Background: The combination of serum β2-microglubulin and albumin levels is highly prognostic in multiple myeloma (MM), defined as the International Staging System (ISS). Recurrent genomic abnormalities present in myeloma cells also have a strong prognostic power. This study aimed to assess, in a routine diagnostic setting, whether genomic aberrations can be used to identify sub-groups in ISS staging, as this system does not incorporate intrinsic myeloma cell variability at the molecular level. Materials and Methods: A prospective population-based study of 123 patients newly diagnosed with MM with ISS staging were included for karyotyping, interphase nuclei fluorescence in situ hybridization (iFISH) and oligo-based array comparative genomic hybridization (oaCGH) analyses. Results: Clonal abnormalities were identified in 27% of analyses by karyotyping, in 83% by iFISH, and in 99% by oaCGH analysis. ISS staging combined with oaCGH aberrations identified ISS sub-groups. Conclusion: oaCGH analysis is a valuable asset in detecting prognostically relevant genomic abnormalities. The combination of oaCGH data with ISS staging might help define new sub-groups in MM.