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: 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. FINDINGS: 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). INTERPRETATION: FUNDING: Medical Research Council (London, UK), Novartis, Schering Health Care, Chugai, Pharmion, Celgene, and Ortho Biotech.
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Authors | Gareth J Morgan, J Anthony Child, Walter M Gregory, Alex J Szubert, Kim Cocks, Sue E Bell, Nuria Navarro-Coy, Mark T Drayson, Roger G Owen, Sylvia Feyler, A John Ashcroft, Fiona M Ross, Jennifer Byrne, Huw Roddie, Claudius Rudin, Gordon Cook, Graham H Jackson, Ping Wu, Faith E Davies, National Cancer Research Institute Haematological Oncology Clinical Studies Group |
Journal | The Lancet. Oncology
(Lancet Oncol)
Vol. 12
Issue 8
Pg. 743-52
(Aug 2011)
ISSN: 1474-5488 [Electronic] England |
PMID | 21771568
(Publication Type: Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011 Elsevier Ltd. All rights reserved. |
Chemical References |
- Bone Density Conservation Agents
- Diphosphonates
- Imidazoles
- Clodronic Acid
- Zoledronic Acid
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Topics |
- Administration, Oral
- Adult
- Aged
- Aged, 80 and over
- Bone Density Conservation Agents
(administration & dosage, therapeutic use)
- Clodronic Acid
(administration & dosage, therapeutic use)
- Diphosphonates
(administration & dosage, therapeutic use)
- Female
- Fractures, Spontaneous
(etiology, prevention & control)
- Humans
- Imidazoles
(administration & dosage, therapeutic use)
- Infusions, Intravenous
- Male
- Middle Aged
- Multiple Myeloma
(complications, drug therapy)
- Neoplasm Staging
- United Kingdom
- Zoledronic Acid
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