Facts and Hopes in Multiple Myeloma Immunotherapy

Abstract

Among the hallmarks of cancer is the ability of neoplastic cells to evade and suppress immune surveillance to allow their growth and evolution. Nowhere is this as apparent as in multiple myeloma, a cancer of antibody-producing plasma cells, where a complex interplay between neoplastic cells and the immune microenvironment is required for the development and progression of disease. Decades of research has led to the discovery of a number of therapeutic agents, from cytotoxic drugs to genetically engineered cells that mediate their antimyeloma effects at least partially through altering these immune interactions. In this review, we discuss the history of immunotherapy and current practices in multiple myeloma, as well as the advances that promise to one day offer a cure for this deadly disease.

Figure 1.

Schematic overview of immune therapies in multiple myeloma. Monoclonal antibodies recognize tumor antigens leading to inhibition of normal signaling or function of receptors, direct induction of apoptosis, antibody-directed cellular phagocytosis, antibody directed cellular cytotoxicity, complement-dependent cytotoxicity, immune stimulation, and via direct delivery of toxic payloads to tumor cells in the case of antibody-drug conjugates (ADCs). Chemotherapeutics such as bortezomib can induce immunogenic cell death leading to release of damage-associated molecular patterns (DAMPs) and stimulation of dendritic cells (DCs). CAR, chimeric antigen receptor; NK, natural killer; Treg, regulatory T-cell. Created with BioRender.com.

Figure 2.

Myeloma cells grow and evolve within a supportive bone marrow microenvironment. Mesenchymal stromal cells (MSCs) and tumor associated macrophages (TAMs) secrete supportive cytokines and growth factors that promote growth of myeloma cells. T-regulatory cells, myeloid-derived suppressor cells (MDSCs), and plasmacytoid dendritic cells (pDC) suppress natural immune targeting and protect malignant plasma cells from therapy. Myeloma cells suppress normal osteoblasts and promote osteoclast-mediated bone turnover to disrupt the normal microenvironment. Created with BioRender.com.

Figure 3.

Schematic of immunogenic cell death. XRT, X-ray therapy; UPR, unfolded protein response; DAMP, damage-associated molecular pattern; DC, dendritic cell. Created with BioRender.com.

Figure 4.

Schematic of T-cell engagers and chimeric antigen receptors. Bispecific T-cell engagers (BiTEs) have a CD3 binding moiety that can interact with the native T-cell receptor (TCR) fused to an antigen binding moiety that can target tumor antigens such as B-cell maturation antigen (BCMA) bringing T-cells into proximity of the tumor and inducing immune synapse and cytotoxicity. Chimeric antigen receptor (CAR) T-cells contain are genetically engineered to express a chimeric protein that includes an extracellular scFv domain capable of binding tumor antigens such as BCMA fused to a transmembrane (TM) domain, the CD3ζ stimulatory domain and a costimulatory (costim) domain, typically 4-1BB or CD28. Binding of the CAR to antigen leads to immune synapse formation and cytotoxicity. Created with BioRender.com.