Because of the wide variation in multiple myeloma (MM) survival, numerous studies have focused over the past 40 years on the biological and cytogenetic prognostic values in MM patients. Since 2005, the MM International Staging System (ISS) has recognized the combination of beta-2 microglobulin (beta2M) with serum albumin (SA) concentrations as the most simple and potent combination to determine the prognosis in MM patients. Curiously, the reasons for the efficiency of the combination of beta2M with SA remain not clear-cut. In 2007, Fonseca and San Miguel (Prognostic factors and staging in multiple myeloma. Hematol Oncol Clin North Am 2007; 21:1115-40) underlined that cytogenetic assessment might also be useful for evaluating MM prognosis. Furthermore, new perspectives recently appeared with the genomic approach. Here, we (1) question the specific rationale for beta2M and SA as prognostic markers in MM, (2) emphasize the well-documented prognostic implications of beta2M and SA as potent biomarkers of comorbidity in older adults, and (3) conclude that the current MM-ISS is rather a staging system for age-related comorbidity burden (ie, aging system) than a specific MM staging system, and should not be used alone. Thus, we suggest that: (1) cytogenetics with the superscript MM-ISS could be the standard method; (2) some factors discovered using genomics could reflect the comorbidity burden and the intrinsic malignancy of MM clone, and thus needs more investigation; and (3) while waiting for standard genomic classification.