Multiple Myeloma (MM) is a cancer of plasma cells resulting from the abnormal proliferation of malignant plasma cells within the bone marrow (BM) microenvironment. MM accounts for 1.3% of all malignancies and 12% of hematologic cancers, and is the second most commonly diagnosed blood cancer after non-Hodgkin lymphoma. The hallmark characteristics of MM include: high levels of intact monoclonal immunoglobulin or its fragment (free light chain) in serum or urine, and excess monotypic plasma cells in the bone marrow in conjunction with evidence ofend organ damage related to MM: (1) hypercalcemia, (2) renal failure, (3) anemia, and (4) osteolytic bone lesions or severe osteopenia, known as CRAB criteria.Even though novel agents targeting MM cells in the context of the BM microenvironment such as proteasome inhibitors, immunomodulatory drugs (IMiDs), and monoclonal antibodies have significantly prolonged survival in MM patients, the disease remains incurable. A deeper understanding of the molecular mechanisms of MM growth, survival, and resistance to therapy, such as genomic instability, clonal heterogeneity and evolution, as well as MM-BM microenvironmental host immune and other factors, will provide the framework for development of novel therapies to further improve patient outcome....