The role of the bone marrow microenvironment in multiple myeloma

The bone marrow microenvironment (BMME) is recognized as having a crucial role in the development and survival of multiple myeloma (MM). It is known to support MM tumor cells in a complex and dynamic way allowing evasion of apoptosis from anti-MM agents. This facilitates the acquisition of an increasingly drug resistant phenotype culminating in refractory terminal disease, thus mandating the need for new and insightful therapies in the context of the BMME. Cytokine-mediated drug resistance (CM-DR) can be caused by a variety of soluble factors that may act alone or in concert, for example, IL-6, IGF-1, VEGF, BAFF, APRIL, HGF, SDF-1, and IFN-I?. Likewise, cell adhesion-mediated drug resistance (CAM-DR) has also been described in MM. CAM-DR may result from MM cell interactions with VLA-4 and fibronectin (FN) and more recently other proteins with a potential role in CAM-DR, including CD138 and CS1, have been implicated. These soluble and contact-mediated stimuli lead to the activation of essential signaling pathways including JAK/STAT, PI3K/AKT, RAS/MAPK, and NFI?B that engender an antiapoptotic state. Models of the BMME provide some insight into the mechanisms of BMME-mediated drug resistance but have many practical limitations. Similarly, while MM cell lines allow for the reproducible evaluation of potential therapeutics they clearly are not representative of MM cells in vivo. Only through the development of reproducible and manageable coculture models of MM-BMME interactions will investigators be able to identify relevant drug targets that may overcome the survival advantage engendered by the BMME