Multiple myeloma is a disorder in which malignant plasma cells accumulate, generally derived from one clone in the bone marrow. Intricate interactions occur between the bone-marrow microenvironment and the myeloma cells, frequently causing bone destruction, which in turn stimulates tumor growth. Often it is preceded by a premalignant tumor called monoclonal gammopathy of undetermined significance (MGUS). Multiple oncogenic events have been identified that have contributed to the pathogenesis of myeloma. Among the earliest genetic events are translocations of the immunoglobulin heavy-chain gene locus, which leads to dysregulation of oncogenes at translocation partner regions (cyclin D1 at 11q13, FGFR3/MMSET at 4p16.3, c-MAF at 16q23, and cyclin D3 at 6p21), and deletions of 13q14, the site of a putative tumor suppressor gene. Additional molecular events include epigenetic changes and activation of oncogenes (mutations of N-RAS and K-RAS, and changes in c-MYC), which are usually associated with disease progression.
