The Cancer-Immunity Cycle in Multiple Myeloma

Abstract

Multiple myeloma is a plasma cell malignancy that primarily affects the elderly. The global burden of multiple myeloma is increasing in many countries due to an aging population. Despite recent advances in therapy, myeloma remains an incurable disease, highlighting the pressing need for new therapies. Accumulating evidence supports that triggering the host immune system is a critical therapeutic mechanism of action by various anti-myeloma therapies. These anti-myeloma therapies include proteasome inhibitors, immunomodulatory drugs, monoclonal antibody drugs, and autologous stem cell transplantation. More recently, T cell-based immunotherapeutics (including chimeric antigen receptor T-cell therapies and bispecific T-cell engagers) have shown dramatic clinical benefits in patients with relapsed or refractory multiple myeloma. While immune-based therapeutic approaches are recognized as key modalities for improved clinical outcomes in myeloma patients, understanding the immune system in multiple myeloma patients remains elusive. The cancer-immunity cycle is a conceptual framework illustrating how immune cells recognize and eliminate tumor cells. Based on this framework, this review will provide an overview of the immune system in multiple myeloma patients and discuss potential therapeutic approaches to stimulate anti-tumor immunity.

Keywords: immune checkpoint; immunosuppression; immunotherapy; multiple myeloma.

Figure 1

The cancer-immunity cycle in multiple myeloma and its negative regulation. A schematic illustrating seven steps of the cancer-immunity cycle and their negative regulatory mechanisms in multiple myeloma (blue boxes).

Figure 2

Therapeutic approaches to stimulate the cancer-immunity cycle in multiple myeloma. A schematic illustrating how anti-myeloma therapies differentially stimulate the cancer-immunity cycle. Myeloma antigen-presentation can be augmented by immunogenic cell death inducers, enhancing phagocytosis or DC-based vaccine. Regulatory T (Treg) cells are critical regulators for T-cell priming, and thus mAbs against CTLA-4 or CD38 stimulate T-cell priming. Immunomodulatory drugs and immune checkpoint inhibitors improve recognition and killing of myeloma cells by cytotoxic lymphocytes. Chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engager antibodies allow T cells to recognize and eliminate tumor cells in a MHC-independent fashion. Autologous stem cell transplant has pleiotropic impacts on the cancer-immunity cycle.