Consolidation Followed By Maintenance Therapy Versus Maintenance Alone in Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma (MM): A Randomized Phase 3 Study of the European Myeloma Network (EMN02/HO95 MM Trial)

Abstract

Background The role of up-front consolidation for newly diagnosed, transplant eligible MM (NDMM) patients (pts) has not yet been prospectively addressed in the novel agents era. Methods The EMN02/HO95 trial was designed to randomly (R) compare (R1) 4 cycles of bortezomib-melphalan-prednisone (VMP) vs high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT), either single or double, as intensification therapy after induction with bortezomib-cyclophosphamide-dexamethasone (VCD) (M Cavo et al, ASCO 2016, abstract #8000). A second randomization to consolidation therapy with 2 cycles of VRD vs no consolidation (R2) was performed after intensification, to be followed by lenalidomide maintenance (lenalidomide 10 mg continuously) until progression or toxicity in both arms. (VRD: bortezomib 1.3 mg/m2 intravenously days 1, 4, 8, 11; lenalidomide 25 mg orally days 1 - 21; dexamethasone 20 mg orally days 1, 2, 4, 5, 8, 9, 11, 12 of a 28 days cycle). Primary study end points were progression-free survival (PFS) from R1 and PFS from R2. A first planned interim analysis for R2 was performed in July 2016 when at least 33% (= 172) of the required events for PFS had been observed. Results From February 2011 to April 2014, 1510 pts aged ≤ 65 years with symptomatic MM were enrolled, of whom 1499 were eligible. Of these, 1211 were randomized (stratification by ISS stage) to VMP (505 pts) or HDM (1 or 2 ASCT) (706 pts). For R2 903 eligible patients were randomized to consolidation (459 pts) or no consolidation (444 pts). Median follow up from R2 was 25 months (maximum 53). Response status at time of R2 was ≥ CR (23%), ≥ VGPR (67%), ≥ PR (93%), and will be updated for status at start of maintenance. At the time of analysis, 258 events for PFS after R2 had been reported. 3-year. PFS from R2 was 62% in all patients, i.e., 60% without consolidation and 65% in patients with consolidation, and median PFS had not yet been reached. PFS from R2 with adjustment for R1 was prolonged in pts randomized to VRD (HR=0.78; 95% CI=0.61-1.00; P=0.045), a benefit retained across predefined subgroups with revised ISS stage III (HR=0.67; P=0.26) and in patients randomized in R1 to VMP (HR=0.76; P=0.19) and to HDM (HR=0.79; P=0.13). The benefit of consolidation was observed in patients with low-risk cytogenetics (HR=0.68; P=0.03), but not in patients with high-risk cytogenetics (del(17p) and/or t(4;14) and/or t(14;16); HR=1.03; P=0.91). At 3 years OS from R2 was 86% and 87%, respectively. Toxicity from VRD was limited with 5% CTCAE grade 4, mainly hematological. Conclusions Consolidation treatment with VRD followed by Lenalidomide maintenance until progression or toxicity shows promising results as compared to maintenance alone for younger NDMM pts, but further study follow-up is needed. This trial was registered at www.trialregister.nl as NTR 2528, EudraCT 2009-017903-28 This trial was supported by unrestricted grants from Celgene and Janssen. Disclosures Sonneveld: Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Dimopoulos:Celgene: 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; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Carella:Millenium: Speakers Bureau; Genentech: Speakers Bureau. Ludwig:Janssen: Speakers Bureau; BMS: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Driessen:janssen: Consultancy; celgene: Consultancy; Mundipharma-EDO: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gay:Celgene: Honoraria; Mundipharma: Other: Advisory Board; Amgen: Honoraria; BMS: Honoraria; Janssen-Cilag: Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board. Mellqvist:Mundipharma: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Consultancy, 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. Zweegman:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Schjesvold:Janssen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Palumbo:Takeda: Employment, Honoraria; Janssen Cilag: Honoraria. Cavo:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria.

Response-adapted intensification with cyclophosphamide, bortezomib, and dexamethasone versus no intensification in patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial

“…Median progressionfree survival was 30 months (95% CI [25][26][27][28][29][30][31][32][33][34][35][36] in the CVD group and 20 months (15-28) in the no CVD group (HR 0·60, 95% CI 0·48-0·75, p<0·0001; figure 2A). Similar results were seen in the trans plantationeligible pathway: median progressionfree survival was 48 months (95% CI 35-not reached) in the CVD group and 28 months (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33) in the no CVD group (HR 0·50, 95% CI 0·36-0·68, p<0·0001; appendix p 9); and the transplantationineligible pathway: median progression free survival was 20 months (95% CI 15-23·7) in the CVD group and 9 months (6-15) in the no CVD group (HR 0·73, 95% CI 0·52-1·02, p=0·061; appendix p 9).…”

“…No difference in progression free survival or overall survival was identified between randomisation groups. In the EMN02 study, 24 patients were enrolled before commencing treatment and treated with four cycles of CVD induction before being randomly assigned to autologous haemopoietic stem cell transplantation (one or two transplants depending on centre) or four cycles of bortezomib, melphalan, and prednisolone. There was a subsequent randomisation between two cycles of VRD or no consolidation.…”

Multiple myeloma: Role of autologous transplantation

“…Regimens combining a PI (bortezomib or carfilzomib) and an IMiD (thalidomide or lenalidomide) with or without dexamethasone have demonstrated enhanced response rates [16,62,65,78,79]; however, the effect on PFS has been debatable since randomized trials have shown contradictory results. More specifically, although the EMN02 study has demonstrated a PFS advantage with VRD consolidation, the STAMINA trial did not support the superiority of VRD consolidation over no consolidation in terms of survival [46,80]. Thus, the additional benefit and the necessity of consolidation has not been determined yet and it remains under investigation.…”

Pursuing a Curative Approach in Multiple Myeloma: A Review of New Therapeutic Strategies

“…In the STAMINA trial, the 38-month probability for PFS was respectively 58% with single ASCT + VRd consolidation, 58% with tandem ASCT and no consolidation, and 53% with single ASCT and no consolidation, with no statistical differences [83]. In the EMN02/HO95 study, VRd consolidation after ASCT/bortezomib-melphalan-prednisone (VMP) showed a PFS advantage, with a 5-year PFS of 48% in the VRd consolidation arm and 41% in the no consolidation arm [83,84].…”