More than a year ago, at the 2016 ASH Annual Meeting, Michele Cavo, MD, from the Serágnoli Institute of Hematology at Bologna University School of Medicine in Italy, presented preliminary results from the phase III EMN02/H095 trial, which found that following bortezomib-based induction therapy, double autologous hematopoietic cell transplantation (AHCT) led to longer progression-free survival (PFS) than single AHCT in patients with newly diagnosed multiple myeloma (MM). At the 2017 ASH Annual Meeting, Dr. Cavo presented updated results, which confirmed the previous findings and revealed an overall survival (OS) benefit with double AHCT.
This intergroup, multicenter study enrolled 695 patients with newly diagnosed, symptomatic MM (median age = 58 years; range = 18-64 years) between February 2011 and April 2014. A total of 415 patients were eligible for analysis at the time of data cutoff (date not provided).
All 1,503 participants were initially treated with standard dose-intensification therapy (bortezomib, melphalan, prednisone; VMP); 1,192 were then randomized to receive standard-dose intensification therapy with VMP for four 42-day cycles or high-dose–intensification therapy (melphalan 200 mg/m2; HDM) plus AHCT. A second randomization assigned people to receive either single AHCT (n=208) or double AHCT (n=207). The second AHCT occurred within 60 days of the first, and patients received two sequential courses of HDM, administered two to three months apart.
Post-AHCT, patients received lenalidomide maintenance therapy until disease progression.
Median follow-up from first randomization was 38 months (range = 29-47 months); for patients in the single- and double-AHCT groups, median follow-up was 36 and 39 months, respectively (ranges not provided). Patient characteristics were similar between the two study arms. The frequency of International Staging System (ISS) stage III was 19 percent in both groups, and about half of each group had a high-risk cytogenetic profile (55% in the single-AHCT arm, 50% in the double-AHCT arm), defined as t(4;14)-, t(14;16)-, or del17p-positivity.
On an intention-to-treat basis, the three-year estimate of progression-free survival (PFS; measured from the day of first randomization) was:
- 73% (95% CI 66%-79%) for the double-AHCT group
- 64% (95% CI 57%-71%) for the single-AHCT group
This represented a 30 percent reduction in the risk of progression or death, compared with the single-AHCT group (hazard ratio [HR] = 0.70; 95% CI 0.50-0.98; p=0.040).
Confirmation of PFS benefit with double-ACHT was seen across all subgroups of enrolled patients, compared with single-AHCT, including those with:
- high-risk cytogenetic profile (cyto-3; the presence of t(4;14), t(14;16), or del17p): HR=0.42 (95% CI 0.21-0.84; p=0.014)
- revised ISS (R-ISS) stage II+III: HR=0.64 (95% CI 0.43-0.97; p=0.034)
- older age (>55 years): HR=0.64 (95% CI 0.43-0.96; p=0.033)
- highest-risk cytogenetic profile (cyto-5; the presence of amp1q, del1p, and t(4;14), t(14;16), or del17p): HR=0.65 (95% CI 0.42-1.01; p=0.059)
- very good partial response or better (≥VGPR): HR=0.64 (95% CI 0.44-0.94; p=0.023)
Double-AHCT also appeared to “overcome the adverse prognosis associated with cyto-3 risk profiles,” Dr. Cavo noted, with similar three-year PFS rates between those with high- and standard-risk cytogenetic risk profiles (3-year PFS: 76% vs. 69%; p=0.482).
In multivariate Cox regression analyses, the leading independent predictors of PFS were randomization to double-AHCT, R-ISS stage I, absence of cyto-5 risk profile, and achieving a ≥VGPR.
At the 2016 presentation, OS data were not yet mature, but with longer follow-up, Dr. Cavo and researchers were able to confirm that double-ACHT was associated with prolonged OS, compared with single-AHCT. From the time of first randomization, the three-year OS rate was 89 percent with double-AHCT versus 82 percent with single-AHCT (HR=0.52; 95% CI 0.31-0.86; p=0.011).
As a potential limitation of this study, Dr. Cavo noted that a risk-adapted approach, which wasn’t evaluated in this trial, might identify patients who do not require additional treatment intensification after first AHCT.
The authors report relationships with Takeda, the manufacturer of bortezomib.
Cavo M, Gay FM, Patriarca F, et al. Double autologous stem cell transplantation significantly prolongs progression-free survival and overall survival in comparison with single autotransplantation in newly diagnosed multiple myeloma: an analysis of phase 3 EMN02/H095 study. Abstract #401. Presented at the 2017 American Society of Hematology Annual Meeting, December 10, 2017; Atlanta, GA.