In Newly Diagnosed, Transplant-Eligible Patients with MM, Consolidation Treatment with VRD Followed by Lenalidomide Maintenance versus Maintenance Alone

2020 Year in Review - Multiple Myeloma —February 1, 2021

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Multiple Myeloma

Comparing consolidation treatment with bortezomib + lenalidomide + dexamethasone (VRD) followed by lenalidomide maintenance with lenalidomide maintenance alone, the former approach was superior regarding progression-free survival (PFS) and myeloma response in patients with newly diagnosed multiple myeloma (MM) with an acceptable toxicity profile.

The role of consolidation treatment for patients with newly diagnosed, transplant-eligible MM was evaluated in this randomized, phase 3 trial of the European Myeloma Network. In the original randomization (R1) of this study (EMN02/HOVON95), intensification therapy was compared based on 4 cycles of bortezomib + melphalan + prednisone (VMP) versus high-dose melphalan (HDM) plus single or double autologous stem-cell transplantation (ASCT), after induction with bortezomib + cyclophosphamide + dexamethasone (VCD); R1 analysis results were presented previously. Reported in this article are the differential effects of a second randomization (R2) between consolidating treatment with 2 cycles of VRD versus no consolidation, then followed by maintenance therapy with lenalidomide (10 mg) in both arms until disease progression or unacceptable toxicity. Consolidation treatment consisted of two 28-day cycles of VRD (bortezomib 1.3 mg/m2 either intravenous or subcutaneous on days 1, 4, 8, and 11 combined with lenalidomide 25 mg orally on days 1-21, and dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12). Primary end points were PFS from R1 and R2. Secondary end points of response and survival were also included in the study.

Patients randomized (N = 1212) for R1 were aged ≤65 years with symptomatic MM. Patients were stratified by the International Staging System (ISS) stage. A total of 495 patients were included in the VMP arm, whereas 702 patients were included in the HDM arm (followed by 1 or 2 ASCT). A total of 894 patients were eligible for R2, 878 of whom were included in R1. These patients were randomized to VRD consolidation (N = 451) or no consolidation (N = 427). Response status was equal in both arms (ie, complete response or better in 20%, very good partial response or better in 67%, and partial response or better in 92% of patients, respectively) at the time of R2.

Median follow-up was 71.3 months (interquartile range, 63-80 months) for the R2 population data analysis. A total of 512 events for PFS were reported at final analysis of R2 data. The 5-year PFS was 50% (95% confidence interval [CI], 45-55) for the consolidation arm versus 42% (95% CI, 37-46) without consolidation. Median PFS rates for those with and without consolidation were 59 months and 43 months, respectively. PFS rates were longer for those in the VRD consolidation arm even when results were adjusted for R1 (hazard ratio [HR], 0.80; 95% CI, 0.67-0.95; P = .013). Adverse prognostic factors at diagnosis were revised ISS stage III (HR, 2.05; 95% CI, 1.43-2.92) and presence of ampl1q (HR, 1.68; 95% CI, 1.38-2.06). In addition, PFS was determined across several predefined subgroups, and the benefit of consolidation was present in most of them, including revised ISS stage I-III, standard-risk cytogenetics, and both treatment arms of the first randomization (VMP or HDM treatment). Median duration of maintenance treatment was 33 months (range, 0-97+ months); 32% of patients were still receiving treatment at 5 years after the initiation of lenalidomide.

After consolidation, myeloma response was also greater. Complete response (a secondary end point response) was achieved by 34% versus 18% of patients with and without consolidation, respectively (P <.001). While on protocol, patient overall response of complete response or better was 59% versus 45% with and without consolidation, respectively (P <.001). At 4 years from R2 (landmark estimate), the overall survival rate was similar between arms (81%-82%), but at 6 years, the overall survival 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 5% grade 4 adverse events; these were mainly neutropenia (2%) and thrombocytopenia (2%). In both arms, cumulative incidence of second primary malignancies at 6 years from R2, excluding superficial skin cancer, was 5% to 6%.

Consolidation treatment with VRD followed by lenalidomide maintenance, when compared with maintenance alone, improves PFS and response in patients with newly diagnosed MM. 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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Last modified: February 3, 2021

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