BACKGROUNDBisphosphonates scale back the danger of skeletal occasions in sufferers with malignant bone illness, and zoledronic acid has proven potential anticancer results in preclinical and medical research.
We aimed to ascertain whether or not bisphosphonates can have an effect on medical outcomes in sufferers with multiple myeloma.METHODSPatients of age 18 years or older with newly recognized multiple myeloma have been enrolled from 120 centres in the UK.
Computer-generated randomisation sequence was used to allocate sufferers equally, by way of an automatic phone service, to obtain Four mg zoledronic acid as an infusion each 3-Four weeks or 1600 mg oral clodronic acid day by day.
Patients additionally obtained intensive or non-intensive induction chemotherapy. No investigators, workers, or sufferers have been masked to treatment allocation, and bisphosphonate and upkeep remedy continued no less than till illness development.
The main endpoints have been total survival, progression-free survival, and total response fee. We assessed between-group variations with Cox proportional hazards fashions for progression-free survival and total survival, and with logistic regression fashions for total response fee.
Analysis was by intention to deal with. This trial is registered, quantity ISRCTN68454111.RESULTS1970 sufferers have been enrolled between May, 2003, and November, 2007, of whom 1960 have been eligible for intention-to-treat evaluation: 981 in the zoledronic acid group (555 on intensive chemotherapy, 426 on non-intensive chemotherapy); and 979 on clodronic acid (556 on intensive chemotherapy, 423 on non-intensive chemotherapy).
The treatment cutoff was Oct 5, 2009, with sufferers receiving bisphosphonates for a median of 350 days (IQR 137-632) earlier than illness development, with a median of three·7 years’ follow-up (IQR 2·9-4·7).
Zoledronic acid decreased mortality by 16% (95% CI 4-26) versus clodronic acid (hazard ratio [HR] 0·84, 95% CI 0·74-0·96; p=0·0118), and prolonged median total survival by 5·5 months (50·Zero months, IQR 21·Zero to not reached vs 44·5 months, IQR 16·5 to not reached; p=0·04). Zoledronic acid additionally considerably improved progression-free survival by 12% (95% CI 2-20) versus clodronic acid (HR 0·88, 95% CI 0·80-0·98; p=0·0179), and elevated median progression-free survival by 2·Zero months (19·5 months, IQR 9·0-38·Zero vs 17·5 months, IQR 8·5-34·0; p=0·07).
Rates of full, excellent partial, or partial response didn’t differ considerably between the zoledronic acid and clodronic acid teams for sufferers receiving intensive induction chemotherapy (432 sufferers [78%] vs 422 [76%]; p=0·43) or non-intensive induction chemotherapy (215 [50%] vs 195 [46%]; p=0·18).
Both bisphosphonates have been typically nicely tolerated, with related prevalence of acute renal failure and treatment-emergent severe opposed occasions, however zoledronic acid was related with greater charges of confirmed osteonecrosis of the jaw (35 [4%]) than was clodronic acid (3 [<1%]).
CONCLUSIONSConsistent with the potential anticancer exercise of zoledronic acid, total survival improved independently of prevention of skeletal-related occasions, exhibiting that zoledronic acid has treatment advantages past bone well being.
These findings assist speedy treatment with zoledronic acid in sufferers with newly recognized multiple myeloma, not just for prevention of skeletal-related occasions, but in addition for potential antimyeloma advantages.
BACKGROUNDMedical Research Council (London, UK), with unrestricted instructional grants from Novartis, Schering Health Care, Chugai, Pharmion, Celgene, and Ortho Biotech.