Ongoing research has shown that bisphosphonates reduces the risk of skeletal events in patients with malignant bone disease. In preclinical models several bisphosphonates have also demonstrated anticancer activity. Among approved bisphosphonates, zoledronic acid (Zometa?, Novartis) has shown the highest potential anticancer effects in preclinical and clinical studies. New research has shown that regimen including zoledronic acid significantly improve both progression-free survival and overall survival when compared to regimen including oral clodronate.

A newly published study in December 4th 2010 issue of The Lancet suggest that a first-line treatment regimen including zoledronic acid significantly improved overall survival (OS) and progression-free survival (PFS) in newly diagnosed multiple myeloma patients compared with a regimen that included oral clodronate. The impact on survival was independent of the effect of zoledronic acid on bone complications (also known as skeletal-related events or SREs) [1],[2].

The published results are from Medical Research Council (MRC) Myeloma IX, a large, randomized, Phase III clinical trial of nearly 2,000 patients with multiple myeloma [1].

These results were initially reported at ASCO 2010, the 46th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, IL, in June 2010.

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At a median follow-up of 3.7 years, zoledronic acid significantly reduced the risk for death by 16% (hazard ratio [HR] 0.842; 95% confidence interval [CI] 0.74-0.96; P=0.0118) and the relative risk for PFS events by 12% (HR 0.88; 0.80-0.98; P=0.0179) compared with oral clodronate. In addition to demonstrating superiority to clodronate on survival endpoints, zoledronic acid was significantly superior to clodronate in the prevention of SREs associated with multiple myeloma, regardless of SRE history at baseline [1].

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More than 750,000 cases of multiple myeloma are diagnosed each year worldwide, with a median overall survival of three to five years [3]. Nearly 95% of advanced stage multiple myeloma patients have bone disease and half of them will experience SREs (e.g., pathologic fractures, radiation or surgery to bone, spinal cord compression) if not treated [4],[5].

“As a hematologist who treats patients with multiple myeloma, the survival benefit demonstrated by zoledronic acid in this study is very encouraging,” said Professor Gareth Morgan, Head of Haemato-oncology at The Royal Marsden and The Institute of Cancer Research, UK and one of the study’s lead investigators. “We have long known that Zometa is effective in the reduction of SREs, but these results suggest that there is a new role for Zometa in the treatment of multiple myeloma that may extend the life of patients battling this disease.”

Zoledronic acid is indicated for the prevention, reduction or delay of bone complications, including pathological fractures, spinal compression, radiation or surgery to bone, or tumor-induced hypercalcemia, in patients with multiple myeloma, advanced malignancies involving bone and across a broad range of metastatic cancers (breast, prostate, lung and other solid tumors) involving bone, as well as for the treatment of hypercalcemia of malignancy (HCM). It is the most widely used bisphosphonate in the oncology setting and has been used to treat more than 3.9 million patients worldwide.

“It is encouraging to see the improvement in both overall and progression-free survival in these patients with multiple myeloma,” said Herv? Hoppenot, President, Novartis Oncology. “The findings of this large-scale trial add to the growing body of evidence that supports the potential anticancer effect of Zometa in multiple cancer types.”

Study details
The Medical Research Council (MRC) Myeloma IX [1],[6] is a Phase III, prospective, multicenter, randomized, controlled study to compare intravenous (IV) zoledronic acid (4 mg every 3-4 weeks) with oral clodronate (1600 mg daily) based on the severity of bone disease and in improving survival. A total of 1,960 evaluable patients from the United Kingdom and New Zealand with newly diagnosed International Staging System (ISS) Stage I, II or III multiple myeloma entered either an intensive or non-intensive treatment pathway, determined on the basis of performance status, informed decision and consent. Patients were randomized for type of bisphosphonate therapy and first-line therapy (induction chemotherapy) on a 1:1 basis.

The primary study endpoints were OS, PFS and response. Overall survival was defined as the length of time from randomization to death due to any cause. Progression-free survival was defined as the length of time from randomization to disease progression or death. Secondary endpoints included SREs (including bone fractures, radiation to bone, surgery to bone, bone lesions and/or spinal cord compression) and safety. At a median follow-up of 3.7 years, zoledronic acid reduced the relative risk for death by 16% (HR 0.842; 95% CI 0.74-0.96; P=0.0118) and the relative risk for PFS events by 12% (HR 0.88; 0.80-0.98; P=0.0179) compared with oral clodronate. The proportion of patients who experienced an SRE on study was reduced by 24% in patients receiving zoledronic acid versus clodronate (27.0% versus 35.0%, respectively; P=0.0004). The survival advantage demonstrated by zoledronic acid was observed in patients with Stage I, II or III newly diagnosed multiple myeloma. This survival advantage was also observed in addition to and independently of the drug’s benefit on SREs. In an exploratory Cox model including first SRE as a time-dependent covariate, the adjusted improvement in OS with zoledronic acid versus clodronate remained statistically significant. The adjusted result indicated that there was a 15% (HR 0.85; CI 0.74-0.97; P=0.018) reduced risk for death with zoledronic acid compared to clodronate treatment independent of the benefit on SREs. In addition, zoledronic acid reduced the development of new bone lesions regardless of whether a patient had bone lesions when entering the study.

The tolerability profile of zoledronic acid is well-established and results from this study were found to be consistent with the known profile. The incidence of confirmed osteonecrosis of the jaw (ONJ) in the zoledronic acid and clodronate treatment arms was 4.0% and less than 1.0%, respectively. Renal deterioration was reported to be similar between treatment groups.

For more information:
Full Prescribing Information zoledronic acid (Zometa?, Novartis)

References:
[1] Morgan G., Davies F, Gregory W, Cocks K, et al. First-Line and Ongoing Treatment with Zoledronic Acid Improves Overall Survival in Patients with Multiple Myeloma: Results of the MRC Myeloma IX Randomised Controlled Trial. The Lancet. Published Online. December 4, 2010.
[2] Morgan G., Davies F, Gregory W, Bell SE, Szubert A et al. Evaluating the Effects of Zoledronic Acid (ZOL) on Overall Survival (OS) in Patients (Pts) with Multiple Myeloma (MM): Results of the Medical Research Council (MRC) Myeloma IX study. (Abstract #8021). American Society of Clinical Oncology 2010 Annual Meeting.
[3] Podar K, Tai YT, Hideshima T, Vallet S, Richardson PG, Anderson KC. Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127. Review.
[4] Coleman RE. Skeletal complications of malignancy. Cancer. 1997 Oct 15;80(8 Suppl):1588-94. Review
[5] Berenson
JR. Recommendations for zoledronic acid treatment of patients with bone metastases. Oncologist. 2005 Jan;10(1):52-62. Review.
[6] Morgan G., et al. MM IX Protocol. Version 3.0.

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