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Most patients with newly diagnosed multiple myeloma (MM) are aged > 65 years with 30% aged > 75 years. Many elderly patients are also vulnerable because of comorbidities that complicate the management of MM. The prevalence of MM is expected to rise over time because of an aging population. Most elderly patients with MM are ineligible for autologous transplantation, and the standard treatment has, until recently, been melphalan plus prednisone. The introduction of novel agents, such as thalidomide, bortezomib, and lenalidomide, has improved outcomes; however, elderly patients with MM are more susceptible to side effects and are often unable to tolerate full drug doses. For these patients, lower-dose-intensity regimens improve the safety profile and thus optimize treatment outcome. Further research into the best treatment strategies for vulnerable elderly patients is urgently needed. Appropriate screening for vulnerability and an assessment of cardiac, pulmonary, renal, hepatic, and neurologic functions, as well as age > 75 years, at the start of therapy allows treatment strategies to be individualized and drug doses to be tailored to improve tolerability and optimize efficacy. Similarly, occurrence of serious nonhematologic adverse events during treatment should be carefully taken into account to adjust doses and optimize outcomes.