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VRD Consolidation Followed by Lenalidomide Maintenance versus Maintenance Alone in Transplant-Eligible Patients with NDMM

Conference Correspondent  - ASH Highlights

This randomized phase 3 trial of the European Myeloma Network sought to address the role of consolidation treatment for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The original randomization (R1) of this study (EMN02/HOVON95) compared intensification therapy using 4 cycles of bortezomib + melphalan + prednisone (VMP) versus high-dose melphalan (HDM) + single or double autologous stem-cell transplantation (ASCT), after induction with bortezomib + cyclophosphamide + dexamethasone; the R1 analysis results have been presented previously.

Reported here are the differential effects of a second randomization (R2) between consolidation treatment with 2 cycles of bortezomib + lenalidomide + dexamethasone (VRD) versus no consolidation, followed by lenalidomide 10 mg maintenance in both arms until disease progression or unacceptable toxicity. Consolidation treatment consisted of 2 28-day cycles of VRD (bortezomib 1.3 mg/m2 either intravenous or subcutaneous on days 1, 4, 8, and 11, + lenalidomide 25 mg orally on days 1-21, and dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12). Progression-free survival (PFS) from R1 and R2 were primary end points, but the study also included secondary end points of response and survival.

Randomized patients (n = 1212) for R1 were ≤65 years of age and had symptomatic multiple myeloma. Patients were stratified by International Staging System (ISS) stage. The VMP arm included 495 patients, whereas the HDM (followed by 1 or 2 ASCTs) arm included 702 patients. For R2, 894 patients were eligible, 878 of whom were included in R1. These patients were randomized to VRD consolidation (n = 451) or no consolidation (n = 427). At the time of R2, response status was equal between arms (ie, complete response or better [≥CR] in approximately 20%, very good partial response or better in 67%, and partial response or better in 92% of patients).

For the R2 population data analysis, median follow-up was 71.3 months (interquartile range, 63-80 months). At final analysis of R2 data, 512 events for PFS were reported. For the consolidation arm, 5-year PFS was 50% (95% confidence interval [CI], 45-55) versus 42% (95% CI, 37-46) without consolidation. Median PFS for those with and without consolidation was 59 months and 43 months, respectively, and PFS was longer for those in the VRD consolidation arm even when results were adjusted for R1 (hazard ratio [HR], 0.81; 95% CI, 0.68-0.96; P = .016). Revised ISS stage (HR, 2.05; 95% CI, 1.43-2.92) and presence of ampl1q (HR, 1.68; 95% CI, 1.38-2.06) were adverse prognostic factors at diagnosis. PFS was also determined across several predefined subgroups, and the benefit of consolidation was present in most of them, including revised ISS stage I to III, standard-risk cytogenetics, and both treatment arms of R1 (VMP or HDM treatment). The median duration of maintenance treatment was 33 months (range, 0-97+ months), and 32% of patients were still on treatment at 5 years after the initiation of lenalidomide.

Myeloma response was also greater after consolidation. CR (a secondary end point response) was achieved by 34% versus 18% of patients with and without consolidation, respectively (P <.001). Overall response ≥CR while on protocol was 59% versus 45% with and without consolidation, respectively (P <.001). Overall survival (OS) rate at 4 years from R2 (landmark estimate) was similar between arms (81%-82%), but at 6 years, the OS rate was 75% (95% CI, 71-79) in the consolidation arm versus 69% (95% CI, 64-73) without consolidation. VRD toxicity was acceptable and included a 5% incidence of grade 4 adverse events, which were mainly neutropenia (2%) and thrombocytopenia (2%).

When compared with maintenance alone, consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and response in NDMM. Toxicity and secondary malignancy profiles are acceptable.


Reference

Abstract 550. ASH 2020. December 7, 2020. Consolidation Treatment with VRD Followed by Maintenance Therapy Versus Maintenance Alone in Newly Diagnosed, Transplant-Eligible Patients with Multiple Myeloma (MM): A Randomized Phase 3 Trial of the European Myeloma Network (EMN02/HO95).

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