To provide an update on recent advances in the management of patients with multiple myeloma who are not eligible for autologous stem-cell transplantation. A comprehensive review of the literature on diagnostic criteria is provided, and treatment options and management of adverse events are summarized. Patients with symptomatic disease and organ damage (ie, hypercalcemia, renal failure, anemia, or bone lesions) require immediate treatment. The International Staging System and chromosomal abnormalities identify high- and standard-risk patients. Proteasome inhibitors, immunomodulatory drugs, corticosteroids, and alkylating agents are the most active agents. The presence of concomitant diseases, frailty, or disability should be assessed and, if present, treated with reduced-dose approaches. Bone disease, renal damage, hematologic toxicities, infections, thromboembolism, and peripheral neuropathy are the most frequent disabling events requiring prompt and active supportive care. These recommendations will help clinicians ensure the most appropriate care for patients with myeloma in everyday clinical practice.