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.