May 17, 2012 — None of the bisphosphonates used as supportive therapy in multiple myeloma is superior to any of the others, according to a meta-analysis published online May 16 in the Cochrane Database of Systematic Reviews.
The last Cochrane review on this topic was published in 2010. In this update, 2 studies were added; the cohort is now 6692 patients from 20 trials.
This updated review concludes that zoledronate (Zometa) appears to be superior to both etidronate (Didronel) and placebo. However, it was not superior to pamidronate (Aredia) or clodronate (Bonefos) for improving overall survival or any other outcome, such as vertebral and nonvertebral fractures.
It is difficult to recommend any drug as a preferential treatment for clinical practice.
"Whether zoledronate is superior to any other bisphosphonate drug remains an open question," lead researcher Ambuj Kumar, MD, MPH, from the Center for Evidence-Based Medicine and Health Outcomes Research at the University of South Florida in Tampa, said in a statement.
"In light of the inconsistencies we see in the data, it is difficult to recommend any drug as a preferential treatment for clinical practice," he explained.
The choice of bisphosphonate for multiple myeloma patients "should ideally be based on evidence from comparative trials," the authors write, but they point out that to date, there are only 4 head-to-head comparative studies of these agents.
Questions About Superiority
The question of whether zoledronate is superior to other bisphosphonates was raised after a randomized trial showed an improvement in overall survival, independent of the prevention of skeletal-related events.
The data from that study, originally presented at the 2010 annual meeting of the American Society of Clinical Oncology and published later that year (Lancet. 2010;376:1989-1999), showed that zoledronate was significantly better than clodronate in preventing skeletal-related events (27.0% vs 35.3%; P = .0004).
Compared with clodronate, zoledronate also significantly reduced the risk for death by 16%, significantly improved median overall survival (50.0 vs 44.5 months; P = .0118), and significantly improved progression-free survival (19.5 vs 17.5 months; P = .0179).
Despite these promising results, Jeffrey Davies, PhD, BM, a medical oncologist from the Dana-Farber Cancer Institute in Boston, Massachusetts, cautioned that it is still too early to consider changing clinical practice. In a Lancet podcast that accompanied the publication of those data, he pointed out that the study authors postulate that zoledronate might have direct antimyeloma activity, in addition to its effect on preventing bone disease. They suggest that all myeloma patients should receive zoledronate from the time of their initial diagnosis, whether or not they have bone disease.
Dr. Davies explained that administering bisphosphonates is already part of standard clinical practice for myeloma patients who present with bone disease; however, it is not known if zoledronate "is superior to other bisphosphonates such as pamidronate (which is commonly used), has a similar mechanism of action, is less expensive, or is associated with less toxicity," he said.
According to Dr. Davies, the study findings did not demonstrate a clear survival benefit with zoledronate in the one third of myeloma patients who did not have bone disease at the time of diagnosis. "It remains unclear to me whether this subset of patients will benefit from prophylactic treatment with zoledronate or any other bisphosphonate," he said.
No Significant Differences
The updated Cochrane meta-analysis comprised 16 randomized controlled trials comparing a bisphosphonate with placebo or no treatment, plus 4 trials that had a different bisphosphonate as the comparator.
Although the pooled results showed no direct effect of bisphosphonates on overall survival, compared with placebo or no treatment (HR, 0.96, P =.64), there was a statistically significant heterogeneity among the trials for overall survival (I², 55%; P = .01).
A network meta-analysis was conducted of the bisphosphonates that were not compared in head-to-head trials. These results showed that overall survival was better with zoledronate than with etidronate (HR, 0.43) or placebo (HR, 0.61), but there were no differences between zoledronate and other bisphosphonates.
The pooled analysis showed that bisphosphonate use was not associated with a statistically significant improvement in progression-free survival, compared with placebo or no treatment. The pooled HR for progression-free survival was 0.70 (P = .18); there was no heterogeneity among these trials (I², 35%; P = .20).
There was, however, a beneficial effect of bisphosphonates, compared with placebo or no treatment, for preventing pathologic vertebral fractures (relative risk [RR], 0.74; I² = 7%) and skeletal-related events (RR, 0.80; I², 2%), and decreasing pain (RR, 0.75; I², 63%). Rates of osteonecrosis of the jaw seen in the 9 observational studies (1400 patients) ranged from 0% to 51%.
No Preferential Treatment
In the "context of multiple treatment comparison uncertainty analysis, zoledronate ranked as the best treatment, followed by clodronate and pamidronate," the authors note. But no difference was observed when pamidronate was compared with clodronate or zoledronate for all outcomes.
It would...be difficult to recommend zoledronate as a preferential treatment for clinical practice.
"It would, however, be difficult to recommend zoledronate as a preferential treatment for clinical practice in the light of inconsistencies seen across the types of analysis," they conclude. "These findings underscore the need for comparative evaluation of the newer potent aminobisphosphonates, especially zoledronate vs pamidronate, in an RCT to enable appropriate healthcare decision making."
The study was supported by Center for Evidence-Based Medicine at the University of South Florida, the Department of Internal Medicine at the University of Bonn in Germany, Leukämie-Initiative Bonn e.v. in Germany, and the Cochrane Haematological Malignancies Group in Germany. The authors have disclosed no relevant financial relationships.
Cochrane Database Syst Rev. 2012;5:CD003188. Abstract
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