High-dose gemcitabine, busulfan, and melphalan for autologous stem-cell transplant in patients with relapsed or refractory myeloma: a phase 2 trial and matched-pair comparison with melphalan: Beyond the Abstract

High-dose chemotherapy with single-agent melphalan followed by an autologous stem-cell transplant (ASCT) results in significant benefit as a front-line consolidation therapy for chemosensitive myeloma. In contrast, the efficacy of high-dose melphalan for relapsed or refractory myeloma is much lower, with only 5–10% of patients achieving complete remission (CR) and median progression-free survival (PFS) of about 12 months after ASCT. 

The poor performance of single-agent melphalan in this setting prompted us to prospectively study a new high-dose combination of infusional gemcitabine, busulfan, and melphalan (Gem/Bu/Mel). In our prior work in the lab we observed a remarkable and synergistic antitumor activity of Gem/Bu/Mel, based on the DNA damage repair inhibitory effect of gemcitabine. Those preclinical observations led us to the clinical testing of Gem/Bu/Mel, in which we infused gemcitabine at 10 mg/m2 per min, a dose rate that avoids saturation of its intracellular activating enzymes and optimizes the formation of the active intracellular metabolite, gemcitabine triphosphate. 

This prolonged infusion schedule contrasts with the more common 30-min infusions, which result in suboptimal intracellular activation and have shown no objective responses in patients with resistant myeloma. In addition, the intravenous formulation of busulfan, developed by our collaborator Borje Andersson, avoids the risk of hepatic veno-occlusive disease associated with previous oral formulations of this drug, which is further optimized by pharmacokinetic-guided dosing, as employed in our trial.

In the present phase II trial we enrolled 74 patients with myeloma, median age 58 years (range, 39-65), pretreated with a median number of 2 lines of therapy (1-10); more than half of them with high-risk cytogenetics; 17 of them were unresponsive to all previous treatments, and 32 received a salvage ASCT (i.e., after relapse after a prior ASCT). We then compared their outcomes to those of a concurrently treated matched-pair cohort of 111 patients who were transplanted at our department with melphalan at 200 mg/m2. The Gem/Bu/Mel and the control melphalan cohorts were matched for age, sex, disease status, double refractory status (refractory to a proteasome inhibitor and immunomodulatory imide drug), cytogenetic risk, and time from diagnosis to ASCT. In addition to the matched group comparison, we made prespecified subgroup comparisons between patients receiving a first ASCT or a salvage ASCT, and those with high-risk cytogenetics.

Among patients with measurable disease at the time of ASCT, the Gem/Bu/Mel group had a higher stringent CR rate after ASCT than the melphalan control cohort (24.6% vs. 12.6%, P=0.04), but similar overall response rates (72% in each). At median follow up of 3 years in both cohorts, the Gem/Bu/Mel cohort enjoyed significantly longer median PFS than the matched control cohort (15·1 months vs. 9·3 months) with a markedly reduced risk of progression or death (HR 0·55, P=0·03). Importantly, the Gem/Bu/Mel cohort had significantly longer median overall survival (37·5 months vs 23 months) and a lower risk of death (HR 0·60, P=0·009). Transplant-related mortality was similar in both cohorts. The superiority of Gem/Bu/Mel over melphalan was observed across the subgroups of patients receiving either a first or a salvage ASCT, or among those with high-risk cytogenetics.

In conclusion, Gem/Bu/Mel is a safe and effective ASCT regimen for patients with refractory or relapsed myeloma, with better outcomes than a concurrent matched cohort receiving melphalan. This will need to be confirmed in a prospective, randomized trial.

Written By: Yago Nieto, MD PhD and Ben Valdez, PhD

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