title: Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial.
abstract: BACKGROUND
  Bisphosphonates are the standard of care for reducing the risk of skeletal-related events in patients with bone lesions from multiple myeloma. The MRC Myeloma IX study was designed to compare the effects of zoledronic acid versus clodronic acid in newly diagnosed patients with multiple myeloma. Here, we report the secondary outcomes relating to skeletal events.
  
  
  METHODS
  Patients (≥18 years) with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK and received intensive or non-intensive antimyeloma treatment. A computer-generated randomisation sequence was used to allocate patients in a 1:1 ratio, through an automated telephone service to intravenous zoledronic acid (4 mg every 21-28 days) or oral clodronic acid (1600 mg/day), and the drugs were continued at least until disease progression. No investigators, staff, or patients were masked to treatment allocation. The primary endpoints--overall survival, progression-free survival, and overall response rate--and adverse events have been reported previously. We assessed between-group differences with Cox proportional hazards models for time to first skeletal-related event and incidence of skeletal-related events. These were defined as fractures, spinal cord compression, radiation or surgery to bone, and new osteolytic lesions. Data were analysed until disease progression. Analyses were by intention to treat. This trial is registered, number ISRCTN68454111.
  
  
  RESULTS
  1960 patients were randomly assigned and analysed--981 in the zoledronic acid group and 979 in the clodronic acid group. This trial is fully enrolled, and follow-up continues. At a median follow-up of 3·7 years (IQR 2·9-4·7), patients in the zoledronic acid group had a lower incidence of skeletal-related events than did those in the clodronic acid group (265 [27%] vs 346 [35%], respectively; hazard ratio 0·74, 95% CI 0·62-0·87; p=0·0004). Zoledronic acid was also associated with a lower risk of any skeletal-related event in the subsets of patients with (233 [35%] of 668 vs 292 [43%] of 682 with clodronic acid; 0·77, 0·65-0·92; p=0·0038) and without bone lesions at baseline (29 [10%] of 302 vs 48 [17%] of 276 with clodronic acid; 0·53, 0·33-0·84; p=0·0068). Fewer patients in the zoledronic acid group had vertebral fractures than did those in the clodronic acid group (50 [5%] in the zoledronic acid group vs 88 [9%] in the clodronic acid group; p=0·0008), other fractures (45 [5%] vs 66 [7%]; p=0·04), and new osteolytic lesions (46 [5%] vs 95 [10%]; p<0·0001).
  
  
  CONCLUSIONS
  The results of this study support the early use of zoledronic acid rather than clodronic acid in patients with newly diagnosed multiple myeloma for the prevention of skeletal-related events, irrespective of bone disease status at baseline.
  
  
  BACKGROUND
  Medical Research Council (London, UK), Novartis, Schering Health Care, Chugai, Pharmion, Celgene, and Ortho Biotech.
authors.affiliation: Section of Haemato-Oncology, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, London, UK. gareth.morgan@icr.ac.uk
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
authors.forename: J Anthony
authors.initials: JA
authors.lastname: Child
authors.forename: Walter M
authors.initials: WM
authors.lastname: Gregory
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Szubert
authors.forename: Kim
authors.initials: K
authors.lastname: Cocks
authors.forename: Sue E
authors.initials: SE
authors.lastname: Bell
authors.forename: Nuria
authors.initials: N
authors.lastname: Navarro-Coy
authors.forename: Mark T
authors.initials: MT
authors.lastname: Drayson
authors.forename: Roger G
authors.initials: RG
authors.lastname: Owen
authors.forename: Sylvia
authors.initials: S
authors.lastname: Feyler
authors.forename: A John
authors.initials: AJ
authors.lastname: Ashcroft
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Ross
authors.forename: Jennifer
authors.initials: J
authors.lastname: Byrne
authors.forename: Huw
authors.initials: H
authors.lastname: Roddie
authors.forename: Claudius
authors.initials: C
authors.lastname: Rudin
authors.forename: Gordon
authors.initials: G
authors.lastname: Cook
authors.forename: Graham H
authors.initials: GH
authors.lastname: Jackson
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.forename: Faith E
authors.initials: FE
authors.lastname: Davies
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004002:Clodronic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D004164:Diphosphonates / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005598:Fractures, Spontaneous / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000150:complications / Q000188:drug therapy*; D009367:Neoplasm Staging; D006113:United Kingdom; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D004002:Clodronic Acid; D000077211:Zoledronic Acid