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 (pts) progressing on bortezomib-based therapy (BBT) suggests cross-resistance.
Methods: After IRB approval, all pts with symptomatic MM over the past 10 years at the Michael E. Debakey VA Medical Center with initial BBT followed by salvage CBT at progression were included. Primary aim was to evaluate ORR (PR + VGPR+CR) and PFS by IMWG criteria, in relapsed/refractory pts treated with salvage CBT based on initial BBT response (i.e., primary refractory + stable vs CR+PR+VGPR) or not.
Results: In this cohort, the median overall survival was 45 months. Pts initially treated with BBT had an ORR of 17/19 (89.4%) and median PFS of 7.7 mo. For 12 pts attaining PR, PFS was 4.3 mo. and for those achieving CR/VGPR, PFS was 9.1 mo. P = .03. Two pts were primary refractory to BBT and to CBT. For initial BBT responders, the ORR with CBT was 68.4% (13/19), median PFS was 5.26 mo 6/19 pts (32%) were CBT refractory. PFS during BBT for CBT responders vs CBT refractory pts was not statistically different. Among those who responded to both CBT and BBT, there was no significant correlation between the PFS (CR vs VGPR vs PR) with initial BBT and PFS with CBT.
Conclusions: In our retrospective analysis, pts who exhibited initial resistance to primary 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 pts with primary refractoriness to BBT.