title: 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.
abstract: 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/m(2) plus salvage ASCT or oral cyclophosphamide (400mg/m(2) 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.
  
  
  RESULTS
  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]; p<0·0001). Frequently reported (in >10% 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).
  
  
  CONCLUSIONS
  This study provides evidence for the improved efficacy of high-dose melphalan plus salvage ASCT when compared with cyclophosphamide in patients with relapsed multiple myeloma eligible for intensive therapy, which might help to guide clinical decisions regarding the management of such patients.
  
  
  BACKGROUND
  Cancer Research UK.
authors.affiliation: St James's Institute of Oncology, Leeds Teaching Hospitals NHS Trust and University of Leeds, Leeds, UK. Electronic address: g.cook@leeds.ac.uk.
authors.forename: Gordon
authors.initials: G
authors.lastname: Cook
authors.affiliation: Centre for Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK.
authors.forename: Cathy
authors.initials: C
authors.lastname: Williams
authors.affiliation: Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Brown
authors.affiliation: Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Cairns
authors.affiliation: Department of Haematology, Barts and The London NHS Trust, London, UK.
authors.forename: Jamie
authors.initials: J
authors.lastname: Cavenagh
authors.affiliation: Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust and University of Sheffield, Sheffield, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Snowden
authors.affiliation: Mid Yorkshire Hospitals NHS Trust, Wakefield, UK.
authors.forename: A John
authors.initials: AJ
authors.lastname: Ashcroft
authors.affiliation: Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.
authors.forename: Marie
authors.initials: M
authors.lastname: Fletcher
authors.affiliation: St James's Institute of Oncology, Leeds Teaching Hospitals NHS Trust and University of Leeds, Leeds, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Parrish
authors.affiliation: Department of Haematology, University College Hospital, London, UK.
authors.forename: Kwee
authors.initials: K
authors.lastname: Yong
authors.affiliation: Department of Haematology, The Christie NHS Foundation Trust, Manchester, UK.
authors.forename: Jim
authors.initials: J
authors.lastname: Cavet
authors.affiliation: Department of Haematology, Plymouth Hospitals NHS Trust, Plymouth, UK.
authors.forename: Hanna
authors.initials: H
authors.lastname: Hunter
authors.affiliation: Department of Haematology, United Bristol Hospitals NHS Trust, Bristol, UK.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Bird
authors.affiliation: Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Chalmers
authors.affiliation: Haematology Malignancy Diagnostic Service, Leeds Teaching Hospitals NHS Trust and University of Leeds, Leeds, UK.
authors.forename: Sheila
authors.initials: S
authors.lastname: O'Connor
authors.affiliation: University of Birmingham, Birmingham, UK.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Drayson
authors.affiliation: Queen's University, Belfast, UK.
authors.forename: Treen C M
authors.initials: TC
authors.lastname: Morris
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D060830:Consolidation Chemotherapy / Q000379:methods*; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects; D003907:Dexamethasone / Q000008:administration & dosage; D018450:Disease Progression; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy / Q000009:adverse effects; D057194:Intention to Treat Analysis; D008297:Male; D008558:Melphalan / Q000008:administration & dosage*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics / Q000628:therapy*; D009503:Neutropenia / Q000139:chemically induced; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D016016:Proportional Hazards Models; D011719:Pyrazines / Q000008:administration & dosage; D012008:Recurrence; D019233:Retreatment; D016879:Salvage Therapy; D033581:Stem Cell Transplantation / Q000009:adverse effects; D013921:Thrombocytopenia / Q000139:chemically induced; D013997:Time Factors; D014182:Transplantation, Autologous
chemical_list: D018906:Antineoplastic Agents, Alkylating; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; D008558:Melphalan