Background: The presence of high numbers of cPCs in patients with SMM, detected by a slide-based immunofluorescence assay, has been associated with a shorter time to progression (TTP) to multiple myeloma (MM). The significance of quantifying cPCs via MFC, a much more readily available diagnostic modality, in patients with SMM has not been evaluated. Methods: This study evaluated patients with a known or new diagnosis of SMM who were seen at the Mayo Clinic, Rochester from January 2008 until December 2013 and who had their peripheral blood evaluated for cPCs by six-color MFC. cPCs were selectively analyzed through combinatorial gating using light scatter properties and CD38, CD138, CD19, and CD45. The cPCs detected were reported out as the number of clonal events/150,000 collected total events. Survival analysis was performed by the Kaplan-Meier method and differences assessed using the log rank test. Results: There were 100 patients with a known diagnosis of SMM who had their peripheral blood evaluated by MFC for clonal cPCs prior to disease progression. The median follow up was 37 months (95% CI: 32 – 41). There were 31 (31%) patients who had progressed to MM requiring treatment at the time of last follow up. There were 24 patients who had detectable cPCs. The median number of cPCs was 78 per 150,000 events analyzed (Range: 20 – 3124). Patients with 150 or more cPCs (N = 9) had a 97% specificity and 78% PPV for progression to MM within 2 years and hence the presence of 150 or more cPCs was chosen as a cutoff to define high levels of cPCs (due to its nearly 80% PPV). The median TTP of patients with 150 or more cPCs was 9 months compared to not reached for patients with less than 150 cPCs (P < 0.001). The estimated three and five year OS was 79% and 67% for patients with 150 or more cPCs and 97% and 95% for patients with less than 150 cPCs (P = 0.043). Conclusions: Quantification of cPCs via MFC identifies patients with SMM at very high risk of progression to MM within 2 years and warrants confirmation in larger studies. In the future, this may allow reclassification of such patients as having MM requiring therapy prior to them enduring end-organ damage.