Significant progress has been made in the treatment of multiple myeloma (MM), with the introduction of several new drugs with different mechanisms of action. The treatment of newly diagnosed MM has evolved dramatically with the development of highly effective combinations that include 1 or more of the new drugs. Despite the continuing improvement in the overall survival of patients with MM, nearly a quarter of the patients have significantly inferior survival, often driven by a combination of factors, including tumor genetics and host frailty. The focus of initial therapy remains rapid control of the disease with reversal of the symptoms and complications related to the disease with minimal toxicity and a reduction in early mortality. The selection of the specific regimen, to some extent, depends on the ability of the patient to tolerate the treatment and the underlying disease risk. It is typically guided by results of randomized clinical trials demonstrating improvements in progression-free and/or overall survival. While increasing risk calls for escalating the intensity of therapy by using quadruplet combinations that can provide the deepest possible response and the use of autologous stem cell transplant, increasing frailty calls for a reduction in the intensity and selective use of triplet or doublet regimens. The choice of subsequent consolidation treatments and maintenance approaches, including duration of treatment, also depends on these factors, particularly the underlying disease risk. The treatment approaches for newly diagnosed myeloma continue to evolve, with ongoing trials exploring bispecific antibodies as part of initial therapy and CAR T cells for consolidation.