Perspectives Promising therapies in multiple myeloma

Progress in medical research has enhanced our understanding of tumor biology, delineated genetic and molecular mechanisms of tumor growth and survival, and defined the impact of the microenvironment in cancer pathogenesis. As a consequence of these advances, cancers deemed rapidly fatal only a few decades ago can now be treated effectively, with prolonged survival in an increasing proportion of patients. This is particularly true formultiplemyeloma (MM), inwhich the introduction of drugs targeting the tumor in its microenvironment, such as the proteasome inhibitor bortezomib and the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, into initial, consolidation, maintenance, and salvage therapies has markedly improved patient outcome. In this perspective, we discuss the most promising therapies to even further improveMM treatment, with a focus on drugs inhibiting the ubiquitin-proteasome pathway; histone deacetylase (HDAC) inhibitors (HDACIs); immune therapies including IMiDs, monoclonal antibodies (mAbs), immune checkpoint inhibitors, agents targeting accessory plasmacytoid dendritic cells (pDCs), vaccines, and chimeric antigen receptor–engineeredT (CAR-T) cells; drugs targeting tumor cell homing to, and exploitinghypoxia in, the bonemarrow (BM) microenvironment; molecularly targeted therapies against kinesin spindle protein (KSP), v-aktmurine thymomaviral oncogene homolog 1 (AKT), exportin 1 (XPO1), cyclin-dependent kinases (CDKs), bromodomain and extraterminal (BET) bromodomain 4, and serine/ threonine kinase 4 (STK4); as well as delineating the impact of genomics on MM therapy. These advances in understanding the biology of MM will allow for earlier treatment of patients using rationally informed combination therapies with curative potential.