The Myeloma Beacon » Denosumab

Recent Advances In The Treatment Of Myeloma Bone Disease

David Roodman, M.D., Ph.D. — Fri, 23 Sep 2011 20:46:53 +0000

Multiple myeloma is the most frequent cancer to involve the skeleton, with up to 80 percent of patients having bone disease. Although fewer patients appear to have bone involvement more recently, it is still a major source of both complications and death among patients with myeloma.

Bone disease is so severe in myeloma because the normal bone remodeling process is disrupted. In normal individuals, damaged bone is removed by bone-destroying cells, the osteoclasts, and then bone is replaced by bone-forming cells, the osteoblasts. In myeloma, the number and activity of the bone-destroying cells are increased, while the bone-building cells are decreased in number or nonexistent in areas affected with myeloma cells.

This bone destruction results in severe bone pain, pathologic fractures, and high calcium levels. It can require surgery and radiotherapy to bone. Bisphosphonates can also be used to impair the activity and formation of bone-destroying cells. The bisphosphonates Aredia (pamidronate) and Zometa (zoledronic acid) are the mainstay of treatment of myeloma bone disease.

The importance of bone involvement in myeloma has been highlighted by the recent results from the MRC Myeloma IX trial from England. In this clinical trial, almost 2,000 myeloma patients were treated with Zometa or a weaker bisphosphonate in addition to chemotherapy.

The results of this trial showed that targeting the bone with Zometa as part of treatment significantly improved survival of patients with myeloma. These results show that preventing and treating myeloma bone disease has beneficial effects beyond just controlling bone pain and preventing fractures; it also increases survival.

As myeloma becomes a chronic disease or a curable disease, reversing the bone destruction in myeloma will become even more important. This is because areas of bone affected by myeloma rarely fill in with new bone but fill in with fibrous tissue. This lack of bone healing occurs even though the myeloma cells may not be present in the bone for many years. Once bones become thin, patients will continue to be at risk for fracture.

Recent research has identified several factors that may be responsible for blocking new bone formation. These include DKK-1 and Activin A, which are produced or induced by myeloma cells in the bone marrow and inhibit development of osteoblast precursors to mature bone-building cells. Treatments to block DKK-1 or Activin A in myeloma have been developed and now are in clinical trial.

An antibody called BHQ880 is one of the promising bone disease treatments under clinical development. It targets DKK-1 and helps to restore bone formation. Several ongoing Phase 2 studies are investigating the effect BHQ880, alone or in combination with Zometa, has on myeloma bone disease.

Another promising treatment being studied is called ACE-011, which blocks Activin A. Preclinical studies have demonstrated that it prevents the development of myeloma bone lesions in mice. A Phase 2 clinical trial is ongoing to determine the effects of blocking Activin A in myeloma patients with bone disease receiving melphalan (Alkeran), thalidomide (Thalomid), and prednisone.

In addition, a new inhibitor of bone destruction, Xgeva (denosumab), has been approved for the treatment of bone disease in solid tumors and is being studied in clinical trials involving myeloma patients. Xgeva blocks formation and survival of osteoclasts that break down bone. Studies indicate that Xgeva may be at least as effective as Zometa.

Further, newer treatments for myeloma, such as Velcade (bortezomib), can also stimulate new bone formation, although the increase in bone formation is only transient, rather than permanent, in most patients.

Studies in mice have shown that Forteo (parathyroid hormone), which is used to treat bone disease in patients with osteoporosis, may be safe for patients with myeloma. Clinical trials will have to determine whether this is the case.

Hopefully in the next several years, we will have agents that will help build bone in myeloma patients as we control their myeloma.

Major questions still remain, though, for treating bone disease in myeloma. Should all patients receive Zometa, regardless of whether they have bone disease? How often and how long should patients be treated with Zometa or other bisphosphonates? These and other important issues are ongoing areas of research.

Dr. David Roodman is director of the Multiple Myeloma Center at the University of Pittsburgh Cancer Institute and director of the Center for Bone Biology at the University of Pittsburgh Medical Center. His research focuses on multiple myeloma and Paget’s disease. Dr. Roodman writes a quarterly column for The Myeloma Beacon.

ASCO 2011 Multiple Myeloma Update – Day Three, Part Two

The Myeloma Beacon Staff — Wed, 08 Jun 2011 00:05:13 +0000

This past Sunday was the third day of the American Society of Clinical Oncology (ASCO) 2011 annual meeting, and it was a particularly busy day for meeting attendees interested in multiple myeloma.

The Beacon published an update yesterday covering two sets of presentations made at Sunday’s oral session about multiple myeloma. This article covers the other set of presentations, which was about myeloma bone disease, as well as material from an afternoon education session focused on myeloma.

Myeloma Bone Disease

The presentations during the oral session that were about myeloma bone disease focused, in particular, on the use of bisphosphonates to treat bone disease. The presentations also concentrated on results from the UK “Myeloma IX” clinical trial, which included two groups of patients that were treated with different bisphosphonates to see if the drugs had a different effect on the patients. Bisphosphonates are a class of drugs that reduce bone thinning.

In the Myeloma IX trial, one group of myeloma patients was prescribed the bisphosphonate Zometa (zoledronic acid), while another group was prescribed Bonefos (clodronate), a bisphosphonate that is not sold in the United States. Both groups of patients also received additional drugs specifically to treat their myeloma.

Previously published results from the Myeloma IX trial have shown that the patients who received Zometa not only had fewer “skeletal related events” (SREs) than the patients treated with Bonefos, but they also had higher overall survival rates. SREs include bone fractures, spinal cord compression, and significant bone pain requiring surgical or radiation treatment. (See related Beacon articles on myeloma bone disease.)

The two presentations on myeloma bone disease at Sunday’s ASCO oral session gave updated insights into the results of the Myeloma IX trial.

First, Dr. Gareth Morgan of the Royal Marsden Hospital in London presented data intended to address the question: Should all myeloma patients be treated with bisphosphonates, or only patients who have bone disease?

Dr. Morgan reported that, in the Myeloma IX trial, Zometa showed an improvement in survival versus Bonefos in patients who had bone disease when their myeloma was diagnosed. There was no evidence of a survival benefit to Zometa, however, in patients who did not have bone disease when their myeloma was diagnosed.

In contrast to the survival results, Zometa did show a benefit versus Bonefos in both patient groups – those with and without bone disease at initial diagnosis – in terms of SREs experienced by patients during their first year of treatment.

Patients with bone disease had a 20 percent lower risk of developing SREs in their first year compared to the patients with bone disease who were treated with Bonefos. For patients without bone disease at initial diagnosis, Zometa reduced the risk of SREs in the first year by 40 percent versus Bonefos.

Based on these results, Dr. Morgan believes all newly diagnosed myeloma patients should be treated with Zometa.

The second presentation was by Dr. Faith Davies from the Institute of Cancer Research in the United Kingdom. Dr. Davies also discussed results from the Myeloma IX trial, focusing on the timing of Zometa’s benefit to myeloma patients.

The results presented by Dr. Davies show that Zometa’s survival benefit versus Bonefos was already apparent after just two months of treatment, and it was substantial by four months of treatment. Thus, Dr. Davies believes Zometa should be given to myeloma patients very soon after they have been diagnosed.

Dr. Davies also presented results showing that Zometa’s benefit in reducing SREs persisted over multiple years of treatment. This, she believes, argues in favor of continuous, ongoing treatment of myeloma patients with Zometa.

Following the presentations by Dr. Morgan and Dr. Davies, Dr. David Roodman from the University of Pittsburgh presented a summary and discussion of the results.

Dr. Roodman began his discussion by noting that, although the Myeloma IX study suggests that Zometa has anti-myeloma effects, a previous study showed that Zometa, when used to treat patients with smoldering multiple myeloma, did not affect how long those patients took to progress to active multiple myeloma. Those results suggest that Zometa may not have an anti-myeloma effect.

In regard to whether all newly diagnosed patients should be treated with Zometa, Dr. Roodman reminded the audience that Zometa shows no survival benefit in patients who did not have bone disease at initial diagnosis. In addition, although Zometa does reduce the risk of SREs in patients without bone disease, the absolute reduction is relatively small, and treating patients with Zometa requires them to take on the risk of getting osteonecrosis of the jaw (ONJ), a side effect of bisphosphonate treatment where parts of the jaw bone rot and die.

For these reasons, Dr. Roodman believes there is still not a definitive answer to the question of whether all newly diagnosed patients should be treated with a bisphosphonate.

Dr. Roodman then discussed whether treatment with Zometa should be continued indefinitely. He agrees that a long-term benefit to Zometa treatment has been shown. However, despite the reduction in ONJ risk that has been achieved in recent years through improved monitoring and preventive measures, longer treatment with Zometa will increase a patient’s risk of getting ONJ.

Dr. Roodman concluded his review with three questions that he believes deserve further attention:

Do anti-myeloma treatments that reduce bone disease, such as regimens containing Velcade (bortezomib), also reduce the benefit of bisphosphonate treatment?
Would it be better to treat myeloma patients who do not have bone disease with Zometa administered less frequently, or with bisphosphonates that have a lower risk of ONJ?
Does the lower risk of ONJ that has been achieved through preventative measures remain low for patients receiving long-term treatment with Zometa?

After Sunday’s oral presentation session, the next myeloma-related set of presentations was an afternoon education session focused on multiple myeloma.

Because the three presentations during this session summarized research results that already have been published or presented at previous conferences, this update will focus on the key themes and insights of the presentations. The Beacon’s multiple myeloma forums, however, have substantial summaries of each presentation, starting with this posting.

Smoldering Multiple Myeloma

The first presentation during the education session was by Dr. Ivan Borrello of Johns Hopkins University, who spoke about smoldering myeloma.

A key theme of Dr. Borrello’s presentation was that physicians and patients no longer should think of there being just one kind of smoldering multiple myeloma. At a minimum, smoldering myeloma patients should be classified as being either at a low risk or high risk of progressing to active disease. There are at least two different methods available for making that classification; one from the Mayo Clinic and another from the Spanish Myeloma Group.

A critical question right now is whether high-risk smoldering myeloma patients should be actively treated. There is evidence from an ongoing clinical trial in Spain that treating high-risk smoldering myeloma patients with Revlimid (lenalidomide) may provide a survival benefit. Currently, however, the standard of care is that smoldering myeloma patients should not be actively treated.

Newly diagnosed smoldering myeloma patients should receive a baseline bone marrow biopsy and skeletal survey, and testing should then be repeated in 2 to 3 months. If the patient’s disease status remains stable, the testing should be repeated again every 4 to 6 months for a year. If the patient continues to be stable, testing should then be repeated every 6 to12 months.

More On Myeloma Bone Disease

Following Dr. Borrello’s presentation, Dr. David Roodman of the University of Pittsburgh spoke on “Bone Disease and Its Management in Multiple Myeloma.”

Dr. Roodman began his presentation by noting that there are a variety of options for treating myeloma bone disease, including lifestyle changes (exercise, calcium supplementation, and making an effort to avoid falls), radiotherapy, surgery (vertebroblasty, kyphoplasty, and other options), vitamin D supplementation, treatment with a bisphosphonate, and the treatment of the patient’s myeloma in and of itself.

After briefly discussing the pros and cons of several of these options, Dr. Roodman spent a substantial part of his presentation returning to the theme of his discussion during the day’s oral session: bisphosphonates and bone disease.

He noted, for example, that Aredia (pamidronate) and Zometa, two bisphosphonates commonly prescribed to myeloma patients in the United States, have been found to be equally potent compared to placebo in reducing SREs. In addition, both Aredia and Zometa also bring about an equal delay in a typical patient’s time to first SRE.

A key recent development in the use of bisphosphonates to treat myeloma bone disease is the evidence that the drugs – particularly Zometa – may have an anti-myeloma effect.

This evidence, however, is mainly from the UK-based Myeloma IX trial, and Dr. Roodman noted that the treatment of multiple myeloma in the UK is generally perceived to be not as aggressive as it is in the U.S. This makes him wonder whether the anti-myeloma effect seen in the UK data would be seen in data from a U.S.-based trial. This, in turn, is one reason he remains hesitant to recommend that all myeloma patients be treated with bisphosphonates.

Dr. Roodman concluded his presentation by emphasizing that it is still important to develop new therapies for myeloma bone disease.

In this regard, he believes there are a number of potential options.

Xgeva (denosumab), for example, has been shown to be more effective than Zometa in preventing SREs. Its side effects are similar to Zometa’s, including the risk of ONJ. Moreover, Xgeva is given subcutaneously rather than intravenously, and Xgeva does not appear to negatively affect the kidney the way Zometa sometimes can.

Dr. Roodman believes several other drugs have potential as treatments for myeloma bone disease, including BHQ880 and RAP-011.

Managing The Complications Of Myeloma Therapy

The last education session presentation on Sunday was given by Dr. Sikander Ailawadhi of the University of Southern California. He spoke on “Complications of Anti-Myeloma Therapies.”

Dr. Ailawadhi’s presentation covered a laundry list of complications that can develop from the treatments myeloma patients receive for their disease. These include reduced blood cell and platelet counts, peripheral neuropathy, blood clots, bacterial and viral infections, gastrointestinal issues, and ONJ.

For each of these potential side effects, Dr. Ailawadhi discussed the treatments they are associated with, and strategies for reducing or avoiding the side effects. He also noted that, in general, the risk of treatment-related side effects increases the greater the number of anti-myeloma agents a patient is taking. Combination treatments may offer great promise in terms of their efficacy in combating myeloma, but they also noticeably increase the challenge of controlling treatment side effects.

For coverage of the final day of myeloma-related activities at ASCO, see the postings in this thread in the Beacon discussion forums. The day’s myeloma presentations also will be summarized in an ASCO daily update to be published tomorrow. Additional coverage of key research results from the meeting will continue throughout the rest of the week in individual, topic-specific news articles. For all Beacon articles related to this year’s ASCO meeting, see The Beacon’s full ASCO 2011 coverage.

ASCO 2011 Multiple Myeloma Update – Days One And Two

Julie Shilane — Sat, 04 Jun 2011 20:09:54 +0000

This year’s American Society of Clinical Oncology (ASCO) annual meeting, which began on Friday and goes through Tuesday, is being held in Chicago.

On the first day of the meeting, there was only one talk related to multiple myeloma. During an afternoon education session, in which current practice and recent research results are reviewed, Dr. Raphael Fonseca from the Mayo Clinic in Scottsdale, Arizona, spoke about high-risk multiple myeloma.

The second day of the meeting included a morning and an afternoon session in which myeloma researchers presented their findings in the form of posters.

The highlights from the morning poster session included four Phase 2 studies on carfilzomib, a new agent being studied for the treatment of multiple myeloma. Carfilzomib works similarly to Velcade (bortezomib) but appears to cause less peripheral neuropathy (pain and tingling in the extremities). It is expected to be approved by the U.S. Food and Drug Administration for use in the United States by the end of the year.

The first study, a Phase 2 clinical trial in relapsed / refractory multiple myeloma patients, showed that the combination of carfilzomib, Revlimid (lenalidomide), and low-dose dexamethasone (Decadron) is effective and that the side effects of the combination are tolerable (abstract). The overall response rate was 78 percent (24 percent complete or near complete response, 18 percent very good partial response, and 37 percent partial response). Most patients responded within the first two months of treatment, but responses improved with longer treatment. The most severe side effects were primarily low blood cell counts. Fatigue and diarrhea were also common. A Phase 3 study comparing this combination versus Revlimid and dexamethasone alone opened in July and is recruiting patients.

An ongoing Phase 2 study presented during the poster session is evaluating the efficacy of carfilzomib in patients with relapsed myeloma who have never before been treated with Velcade (abstract). Two dosing regimens were used. Higher dosing yielded better results. For patients receiving the higher dosing, the overall response rate was 51 percent (26 percent very good partial response, 25 percent partial response). The median duration of response was 13.1 months for the lower dosing and not yet reached at 10.3 months follow-up time for the higher dosing. Like the previous study, the main serious side effects were low blood cell counts. Fatigue, nausea, and shortness of breath were also common. While on therapy, around 16 percent of participants developed mild peripheral neuropathy and one case of severe neuropathy was reported.

A long-term follow-up analysis from a Phase 2 study of carfilzomib in patients with advanced relapsed / refractory multiple myeloma showed an overall response rate of 24 percent (0.4 percent complete response, 5 percent very good partial response, 18 percent partial response) with a median duration of response of 7.8 months (abstract). Patients who had chromosomal abnormalities responded similarly with an overall response rate of 30 percent and a median duration of response of 7 months. Velcade-refractory patients had an overall response rate of 17 percent. For the entire group of study participants, progression-free survival was 3.7 months and median overall survival was 15.6 months. Like the previous two studies, the main serious side effects were low blood cell counts, and new cases of peripheral neuropathy were uncommon.

Another Phase 2 study of carfilzomib in relapsed / refractory multiple myeloma patients likewise showed that carfilzomib-based therapy is effective in myeloma patients with very advanced disease (abstract). Carfilzomib was administered in combination with dexamethasone, and other therapies could be added after the first cycle. In this study, the overall response rate was 37 percent (18 percent complete or near complete response, 19 percent partial response). Event-free survival was 21 percent at 6 months and 11 percent at 12 months. Overall survival was 54 percent at 6 months and 42 percent at 12 months. Almost all participants experienced low blood cell, high blood sugar, low potassium, and low phosphate levels; and most experienced fatigue.

The poster session concluded with a discussion of some of the posters. Dr. Jonathan Kaufman from Emory University spoke about the first three carfilzomib studies. He was an investigator on two of the studies.

Dr. Kaufman said that all three studies demonstrate that carfilzomib is effective in relapsed / refractory myeloma patients and that it is associated with low rates of peripheral neuropathy. He said, however, that a number of questions remain: What is the optimal dosing for carfilzomib? Does carfilzomib, alone or in combination, provide a survival advantage compared to the current standard of care? How does the safety and efficacy of carfilzomib compare to Velcade, especially now that weekly and subcutaneous administration of Velcade have been shown to be safer?

There were two presentations from the afternoon session that may be of interest for myeloma patients.

The first study investigated GDC-0941, a new oral drug that is in the early stages of clinical testing. The dosing of GDC-0941 was studied in this Phase 1 trial in patients with advanced solid tumors or multiple myeloma (abstract). Initial results in patients with solid tumors show that GDC-0941 is generally well tolerated below 450 mg daily. Serious side effects included rash, fatigue, low white blood cell counts, and high blood sugar levels. Common side effects included nausea, diarrhea, fatigue, vomiting, abnormal taste, and loss of appetite. GDC-0941 appeared to have anti-tumor effects in several patients. Results are not yet available for the study participants with multiple myeloma.

Results from a large Phase 3 trial comparing subcutaneous Xgeva (denosumab) with intravenous Zometa (zoledronic acid) was also presented during the afternoon poster session. Xgeva and Zometa are both used to treat cancer patients with bone disease. This particular study included patients with bone metasteses from solid tumors or bone lesions due to multiple myeloma. The results showed that patients receiving denosumab were 10 percent less likely to experience a skeletal-related event as compared to patients receiving Zometa.

For additional summaries of the day’s sessions, see The Myeloma Beacon’s extensive Day 1 and Day 2 coverage in the Beacon multiple myeloma forums. News from the rest of the ASCO meeting will also be summarized in the forums and in daily updates like this one.

Xgeva Receives FDA Approval For Bone Disease In Solid Tumors, But Not Multiple Myeloma

Julie Shilane — Sat, 20 Nov 2010 00:35:12 +0000

The U.S. Food and Drug Administration announced earlier today that denosumab, which will be marketed by Amgen under the brand name Xgeva, has been approved to help prevent fractures and to slow bone disease in patients with solid tumors. It was not approved at this time for use in patients with multiple myeloma.

“It wasn’t approved [for myeloma] because the Xgeva-treated subset of multiple myeloma patients had more deaths than the control arm,” said Erica Jefferson, a spokesperson for the Food and Drug Administration (FDA).

Xgeva is an antibody that prevents bone removal and degradation. It is currently marketed at lower doses under the brand name Prolia for the treatment of postmenopausal women with osteoporosis and a high risk of bone fractures.

Two Phase 3 trials showed that Xgeva was superior to Zometa (zoledronic acid) at delaying skeletal complications in breast cancer and prostate cancer patients. A third trial that included patients with different solid tumors and multiple myeloma demonstrated that Xgeva achieved similar results in the study participants as Zometa (see related Beacon news). In all three trials, the median time until a patient’s first skeletal complication was at least 20 months for patients treated with Xgeva. These trials were the basis of Xgeva’s approval for use in solid tumors.

However, an analysis of the multiple myeloma patients in the third trial showed that there was a two-fold higher risk of death in patients receiving Xgeva than those receiving Zometa.

“Myeloma was only about 10 percent of the treatment population in that study,” said Lisa Rooney, a spokesperson for Amgen. “Mortality was higher in the Xgeva subgroup analysis of patients with multiple myeloma in that trial, but it was a very limited number of patients in that subgroup. So it precludes a definitive conclusion.” The trial included a total of 1,776 patients.

“I fully agree with the FDA decision,” said Dr. S. Vincent Rajkumar of the Mayo Clinic. “The statistically significant, greater than two-fold inferior overall survival with denosumab [Xgeva] compared with zoledronic acid [Zometa] is disconcerting, despite being a subgroup analysis. I would not recommend the use of denosumab in myeloma patients, outside of clinical trials.”

Ms. Rooney stated that Amgen will continue to pursue approval of Xgeva for multiple myeloma and will be conducting a separate study to look specifically at the safety and efficacy of Xgeva in myeloma patients. That clinical trial is not yet recruiting patients.

The most common side effects seen in the Xgeva trials included fatigue, weakness, low phosphate levels, and nausea. The most common severe side effect was shortness of breath.

Osteonecrosis of the jaw, a severe complication associated with bone disease treatments, occurred in 1.8 percent of patients treated with Xgeva and 1.3 percent of patients treated with Zometa.

“Zoledronic acid [Zometa] has recently shown an overall survival benefit in myeloma,” said Dr. Rajkumar. “Therefore, bisphosphonates, especially pamidronate [Aredia] and zoledronic acid, remain the standard of care to prevent skeletal-related events in patients with myeloma who have evidence of bone disease.”

For more information, see the FDA and Amgen press releases.

Beacon BreakingNews – Xgeva Receives FDA Approval For Bone Disease In Solid Tumors, But Not Multiple Myeloma

The Myeloma Beacon Staff — Fri, 19 Nov 2010 19:35:39 +0000

The U.S. Food and Drug Administration announced today that it approved Amgen’s Xgeva to help prevent fractures and to slow bone disease in patients with solid tumors that have spread to and caused damage to bone. Xgeva was not approved, however, for multiple myeloma patients with bone damage.

Xgeva is the new brand name given to denosumab when used for the treatment of cancer-related bone disease. Denosumab at lower doses is marketed under the brand name Prolia for the treatment of postmenopausal women with osteoporosis and a high risk of bone fractures.

For more information, see the U.S. Food and Drug Administration website, and check back for further coverage on The Myeloma Beacon.

Update: Please see The Myeloma Beacon’s full coverage.

Prolia May Delay The Onset Of Bone Complications More Effectively Than Zometa In Multiple Myeloma Patients

Jessica Langholtz — Wed, 27 Oct 2010 17:11:57 +0000

The pharmaceutical company Amgen recently announced that its new drug Prolia more effectively prevents bone pain and fractures in patients with advanced bone disease than Zometa. Prolia was noted to have higher efficacy in patients with various types of cancers, including multiple myeloma. The announcement followed the presentation of results from recent Phase 3 trials at the European Society of Medical Oncology Annual Meeting.

Bone disease is frequently associated with multiple myeloma and can cause bone pain and lead to serious bone complications, such as lesions and fractures, that are collectively referred to as skeletal-related events, or SREs.

The current standard of care for the prevention of SREs are bisphosphonates. The two most commonly used bisphosphonates in multiple myeloma are Zometa (zoledronic acid) and Aredia (pomidronate).

Recently, several alternative drug therapies have been evaluated for the prevention of SREs in cancer patients. One of these new preventive drugs is Prolia (denosumab), a human monoclonal antibody that specifically targets a protein that regulates the cells responsible for the breakdown of bone.

Amgen compared the efficacies of Prolia and Zometa in three Phase 3 trials. The trials included more than 5,700 patients with multiple myeloma or breast cancer, prostate cancer, or other solid tumor bone metastases. Patients received either 120 mg of Prolia or 4 mg of Zometa every four weeks.

An integrated analysis of the three studies found that in comparison to Zometa, Prolia more effectively delayed time to the first SRE. The median time to the first SRE was 27.7 months for Prolia and 19.5 months for Zometa. The overall disease progression and survival rates were comparable for both treatment groups.

The frequency of side effects was similar in both groups and consistent with previous studies. Patients who received Prolia did not experience as many kidney-related side effects, but many of them experienced low serum calcium levels.

According to Dr. Ravi Vij of Washington University in St. Louis, the decrease in calcium levels is not concerning and may even be beneficial for multiple myeloma patients. “Hypercalcemia [elevated calcium levels] is often a problem in patients with myeloma,” said Dr. Vij in email correspondence with The Beacon. He added that future studies may show that the calcium-level-reducing effects of Prolia could help bring calcium to normal levels in myeloma patients.

A separate survey-based analysis of the three clinical trials suggested that Prolia more effectively prevented bone pain than Zometa. Patients assessed the severity of their pain (range 0 to 10) in a Brief Pain Inventory on a monthly basis throughout the study.

Patients treated with Prolia had a median of 181 days before reporting worsening of clinically significant pain, compared to 169 days for patients treated with Zometa.

While the results of these clinical trials seem promising for Prolia, Dr. Vij pointed out that it is too early to predict Prolia’s future influence on the standard of care for bone pain and SREs. “The data set comparing the efficacy of Zometa with Prolia is very limited,” stated Dr. Vij. “An adequately powered study needs to be done in order to answer this question.”

For more information, please refer to the Amgen press release.

Recent Advances In Treating Myeloma Bone Disease (ASCO 2010)

Pat Killingsworth — Fri, 18 Jun 2010 12:12:11 +0000

The majority of multiple myeloma patients suffer from bone disease, and drugs called bisphosphonates are commonly used to help improve bone health in myeloma patients. Dr. David Roodman of the University of Pittsburgh discussed the current use of bisphosphonates in multiple myeloma during an education session on June 7 at the annual American Society of Clinical Oncology (ASCO) meeting.

Treatment of myeloma bone disease is important, since 20 percent of multiple myeloma patients experience a fracture at the time of their myeloma diagnosis, and 60 percent of multiple myeloma patients experience a fracture during their cancer. Additionally, bone disease has a negative impact on the patient’s response to treatment.

“The gold standard [for treatment of myeloma bone disease] is bisphosphonate therapy,” said Dr. Roodman. “Of course the best treatment for myeloma bone disease is treatment of the disease itself.”

Both Aredia (pamidronate) and Zometa (zolendronic acid) decrease the risk of a fracture by an average of almost 50 percent following the first nine months of use. These bisphosphonates also help slow further bone deterioration.

ASCO and Mayo Clinic guidelines currently recommend that myeloma patients with bone disease receive two years of monthly intravenous therapy using Aredia or Zometa. Only patients with active bone disease should continue treatment after two years.

With recent findings, however, physicians are asking whether bisphosphonates should be used longer and in more patients. Besides improving bone health, bisphosphonates may also help fight multiple myeloma.

There was no evidence that bisphosphonates have anti-tumor activity until a presentation on June 6 in which Dr. Gareth Morgan of the Royal Marsden Hospital in London reported on a new study showing that Zometa extends survival in multiple myeloma patients by 5.5 months as compared to Bonefos (clodronate).

According to Dr. Morgan’s study, it appears that bisphosphonates may benefit myeloma patients in terms of survival even if they do not have bone complications. Additional data confirming these findings is expected to be released at the American Society of Hematology meeting in December.

“Bisphosphonates are very effective in treating myeloma bone disease and have really revolutionized the treatment of myeloma bone disease,” said Dr. Roodman.

However, the use of bisphosphonates is not without risk. A patient’s kidneys may be damaged with prolonged use. Bisphosphonates can also cause osteonecrosis of the jaw (ONJ), in which there is a loss of blood supply to the jaw resulting in jawbone death. The complication is more common after long-term use of bisphosphonates, but all three doctors on the educational panel gave anecdotal evidence of seeing fewer and fewer cases of ONJ now that patients are urged to maintain and monitor their dental health.

Dr. Roodman highlighted that a new, experimental drug, denosumab, is looking promising. He also pointed out that Velcade (bortezomib) encourages new bone formation in some patients.

In the question and answer period following the formal presentations, Dr. Todd Zimmerman from the University of Chicago reminded those in attendance that up to 17 percent of newly diagnosed myeloma patients are vitamin D deficient, or have other vitamin D-related issues at diagnosis. He stressed that bisphosphonates are not as effective without enough vitamin D. Therefore, deficiency needs to be corrected.

ASCO 2010 Multiple Myeloma Update – Day Four

Pat Killingsworth — Tue, 08 Jun 2010 21:01:57 +0000

Yesterday was the fourth day of the American Society of Clinical Oncology (ASCO) annual meeting in Chicago. Although today is the final day of the meeting, the multiple myeloma-related sessions concluded yesterday.

The day began with a meeting-wide session to review the highlights of the previous day across all cancer types. There were six presentations, and despite all of the types of cancers being discussed at the meeting, an entire presentation was devoted to myeloma.

Dr. Jean-Luc Harousseau from the Rene Gauducheau Cancer Center in France presented the myeloma highlights. He described several of the studies that The Beacon has summarized in our ASCO updates, with particular emphasis on studies involving autologous stem cell transplants in the era of novel agents, supportive care, and newer agents under development.

There were also two poster sessions, one in the morning and one in the afternoon, that had just a few myeloma-related posters.

The morning’s poster session was about “Trials in Progress.” The session—a first for ASCO—was designed to facilitate awareness of open, ongoing clinical trials. Two ongoing myeloma research studies were featured.

The first poster highlighted a large Phase 2 study designed to see if lower dose, once weekly Velcade (bortezomib) treatments in combination with dexamethasone (Decadron) can be as effective as standard twice-weekly dosing.

The second involved another Phase 2 study, this one combining Velcade with panobinostat and dexamethasone in relapsed/refractory multiple myeloma patients. The goal of the study is to see if adding panobinostat can help overcome Velcade resistance.

Both studies are a long way from complete. As a matter of fact, the panobinostat study is still recruiting patients. The study is facing the challenge of finding enough patients who recently became resistant to Velcade.

The afternoon’s poster session was about “Patient and Survivor Care.” Both of the myeloma posters in this session compared Prolia (denosumab) to Zometa (zoledronic acid) for the treatment of bone disease related to myeloma as well as other advanced cancers.

The first poster presented results from a Phase 3 study that showed Prolia delayed the time until the first fracture and also reduced the number of fractures that the patients experienced compared to treatment with Zometa. The researchers suggested that Prolia is more potent than Zometa and are testing it in prostate and breast cancer to see if it has anti-cancer activity.

Among the typical safety concerns related to bone disease treatments, Prolia did not cause kidney problems because it is not cleared from the body by the kidneys. Prolia caused a higher rate of high calcium levels in the blood, which the researchers attributed to Prolia’s greater efficacy. Finally, both treatments had similar rates of osteonecrosis of the jaw.

The second study showed that Prolia was more effective than Zometa at reducing bone disease-related pain.

The afternoon’s information-packed session, “Complications of Myeloma and Myeloma Therapy,” focused on minimizing drug-related side effects in multiple myeloma patients.

Dr. Todd Zimmerman of the University of Chicago spoke about the complication deep vein thrombosis (a blood clot in a deep vein) in multiple myeloma patients. He explained that myeloma puts patients at an increased risk of developing blood clots.

Treatment for multiple myeloma, in particular treatment with high-dose dexamethasone or other multi-agent therapies, can significantly increase the risk of blood clots. Dr. Zimmerman recommended that aspirin, warfarin (Coumadin), or low-molecular weight heparin be used to minimize the risk of clotting.

Next, Dr. Paul Richardson of the Dana-Farber Cancer Institute reviewed the latest studies involving peripheral neuropathy (PN).

Just like with deep vein thrombosis, myeloma can also cause PN and treatment further increases the risk. Thalidomide and Velcade often cause PN. Additionally, myeloma patients with Vitamin B-12 deficiencies are at even higher risk of developing PN.

Because thalidomide-induced PN is often irreversible, Dr. Richardson recommended discontinuation of thalidomide at the first sign of neuropathy. Velcade-induced PN, on the other hand, is often reversible, so Dr. Richardson recommended managing PN by reducing the dose and frequency of Velcade.

Dr. Richardson also recommended a list of vitamins and supplements as well as cocoa butter massages to help reduce PN.

The final speaker, Dr. David Roodman of the University of Pittsburgh, concentrated on the use of bisphosphonates to help improve patient bone health. This is important, since a majority of multiple myeloma patients suffer from bone damage.

ASCO and Mayo Clinic guidelines currently call for two years of monthly intravenous therapy using Aredia (pamidronate) or Zometa. Only patients with active bone disease should continue treatment longer.

Both Aredia and Zometa decrease the risk of a fracture by an average of almost 50 percent, and these bisphosphonates also help slow further bone deterioration. However, the use of bisphosphonates is not without risk, such as kidney damage and osteonecrosis of the jaw.

Dr. Roodman highlighted that a new, experimental drug, Prolia, looks promising for the management of myeloma-related bone disease.

In the question and answer period following the formal presentations, one attendee asked about why constipation was so common among patients taking thalidomide. Dr. Zimmerman’s answer: Neuropathy.

The questioner then asked about another common side effect caused by thalidomide: patient confusion and disorientation. Dr. Richardson felt that was a result of the drug getting past the blood-brain barrier. He stressed patients should immediately be taken off the drug if this occurs.

Beacon NewsFlashes – October 23, 2009

Michael Salgado — Sat, 24 Oct 2009 00:42:47 +0000

FDA Requests Additional Information For Prolia Approval – Amgen Inc. announced on Monday that the U.S. Food and Drug Administration (FDA) has requested additional information needed for the agency to complete its review of Prolia (denosumab). Amgen has applied to the FDA to have Prolia approved for the treatment and prevention of postmenopausal osteoporosis. In its recent information request, the FDA asked Amgen for all updated Prolia safety data as well as more details about Amgen’s proposed post-marketing surveillance program for Prolia. The Agency also informed Amgen that a new clinical trial program will be necessary for the FDA to be able to approve Prolia for the prevention of postmenopausal osteoporosis. Prolia is currently being tested in multiple myeloma patients to see if it can delay skeletal events (see related Beacon article). For more information, please see the Amgen press release.

Race For Research 5K Walk/Run – On November 1, the Multiple Myeloma Research Foundation will be sponsoring the Race for Research 5K Walk/Run in Atlanta, Georgia. Registration starts at 7 a.m. and the race beings at 8:30 a.m. The MMRF is looking for participants and donations for this event. For more information, please visit the MMRF Web site.

RHS Open – On November 2, the International Myeloma Foundation is holding the Inaugural RHS open in Mt. Pleasant, SC. This annual golf tournament is held in honor of IMF Board Member, Rich Saletan. For more information, to register, or to sponsor a golfer, please visit the IMF Web site.

For a more detailed listing of myeloma related events, please check the Myeloma Beacon Events Calendar.

Phase 3 Trial Indicates Denosumab Delays Skeletal Related Events In Cancer Patients

Jessica Langholtz — Tue, 22 Sep 2009 17:13:45 +0000

On Monday, Amgen released results from its Phase 3 clinical trial that compared denosumab with Zometa (zoledronic acid) in multiple myeloma patients and advanced cancer patients whose tumors have spread to the bone. The results indicated that denosumab delayed skeletal related events in this group of cancer patients.

Bone tumors often weaken and destroy the bone surrounding the tumor, resulting in serious complications that include bone fractures, spinal cord compression, the need for radiation, and the need for bone surgery. These complications are collectively named “skeletal related events,” or SREs for short. Nearly 100 percent of myeloma patients experience SREs.

Denosumab specifically targets RANK Ligand, which regulates the cells that break down bone. The Phase 3 trial evaluated the efficacy of denosumab in the treatment of bone disease by comparing it to Zometa, a current standard treatment for bone disease in cancer patients. Zometa is a bisphosphonate that is used to prevent skeletal fractures in myeloma patients and to treat pain related to bone tumors.

The trial enrolled 1,776 advanced cancer patients in a randomized, double-blind study. Half of the patients were randomly selected to receive 120 mg of denosumab subcutaneously every four weeks, while the other half received Zometa administered intravenously at a dose of 4 mg delivered as a single, 15-minute infusion every four weeks.

Patients receiving denosumab had a median time of 20.6 months until the occurrence of their first SRE, whereas patients receiving Zometa had a median time of 16.3 months. Despite being numerically greater, the average time until the first SRE was not statistically greater for denosumab compared to Zometa. The rate of adverse events (96 percent denosumab, 96 percent Zometa) and rate of serious adverse events (63 percent denosumab, 66 percent Zometa) were similar for the two treatment groups, which is consistent with previous reports for these two drugs.

“The positive results of this study, combined with the convenience of a monthly subcutaneous injection and without the flu-like symptoms associated with Zometa administration, make this an exciting potential treatment option for advanced cancer patients,” said Dr. David Henry of Pennsylvania Hospital in Philadelphia.

For more information, please read the Amgen press release.