<p>Multiple myeloma (MM) is a neoplasm involving plasma cells in the bone marrow. Drug resistance and progression are common, underscoring the need for new drug combinations. Utilizing a high-throughput screen of tool compounds to limit gro­­­­wth of human MM cell lines and <i>i</i><i>n silico</i> robust regression analysis of drug responses, potential synergistic combinations were identified. Further selection of effective combinations that reduce oncogenic MYC expression and enhance tumor suppressor p16 activity was based on earlier genetic and drug studies that identified MYC and p16 as appropriate targets in MM. Furthermore, the top three combinations synergistically reduced drug sensitive and resistant cell viability <i>in vitro</i> and the were effective in <i>ex vivo</i> treated patient cells Combination-associated survival was also prolonged in a transplantable Ras-driven allograft model of advanced MM that closely recapitulates MM in humans. One top drug combination was selected for further preclinical development. Targets, mechanism of action, and efficacy of the combination were evaluated through several <i>in vitro</i> and <i>in vivo </i>models, as well as <i>ex vivo</i> in myeloma patient cells. Effective targeting of the combination resulted in synergistic inhibition of proteasome inhibitor (PI) sensitive MM cells, as well as cell with induced PI resistance. Additionally, the combination was effective at delaying L363 MM xenograft growth in NSG mice and prolonging survival compared to single agent therapy. Finally, a cooperative signature of combined targeting was elucidated via RNA sequencing. These data identify potentially useful drug combinations for preclinical evaluation in drug-resistant MM and may ultimately reveal novel mechanisms of combined drug sensitivity.</p>