Phase 2 Clinical Trial of High-Dose Gemcitabine/Busulfan/Melphalan for Autologous Stem-Cell Transplantation in Relapsed/Refractory Myeloma: Matched-Pair Comparison with Melphalan

BACKGROUND: High-dose melphalan is of limited benefit as autologous stem-cell transplantation (ASCT) regimen for relapsed/refractory myeloma. Its poor results in this setting prompted us to study a new high-dose combination of infusional gemcitabine/busulfan/melphalan (Gem/Bu/Mel). METHODS: We conducted a phase 2 trial of Gem/Bu/Mel in patients with primary refractory or relapsed disease after bortezomib and/or an immunomodulatory drug (IMiD), or receiving a salvage ASCT. Gemcitabine (1,875 mg/m(2) over 3 hours × 2 days) was followed by busulfan (target AUC 4,000/day × 4 days) and melphalan (60 mg/m(2)/day × 2 days). The primary endpoint of this trial was to determine the stringent complete remission (sCR) rate of Gem/Bu/Mel in this population. We then retrospectively compared the study patients with all other concurrent patients eligible for this trial who, instead, received melphalan at 200 mg/m(2) IV at our center. For survival outcomes, we used a statistical algorithm to select a subset from the control cohort that matched with the Gem/Bu/Mel patients by gender, age, disease status, double refractoriness to proteasome inhibitors/IMIDs, duration from diagnosis to transplant and cytogenetic risk, in a 1–2:1 ratio. All analyses are per protocol. This is the final analysis of the clinical trial. Trial registered at NCI.gov (NCT01237951). FINDINGS: We enrolled 74 patients on the Gem/Bu/Mel trial, median age 58 (interquartile range [IQR], 11), median 2 prior therapy lines (IQR, 3), 38 high-risk cytogenetics, 17 unresponsive to all prior treatments, and 33 receiving a salvage ASCT. Toxicities of Gem/Bu/Mel included grade 3 mucositis (N=12), grade 3 dermatitis (N=5), grade 3 transaminase elevation (N=7), grade 3 diarrhea (N=2), grade 5 sudden death (N=1) and grade 5 sepsis (N=2). The study patients and the 184 concurrent controls received similar post-ASCT maintenance. Gem/Bu/Mel resulted in more sCR (24.6% v 12.6%, P=0.040), similar overall responses (73.8% v 74.1%, P=0.77) and similar transplant-related mortality (4.0% v 3.8%, P=0.90). The median follow-up times for the Gem/Bu/Mel patients and the matched subset (N=111) were 36 months (IQR, 15.2) and 34 months (IQR, 27), respectively. Gem/Bu/Mel resulted in improved progression-free survival (median 15.1 v 9.3 months, P=0.0030; hazard ratio=0.60; P=0.021) and overall survival (median 37.5 v 23 months, P=0.0092; hazard ratio=0.65, P=0.0087). INTERPRETATION: Gem/Bu/Mel is a safe and active ASCT regimen for refractory/relapsed myeloma, with better outcomes than a concurrent matched cohort receiving melphalan. FUNDING: Supported by a grant from Otsuka Pharmaceutical Development & Commercialization Inc. and NCI Grant P30 CA016672.