ABSTRACT
Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School,
Boston, Massachusetts, U.S.A.
BACKGROUND
Multiple myeloma (MM) is the second most common hematological malignancy with an incidence of 4.3 per 100,000 in the general population, and a median survival of 3-5 years (1). It is a malignancy of the plasma cells, usually immature plasmablasts that exhibit chromosomal abnormalities. These early chromosomal abnormalities, such as translocations, result in overexpression of several important oncogenes (2-4). Eventually, malignant clones carrying these mutations progress and undergo further genetic insults leading to advanced disease. Environmental factors play an equally important role in the progression of the disease (Fig. 1). The malignant plasma cells home to the bone marrow (BM) where subsequent interactions promote MM cell growth, survival, and migration, as well as the development of drug resistance. The BM microenvironment (BMM) consists of extracellular matrix proteins such as laminin, collagen, fibronectin and osteopontin (5). The complex landscape of cells in the BMM includes hematopoietic stem cells, BM stromal cells (BMSC), BM endothelial cells, fibroblasts, osteoclasts and osteoblasts. Within the BMM, multiple signaling pathways and proteins are dysregulated in MM compared to normal plasma cells (6), including PI3K/Akt, MAPK, JAK/STAT, IKK/IkB/NF-kB, and HSP90, which therefore represent novel targets in MM (Fig. 2).
