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)
Authors: Sonneveld Pieter , Beksac Meral , Van Der Holt Bronno , Dimopoulos Meletios A , Carella Angelo Michele , Ludwig Heinz , Zweegman Sonja , Zander Thilo , Wester Ruth , Hajek Roman , Pantani Lucia , Dozza Luca , Gay Francesca , Cafro Anna Maria , De Rosa Luca , Fioritoni Francesca , Mellqvist Ulf-Henrik , Troia Rossella , Andersen Niels Frost , Wu Ka Lung , Driessen Christoph , Carvalho Susana , Croockewit Alexandra J. , Schjesvold Fredrik , Offidani Massimo , Cavo Michele , Boccadoro Mario 
Published: February 2021

Background
The role of consolidation treatment for newly diagnosed, transplant eligible MM (NDMM) patients has never been prospectively addressed in a randomised trial.
Methods
The EMN02/HOVON95 trial was designed to compare intensification therapy using 4 cycles of bortezomib-melphalan-prednisone (VMP) vs high-dose melphalan (HDM) plus single or double autologous stem cell transplantation (ASCT), after induction with VCD (R1) (M. Cavo et al. Lancet Haemat 2020, 7, e456-68). A second randomisation was performed after intensification for consolidation treatment with 2 cycles of bortezomib-lenalidomide-dexamethasone (VRD) vs no consolidation (R2), in both arms followed by lenalidomide (10 mg) maintenance until progression or unacceptable toxicity. Patients assigned to consolidation treatment received two 28-day cycles of VRD, each comprising bortezomib (1·3 mg/m2 either i.v. or s.c., on days 1, 4, 8, and 11) combined with lenalidomide (25 mg orally, on days 1 through 21), and dexamethasone (20 mg orally, on days 1, 2, 4, 5, 8, 9, 11, and 12). Primary study end points were progression-free survival (PFS) from R1 and PFS from R2. Secondary endpoints included response and survival. Here we report the final analysis for R2 which was performed in July 2020.
Results
From February 2011 to April 2014, 1503 pts aged ≤ 65 years with symptomatic MM were enrolled in 172 EMN centres, of whom 1500 were eligible. Of these, 1212 were randomised (stratification by ISS stage) to VMP (495 pts) or HDM (1 or 2 ASCT) (702 pts). For R2 894 patients were eligible, of whom 878 had also been included in R1. These 878 patients were randomised to consolidation (451 pts) or no consolidation (427 pts). Median follow-up from R2 was 71.3 months (IQR 63-80). Response status at time of R2 was equal in both arms, ie ≥ CR (20%), ≥ VGPR (67%), ≥ PR (92%). At the time of this final analysis, 512 events for PFS after R2 had been reported. 5-year PFS from R2 was 50% (95% confidence interval (CI) 45-55) with consolidation and 42% (95% CI 37-46) without, while median PFS from R2 was 59 vs 43 months, respectively. PFS from R2 with adjustment for R1 was prolonged in pts randomised to VRD consolidation (hazard ratio (HR)=0.80; 95% CI=0.67-0.95; P=0.013), which is consistent with the results of the first and second interim analyses (P. Sonneveld et al. ASH 2016, abstract #242; EHA 2018, abstract #1525). With Cox regression analysis revised ISS3 stage (HR 2.05, 95%CI 1.43-2.92) and ampl1q (HR 1.68, 95%CI 1.38-2.06) were adverse prognostic factors at diagnosis. The PFS benefit was observed across most predefined subgroups, including revised ISS stage I-III, standard-risk cytogenetics and both treatment arms of the first randomisation (VMP or HDM treatment). The median duration of maintenance treatment was 33 months (0-97+ months), with 32% of patients still on treatment at 5 years after start of lenalidomide. The secondary endpoint response &gt;=CR after consolidation vs no consolidation before start of maintenance was 34% vs 18%, respectively (p&lt;0.001) Overall response &gt;=CR on protocol was 59% with consolidation and 45% without, respectively (p&lt;0.001). At 4 years from R2 overall survival (OS) was 81-82% in both arms, while at 6 years OS was 75% (95% CI 71-79) in the consolidation arm versus 69% (95% CI 64-73) without consolidation, indicating that longer follow-up is required. Toxicity from VRD was acceptable and manageable with 5% CTCAE grade 4, mainly neutropenia (2%) and thrombocytopenia (2%). The cumulative incidence of second primary malignancies at 6 years from R2 excluding superficial skin cancer was 5-6% in both arms.
Conclusions
Consolidation treatment with VRD followed by continuous lenalidomide maintenance improves PFS and quality of response in NDMM as compared to maintenance alone. The rate of toxicity and second primary malignancies is acceptable. This study is registered with EudraCT number 2009-017903-28 and ClinicalTrials.gov NCT01208766, and has completed recruitment.
This independent trial was supported by the Dutch Cancer Society (grant 2010-4798), and unrestricted grants from Celgene and Janssen
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Disclosures
Sonneveld: Takeda: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Ludwig:Takeda: Research Funding; Amgen: Other: Advisory Boards, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Janssen: Other: Advisory Boards, Speakers Bureau; Bristol Myers: Other: Advisory Boards, Speakers Bureau; Sanofi: Other: Advisory Boards, Speakers Bureau; Seattle Genetics: Other: Advisory Boards. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Hajek:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pharma MAR: Consultancy, Honoraria. Gay:GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mellqvist:Janssen. Celgene, Amgen: Honoraria. Schjesvold:Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, Takeda: Consultancy; Celgene, Amgen, Janssen, Oncopeptides: Research Funding; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX, Takeda: Honoraria. Offidani:BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Boccadoro:Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees.