Treatment paradigms for management of newly diagnosed (ND) multiple myeloma have been evolving over the past 20 years as a consequence of the development of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies. While recent studies have continued to confirm the progression-free survival benefit of consolidation with upfront autologous stem cell transplant in those considered transplant eligible (TE), the line between induction strategies for TE and transplant-ineligible (TI) patients has blurred, based on studies evaluating both populations. Here, we present an overview of the data guiding current treatment approaches in the ND setting and discuss areas of ongoing investigation, including the role of quadruplet combination therapies in TE patients, the optimal strategies for frail TI patients, and management of high-risk disease.