Consolidation Treatment with VRD Followed By Maintenance with Lenalidomide in Multiple Myeloma Improves Overall Survival: Long-Term Follow-up of the EMN02/HOVON95 Randomized Phase 3 Trial

AIM. To evaluate the long-term overall survival (OS) associated with bortezomib-lenalidomide-dexamethasone (VRD) consolidation treatment in transplant-eligible patients with newly diagnosed multiple myeloma (NDTE-MM).

METHODS. The EMN02/HOVON95 trial compared consolidation treatment with 2 cycles of VRD or no consolidation followed by continuous lenalidomide maintenance until progression or intolerance. The primary study endpoint was progression-free survival (PFS). Here we report the secondary endpoint OS. This trial is registered with the EU Clinical Trials Register (EudraCT 2009-017903-28) and ClinicalTrials.gov (NCT01208766).

RESULTS. In the EMN02/HOVON95 trial, 1503 NDTE-MM patients were enrolled, 1500 of whom were eligible. Patients received induction treatment with bortezomib-cyclophosphamide-dexamethasone (VCD) followed by the first randomisation (R1) for intensification with single or double high-dose melphalan plus autologous stem-cell transplantation (HDM1/2-ASCT) or bortezomib-melphalan-prednisone (VMP; Cavo et al. Lancet Haematology 2020; 7(6): e456-e468). Subsequently, eligible patients were randomized (R2) to receive VRD consolidation (n=451) or no consolidation (n=427). As reported before, the rates of complete response or better (≥CR) after consolidation vs no consolidation before the start of lenalidomide maintenance were 34% vs 18%, respectively (p<0.001). The median duration of maintenance was 33 months in the no consolidation vs 36 months in the consolidation arm. Response ≥CR on protocol including maintenance was 59% with consolidation vs 48% without (p=0.001). After a median follow-up of 110 months after R2, 545 patients were still alive: 239 in the no consolidation vs 306 in the consolidation arm. 10-year OS after R2 was 50% (95% CI 44-55%) in the no consolidation vs 64% (95% CI 58-68%) in the consolidation arm. As the Kaplan-Meier curves were crossing after about 3.5 years, and the proportional hazards assumption was violated, the restricted mean survival time (RMST) method was used to compare OS between the consolidation vs no consolidation arms. The RMST at 9 years was 4.7 months longer in the consolidation vs no consolidation arm (95% CI 0.3-9.1; p=0.035). The OS benefit was observed in all treatment groups stratified according to R1: i.e., HDM1 (10-year OS, 54% vs 61%), HDM1+2 (58% vs 74%), and VMP (39% vs 62%). Favorable OS in the consolidation arm was observed in most of the predefined subgroups, according to International Staging System (ISS) stage, cytogenetic risk, and Revised (R-)ISS stage, although not in patients with high-risk cytogenetic abnormalities (HRCA) and especially not in patients with del(17p13). ISS stage 3, HRCA, and R-ISS stage 3 were significantly associated with adverse OS in univariable analyses. Toxicity from VRD was acceptable and manageable. The cumulative incidence of second primary malignancies (excluding skin cancer) at 10 years after R2 was 10% vs 12% in the consolidation vs no consolidation arms.

CONCLUSIONS. To the best of our knowledge, this is the first randomized trial that demonstrated a survival advantage of consolidation treatment in transplant-eligible patients with newly diagnosed multiple myeloma.

SUPPORT. This independent trial was supported by the Dutch Cancer Society (grant 2010-4798), the HOVON Dutch trial group, the European Myeloma Network, and by unrestricted grants from Celgene (Bristol Myers Squibb) and Janssen (Johnson & Johnson).

Sonneveld:Oncopeptides: Patents & Royalties; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; European Myeloma Network: Other: President; Pfizer: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Bristol Myers Squibb: 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, Patents & Royalties, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dimopoulos:Swixx: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria, 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini: 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; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Beksac:Amgen: Speakers Bureau; GSK: Research Funding; Menarini: Consultancy, Other: advisory; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Speakers Bureau; Sanofi: Speakers Bureau; Janssen: Research Funding, Speakers Bureau. van der Holt:Intergroupe Francophone du Myelome (IFM): Other: Honoraria for data safety monitoring board membership. Gay:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Ludwig:Bristol Myers Squibb: Other: Honoraria (speakers bureau, advisory boards, DMC); Pfizer: Other: Honoraria (speakers bureau, advisory boards, DMC); Janssen: Other: Honoraria (speakers bureau, advisory boards, DMC); GlaxoSmithKline: Other: Honoraria (speakers bureau, advisory boards, DMC); Takeda: Other: Honoraria (speakers bureau, advisory boards, DMC); Amgen: Research Funding; Sanofi: Other: Honoraria (speakers bureau, advisory boards, DMC), Research Funding; Menarini: Other: Honoraria (speakers bureau, advisory boards, DMC); Oncopeptides: Other: Honoraria (speakers bureau, advisory boards, DMC). Zweegman:Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Petrucci:Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSF: 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; Amgen: Honoraria, 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; Jansen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Corradini:Daiichi Sankyo: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Roche: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Gilead/Kite: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; GlaxoSmithKline: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Takeda: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; SOBI: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Bristol Myers Squibb: Other: Support for travel and accommodations; Sanofi: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Incyte: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Janssen: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Kyowa Kirin: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Pfizer: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); Novartis: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Celgene: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; Amgen: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations; AbbVie: Other: Honoraria (for consultancy, participation in advisory boards, or lectures); support for travel and accommodations. Patriarca:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Menarini: Honoraria. Belotti:Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Menarini Stemline: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Quaresima:Novartis: Membership on an entity's Board of Directors or advisory committees. Offidani:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Paris:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodation; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodation; Takeda: Honoraria, Other: Travel, accommodation; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodation. Liberati:Servier: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; IQVIA: Honoraria, Other: Support for travel; PSI: Research Funding; Bristol Myers Squibb: Honoraria, Other: Support for travel, Research Funding; BeiGene: Research Funding; LoxoOncology: Research Funding; Dr. Reddy's Lab.: Research Funding; Fibrogen: Research Funding; Archigen: Research Funding; Onconova: Research Funding; Karyopharm: Research Funding; Oncopeptides: Research Funding; GlaxoSmithKline: Research Funding; Morphosys: Research Funding; Novartis: Other: Support for travel, Research Funding; Verastem: Other: Support for travel, Research Funding; Sanofi: Other: Support for travel, Research Funding; Janssen: Honoraria, Other: Support for travel, Research Funding; Millennium: Research Funding; AbbVie: Honoraria, Other: Support for travel, Research Funding; Celgene: Honoraria, Other: Support for travel, Research Funding; Roche: Other: Support for travel, Research Funding; Takeda: Other: Support for travel, Research Funding. Zambello:Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSMithKline: Membership on an entity's Board of Directors or advisory committees; Menarini Stemline: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Ypma:Novartis: Other: Remuneration as a speaker for conference without personal financial compensation; Johnson & Johnson: Other: Partial reimbursement of conference attendance costs; remuneration as a speaker for conference without personal financial compensation. Boccadoro: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; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding.

This presentation includes discussion of the off-label use of a drug or drugs for the treatment of multiple myeloma (bortezomib, lenalidomide, dexamethasone, cyclophosphamide, melphalan, and prednisone).