ArticlesChemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial
Introduction
High-dose therapy with autologous stem-cell transplantation (ASCT) prolongs progression-free survival and overall survival compared with conventional chemotherapy in patients with newly diagnosed multiple myeloma, and this strategy is currently the standard of care for patients eligible for high-dose chemotherapy aged 65 years or younger.1, 2, 3 Immunomodulatory drugs (eg, thalidomide and lenalidomide) and proteasome inhibitors (eg, bortezomib) significantly improved survival in transplant-eligible and transplant-ineligible patients.4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 In view of reported survival in transplant-ineligible patients and the substantial toxic effects recorded with high-dose melphalan (200 mg/m2 dose), the role of ASCT has become an area of debate, and comparison with less toxic, oral, novel agents is a research priority. The combination of cyclophosphamide, lenalidomide, and dexamethasone led to 85% of patients achieving a partial response, and had a good safety profile.16 To date, one study has compared high-dose melphalan plus ASCT with melphalan, prednisone, and lenalidomide, showing an improvement in progression-free survival and overall survival with high-dose melphalan and ASCT.17 Two other trials are ongoing to compare high-dose chemotherapy plus ASCT with bortezomib, melphalan, and prednisone and with bortezomib, lenalidomide, and dexamethasone (ClinicalTrials.gov: NCT01208766; and NCT01191060 and NCT01208662).
Immunomodulatory drugs and proteasome inhibitors have been used as part of maintenance strategies to extend progression-free and overall survival.18 In four randomised studies, lenalidomide maintenance significantly reduced the risk of progression (hazard ratio [HR] 0·34–0·50) by comparison with no maintenance, but the survival advantage was inconsistent.13, 14, 15, 17 A randomised trial showed a significant progression-free survival benefit in patients receiving maintenance with pharmacological (50 mg every other day) versus physiological doses of prednisone.19 Maintenance with thalidomide plus prednisone prolonged progression-free survival, with conflicting results for overall survival.20, 21
In this study, we aimed to compare the efficacy and safety of consolidation with chemotherapy (cyclophosphamide and dexamethasone) plus lenalidomide versus high-dose melphalan plus ASCT, followed by maintenance with lenalidomide plus prednisone versus lenalidomide alone, in patients with newly diagnosed multiple myeloma who were eligible for transplantation.
Section snippets
Study design and participants
We did a 2 × 2 partial factorial, randomised, open-label, phase 3 trial. We recruited patients from 59 centres in Australia, Czech Republic, and Italy (appendix pp 20, 21). Patients were eligible for study inclusion if they were aged 65 years or younger and had symptomatic, measurable, newly diagnosed multiple myeloma, defined according to standard criteria.22 Other inclusion criteria were: Karnofsky performance status of 60 or higher; life expectancy longer than 6 months; absolute neutrophil
Results
Between July 6, 2009, and May 6, 2011, 389 patients were enrolled to the study, of whom 387 entered the induction and mobilisation phase (figure 1). After the induction and mobilisation phase, the random assignment was disclosed for 256 patients who were eligible for consolidation; 129 patients were assigned chemotherapy (cyclophosphamide and dexamethasone) plus lenalidomide and 127 were assigned high-dose melphalan and ASCT. The main reason for discontinuation during the induction and
Discussion
In this randomised trial in patients with newly diagnosed multiple myeloma, consolidation with chemotherapy (cyclophosphamide and dexamethasone) plus lenalidomide significantly increased the risk of progression or death and shortened overall survival compared with high-dose melphalan and ASCT. With the present follow-up, maintenance with lenalidomide plus prednisone did not significantly improve progression-free survival or overall survival compared with lenalidomide alone. These results
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