Recently, the Revised International Staging System (RISS) was introduced for clinical use and is being adopted by the International Myeloma Working Group. The RISS was developed using data from patients enrolled in clinical trials. To assess the effect of RISS in real world patients, we studied 381 patients with newly diagnosed multiple myeloma and confirmed the role of RISS in unselected nonclinical trial patients. Background: A variety of validated prognostic markers for multiple myeloma has been described to help inform clinical practice. Recently, a robust system has been introduced for clinical use and is being adopted by the International Myeloma Working Group Revised International Staging System (RISS). The RISS was developed using data from patients enrolled in clinical trials. Consequently, its utility is less clear in unselected patients with myeloma. Materials and Methods: All consecutive patients newly diagnosed with multiple myeloma treated and followed up at Tom Baker Cancer Center from January 2004 to October 2015 were included in the present study. A total of 381 consecutive patients were identified and retrospectively classified as having RISS I, II, and III. Results: RISS I exhibited a median overall survival and progression-free survival of not reached and 38.9 months compared with 77.9 and 26.9 months and 29.9 and 15.3 months for RISS II and III, respectively. These results correlated well with those seen in the International Staging System (ISS). Multivariate analysis showed that age > 65 years, ISS stage III, abnormal lactate dehydrogenase and high-risk chromosomal abnormalities by fluorescence in situ hybridization [t(4:14), deletion 17p, and t(14;16)] are independent prognostic factors for overall survival and progression-free survival, and beta(2)-microglobulin >= 5.5 mg/L, C-reactive protein > 20 mg/L, and creatinine > 200 mu mol/L are not. Conclusion: We have confirmed the role of RISS in unselected nonclinical trial patients and suggest that increased serum lactate dehydrogenase and high-risk cytogenetics are very robust prognosticators when combined with the ISS.