High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial

Summary Background Relapsed multiple myeloma has no standard treatment, and the role of autologous stem-cell transplantation (ASCT) has not been fully defined. We aimed to compare high-dose melphalan plus salvage ASCT with cyclophosphamide in patients with relapsed multiple myeloma who had previously undergone ASCT. Methods This multicentre, randomised, open-label, phase 3 study recruited patients aged at least 18 years with multiple myeloma who needed treatment for first progressive or relapsed disease at least 18 months after a previous ASCT from 51 centres across the UK. Before randomisation, eligible patients received bortezomib, doxorubicin, and dexamethasone (PAD) induction therapy and then underwent peripheral blood stem-cell mobilisation and harvesting if applicable. Eligible patients (with adequate stem-cell harvest) were randomly assigned (1:1), using an automated telephone randomisation line, to either high-dose melphalan 200 mg/m2 plus salvage ASCT or oral cyclophosphamide (400mg/m2 per week for 12 weeks). Randomisation was stratified by length of first remission or plateau and response to PAD re-induction therapy. The primary endpoint was time to disease progression, analysed by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00747877 , and EudraCT, number 2006-005890-24. Findings Between April 16, 2008, and Nov 19, 2012, 297 patients were registered, of whom 293 received PAD re-induction therapy. Between Aug 26, 2008, and Nov 16, 2012, 174 patients with sufficient PBSCs were randomised to salvage ASCT (n=89) or cyclophosphamide (n=85). After a median follow-up of 31 months (IQR 19–42), median time to progression was significantly longer in the salvage ASCT than in the cyclophosphamide group (19 months [95% CI 16–25] vs 11 months [9–12]; hazard ratio 0·36 [95% CI 0·25–0·53]; p10% of patients) grade 3–4 adverse events with PAD induction, salvage ASCT, and cyclophosphamide were: neutropenia (125 [43%] of 293 patients after PAD, and 63 [76%] of 83 patients in the salvage ASCT group vs 11 [13%] of 84 patients in the cyclophosphamide group), thrombocytopenia (150 [51%] after PAD, and 60 [72%] vs four [5%], respectively), and peripheral neuropathy (35 [12%] after PAD, and none vs none, respectively). Interpretation This study provides evidence for the improved efficacy of high-dose melphalan plus salvage ASCT when compared with cyclophosphamide in patients with relapsed multiple mye