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Figure 1. Novel agents targeting the myeloma cell and its bone marrow microenvironment. The interaction of MM cells with BMSCs, as well as other components in the BM milieu (i.e., OB, OC, vascular endothelial cells) is crucial in MM cell pathogenesis and drug resistance. Novel agents that target tumor and stromal compartments can be categorized as those that target protein dynamics (e.g., HSP90 and ubiquitin-proteasome system), intracellular signaling kinases (e.g., JAK/STAT, PI3k/Akt/mTOR, MAPK pathways), cell cycle molecular machinery (e.g., CDKIs and Aurora kinase inhibitors), membrane-bound receptors (e.g., IGF-1, VEGF and CD40), epigenetic modulators (e.g., DNA methyltransferase and HDAC), tumor vasculature and microenvironment (e.g., angiogenesis and integrins) and IMiDs. BAFF: B cell-activating factor; BM: Bone marrow; BMSC: Bone marrow stromal cell; CDK: Cyclin-dependent kinase; FTI: Farnesyl transferase inhibitor; HDAC: Histone deacetylase; HSP90: Heat-shock protein 90; IKK: IkB kinase; IMiD: Immunomodulatory analog; LT: Leukotriene; MM: Multiple myeloma; NK: Natural killer; OB: Osteoblast; OC: Osteoclast; SAHA: Suberoylanilide hydroxamic acid.
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Overview
Multiple myeloma (MM) is a clonal B-cell malignancy characterized by aberrant expansion of plasma cells within the bone marrow, as well as extrameduallary sites. The American Cancer Society estimated that approximately 20,580 new cases of MM (11,680 in men and 8900 in women) would be diagnosed in 2009. Advances in treatment have led to improvements in survival over the past decade. The 5-year survival rate reported in the Surveillance Epidemiology and End Results database has increased from 25% in 1975 to 34% in 2003. These improvements are largely a reflection of outcomes seen in the age group younger than 50 years, leading to 5- and 10-year relative survival rates of 56.7 and 41.3% in 2002-2004, respectively, and in the age group 50-59 years, leading to 5- and 10-year relative survival rates of 48.2 and 28.6%, respectively [1]. However, only modest improvement was seen in the age group 60-69 years, and essentially no improvement was noted among older patients. Novel biologically based therapeutic approaches that target not only the MM cell but also its interaction with other cells and cytokines in the bone marrow milieu have the potential to overcome resistance to conventional agents and improve patient outcomes in MM. The exciting progress in understanding the biology of MM has resulted in the...