The malignant clone and the bone-marrow environment.

Multiple myeloma (MM) is characterized by the clonal expansion of monoclonal immunoglobulin-secreting plasma cells within the bone marrow (BM). It has become clear that the intimate reciprocal relationship between the tumor cell clone and the niches of the BM microenvironment plays a pivotal pathophysiologic role in MM. We and others have identified several new molecular targets and derived novel therapies which induce cytotoxicity against MM cells in the BM milieu, including thalidomide, bortezomib, and lenalidomide. Importantly, these agents induce tumor-cell death, as well as inhibit MM-cell-BM-stromal-cell (BMSC) adhesion and related tumor-cell growth, survival, and migration. Moreover, they block both constitutive and MM-cell binding-induced growth factor and cytokine secretion in BMSCs. Further, they also block tumor angiogenesis and can augment anti-MM immunity. Although all three of these agents are now FDA-approved to treat MM, patients inevitably relapse, and further improvements remain urgently needed. Here we review our current knowledge of the MM cell clone, as well as the impact of the BM microenvironment on tumor-cell growth, survival, migration and drug resistance. Delineating the mechanisms and sequelae of the reciprocal relationship between the MM cell clone, distinct BM extracellular matrix proteins, and accessory cell compartments may provide the basis for new effective therapeutic strategies to re-establish BM homeostasis and thereby improve MM patient outcome.