Novel therapeutic strategies for multiple myeloma

Abstract

Multiple myeloma (MM) is a plasma-cell malignancy which remains incurable despite the recent emergence of multiple novel agents. Importantly, recent genetic and molecular analyses have revealed the complexity and heterogeneity of this disease, highlighting the need for therapeutic strategies to eliminate all clones. Moreover, the bone marrow microenvironment, including stromal cells and immune cells, plays a central role in MM pathogenesis, promoting tumor cell growth, survival, and drug resistance. New classes of agents including proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors have shown remarkable efficacy; however, novel therapeutic approaches are still urgently needed to further improve patient outcomes. In this review, we discuss the recent advances and future strategies to ultimately develop MM therapies with curative potential.

Figure 1. The overview of novel therapeutic approaches for multiple myeloma (MM)

The scheme of novel therapeutic targets and treatment options (#1–13) discussed in this review article are highlighted. The specific treatment options and representative drugs are also shown below. 1: IRE1α inhibitors (MKC-3946 [42], STF-083010 [45]), 2: HSP90 inhibitors (17-AAG, TAS-116 [30]), 3: PI3K inhibitors (CAL-101 [76]), 4: Akt inhibitors (perifosine, afuresertib [74], TAS-117 [23], MK-2206 [72]), 5: mTOR inhibitors (rapamycin, everolimus, temsirolimus), 6: MEK inhibitors (selumetinib), 7: NF-κB inhibitors (PBS-1086 [87]), 8: HDAC inhibitors (vorinostat, panobinostat, ricolinostat [107], BG45 [112]), 9: EZH2 inhibitors (UNC1999 [120]), 10: synthetic miRNAs (miR-29b [123], miR-34a [124]), 11: Bromodomain inhibitors (JQ1 [128]), 12: PD-1/PD-L1 antibodies (CT-011 [143]), 13: PDE5 inhibitors PIs (proteasome inhibitors): bortezomib, carfilzomib, ixazomib, marizomib IMiDs (immunomodulatory drugs): thalidomide, lenalidomide, pomalidomide Anti-SLAMF7 antibody: elotuzumab Anti-CD38 antibody: daratumumab