Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study

Summary

Background

The phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study.

Methods

In this randomised, open-label, phase 3 study, patients aged 18–65 years with previously untreated symptomatic multiple myeloma and a Karnofsky Performance Status of 60% or higher were enrolled at 73 centres in Italy. Patients were randomised (1:1) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily orally for the first 14 days and 200 mg daily thereafter) plus dexamethasone (total 320 mg per cycle; 40 mg on days 1–2, 4–5, 8–9, and 11–12 in the VTD regimen, and 40 mg on days 1–4 and 9–12 in the TD regimen), either alone (TD group) or with bortezomib (1·3 mg/m² intravenously on days 1, 4, 8, and 11; VTD group). After double autologous HSCT, patients received two 35-day cycles of either the VTD or TD regimen, according to random assignment, as consolidation therapy. The primary outcome was the rate of complete response and near complete response after induction (already reported). In this updated analysis we assessed long-term progression-free survival and overall survival (secondary endpoints of the study) with an extended 10-year median follow-up, and analysed the variables influencing survival. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, NCT01134484.

Findings

Between May 10, 2006, and April 30, 2008, 480 patients were enrolled and randomly assigned to receive VTD (241 patients) or TD (239 patients). Six patients withdrew consent before start of treatment. 236 (99 [42%] women) in the VTD group and 238 (102 [43%] women) in the TD group were included in the intention-to-treat analysis. The data cutoff date for this analysis was May 31, 2018. Median follow-up for surviving patients was 124·1 months (IQR 117·2–131·7). The 10-year progression-free survival estimate for patients in the VTD group was 34% (95% CI 28–41) compared with 17% (13–23) for the TD group (hazard ratio [HR] 0·62 [95% CI 0·50–0·77]; p<0·0001). 60% (95% CI 54–67) of patients in the VTD group were alive at 10 years versus 46% (40–54) of patients in the TD group (HR 0·68 [95% CI 0·51–0·90]; p=0·0068). VTD was an independent predictor of improved progression-free survival (HR 0·60 [95% CI 0·48–0·76]; p<0·0001) and overall survival (HR 0·68 [0·50–0·91]; p=0·010). The incidence of second primary malignancies per 100 person-years was 0·87 (95% CI 0·49–1·44) in the VTD group compared with 1·41 (0·88–2·13) in the TD group.

Interpretation

Incorporation of VTD into double autologous HSCT resulted in clinically meaningful improvements in long-term progression-free survival and overall survival, confirming that a regimen including bortezomib and an immunomodulatory drug is the gold standard treatment for patients with newly diagnosed myeloma who are fit for high-dose chemotherapy.

Funding

Seràgnoli Institute of Haematology, University of Bologna, and BolognAIL.

Introduction

The treatment landscape of multiple myeloma has evolved considerably over the past decades because of the widespread use of autologous haematopoietic stem-cell transplantation (HSCT) and the availability of highly active therapies targeting the tumour clone in the bone marrow milieu, including immunomodulatory drugs and proteasome inhibitors.1, 2 Incorporation of these novel drugs into the sequential therapeutic phases of the transplantation programme has transformed the actual treatment paradigm for patients who can tolerate high-dose chemotherapy.³ Results from a pooled analysis of several randomised phase 3 trials showed improved outcomes with bortezomib-based induction regimens compared with treatments that did not incorporate bortezomib.⁴ Moreover, the addition of a third agent to the bortezomib–dexamethasone backbone, such as thalidomide,5, 6 doxorubicin,⁷ cyclophosphamide,⁸ or lenalidomide,⁹ boosted the efficacy of the doublet regimen. The phase 3 GIMEMA-MMY-3006 study was the first to compare a bortezomib, dexamethasone, and thalidomide (VTD) regimen with a thalidomide and dexamethasone (TD) regimen as induction therapy before and consolidation therapy after double autologous HSCT. At the original data cutoff date of June 30, 2010, the study met the primary endpoint, with the rate of complete and near complete responses after induction therapy significantly higher with VTD than with TD.⁵ The rate of complete and near complete responses continued to increase throughout the subsequent treatment phases.⁵ As a result, progression-free survival was significantly enhanced in the VTD group compared with the TD group; however, there was no overall survival difference between the treatment groups at a median follow-up of 36 months.⁵ On the basis of these data and data from other studies, VTD was granted approval by the European Medicines Agency as induction therapy in preparation for autologous HSCT and it is listed as one of the preferred treatment options in European guidelines.¹ However, none of the phase 3 trials have shown an overall survival benefit from the incorporation of a bortezomib-based triplet into the autologous HSCT programme. These findings might reflect the inadequate follow-up at the time of the initial analyses and suggest the relevance of long-term updates. Moreover, improvements in depth of response and overall outcomes have prompted interest in a more detailed identification of long-term survivors and have raised the question of a potential cure.

In this final analysis of the GIMEMA-MMY-3006 study, we aimed to evaluate the long-term effect of VTD and double autologous HSCT on progression-free survival and overall survival with an extended 10-year median follow-up. We also explored the outcomes after relapse or progression and long-term adverse events with a focus on second primary malignancies. We also analysed the factors influencing survival to generate a prognostic score and to assess the evolution of prognosis over time.