title: The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial.
abstract: BACKGROUND
  The Myeloma X trial previously reported improved durability of response (time to disease progression) in patients with relapsed multiple myeloma with salvage autologous stem-cell transplantation (ASCT) compared with oral cyclophosphamide in patients with multiple myeloma relapsing after a first ASCT. We report the final overall survival results of the trial.
  
  
  METHODS
  BSBMT/UKMF Myeloma X was a multicentre, randomised, open-label, phase 3 trial done at 51 centres in the UK. Eligible patients with multiple myeloma relapsing after a previous ASCT were re-induced with intravenous bortezomib (1·3 mg/m(2) on days 1, 4, 8, 11), intravenous doxorubicin (9 mg/m(2) per day on days 1-4), and oral dexamethasone (40 mg/day on days 1-4, 8-11, and 15-18 during cycle 1 and days 1-4 during cycles 2-4), with supportive care as per local institutional protocols before randomisation in a 1:1 ratio to either high-dose melphalan (200 mg/m(2)) and salvage ASCT or weekly oral cyclophosphamide (400 mg/m(2) per week for 12 weeks). Randomisation was by permuted blocks stratified by length of first remission and response to re-induction treatment. The primary endpoint was time to disease progression; the study was also powered to detect a difference in the secondary endpoint, overall survival. Further secondary endpoints were the proportion of patients achieving an objective response, progression-free survival, overall survival, toxic effects and safety, pain, and quality of life. Prespecified exploratory endpoints included time to second objective disease progression (PFS2). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747877, and the European Clinical Trials Database, number 2006-005890-24, and is now in long-term follow-up.
  
  
  RESULTS
  Between April 16, 2008, and Nov 19, 2012, 297 patients were registered into the study and 174 were randomly assigned to receive either high-dose melphalan and salvage ASCT (n=89) or oral weekly cyclophosphamide (n=85). 173 (58%) of 297 patients relapsed after more than 24 months from first ASCT. 75 (43%) of 174 randomised patients had died at follow-up: salvage ASCT (n=31 [35%]) versus oral weekly cyclophosphamide (n=44 [52%]). Updated time to disease progression shows continued advantage in the salvage ASCT group compared with the weekly cyclophosphamide group (19 months [95% CI 16-26] vs 11 months [9-12]; hazard ratio [HR] 0·45 [95% CI 0·31-0·64] log-rank p<0·0001). Median overall survival was superior in the salvage ASCT group compared with weekly cyclophosphamide group (67 months [95% CI 55-not estimable] vs 52 months [42-60]; log-rank p=0·022; HR 0·56 [0·35-0·90], p=0·0169). Time to second objective disease progression was superior in the salvage ASCT group compared with the weekly cyclophosphamide group (67 months [52-not estimable] vs 35 months [31-43]; HR 0·37 [0·24-0·57], log-rank p<0·0001). During extended follow-up, no further treatment-related or treatment-unrelated adverse events were reported. 15 second primary malignancies were reported in 12 patients (salvage ASCT [n=7] vs oral weekly cyclophosphamide [n=5]). The cumulative incidence of second primary malignancies at 60 months after trial entry was 5·2% (2·1-8·2).
  
  
  CONCLUSIONS
  Salvage ASCT increases overall survival during consolidation of re-induction treatment in patients with multiple myeloma at first relapse after a first ASCT. The delay of salvage ASCT to third-line treatment or later might not confer the same degree of advantage as seen with salvage ASCT at first relapse.
  
  
  BACKGROUND
  Cancer Research UK, Janssen-Cilag, and Chugai Pharma UK.
authors.affiliation: Leeds Institute of Cancer & Pathology, University of Leeds, Leeds, UK. Electronic address: g.cook@leeds.ac.uk.
authors.forename: Gordon
authors.initials: G
authors.lastname: Cook
authors.affiliation: Mid-Yorks 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: David A
authors.initials: DA
authors.lastname: Cairns
authors.affiliation: Department of Haematology, Centre for Clinical Haematology, Nottingham City Hospitals, Nottingham, UK.
authors.forename: Cathy D
authors.initials: CD
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: Department of Haematology, Barts & The London NHS Trust, London, UK.
authors.forename: Jamie D
authors.initials: JD
authors.lastname: Cavenagh
authors.affiliation: Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Snowden
authors.affiliation: Leeds Institute of Cancer & Pathology, University of Leeds, Leeds, UK.
authors.forename: Christopher
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 Trust, Plymouth, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Hunter
authors.affiliation: Department of Haematology, University Hospitals Bristol NHS Trust, Bristol, UK.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Bird
authors.affiliation: Department of Haematology, Heart of England NHS Trust, Birmingham, UK.
authors.forename: Guy
authors.initials: G
authors.lastname: Pratt
authors.affiliation: Department of Haematology, Gloucestershire Hospitals Trust, Gloucester, UK.
authors.forename: Sally
authors.initials: S
authors.lastname: Chown
authors.affiliation: Department of Haematology, Glan Clwyd Hospital BCUHB NHS Trust, Bodelwyddan, UK.
authors.forename: Ernest
authors.initials: E
authors.lastname: Heartin
authors.affiliation: HDMS, Leeds Teaching Hospitals Trust, 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: Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Hockaday
authors.affiliation: Queen's University, Belfast, UK.
authors.forename: Treen C M
authors.initials: TC
authors.lastname: Morris
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D016879:Salvage Therapy; D033581:Stem Cell Transplantation; D015996:Survival Rate; D014182:Transplantation, Autologous