A model of disease progression. Multiple myeloma is characterized by the clonal expansion of malignant plasma cells driven by initiating genetic events, such as oncogene activating translocations, for example, t(4;14), hyperdiploidy, deletion of chromosome 13, and deletion of 17p13. During subclinical growth, an inherent genomic instability characteristic of these terminally differentiated cells leads to secondary genetic events, such as gains of chromosome 1q and deletion of 1p as well as gains of 8q24, that provide a growth and/or survival advantage to a subpopulation of cells. A gene expression–based signature, reflective of a minimum proportion of cells with these secondary lesions, can define high-risk disease. Following therapy, such as stem-cell supported high-dose melphalan, a sizeable portion of patients achieve complete remission that can be monitored by MFC. Toward relapse, both the percentage of tumor cells with gains of chromosome 1q and molecular risk score invariably increase. These data suggest that a subpopulation of high-risk cells survives therapy and eventually contributes to progressively resistant relapses. The use of MFC to measure MRD, as reported by Paiva et al, appears well suited for the identification of cell-surface marker(s) discriminating tumor subpopulations, exhibiting differential cytoreduction and regrowth kinetics, with significant impact on the clinical management of the disease.