FOR NEWLY DIAGNOSED patients with multiple myeloma considered to be at high risk of disease progression, double autologous stem cell transplantation (ASCT) significantly prolongs progression-free and overall survival, vs single transplant, according to the phase III EMN02/HO95 study. The findings were presented at the 2017 American Society of Hematology (ASH) Annual Meeting & Exposition by Michele Cavo, MD, of the Bologna University School of Medicine in Italy.¹

Michele Cavo, MD

“The use of double transplant is still controversial,” Dr. Cavo noted. “Recent guidelines say double transplant is an option for patients not achieving a very good partial response after the first transplant and for patients at high-risk cytogenetically. Studies that prospectively compare single vs double ASCT are needed.”

One such study was reported at the Plenary Session of the 2016 ASH Annual Meeting, the 54-center STaMINA trial,² which found no benefit for tandem transplant, even in high-risk patients, which constituted 24% of the population. In STaMINA, progression-free survival at a median follow-up of about 3 years was 52% for single transplant and 56% for double transplant (P = .37), and overall survival rates were 86% and 83%, respectively. The authors concluded that the additional interventions offered no benefit over transplant alone.

EMN02/HO95 Details

IN EMN02/HO95, 1,499 patients with newly diagnosed myeloma received 3 or 4 cycles of bortezomib (Velcade), cyclophosphamide, and dexamethasone as induction therapy, and afterward 1,192 were randomized to receive standard-dose intensification treatment with bortezomib, melphalan, and prednisone (VMP) 

for four 42-day cycles or high-dose melphalan at 200 mg/m2 plus ASCT. A second randomization to receive or not receive consolidation therapy was planned after the intensification phase, followed by lenalidomide (Revlimid) maintenance in both arms.

In centers committed to a double ASCT policy, patients were randomized (1:1:1) to receive VMP or single ASCT (ASCT-1) or two sequential courses of high-dose melphalan (administered 2 to 3 months apart) plus double ASCT (ASCT-2) to prospectively compare ASCT-1 vs ASCT-2.

Progression-free survival from the first randomization (VMP vs ASCT) was the primary endpoint. A secondary endpoint was progression-free survival from the first randomization comparing one vs two transplants, and this comparison was made for 415 patients. Median follow-up from the first randomization was 38 months.

Survival Benefit

ON AN INTENTION-TO-TREAT basis, 3-year progression-free survival was 72.5% for ASCT-2 vs 64.0% for ASCT-1 (hazard ratio [HR] = 0.70; P = .040). Among patients with high-risk cytogenetics, these rates were 69% vs 40%, respectively (HR = 0.42; P = .014).

“Benefit was seen across standard-and high-risk patients, but the most benefit was in the high-risk group, who had a 60% reduced risk of progression or death,” Dr. Cavo noted. “Double transplant was able to overcome the poor prognosis imparted by high-risk cytogenetics.”

He suggested that longer follow-up is needed to “capture the possible benefit” in standard-risk patients, in whom double transplant sometimes had marginal value. “At this time, the results are most striking in patients at high risk.”

In the multivariate analysis, randomization to double transplant remained significant (HR = 0.66; P = .029), along with revised International Staging System stage I, standard-risk cytogenetics, and achievement of at least a very good partial response.

“Approximately one-fourth of patients upgraded the depth of response after the second planned transplant, and more than 50% of them achieved at least a complete remission,” Dr. Cavo added.

Overall survival from the first randomization was significantly prolonged with ASCT-2 as compared with ASCT-1, with rates at 3 years being 89.0% vs 81.5% (HR = 0.51; P = .011); this favorable effect on survival was seen across subgroups with an adverse prognosis. Survival rates were 85% for patients with high-risk cytogenetics or International Staging System stage II–III, vs approximately 74% after a single transplant.

Dr. Cavo acknowledged his outcomes were different from those of the STaMINA trial, commenting, “The two studies are very different in design, so it’s impossible to try to align the conflicting results.”

“Our results support the use of upfront double transplant, particularly in patients at high risk,” he concluded. In the future, he added, detection of minimal residual disease will be applied in determining whether a second transplant is needed. “At this time, though, this is the recommendation we have.” ■

DISCLOSURE: Dr. Cavo has received honoraria from Celgene, Amgen, Bristol-Myers Squibb, and Takeda.

REFERENCES

1. Cavo M, Gay FM, Patriarca F, et al: 2017 ASH Annual Meeting. Abstract 401. Presented December 10, 2017.

2. Stadtmauer EA, Pasquini MC, Blackwell B, et al: 2016 ASH Annual Meeting. Abstract LBA-1. Presented December 6, 2016.