mSMART recommendations for a risk-adapted approach to therapy. Clinical trials are preferred for all patients, especially those with high-risk disease. *Note that a subset of patients with standard or intermediate risk will be classified as high-risk by GEP. †LDH > ULN and beta-2 microglobulin > 5.5 indicate a worse prognosis. ‡Prognosis is worse when associated with high beta-2 microglobulin and anemia. §t(11;14) may be associated with plasma cell leukemia. |Bortezomib-containing regimens are preferred in renal failure or if rapid response is needed. ¶If age > 65 years or there have been > 4 cycles of lenalidomide, consider G-CSF plus Cytoxan or plerixafor. #Continuing lenalidomide is an option for patients responding to it with low toxicities; dexamethasone is usually discontinued after the first year. Abbreviations: Rd–lenalidomide and dexamethasone, CyBorD–cyclophosphamide bortezomib and dexamethasone, MPT–melphalan prednisone and thalidomide, VRd–bortezomib lenalidomide and dexamethasone.