head-to-head comparison of upfront autologous stem cell transplantation (ASCT) with chemotherapy alone suggests that even in the age of potent anti-myeloma therapies, upfront ASCT remains a preferred treatment for younger patients with newly diagnosed multiple myeloma.
That is the consensus opinion of European investigators, based on preliminary data from a randomized phase III clinical trial, results of which were presented at the American Society of Clinical Oncology 2016 annual meeting.
“Patients randomized to upfront high-dose chemotherapy and autologous stem cell transplantation had a significant reduction in the risk of progression or death compared with those receiving only chemotherapy including the novel agent bortezomib,” said the study’s lead author, Michele Cavo, MD, head of the Seràgnoli Institute of Hematology at the University of Bologna in Italy, speaking at a news briefing prior to presentation of the data.
“The superior efficacy of high-dose chemotherapy and ASCT with chemotherapy including bortezomib is further supported by the significantly enhanced probability of achieving a high-quality response,” he added.
The findings echo those of a 2015 study from the Intergroupe Francophone Du Myelome, reported at the 2015 American Society of Hematology Annual Meeting, which showed that treatment-naïve patients randomized to receive a combination of lenalidomide, bortezomib, and dexamethasone plus ASCT had significantly better progression-free survival (PFS) and higher complete response rates than patients who received the three-drug combination with stem-cell mobilization but no ASCT.
A nearly identical trial is being conducted in the United States, with the principal difference being the duration of maintenance therapy with lenalidomide. In the French study, maintenance was scheduled to last 1 year; in the U.S. study, maintenance is continued until disease progression.
Cavo reported preliminary results of the EMN02/HO95 trial. The study has 3 goals:
- A comparison of a combination regimen of bortezomib, melphalan, and prednisone (VMP) with high-dose melphalan, followed by ASCT;
- A comparison of a consolidation regimen consisting of bortezomib, lenalidomide, and dexamethasone (VRD) versus no consolidation; and
- A comparison of single versus tandem high-dose melphalan with ASCT.
Patients age 18 through 65 with newly diagnosed, symptomatic multiple myeloma with International Staging System (ISS) stage 1-3 disease were enrolled and started on bortezomib-based therapy for three to four cycles, with stem cell mobilization and collection. Patients were then randomly assigned to receive either standard-dose chemotherapy with VMP for four cycles (754 patients) or high-dose melphalan (HDM) chemotherapy for one or two courses followed by single or tandem ASCT. In centers where single ASCT is the standard, patients were randomized to either VMP or HDM. In centers where double transplants are the norm, patients were randomized to VMP or HDM for one course, or HDM for two courses.
Following the completion of the first randomized therapy, patients were again randomized to either two cycles of bortezomib-based consolidation therapy or no consolidation. Additionally, all patients received lenalidomide maintenance until disease progression.
The primary outcome is PFS from the time of the first randomization.
Cavo and colleagues reported results from the first planned interim analysis, performed in January 2016, after at least 33% of the pre-specified events had occurred.
At a median follow-up of 23.9 months, median PFS had not been reached. For the overall population, the hazard ratio for PFS at 36 months among patients who underwent upfront transplants compared with those who had VMP alone was 0.76 (P=0.01).
The advantage of upfront ASCT was even pronounced among patients with revised ISS III disease (the presence of β2-microglobulin level greater than 5.5 mg/L and high lactate dehydrogenase (LDH) values, or deletion 17p and/or translocation 4;14 and/or translocation 14;16 positivity). In these patients, the HR for progression was 0.52 (P=0.01), and among patients with high-risk cytogenetic, the HR was 0.72 (P=0.01), again in favor of HDM and upfront ASCT.
In multivariate analysis examining factors that predict PFS, “we found that randomization to upfront autologous transplant was an independent variable positively affecting patient outcomes,” Cavo said.
The HR for randomization to ASCT was 0.61 (P=0.001). Other independent predictors of better PFS were ISS 1 (HR 0.44, P<0.0001) and standard-risk cytogenetics (HR 0.57,P<0.0001).
“In comparison with patients who did not have an auto-transplant, those randomized to high-dose chemotherapy and upfront autologous stem cell transplantation had a significantly higher probability of achieving at least a 90% reduction in tumor burden,” Cavo said.
An interim analysis of data from the second randomization is ongoing, with results to be reported in the future, he added. Overall survival data for the study are not mature, and will also be reported at a later date.
He said that he and his co-investigators plan to follow all patients for a minimum of 10 years after enrollment.