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Multiple myeloma evolves clinically from monoclonal gammopathy of undetermined significance through smoldering disease, active myeloma with end organ damage to a preterminal phase of extramedullary disease and marrow collapse. The molecular equivalents of such clinical observation can now be defined as genetically dormant, genetic crisis and genetic chaos (popularly termed malignant myeloma). Patients may present for the first time in any one of these stages. Not surprisingly, clinical outcomes for multiple myeloma are variable and the prospects for therapeutic responsiveness are defined by the stage at presentation. We describe here a genetically driven definition of high- and low-risk myeloma and offer guidelines for the adoption of routine diagnostic testing. We define high-risk disease as the presence of t(4;14), t(14;16), deletion 17p13 by FISH or the presence of hypodiploidy or deletion of chromosome 13 by conventional cytogenetics. By default, other patients are not considered high risk. Thus, as a minimum, we recommend routine testing for t(4;14) and 17p13 deletion by FISH and conventional cytogenetics. This classification will identify multiple myeloma patients at high genetic risk for early progression after conventional therapies.