A Phase I/II Trial of Carfilzomib, Pegylated Liposomal Doxorubicin, and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma
Mené sur 23 puis 17 patients atteints d'un myélome multiple récidivant ou réfractaire, cet essai de phase I/II évalue la dose maximale tolérée, l'efficacité, du point de vue du taux de réponse globale, et la toxicité du carfilzomib (un inhibiteur sélectif du protéasome) en combinaison avec le bortézomib et la doxorubicine liposomale pégylée
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. Experimental Design: We performed a phase I/II trial of carfilzomib, PLD, and dexamethasone (KDD) with the primary endpoints being safety and efficacy (NCT01246063). Twenty-three patients were enrolled in the phase I portion and the maximum tolerated dose (MTD) of carfilzomib was determined to be 56 mg/m2(Days 1, 2, 8, 9, 15, and 16) when combined with PLD (30 mg/m2on Day 8) and dexamethasone (20 mg on Days 1, 2, 8, 9, 15, and 16). 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 non-hematologic 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 to other carfilzomib containing salvage regimens.