Understanding multiple myeloma pathogenesis in the bone marrow microenvironment

Multiple myeloma (MM) is the second most common hematologic malignancy and is characterized by accumulation of monoclonal plasma cells in the bone marrow (BM) with complex heterogeneous cytogenetic abnormalities. It remains incurable and novel biologically based therapies are urgently needed. Similar to other cancers frequently causing bone metastases (ie., breast, prostate and lung cancers), MM cells interact with different types of cellular components, including BM stromal cells, osteoblast, osteoclast and vascular endothelial cells in the BM microenvironment. The interaction of MM cells with these cells is mediated by soluble factors (i.e., cytokines, chemokines) and cell-cell contact via cell adhesion molecules (i.e., integrins). This interaction triggers activation of intracellular signaling pathways in MM cells, such as Ras/MEK/ERK, Jak2/STAT3, PI3K/Akt and IKK/NF-κB cascades. It also induces cell adhesion-mediated drug resistance (CAM-DR) to overcome conventional therapeutic agents. Moreover, existence of crosstalk between these signaling cascades shows the complexity of signal transduction network in MM cells in the BM microenvironment. Importantly, MM cells also mediate activation, differentiation and/or proliferation of osteoblast and osteoclast. Targeting the BM microenvironment therefore represents a novel therapeutic strategy in MM. Indeed, novel therapeutic agents have been showing remarkable clinical activities in MM patients by targeting both MM tumor cells and their BM microenvironment.