Molecular pathogenesis of multiple myeloma: basic and clinical updates

Abstract

Multiple myeloma is divided into two distinct genetic subtypes based on chromosome content. Hyperdiploid myeloma is characterized by multiple trisomies of chromosomes 3, 5, 7, 9 11, 15, 19 and 21, and lacks recurrent immunoglobulin gene translocations. Non-hyperdiploid myeloma in contrast is characterized by chromosome translocations t(4;14), t(14;16), t(14;20), t(6;14) and t(11;14). A unifying event in the pathogenesis of multiple myeloma is the dysregulated expression of a cyclin D gene, either directly by juxtaposition to an immunoglobulin enhancer, as a result of ectopic expression of a MAF family transcription factor, or indirectly by as yet unidentified mechanisms. Secondary genetic events include rearrangements of MYC, activating mutations of NRAS, KRAS or BRAF, a promiscuous array of mutations that activate NFkB and deletions of 17p. Among the poor-risk genetic features are t(4;14), t(14;16), t(14;20), del 17p and gains of 1q. Available evidence supports the use of a risk-stratified approach to the treatment of patients with multiple myeloma, with the early and prolonged use of bortezomib particularly in patients with t(4;14) and del 17p.