The combination conditioning regimen of busulfan plus melphalan may be a more effective regimen than standard melphalan alone for patients with newly diagnosed multiple myeloma undergoing autologous hematopoietic cell transplantation (auto-HCT), according to a phase III trial.
“To our knowledge, this is the first randomized phase III trial that shows a significant progression-free survival benefit of busulfan plus melphalan compared with the widely accepted standard-of-care melphalan 200 mg/m2 pre-transplantation conditioning in patients with myeloma,” wrote Qaiser Bashir, MD, of the University of Texas MD Anderson Cancer Center, and colleagues, in Lancet Haematology. “These data are a major advance in the field of auto-HCT for multiple myeloma.”
Past research has tried to improve pre-transplant conditioning regimens for patients with myeloma, but none have shown superiority over single-agent melphalan. Preclinical data suggested that the cytotoxicity of busulfan plus melphalan was “synergistic in myeloma cell lines.”
In this study, 205 patients with myeloma age 70 or younger were randomly assigned to busulfan plus melphalan or melphalan alone as a conditioning regimen prior to transplant. The primary objective of the study was progression-free survival.
Progression-free survival was measured in 202 patients who received treatment. The majority of patients assigned to the combination (98%) or melphalan alone (97%) achieved a partial response or better.
With a median follow-up of almost a year, the median progression-free survival for the combination group was 64.7 months compared with 43.5 months for melphalan alone (hazard ratio [HR], 0.53; 95% CI, 0.30–0.91; P = .022).
The incidence of grade 2 to 4 nonhematologic toxicity was higher in patients assigned busulfan compared with melphalan alone, but no patient had grade 4 mucositis and only one had a grade 4 adverse event. No treatment-related deaths occurred at 100 days in either arm.
“Unexpectedly, patients in the busulfan plus melphalan group reported significantly higher severity of some symptoms and greater overall symptom interference than patients in the melphalan group before the start of treatment,” the researchers wrote. “It is unknown if this difference in symptom burden before the start of treatment affected the results of the study.”
In an accompanying editorial, María-Victoria Mateos, MD, PhD, and Verónica González-Calle, MD, PhD, of University Hospital Salamanca in Spain, noted that because the superiority of busulfan plus melphalan was seen in all subgroups, “each physician can find in this trial their standard of care for induction or maintenance.”
Although the results were positive, data related to adverse events should be noted, Mateos and Gonzalez-Calle wrote. More frequent grade 3 or 4 adverse events resulted in poorer quality of life for patients assigned busulfan in the weeks after transplant.
Mateos and Gonzalez-Calle wrote that the superiority of busulfan seen in this trial needs to be confirmed elsewhere.
“The future has to move towards a personalized medicine considering efficacy, toxicity, and quality of life,” they wrote. “For this goal to be achieved, we need to investigate and identify biomarkers that inform us which patients will benefit most from receiving autologous stem cell transplantation with busulfan plus melphalan, which ones benefit most if they receive autologous stem cell transplantation with melphalan alone, and which patients do not need autologous stem cell transplantation.”