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e19515 Background: Proteasome inhibitors (PIs) are efficacious in multiple myeloma (MM). In randomized phase 3 studies Carfilzomib doubled the progression free survival (PFS) compared to Bortezomib from 9.4 mo to 18.7 mo (ENDEAVOR study) in relapsed and refractory MM. However concern for suboptimal Carfilzomib based therapy (CBT) response in patients (pt) progressing on Bortezomib based therapy (BBT) suggests “cross-resistance”. Methods: AfterIRB approval, all pt with symptomatic MM over the last 10 years at the Michael E. DeBakey VA Medical Center with initial BBT followed by salvage CBT at progression were included. The primary aim was to evaluate ORR (PR + VGPR+CR) and and PFS by the IMWG criteria, among relapsed/refractory pt treated with salvage CBT whether or not they had an initial BBT response (i.e., primary refractory+stable vs CR+PR+VGPR). Results: In this cohort, the median overall survival was 45 mo. Pt initially treated with BBT had an ORR of 17/19 (89.4%) and median PFS of 7.7 mo. For 12 pt attaining PR, PFS was 4.3 mo, whereas for those achieving CR/VGPR was 9.1 mo, p= 0.03. Two pt were primary refractory to BBT and also to CBT. For initially treated BBT responders the ORR with CBT was 68.4% (13/19), median PFS was 5.26 mo. 6/19 pt (32%) were CBT refractory. PFS during BBT for CBT responders versus CBT refractory patients was not statistically different. Among those who responded to both CBT and BBT there was no significant correlation between the PFS or depth of response (CR vs VGPR vs PR) with initial BBT and PFS with CBT. Conclusions: In our retrospective analysis, pt who exhibited primary resistance to initial BBT did not benefit from salvage therapy with CBT, raising the possibility that hard-wired PI-resistance mechanisms exist. Among BBT responders, CBT ORR was 68%. However the PFS with CBT was significantly shorter than the published literature of CBT in RRMM naïve to PI leading us to hypothesize that uncharacterized resistance mechanisms from “priming” bortezomib leads to inferior outcome with salvage CBT. We conclude that CBT can be attempted in those who respond to BBT independent of depth of response or PFS duration. However, alternative therapies should be considered in pt with primary refractoriness to BBT.