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Xgeva Is Better Than Zometa In Reducing Pain Associated With Bone Disease

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Published: Aug 14, 2012 2:07 pm

Additional results from a Phase 3 study show that Xgeva may be more effective than Zometa in treating bone disease in multiple myeloma patients. Specifically, Xgeva was better than Zometa in reducing bone fractures, limiting the need for bone radiation treatment, and preventing the worsening of pain in cancer patients with bone disease.

Despite these findings, physicians are likely to remain cautious about treating myeloma patients with Xgeva, as there are concerns about the drug’s safety when used in myeloma patients.

Bone disease is a common complication of multiple myeloma. Bone-destroying cells are more active in the bones of myeloma patients than bone-forming cells, which leads to bone destruction.

To slow down and prevent bone destruction, myeloma patients typically receive treatment with drugs known as bisphosphonates, which reduce the activity of the body’s bone-destroying cells. The most commonly prescribed bisphosphonates in multiple myeloma are Zometa (zoledronic acid) and Aredia (pamidronate).

Xgeva (denosumab) also prevents bone removal and degradation by reducing the activity of the body’s bone-destroying cells.  However, Xgeva is an antibody, not a bisphosphonate, and it interferes with the activity of the body’s bone-destroying cells in a way that is different from bisphosphonates.

Xgeva was first marketed by Amgen (NASDAQ: AMGN) at lower doses under the brand name Prolia for the treatment of postmenopausal women with osteoporosis and a high risk of bone fractures.

It has since been investigated for the treatment of bone disease in solid tumors and multiple myeloma.

Several Phase 3 trials showed Xgeva may be at least as effective as Zometa in preventing bone disease in cancer patients. Based on the results of these trials, Xgeva was approved by the U.S. Food and Drug Administration in 2010 for the treatment of bone disease in patients with solid tumors.

Xgeva was not, however, approved for patients with multiple myeloma because twice as many myeloma patients treated with Xgeva died as compared to those treated with Zometa (see related Beacon news).

However, Xgeva continues to be investigated as a potential treatment for bone disease in myeloma.

Researchers recently published additional findings from one of the Phase 3 trials comparing Xgeva and Zometa.  These additional findings include the effect of treatment on the need for bone radiation treatment, pain management, and quality of life.

The Phase 3 trial included 1,776 patients, who were randomly assigned to receive Xgeva, Zometa, or a placebo. Approximately 10 percent of the study participants had multiple myeloma. All other participants had solid tumors.  However, patients with breast or prostate cancer were not included in the study.

Between 64 percent and 66 percent of patients were taking painkillers prior to the clinical trial.

The results showed that Xgeva decreased the need for bone radiation treatment by 22 percent compared to Zometa.  Radiation is often used to reduce the pain associated with bone disease.

Furthermore, fewer patients receiving Xgeva (31 percent) experienced one or more bone fractures, spinal cord compressions, or other bone-related complications, compared to patients receiving Zometa (36 percent).

Xgeva was also more effective than Zometa in delaying pain associated with bone disease. Patients treated with Xgeva had a median of 5.6 months before reporting worsening of clinically significant pain, compared to 4.7 months for patients treated with Zometa.

In patients with no or mild pain prior to the trial, Xgeva was more effective than Zometa in delaying the time to moderate-to-severe-pain (4.7 months versus 3.4 months, respectively).

Health-related quality of life was similar in both treatment groups. However, significantly more patients receiving Zometa (27 percent relative increase) shifted to stronger painkillers over a period of 11 months than patients receiving Xgeva.

Amgen is currently conducting a Phase 3 clinical trial comparing the efficacy and safety and Xgeva and Zometa specifically in multiple myeloma patients. The trial is still recruiting participants.

For more information, please refer to the study in the journal Annals of Oncology (abstract). For more information regarding all ongoing trials involving Xgeva in multiple myeloma, please see the U.S. Clinical Trials Registry.

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4 Comments »

  • suzierose said:

    How was pain measured? Was it a subjective scale? How was mild to moderate pain defined? How was clinically significant pain defined? How did the reduction compare to pain relief from other drugs, i.e. NSAIDs? How was reduction in need for radiation measured? Is there a standard length of time to progress to radiation due to pain?

    Xgeva is a monoclonal antibody, do we see higher mortality in MM patients treated with monoclonal antibodies? IOW’s is this a class effect, do we see this with rituxumab/elotuzumab? If not, not why not?

    What was the cause of death in the MM patients? What was median age and were they relapsed/refractory patients? Was mortality statistically significant simply due to the very small number of MM patients in the subpopulation?

    Was there a causal link established between the treatment and mortality for MM patients?

  • Navneet Ramesh (author) said:

    Dear Suzierose,

    Thank you very much for your questions. I have answered some of the questions below. Unfortunately, the study authors did not report on several of your questions and concerns. I have emailed the lead author, and will post a reply comment when I receive a response.

    How was pain measured? Was it a subjective scale?
    Pain was measured through reports by patients. The Brief Pain Inventory (BPI) method was used to categorize pain. The BPI assesses several criteria, including the severity and location of pain. A change of two points is considered to be the smallest change (in pain) that a patient would find meaningful. Overall, this method is reliable, but still subjective since it relies on patients’ responses.

    How was mild to moderate pain defined?
    A BPI score greater than 4 points defined mild to moderate pain.

    How was clinically significant pain defined?
    A two-point increase in the BPI scale defined clinically significant pain. Xgeva reduced the risk of a two-point increase by 15 percent, relative to Zometa.

    How did the reduction compare to pain relief from other drugs, i.e. NSAIDs?
    Unfortunately, the study does not include this comparative data.

    How was reduction in need for radiation measured?
    The investigators measured the time to the first radiation to the bone.

    Is there a standard length of time to progress to radiation due to pain?
    The length of time to progress to radiation due to pain varies. The severity of pain and stage of myeloma is considered by the patient’s doctor before administering radiation therapy.

    Xgeva is a monoclonal antibody, do we see higher mortality in MM patients treated with monoclonal antibodies? IOW’s is this a class effect, do we see this with rituxumab/elotuzumab? If not, why not?
    There is no evidence that myeloma patients treated with monoclonal antibodies have higher mortality rates. However, a study examining various monoclonal antibodies showed that infusion reactions are common side-effects in patients. These are reactions that cannot be explained by the toxicity profile of the drug. Still, more data is needed to characterize the safety profile of all monoclonal antibodies.

    What was the cause of death in the MM patients?
    The study does not clearly state the cause of death in myeloma patients. However, it does outline serious side effects, including renal failure and cardiac arrest.

    What was median age and were they relapsed/refractory patients?
    The mean age of all trial participants was 60 years (the median was not reported). The study also does not report what percent of patients were newly diagnosed versus relapsed/refractory, other than each patient’s life expectancy had to be at least six months to participate in the trial.

    Was mortality statistically significant simply due to the very small number of MM patients in the subpopulation?
    The study authors hypothesized that the survival difference may be due to differences in the characteristics of the patients enrolled in the two groups or due to differences in specific cancer treatments on-study. However, they said further investigation is necessary.

    Was there a causal link established between the treatment and mortality for MM patients?
    Unfortunately, the study does not link treatment and mortality in solely myeloma patients. The investigators only reported side effects across all patients.

    For more information, please refer to the journal article that summarized the main results of the Phase 3 trial (full text), published in 2011.

  • suzierose said:

    Thank You Beacon Staff!!

    I appreciate your time and all the effort to reply.

    I have some real concerns about this study and the reported outcome of ‘pain relief’, :) along with what could be percieved as TRM. Lots of conflicting data points here. The radiation delay was really puzzling particularly if there is no standard length for progression how then can their be a delay to progression???

    And if patients were not given other pain relieving agents how do we judge whether use of Zometa for pain is a better therapeutic choice.

    There are so many unanswered standard questions (patient population age/diagnosis/cause of death) that I wonder whether the study was done in the USA.

  • nancy shamanna said:

    I think that what is really interesting about Xgeva is that it has a different type of action than do the bishposphonates drugs, Zometa and Aredia. An antibody effect vs. an effect of destroying osteoclasts. Good to know that the Xgeva is useful and approved for some other sorts of bone disease, such as osteoporosis, and solid tumour bone destruction. Maybe in future it will be able to be used for MM bone disease also, if the safety can be improved somehow. I read back about it in the Beacon and unfortunately it also seems to have a side effect of the possibility of osteonecrosis of the jaw (ONJ), as do the bisphosphonates.