Progressive genetic events in MM. Although not every stage is discernible in each patient, there appears to be an ordered progression from a normal plasma cell; to MGUS where the cells are immortalized, but not transformed, and do not progressively accumulate or cause bone destruction; to intra-medullary myeloma, where the cells are confined to the BM micro-environment, accumulate and cause bone destruction; to extra-medullary myeloma, where the cells proliferate more rapidly and grow in the blood (plasma cell leukemia) or other extra-medullary sites; to a myeloma cell line, where the cells may be propagated in vitro. This model summarizes the possible timing of genetic events in relation to clinical progression. When the event may occur at a discrete time, we have indicated this with an arrow. When it is clearly associated with a defined clincal stage we have indicated this with a solid line. When the timing is unclear, we have used a dashed line. We suspect that the 14q32 translocation may be an early event, concordant with isotype switch recombination, so that it may precede MGUS. Some translocations [eg, t(11;14)] may lead more rapidly to fulminant disease. There is evidence of karyotypic instability in MGUS that continues throughout all stages of tumour progression. Monosomy 13 is present in intramedullary myeloma, independent of stage, but there is no evidence as to whether or not it is present in MGUS. Dysregulation of c-myc appears to be common, but the timing is unclear. In patients with ectopic FGFR3 expression caused by t(4;14), a mutation of FGFR3 could lead to ligand independence and clinical progression, as is suggested in one analyzed example. Mutations of N- and K-ras are not present in MGUS, but are present in intramedullary myeloma, with an increasing incidence as the disease progresses. Mutations of p53 are a late event associated with aggressive extra-medullary myeloma.