Immunotherapy for the treatment of multiple myeloma

Abstract

Immunotherapy has recently emerged as a promising treatment for multiple myeloma (MM). There are now several monoclonal antibodies that target specific surface antigens on myeloma cells or the checkpoints of immune and myeloma cells. Elotuzumab (targeting SLAMF7), daratumumab (targeting CD38), and pembrolizumab (targeting PD-1) have shown clinical activity in clinical studies with relapsed/refractory MM. Dendritic cell vaccination is a safe strategy that has shown some efficacy in a subset of myeloma patients and may become a crucial part of MM treatment when combined with immunomodulatory drugs or immune check-point blockade. Genetically engineered T cells, such as chimeric antigen receptor T cells or T cell receptor-engineered T cells, have also shown encouraging results in recent clinical studies of patients with MM. In this paper, we discuss recent progress in immunotherapy for the treatment of MM.

Introduction

Multiple myeloma (MM) is an incurable B-cell malignancy characterized by the aberrant expansion of clonal malignant plasma cells into bone marrow that eventually causes renal failure, anemia, infection, and osteolytic bony lesions (Kyle and Rajkumar, 2004). MM accounts for 1% of all cancers and more than 10% of all hematological malignancies in the United States (Siegel et al., 2015). The incidence of MM in Korea has rapidly increased in recent years (Lee et al., 2010). The prognosis for patients with MM has improved with the development of novel effective agents, and median survival has increased to approximately 6 years (Kumar et al., 2014). However, most patients with MM eventually relapse and develop resistance to their treatments. New therapies that increase the response and survival rates with minimal toxicity are needed.

Immunotherapy has recently emerged as a promising treatment for many cancers. In MM, the efficacy of immunotherapy is based on the observation that allogenic stem cell transplantation is curative for a subset of patients with MM due to the graft-versus-myeloma (GVM) effect (Tricot et al., 1996). In addition, the GVM effect is supported by disease response following donor lymphocyte infusions (Bellucci et al., 2004). However, allogenic stem cell transplantation does not have specific immune activity for myeloma cells and is associated with significant morbidity and mortality, including graft-versus-host disease. Therefore, investigators have focused on developing new tools to elicit myeloma-specific immune responses. An example of a new immunotherapeutic strategy is the development of a monoclonal antibody(mAb)-targeting surface antigen on myeloma cells (Table 1). Daratumumab, targeting CD38 and elotuzumab, targeting signaling lymphocyte activation molecule F7 (SLAMF7), have shown clinical activity in monotherapy or combination therapy with other agents in clinical studies. In addition, cellular immunotherapy using dendritic cell (DC) vaccination and adoptive immunotherapy with chimeric antigen receptor (CAR) T cells or T cell receptor (TCR)-engineered T cells are emerging as promising treatment strategies for MM.

This review focuses on recent preclinical and clinical data from the dominant mAbs, DC vaccine, and genetically engineered T cell therapies for MM.