Background: Translocation (4;14) and deletion 17p in smoldering multiple myeloma (SMM) have been identified as high risk cytogenetic abnormalities (CAs). Risk stratification incorporating CAs and biomarkers are needed to identify high risk SMM patients. The aim of this study was to determine the predictive value of the free light chain (FLC) assay in combination with high-risk CAs. Methods: The study included SMM patients seen at Mayo Clinic from 1991-2010 screened for available FISH and serum FLCs at diagnosis. Receiver operating characteristics analysis determined the optimal involved FLC (iFLC) cut-point to predict progression to MM within 24 months. Univariate analysis and multivariate analysis were performed. Time to progression (TTP) was calculated using Kaplan-Meier analysis. Results: The FLC was measured in 249 patients; t(4;14) was found in 33 (13.3%) and deletion 17p in 6 (2.4%). Median age at SMM diagnosis was 62 years (range, 30-90). The optimal iFLC cut-point was 41 mg/dL. The iFLC was >40 in 23% of the 39 high-risk CA (n=9) and 22% of non-high risk CA patients (n=46). In the high-risk CAs group, median TTP if iFLC >40 was 20 months (95% CI 5-24) versus 30 months (19-60) in the iFLC <40 group. In the low-risk CAs, median TTP if iFLC >40 was 34 months (26-51) versus 62 months (48-86) in the iFLC <40 group (p <0.0001). One and two-year progression rates for iFLC >40 in high-risk CAs were 23% and 89%. In comparison, progression rates were 7% and 14% at one and two years in low-risk CAs with iFLC <40. Table 1 shows the univariate and multivariate analysis. Conclusions: Integration of the FLC assay and CAs may facilitate recognition of SMM patients at highest risk for rapid progression as increasing hazard with each risk factor was demonstrated . Elevation of the iFLC >40 in the presence of adverse CAs identified a high-risk subset with 90% progression at 24 months for whom early intervention strategies may be considered.