With 10 novel therapies approved across the decade, the multiple myeloma (MM) treatment paradigm continues to evolve in breadth and complexity. The current gestalt of the day has been the emergence of data to support 3-drug combinations over their 2-drug counterparts. Current guidelines and consensus statements support this approach. With the recent incorporation of monoclonal antibodies into the fray of myeloma therapy, we have begun to ask what the roles of 4-drug combinations are in both the upfront and the relapsed and refractory settings. The recent approval of daratumumab in combination with bortezomib, melphalan, and prednisone (Dara-VMP/ALCYONE) supports the role of quadruplet therapy in some patients with newly diagnosed disease who do not plan to proceed toward autologous transplant. There are a number of ongoing studies evaluating this type of strategy in both transplant-eligible and non-transplant-eligible newly diagnosed MM patients and in relapsed and refractory MM patients. Many of these seek to enhance standard-of-care treatments with the addition of monoclonal antibodies. We evaluate the historical and current data supporting the role of quadruplet- versus triplet-based therapies in MM.