Pathology and Genetics of Multiple Myeloma

Multiple myeloma (MM) is a genetically complex and heterogeneous disease resulting from multiple genomic events leading to tumor development and progression. Uncovering and dissecting true driver events in MM might provide rational for new potential targets and therapeutic option in the disease. All MM are preceded by a monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). This model of the disease provides a framework to understand the genomic hierarchy in MM. Events found at MGUS stages are likely to be primary events and involved in tumor development. On the contrary, events present at the MM stage and absent in MGUS are likely to be secondary events leading to tumor progression. Similarly, the study of clonal heterogeneity—defining clonal or sub-clonal genomic events—also helps to dissect the phylogeny of tumors. Hierarchically, primary events are usually divided into hyperdiploid (HDR) and nonhyperdiploid subtypes. HRD tumors are characterized by trisomy of chromosomes 3, 5, 7, 9, 11, 15, 19, and/or 21. Non-HRD tumors harbor IGH translocations, mainly t(4;14), t(6;14), t(11;14), t(14;16), and t(14;20). Secondary events are required for tumor progression. Most of the copy number variations (CNV), MYC translocations and somatic mutations in MAPK, NF-kB, and DNA repair pathways are only seen at MM stages and not in pre-malignant stages and are therefore potential secondary events. However, the distinction between driver and passenger events is a current challenge to interpret correctly the genomic landscape of MM.