Background: Multiple Myeloma (MM) is the second most common hematologic malignancy in the United States. Proteasome inhibitors—especially bortezomib (BTZ)—are a mainstay of treatment in MM, but nearly all patients eventually develop resistance to these agents. We hypothesize that resistant cells are escaping BTZ induced cell killing via dedifferentiation to a more primitive state resulting in inhibition of the tumor suppressive activity of PP2A. Methods: MM cell lines (RPMI-Dox, MM1R, and OPM1) were grown in media with increasing concentrations of BTZ over time to select for resistance, and then treated with dasatinib. MTT assays were conducted to confirm BTZ resistance. Sensitive and resistant cells were harvested for protein and RNA and evaluated through standard qRT-PCR, flow cytometry, and immunoblotting methods to determine levels of PP2A-C, Src, and Lyn, as well as the differentiation markers CD138 and IRF4. Results: MTT assays verified significant resistance in cells grown with BTZ (mean IC₅₀ 225.80 ±49.76 nM) compared to parental cells (mean IC₅₀ 7.02 ±3.97 nM). Immunoblotting confirmed differential phosphorylation of the Y307 inhibitory site of PP2A-C in the resistant cells. Levels of Src and Lyn RNA and protein were increased in the resistant cells, and treatment with the multikinase inhibitor dasatinib selectively increased cell death in the resistant cells (IC₅₀ 1.31 ±0.11 nM). Additionally, expression of the differentiation markers CD138 and IRF4 was absent in the BTZ resistant cells while being appropriately expressed in the parental cells. Conclusions: Our experiments show that inhibition of PP2A plays a significant role in acquired resistance to BTZ and that this process is primarily driven by increased expression of Src and Lyn. Inhibition of Src and Lyn activity with dasatinib was able to overcome this effect and selectively resensitize the resistant cells. Our data also imply that the resistant cells may be dedifferentiating to a more primitive state as evidenced by absent IFR4 and CD138 expression. These data suggest a role for kinase inhibitors in myeloma patients with acquired resistance to BTZ.