Purpose: Pegylated liposomal doxorubicin (PLD) combined with bortezomib is an effective salvage regimen for relapsed refractory multiple myeloma (RRMM). Carfilzomib, a second-generation proteasome inhibitor, has clinical efficacy even among bortezomib-refractory patients. Patients and Methods: We performed a phase I/II trial of carfilzomib, PLD, and dexamethasone (KDD) with the primary endpoints being safety and efficacy (NCT01246063). Twentythree patients were enrolled in the phase I portion and theMTD of carfilzomib was determined to be 56 mg/m2 (days 1, 2, 8, 9, 15, and16)when combinedwithPLD(30mg/m2onday 8)and dexamethasone (20mg ondays 1, 2, 8, 9,15, and16). Seventeen additional patients were enrolled in the phase II portion. Results: KDD was determined to be well tolerated with the only common grade 3/4 nonhematologic adverse events of infection. Grade 3/4 hematologic toxicity included lymphopenia (63%), thrombocytopenia (40%), anemia (40%), and neutropenia (28%). In the cohort of patients treated at the MTD, where median prior therapies were 2% and 42% were refractory to bortezomib, the overall response rate was 83% (20/24) with 54% (13/24) having a very good partial response or better. The median progression-free survival was 13.7 months (95% CI, 5.0-21.7). Conclusions: This trial is the first to report outcomes using a triplet regimen of high-dose carfilzomib. KDD was well tolerated and appears efficacious in RRMM. Additional study is needed to more precisely determine patient outcomes with this regimen and its utility compared with other carfilzomib containing salvage regimens.