title: Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment.
abstract: OBJECTIVE
  Medical Research Council (MRC) Myeloma IX was a phase III trial evaluating bisphosphonate and thalidomide-based therapy for newly diagnosed multiple myeloma. Results were reported previously after a median follow-up of 3.7 years (current controlled trials number: ISRCTN68454111). Survival outcomes were reanalyzed after an extended follow-up (median, 5.9 years).
  
  
  METHODS
  At first randomization, patients (N = 1,970) were assigned to bisphosphonate (clodronic acid or zoledronic acid) and induction therapies [cyclophosphamide-vincristine-doxorubicin-dexamethasone (CVAD) or cyclophosphamide-thalidomide-dexamethasone (CTD) followed by high-dose therapy plus autologous stem cell transplantation for younger/fitter patients (intensive pathway), and melphalan-prednisone (MP) or attenuated CTD (CTDa) for older/less fit patients (nonintensive pathway)]. At second randomization, patients were assigned to thalidomide maintenance therapy or no maintenance. Interphase FISH (iFISH) was used to analyze cytogenics.
  
  
  RESULTS
  Zoledronic acid significantly improved progression-free survival (PFS; HR, 0.89; P = 0.02) and overall survival (OS; HR, 0.86; P = 0.01) compared with clodronic acid. In the intensive pathway, CTD showed noninferior PFS and OS compared with CVAD, with a trend toward improved OS in patients with favorable cytogenics (P = 0.068). In the nonintensive pathway, CTDa significantly improved PFS (HR, 0.81; P = 0.007) compared with MP and there was an emergent survival benefit after 18 to 24 months. Thalidomide maintenance improved PFS (HR, 1.44; P < 0.0001) but not OS (HR, 0.96; P = 0.70), and was associated with shorter OS in patients with adverse cytogenics (P = 0.01).
  
  
  CONCLUSIONS
  Long-term follow-up is essential to identify clinically meaningful treatment effects in myeloma subgroups based on cytogenetics.
authors.affiliation: Authors' Affiliations: Institute of Cancer Research, Royal Marsden Hospital, London; Clinical Trials Research Unit, University of Leeds; St James's University Hospital, Leeds; University of Birmingham, Birmingham; Wessex Regional Genetics Laboratory, University of Southampton, Salisbury; and University of Newcastle, Newcastle-upon-Tyne, United Kingdom.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
authors.forename: Faith E
authors.initials: FE
authors.lastname: Davies
authors.forename: Walter M
authors.initials: WM
authors.lastname: Gregory
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bell
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Szubert
authors.forename: Gordon
authors.initials: G
authors.lastname: Cook
authors.forename: Mark T
authors.initials: MT
authors.lastname: Drayson
authors.forename: Roger G
authors.initials: RG
authors.lastname: Owen
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Ross
authors.forename: Graham H
authors.initials: GH
authors.lastname: Jackson
authors.forename: J Anthony
authors.initials: JA
authors.lastname: Child
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000627:therapeutic use; D002869:Chromosome Aberrations; D004164:Diphosphonates / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality*; D013792:Thalidomide / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D013792:Thalidomide