN-γ–dependent myeloma-specific immunity in the context of CD4⁺ T cell help.