The International Staging System (ISS) does not take into consideration the clinical role of imaging modalities in multiple myeloma (MM), even though these are important. Some studies have indicated a lack of impact of ISS in MM patients who receive novel agents. Therefore, accessible novel risk stratification might be needed in elderly MM patients receiving conventional therapy or novel agents. We analyzed 198 newly diagnosed and symptomatic MM patients who were not eligible for transplantation. The initial treatment regimen was therapy with melphalan-prednisone (MP, n = 44), thalidomide-cyclophosphamide-dexamethasone (n = 89) or bortezomib-MP (VMP, n = 65). The magnetic resonance imaging (MRI) pattern was normal in 34 patients, focal in 30 and diffuse/variegated in 134. High-risk cytogenetic abnormalities were not associated with the diffuse/variegated MRI pattern (p = 0.182). ISS stage III [progression-free survival (PFS) p = 0.005; overall survival (OS) p = 0.027], high-risk cytogenetic abnormalities (PFS p = 0.001; OS p < 0.001) and diffuse/variegated MRI pattern (PFS p < 0.001; OS p < 0.001) were independently associated with poorer PFS and OS. Patients were further stratified according to the 3 prognostic factors. The PFS and OS of the 3 groups differed significantly. The addition of the diffuse/variegated MRI pattern may improve the prognostic potential of the current staging system which includes ISS and cytogenetic abnormalities.