In a phase III European Myeloma Network trial (EMN02/HOVON95) reported in the Journal of Clinical Oncology, Sonneveld et al found that consolidation with bortezomib, lenalidomide, and dexamethasone (VRD) vs no consolidation followed by maintenance lenalidomide was associated with significantly improved progression-free survival in newly diagnosed patients with transplant-eligible multiple myeloma.
Study Details
In the open-label trial, 1,197 patients aged ≤ 65 years enrolled between February 2011 and April 2014 from EMN centers received induction therapy and were randomly assigned to receive bortezomib, melphalan, and prednisone (VMP) or high-dose melphalan/autologous stem cell transplantation (ASCT) once or twice. Outcomes of this first randomization were reported previously.
Within 2 months after the last VMP treatment or ASCT, a second random assignment allocated 878 eligible patients to receive two 28-day cycles of VRD consolidation (n = 451) or no consolidation (n = 427); all patients received lenalidomide maintenance at 10 mg once daily on days 1 to 21 of 28-day cycles starting 1 to 2 months after ASCT or consolidation until disease progression or unacceptable toxicity. VRD consisted of: bortezomib at 1.3 mg/m2 once daily on days 1, 4, 8, and 11; lenalidomide at 25 mg once daily on days 1 to 21; and dexamethasone at 20 mg once daily on days 1, 2, 4, 5, 8, 9, 11, and 12. The primary endpoint of the second random assignment was progression-free survival.
Key Findings
At a median follow-up of 74.8 months (interquartile range [IQR] = 64.4–82.3 months), median progression-free survival adjusted for pretreatment was 59.3 months (95% confidence interval [CI] = 49.8–66.9 months) in the consolidation group vs 42.9 months (95% CI = 39.3–50.5 months) in the no-consolidation group (hazard ratio [HR] = 0.81, 95% CI = 0.68–0.96, P = .016). Five-year progression-free survival was 50% (95% CI = 45%–54%) vs 41% (95% CI = 37%–46%).
The progression-free survival benefit of consolidation was observed in most predefined subgroups, including according to revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Among all patients, revised ISS3 stage (HR = 2.00, 95% CI = 1.41–2.86) and ampl1q (HR = 1.67, 95% CI = 1.37–2.04) were associated with poorer outcomes.
Overall survival was 81% to 82% in both groups at 4 years after second random assignment and 76% vs 69% at 6 years, indicating that longer follow-up is needed to fully evaluate overall survival.
The median duration of maintenance was 33 months (IQR = 13–86 months). Complete response or better was observed in 34% vs 18% of patients before start of maintenance (P < .001) and in 59% vs 46% with maintenance (P < .001).
In a subgroup of 226 patients with very good partial response or better prior to the start of maintenance who had measurable residual disease (MRD) samples from before or within 4 months of starting maintenance, 74% of 137 in the consolidation group vs 70% of 89 in the no-consolidation group had MRD-negative status.
The investigators concluded, “Consolidation treatment with VRD followed by lenalidomide maintenance improves progression-free survival and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.”
Pieter Sonneveld, MD, of the Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the Dutch Cancer Society, European Myeloma Network, Celgene, and Janssen. For full disclosures of the study authors, visit ascopubs.org.
