Targeted therapy of multiple myeloma based upon tumor-microenvironmental interactions

Multiple myeloma (MM) remains incurable, but recent advances in genomics and proteomics have allowed for advances in our understanding of disease pathogenesis, identified novel therapeutic targets, allowed for molecular classification, and provided the scientific rationale for combining targeted therapies to increase tumor cell cytotoxicity and abrogate drug resistance. Besides these advances, recognition of the role of the bone marrow (BM) milieu in conferring growth, survival, and drug resistance in MM cells, both in laboratory and animal models, has allowed for the establishment of a new treatment paradigm targeting the tumor cell and its microenvironment to overcome drug resistance and improve patient outcomes in MM. In particular, thalidomide, bortezomib, and lenalidamide all overcome conventional drug resistance, not only by directly inducing tumor cell cytotoxicity, but by inhibiting adhesion of MM cells to BM. This abrogates constitutive and MM-binding-induced transcription and secretion of cytokines, inhibits angiogenesis, and augments host anti-MM immunity. These three drugs have rapidly translated from bench to bedside and in treatment protocols of MM, first in patients with relapsed refractory disease, and then alone and in combination in newly diagnosed patients. Promising novel targeted agents include the novel proteasome inhibitor NPI-0052 and the heat shock protein inhibitor KOS-953. Importantly, gene-array, proteomic, and cell-signaling studies have not only helped to identify in vivo mechanisms of action and drug resistance to novel agents, but also aided in the design of promising combination-therapy protocols.