Mechanisms of cell death and survival in multiple myeloma (MM): Therapeutic implications

Multiple myeloma (MM), a hematologic malignancy, remains fatal despite all available therapies. Initial treatment with conventional drugs effectively induces MM cell death/apoptosis; however, prolonged drug exposures results in the development of de novo chemoresistance. Because MM is a bone marrow (BM) cancer, the progression of disease and drug efficacy is highly influenced by the BM microenvironment. Novel agents, such as proteasome inhibitors (PS-341), 2-methoxyestradiol (2ME2), thalidomide and its immunomodulatory derivatives (IMiDs), and histone deacetylase (HDAC) inhibitors target the MM cell in its BM microenvironment; thereby enhancing anti-MM activity as well as preventing development of drug-resistance. The transcriptional events and signaling pathways, which mediate these responses in MM cells are now being delineated, and may serve to identify novel therapeutic targets based upon interrupting MM cell growth or triggering MM cell death.