First-Line Zoledronic Acid Boosts Survival in Multiple Myeloma

Roxanne Nelson

December 16, 2010

December 16, 2010 — Treatment with zoledronic acid (Zometa) appears to have benefits beyond bone health in patients with multiple myeloma. Researchers in the United Kingdom report that overall survival improved with zoledronic acid, independent of the prevention of skeletal-related events.

The results suggest that suggest that when combined with induction chemotherapy, zoledronic acid is superior to a regimen that includes clodronic acid across several end points.

"Zoledronic acid significantly improved overall survival and progression-free survival, with extension of overall survival by 5.5 months and progression-free survival by 2.0 months, and significantly reduced the proportion of patients with a skeletal-related event," note the authors, led by Gareth J. Morgan, MD, professor of hematology at The Royal Marsden Hospital, London, United Kingdom.

They add that even though the underlying mechanism of action has not been definitively identified, the early improvement observed in overall survival "supports early use of zoledronic acid in multiple myeloma.

The findings were presented at the American Society of Hematology (ASH) 52nd Annual Meeting and published in the December 11 issue of the Lancet.

Last week, new findings on zoledronic acid in breast cancer were presented at the ASH annual meeting. In contrast to previous findings, which showed that the drug increased survival in a population of breast cancer patients, the findings from the AZURE trial showed no overall effect, although there was a significant survival advantage in a subgroup of patients.

Not Ready for Practice Change

In a Lancet podcast interview posted online December 11, Jeffrey Davies, PhD, BM, said that bisphosphonates are commonly used in myeloma patients who present with bone disease to prevent further skeletal events.

"It is also thought that bone fractures may contribute to the growth and dissemination of malignant plasma cells in myeloma," said Dr. Davies, a medical oncologist from the Dana-Farber Cancer Institute in Boston, Massachusetts. "So the bisphosphonates may actually slow the progression of myeloma itself."

Dr. Davies pointed out that the study authors postulate that zoledronate might have direct antimyeloma activity in addition to its effect on osteoclasts in the prevention of bone disease. In light of this, he explained, they suggest that all myeloma patients receive zoledronate from the time of their initial diagnosis, whether or not they have bone disease.

"The study certainly lends weight to evidence that some bisphosphonates may exert a direct antimyeloma effect," he added.

But it appears to be a little premature to change clinical practice right now. Dr. Davies noted that it is already part of standard clinical practice to administer a bisphosphonate to myeloma patients who present with bone disease. "What we don't know [is whether] zoledronic acid is superior to other bisphosphonates, such as pamidronate [Aredia], which is commonly used, has a similar mechanism of action, is less expensive, and is associated with less toxicity," he said.

In addition, the findings do not clearly demonstrate a 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. "And if [they do], with which drug and for how long?"

Improved Survival Outcomes

In a large multicenter phase 3 trial, Dr. Morgan and colleagues randomized 1970 patients with newly diagnosed multiple myeloma to receive 4 mg zoledronic acid as an infusion every 3 to 4 weeks (n = 981) or 1600 mg oral clodronic acid daily (n = 979). Patients also received intensive or nonintensive induction chemotherapy.

The authors sought to establish whether bisphosphonate therapy could affect clinical outcomes in this population; the primary end points were overall survival, progression-free survival, and overall response rate.

Patients received bisphosphonates for a median of 350 days (range, 137 to 632) before disease progression, and follow-up was a median of 3.7 years (range, 2.9 to 4.7).

Compared with clodronic acid, overall survival significantly improved with zoledronic acid during the full follow-up period and during the first 4 months of treatment. Mortality was reduced by 16% during the full follow-up period among users of zoledronic acid (hazard ratio [HR], 0.84 95% confidence interval [CI], 0.74 to 0.96; P = .0118). Zoledronic acid also significantly improved progression-free survival by 12%, compared with clodronic acid (HR, 0.88; 95% CI, 0.80 to 0.98; P = .0179).

Even though the study was not powered to detect a significant difference between groups in the intensive and nonintensive pathways, the authors point out that overall survival was longer with zoledronic acid, although not significantly so. This was true for both the intensive (HR, 0.84; 95% CI, 0.68 to 1.03; P = .0854) and nonintensive pathways (HR, 0.83; 95% CI, 0.69 to 1.00; P = .0492).

Progression-free survival was also extended with zoledronic acid, compared with clodronic acid, in both the intensive (HR, 0.90; 95% CI, 0.78 to 1.05) and nonintensive pathways (HR, 0.87; 95% CI, 0.74 to 1.01). The difference was nonsignificant.

There were also no significant differences between treatment groups in complete, very good partial, and partial response rates; this was the case for patients who received intensive and those who received nonintensive induction chemotherapy.

Adverse events "were as expected" for this patient group, note the authors, and were generally similar for the zoledronic acid and clodronic acid groups and in both the intensive and nonintensive pathways. Serious adverse events were more common with zoledronic acid, but the rates of treatment-emergent serious adverse events was not significantly different between the 2 groups. However, zoledronic acid was associated with higher rates of confirmed osteonecrosis of the jaw (4% vs <1%).

The study was funded by the British Medical Research Council, with unrestricted educational grants from Novartis, Schering Health Care, Chugai, Pharmion, Celgene, and Ortho Biotech. Several of the study authors report relationships with pharmaceutical companies, as indicated in the paper

Lancet. 2010;376:1989-1999. Abstract

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