Myeloma patients not eligible for clinical trials have many treatment options. Choosing the next best therapy starts with careful assessment of the biology and dynamics of the disease at relapse, as well as the condition and situation of the patient. Fit patients should be considered for triplet regimens, whereas intermediate and frail patients warrant dose-reduced triplets or doublets. An indolent serologic relapse may be treated with dose intensification, especially in a maintenance situation, whereas a rapid relapse requires a more aggressive approach with drug class change or a second-generation immunomodulatory drug (IMID) or proteasome inhibitor (PI). Monoclonal antibodies, in combination with PIs and IMIDs, have proven highly efficacious in early and late relapse. Key elements of supportive care include infection prevention, bone health, thromboprophylaxis, and management of active symptoms, such as pain and distress.