ArticlesBortezomib, 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
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.
Section snippets
Study design and patients
The randomised, phase 3, open-label GIMEMA-MMY-3006 study was done at 73 centres in Italy (appendix pp 8–9). The trial compared a VTD regimen versus a TD regimen as induction therapy before and consolidation therapy after double autologous HSCT in patients with newly diagnosed multiple myeloma who were eligible for transplantation. Details of the trial have been reported previously and in the protocol (appendix pp 10–80).5, 10 Key inclusion criteria were aged 18–65 years, previously untreated
Results
As previously reported,5, 10 480 patients were randomly assigned to receive VTD or TD between May 10, 2006, and April 30, 2008, of whom, 474 patients started induction therapy with either VTD (n=236; 99 [42%] women) or TD (n=238; 102 [43%] women) and were included in the intention-to-treat analysis (figure 1). Baseline patient characteristics are reported in the table.5 The median duration of maintenance therapy was 20·3 months (IQR 10·2–38·3). At the time of final data cutoff date (May 31,
Discussion
To our knowledge, this is the longest follow-up analysis of a three-drug regimen including bortezomib and an immunomodulatory drug combined with double autologous HSCT for the treatment of newly diagnosed multiple myeloma. We confirmed a persistent progression-free survival benefit with VTD compared with TD as induction therapy before and consolidation therapy after double autologous HSCT, consistent with our first report.5 Moreover, with an extended median follow-up of approximately 10 years,
Data sharing
Individual participant data will not be shared.
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