Immunotherapy for Multiple Myeloma

Abstract

Despite therapeutic advances over the past decades, multiple myeloma (MM) remains a largely incurable disease with poor prognosis in high-risk patients, and thus new treatment strategies are needed to achieve treatment breakthroughs. MM represents various forms of impaired immune surveillance characterized by not only disrupted antibody production but also immune dysfunction of T, natural killer cells, and dendritic cells, although immunotherapeutic interventions such as allogeneic stem-cell transplantation and dendritic cell-based tumor vaccines were reported to prolong survival in limited populations of MM patients. Recently, epoch-making immunotherapies, i.e., immunomodulatory drug-intensified monoclonal antibodies, such as daratumumab combined with lenalidomide and chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen, have been developed, and was shown to improve prognosis even in advanced-stage MM patients. Clinical trials using other antibody-based treatments, such as antibody drug-conjugate and bispecific antigen-directed CD3 T-cell engager targeting, are ongoing. The manipulation of anergic T-cells by checkpoint inhibitors, including an anti-T-cell immunoglobulin and ITIM domains (TIGIT) antibody, also has the potential to prolong survival times. Those new treatments or their combination will improve prognosis and possibly point toward a cure for MM.

Keywords: allogeneic stem cell transplantation; antibody drug-conjugate (ADC); bispecific antigen-directed CD3 T-cell engager; chimeric antigen receptor T-cell (CAR-T) therapy; immune checkpoint inhibitor; immunotherapy; multiple myeloma; tumor vaccine.

Figure 1

Immune evasion and anti-CD38 monoclonal antibody-targeting cells in the myeloma microenvironment. T-cell immune function is inhibited by the surrounding immunosuppressive cells, such as regulatory T cells (Tregs), regulatory B cells (Bregs), and myeloid-derived suppressor cells (MDSCs), signaling from immune checkpoint receptors. Anti-CD38 antibodies can eliminate myeloma cells as well as immunosuppressive cells.

Figure 2

Combined immunotherapy. Radiotherapy (RT) can induce immunogenic cell death, resulting in dendritic cell (DC) activation through “eat-me (calreticulin-CD91)”, “danger (HMGB1-TRL4)”, and “find-me (ATP-P2RX7)” signals, leading to enhanced cytotoxic T-cell lymphocyte (CTL) function.