Phase III Data Published in Lancet Show Novartis Drug Zometa® Improves Overall Survival in Newly Diagnosed Multiple Myeloma Patients

EAST HANOVER, N.J., Dec. 3, 2010 /PRNewswire/ -- A newly published study in the Lancet suggested that a first-line treatment regimen including Zometa® (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 Zometa 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 the 46th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, IL, in June 2010.

At a median follow-up of 3.7 years, Zometa 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, Zometa was significantly superior to clodronate in the prevention of SREs associated with multiple myeloma, regardless of SRE history at baseline (1).

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 Zometa 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."

Zometa is approved in more than 100 countries for the reduction or delay of bone complications in multiple myeloma and across a broad range of metastatic cancers (breast, hormone-refractory 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 Herve 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."

MRC Myeloma IX study details (1,6)

The Medical Research Council (MRC) Myeloma IX is a Phase III, prospective, multicenter, randomized, controlled study to compare intravenous (IV) Zometa (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, Zometa 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 Zometa versus clodronate (27.0% versus 35.0%, respectively; P=0.0004). The survival advantage demonstrated by Zometa 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 overall survival with Zometa 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 Zometa compared to clodronate treatment independent of the benefit on SREs. In addition, Zometa reduced the development of new bone lesions regardless of whether a patient had bone lesions when entering the study.

The tolerability profile of Zometa 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 Zometa and clodronate treatment arms was 4.0% and less than 1.0%, respectively. Renal deterioration was reported to be similar between treatment groups.

About ZOMETA

ZOMETA is a treatment for hypercalcemia of malignancy (HCM; a condition resulting in high calcium blood levels due to cancer). ZOMETA is also used to reduce and delay bone complications due to multiple myeloma and bone metastases from solid tumors; used with anti-cancer medicines.  ZOMETA is not an anti-cancer therapy. If you have prostate cancer, you should have failed treatment with at least one hormonal therapy prior to taking ZOMETA.

Important Safety Information

Do not use ZOMETA if you have had a severe allergic reaction to zoledronic acid or any components of ZOMETA. These reactions, including rare cases of hives and angioedema (swelling often near your eyes and lips), and very rare cases of life-threatening allergic reactions, have been reported. ZOMETA is in a class of drugs called bisphosphonates, and contains the same active ingredient as that found in Reclast® (zoledronic acid). If you are treated with ZOMETA, you should not be treated with Reclast.  

If you have HCM, you should drink plenty of clear fluids before using ZOMETA.  If you have kidney problems, tell your doctor. The risk of adverse reactions (especially related to the kidney) may be greater for you.  ZOMETA treatment is not for patients with severe kidney problems. Patients with kidney problems on multiple cycles of ZOMETA or other bisphosphonates are at greater risk for further kidney problems. It is important to get your blood tests while you are receiving ZOMETA. Your doctor will monitor your kidney function before each dose.  Tell your doctor if you are on other drugs, including aminoglycosides, loop diuretics, and drugs which may be harmful to the kidney.  

Osteonecrosis of the jaw (ONJ) has been reported mainly in cancer patients treated with intravenous bisphosphonates, including ZOMETA. Many of these patients were also receiving anti-cancer drugs and corticosteroids, which may make it more likely to get ONJ. If you have advanced breast cancer or a type of cancer called multiple myeloma, or if you have had dental extraction, periodontal disease, local trauma, including poorly fitting dentures, you may be at greater risk of getting ONJ. Many reports of ONJ involved patients with signs of local infection, including bone/bone marrow inflammation. You should maintain good oral hygiene and have a dental examination with preventive dentistry prior to beginning ZOMETA. While on treatment, avoid invasive dental procedures, if possible, as recovery may take longer. If you develop ONJ while on bisphosphonate therapy, dental surgery may worsen the condition. If you require dental procedures, there are no data available to suggest whether stopping ZOMETA treatment reduces the risk of ONJ. A causal relationship between bisphosphonate use and ONJ has not been established. Based on your condition, your doctor will determine the treatment plan you will receive.

Do not use ZOMETA if you are pregnant or plan to become pregnant, or if you are breast-feeding.

Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates, including ZOMETA. Do not continue using ZOMETA if severe symptoms develop, as some patients had the symptoms reappear after taking ZOMETA or another bisphosphonate again. In aspirin sensitive patients, bronchoconstriction (tightening of the airways in the lungs) has been observed while taking bisphosphonates.

If you are an HCM patient with liver problems, talk to your doctor about whether ZOMETA is appropriate for you.

HCM patients may experience flu-like symptoms (fever, chills, flushing, bone pain and/or joint or muscle pain). Common side effects in HCM patients include fever, nausea, constipation, anemia, shortness of breath, diarrhea, abdominal pain, worsening of cancer, insomnia, vomiting, anxiety, urinary tract infection, low phosphate levels, confusion, agitation, a fungal infection called moniliasis, low potassium levels, coughing, skeletal pain, low blood pressure, and low magnesium levels. Redness and swelling may occur at the site that you are injected.

Common side effects for patients with multiple myeloma and bone metastases due to solid tumors include bone pain, nausea, fatigue, anemia, fever, vomiting, constipation, shortness of breath, diarrhea, weakness, muscle pain, anorexia, cough, joint pain, lower-limb swelling, worsening of your cancer, headache, dizziness (excluding vertigo), insomnia, decreased weight, back pain, numbness/tingling, and abdominal pain.  

Eye-related side effects may occur with bisphosphonates, including ZOMETA. Cases of swelling related to fluid build-up in the eye, as well as inflammation of the uvea, sclera, episclera, conjunctiva, and iris of the eye have been reported.  

Patients with multiple myeloma and bone metastases from solid tumors should be taking an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of vitamin D daily.

Please see full Prescribing Information and talk to your doctor for more information.

Disclaimer

The foregoing release contains forward-looking statements that can be identified by terminology such as "potential," "will," "encouraging," "suggest," or similar expressions, or by express or implied discussions regarding potential new indications or labeling for Zometa or regarding potential future revenues from Zometa. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with Zometa to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Zometa will be submitted or approved for any additional indications or labeling in any market. Nor can there be any guarantee that Zometa will achieve any particular levels of revenue in the future. In particular, management's expectations regarding Zometa could be affected by, among other things, unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; government, industry and general public pricing pressures; the impact that the foregoing factors could have on the values attributed to the Novartis Group's assets and liabilities as recorded in the Group's consolidated balance sheet, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis

Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG, which provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on healthcare, the Novartis Group offers a diversified portfolio to best meet these needs: innovative medicines, preventive vaccines, diagnostic tools, cost-saving generic pharmaceuticals and consumer health products. The Novartis Group is the only company with leading positions in each of these areas. In 2009, the Group's continuing operations achieved net sales of USD 44.3 billion, while approximately USD 7.5 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 100,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.us.novartis.com.

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References

(1) Morgan G., 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. Lancet. Published Online. December 4, 2010.

(2) Morgan, G., 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., et al. Emerging Therapies for Multiple Myeloma. Expert Opin Emerg Drugs. 2009:14(1):99-127.

(4) Coleman R. E. Skeletal Complications of Malignancy. Cancer. 1997:Supp 1. 1588-1594.

(5) Berenson J.R. Recommendations for Zoledronic Acid Treatment for Patients with Bone Metastases. The Oncologist 2005:10:52-62.

(6) Morgan G., et al. MM IX Protocol. Version 3.0.

SOURCE Novartis Pharmaceuticals Corporation