Following bortezomib-based induction therapy, patients with newly diagnosed multiple myeloma (MM) who received double autologous hematopoietic cell transplantation (AHCT) had longer progression-free survival (PFS) than patients who received a single AHCT, according to preliminary results from a phase III study by the European Myeloma Network. The benefit appeared to be greatest for patients who had disease-related factors associated with poor prognosis, the researchers added.
"In the age of novel therapies for MM, the role of single versus double AHCT needs to be prospectively investigated," lead study author Michele Cavo, MD, of the Seragnoli Institute of Hematology at the Bologna University School of Medicine in Italy, said during his presentation of the study's results at the 2016 ASH Annual Meeting. "[These data] may support the benefits of double transplant in poor-prognosis patients and, in particular, in the subgroup of those who carry high-risk cytogenetic abnormalities."
This intergroup, multicenter study enrolled 695 patients with newly diagnosed, symptomatic MM (median age = 58 years; age 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 (July 1, 2016).
All patients were initially treated with standard dose-intensification therapy (bortezomib-melphalan-prednisone; VMP) or high dose-intensification therapy (melphalan 200 mg/m2; HDM), then randomized to receive either single AHCT (n=208) or double AHCT (n=207). The second procedure was completed within 60 days of the first AHCT, and patients received two sequential courses of HDM, administered two to three months apart. Post-AHCT, patients received lenalidomide maintenance therapy until disease progression.
Patient characteristics were similar between the two groups, Dr. Cavo reported. Eighteen percent and 19 percent of patients had International Staging System (ISS) stage III disease in the single- and double-AHCT groups, respectively, whereas revised ISS stage III disease was present in 9 percent and 11 percent of patients, respectively. Fifty-five percent of patients in the single-AHCT group had a high-risk cytogenetic profile (defined as having at least 1 of 5 chromosomal abnormalities, including t[4;14], del17p, t[14;16], amp[1q], and del[1p]), compared with 54 percent in the double-AHCT group.
After a median follow-up of 27 months from randomization (range = 20-35 months), PFS (the study's primary endpoint) was longer for patients in the double-AHCT group than for the single-AHCT group: Median PFS had not been reached in the double-AHCT group, compared with 45 months in the single-AHCT group (p value not reported).
The three-year estimate for PFS, though, was significantly greater in the double-AHCT group: 73 percent versus 60 percent in the single AHCT group (hazard ratio [HR] = 0.66; 95% CI 0.45-0.96; p=0.030).
The results were consistent in subgroup analyses where, even among patients with greater bone marrow involvement, high lactate dehydrogenase (LDH) levels, or high-risk cytogenetics, the HR for PFS was more favorable for patients in the double-AHCT group than for those in the single-AHCT group:
- Î²2-microglobulin >3.5 mg/L: 0.59 (95% CI 0.34-0.99; p=0.005)
- bone marrow plasma cells >60%: 0.41 (95% CI 0.22-0.77; p=0.006)
- LDH values above the upper limits: 0.52 (95% CI 0.28-0.95; p=0.034)
- revised ISS stage II: 0.50 (95% CI 0.31-0.80; p=0.004)
- high-risk cytogenetics: 0.57 (95% CI 0.35-0.93; p=0.024)
Double AHCT remained a significant independent predictor of PFS (HR=0.62; 95% CI 0.40-0.95; p=0.027) in multivariate Cox regression analysis.
Investigators were unable to report on overall survival, as the data had not yet matured; however, they did note that early indications showed no difference between the groups. Dr. Cavo also noted that a risk-adapted approach, which wasn't studied in this trial, might identify patients who do not require additional treatment intensification after first AHCT.
Cavo M, Petrucci MT, Di Raimondo F. Upfront single versus double autologous stem cell transplantation for newly diagnosed multiple myeloma: an intergroup, multicenter, phase III study of the European Myeloma Network (EMN02/HO05 MM Trial). Abstract #991. Presented at the 2016 ASH Annual Meeting, December 5, 2016; San Diego, California.