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January 2014 Archives : Myeloma Voices

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A new study shows that regular aspirin use reduces the risk of myeloma. Researchers from Brigham and Women's Hospital and Harvard University studied 2,395,458 person-years and showed a 39% lower myeloma risk among individuals with a cumulative average of more than 5 adult strength (325 mg) aspirin tablets per week.

Many details were reviewed and assessed as part of this carefully designed study.  A "4 year lag period" was built in to exclude patients who might have been developing myeloma in the 4 years prior to the study. Length of aspirin use was considered. Greater than 11 years of use gave the most benefit. Men appeared to derive more benefit than women.

But, as they say, "the devil is in the details." Researchers are always worried that something unforeseen may have skewed the results. Some previous studies have shown no impact from regular aspirin use. However, more recently, there are several reports of reduced risk of solid cancers (such as colon cancer) and lymphomas with regular aspirin use.

There is also a need to understand why the aspirin is working. In research lingo, the results have to be "plausible." There are indeed good reasons why aspirin can provide benefit. The anti-inflammatory and anti-oxidant effects involve key pathways such as NF-kB, COX-2, IL-6, and cyclin D1--all known to be important in myeloma progression. Chronic inflammation produces "free radicals" in the tissues, which among other things can damage DNA. Obviously, reducing or preventing chromosome damage is a very good thing.

This is a carefully designed study, but appropriately the authors advise "caution in the interpretation of our findings." Nonetheless, with something as simple as an aspirin a day, which provides many potential health benefits, the added value is worth considering. A key question is: "Can aspirin use reduce or prevent the activation of MGUS or smoldering myeloma into full blown myeloma?" A tantalizing question indeed!  Carefully designed prospective studies are definitely warranted.

It is not clear if a baby aspirin (as used to reduce cardiovascular risks) is sufficient or whether in the case of cancer, a full adult dose (325 mg) provides any additional benefit. Stay tuned for further details. I'm sure new research results will be coming soon.

In the meantime, check with your doctor and unless aspirin use is not possible or not recommended in your situation, "an aspirin a day to keep the doctor away" is perhaps an idea whose time has come while we await definitive long-term results!

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF Hotline staff instead. Specific medical questions posted here will be forwarded to the IMF Hotline. Questions sent to the Hotline are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF Hotline, call 800-452-CURE, toll-free in the US and Canada, or send an email to hotline@myeloma.org. Hotline hours are 9 am to 4 pm PST. Thank you.


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Thanks to the many of you who wrote in about Dr. Durie's blog on the reported effects of daily aspirin on prevention of myeloma.  Rather than answer each of you individually, as we normally do, we thought it best to add this addendum to the blog.

The medical article about daily aspirin use and the incidence of myeloma was certainly good food for thought and further research, but really raises more questions than it answers.  This is incidental data mined from a large study of male doctors over a long period of time. It was not designed to test any specific hypothesis about the long-term effects of aspirin at a given dose.
 
Here are some of the things we still don't know:
 
  • We don't know if aspirin merely lowers the risk of the incidence of myeloma, or if it actually has any anti-myeloma effect once a patient has been diagnosed.
  • We don't know whether the dose of aspirin is significant: in the study, the men taking the pill were using it for pain relief and were taking at least 325 mg (full-strength) daily.  Would 81 mg also be effective?  We have no data.
  • We don't know how much aspirin a person needs to take over what period of time to have an effect. Is the length of time of aspirin consumption--that is, the total cumulative dose--significant?  The benefits of aspirin only became apparent after many years of regular use in the reported study.  How much is enough?
Many times Dr. Durie blogs about interesting medical articles relating to myeloma or cancer research because they are good food for thought and for discussion with one's treating physician, and because they provide a new insight or a new theory that will lead to further research.  

Our present knowledge of daily aspirin use in the myeloma patient community relates only to its use as prophylaxis (prevention) of "venous thromboembolic events," or VTEs (ie blood clots) in a subset of patients who are receiving therapy with an immunomodulatory agent (IMiD, that is, Thalomid, Revlimid, or Pomalyst) AND dexamethasone.  All patients taking a combination IMiD and dex must be assessed for risk of blood clots by the treating physician, and treated according to published guidelines depending upon risk.  

Here is a link to the International Myeloma Working Group guidelines on prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma: http://myeloma.org/pdfs/DVTGuidelinesDec2007.pdf

Please note:
  • Aspirin in an NSAID (non-steroidal anti-inflammatory agent). Those who are not supposed to take NSAIDS, usually because of kidney issues, should not consider daily aspirin use. 
  • Use of aspirin or any other drug specifically to prevent blood clots during therapy with an IMiD alone (for example, during Revmilid maintenance therapy) is NOT recommended by the IMWG. 

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A recent article in the medical journal Cancer Cell documents the widespread chromosomal abnormalities present in myeloma cells. The sobering data from this study, the largest of its kind, also demonstrate why the promise of individual therapies targeted against individual genes is fading--and why the Black Swan Research Initiative approach offers a smarter plan of attack against myeloma.

We've known for several decades that myeloma cells have many chromosomal abnormalities. This is, in fact, the characteristic feature of myeloma at the molecular level. It has also been known and well documented that clonal evolution occurs and multiple subclones exist. Despite that, there has been a strong interest in developing personalized targeted therapies against individual gene mutations. (See my blog, "The Promises and Challenges of 'Personalized Medicine' for Myeloma," April 3, 2012.)

What is new and sobering, as emphasized by the authors, is the total amount of clonal heterogeneity, an amount which is even much, much greater than suspected from prior studies. Many genes are abnormal, and even within the same patient, there are multiple clones with different genetic mutations. As had been noted in the authors' earlier study of 38 patients, there are some recurring patterns of chromosomal abnormalities, including, for example, the BRAF gene. This is important because researchers have developed a cancer therapy targeting BRAF.

However, this idea of targeting individual genes is now seen to be taking us in the wrong direction. For example, not only does anti-BRAF therapy target a small fraction of a patient's myeloma cells but, more importantly, these same myeloma cells have many, many additional mutations. So while it is very interesting to identify mutations in different pathways, such as EGRI, BCL2, NFkB, and D153 and FAM46C (collectively this pair of mutations occurred in 21% of patients), the question of how to proceed in search of appropriate therapy remains unanswered. An especially important point is that an average individual patient sample has at least five subclones, each with multiple genetic mutations.

With awareness of these data, the Black Swan Research Initiative was developed in 2012.  There are several aspects to the BSRI initiative, but key points relevant to clonal heterogeneity are:

  • Best results can be expected by starting therapy before major clonal heterogeneity emerges.
  • After therapy, a much more limited number of clones remain (resistant subclones). This process is called clonal contraction (or restriction), following induction treatment. Fewer clones means many fewer mutations to deal with. 
  • Studies of these residual subclones at the molecular and drug sensitivity level are essential.
  • Using new reproducible tests for assessment of minimal residual disease (MRD), these residual clones can be detected, studied, and treated appropriately. This is the strategy for success: monitor and treat to achieve MRD-Zero.
  • It is assumed that combinations of agents and modalities and multifunctional therapies will be required to produce the best results, overcoming complex chromosomal abnormalities.
Genetic heterogeneity is a challenge, but "forewarned is forearmed." With knowledge of myeloma's widespread genetic heterogeneity, BSRI was designed to implement the best plan of attack against myeloma in 2014 and beyond.

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF Hotline staff instead. Specific medical questions posted here will be forwarded to the IMF Hotline. Questions sent to the Hotline are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF Hotline, call 800-452-CURE, toll-free in the US and Canada, or send an email to hotline@myeloma.org. Hotline hours are 9 am to 4 pm PST. Thank you.

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The International Myeloma Foundation (IMF) Black Swan Research Initiative (BSRI)  is moving into high gear in the new year.

Building on remarkable progress made by the BSRI team during the last months of 2013, our game-changing approach to finding a cure for myeloma has hit key scientific goals ahead of schedule. Additionally, the work is attracting significant financial support from both industry  and private partners.

BSRI is the IMF's signature research project - a multinational consortium of leading myeloma experts who are studying and harnessing new technologies and myeloma treatments. The linchpin to these studies is the quest for determining when zero Minimal Residual Disease (MRD-Zero) has been achieved and sustained.  This is where the most thrilling breakthroughs have occurred.

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Professors Alberto Orfao and Bruno Paiva from Spain presented results of an automated, ultra-sensitive technique for MRD testing at an investigator meeting held in New Jersey in October. The "multiple" in multiple myeloma refers to the frequency of myeloma occurring in different patches or areas of bone. Based on this, they came up with a cocktail of eight antigens that identify myeloma regardless of its state or location in the body.

To eliminate another common variable - the human observer - a computer software program was developed to analyze the read-out from the new test. The sensitivity of the test is one part in 100,000, and probably even lower.

We Can Analyze Hundreds of Thousands of Events

At a follow-up BSRI meeting held before last December's annual meeting of the American Society of Hematology (ASH) in New Orleans, excitement about the new test was palpable. With this new test, "we can analyze hundreds of thousands of events, maybe millions," said Vincent Rajkumar of the Mayo Clinic. "No one person can do that." 

In early 2014, BSRI investigators will host a workshop in Spain to train others to run the Multicolor Flow Cytometry test, as the new technique is called. Once trained, those researchers will return to their own countries to teach others. The next step is achieving consensus on the test, then incorporating the flow cytometry testing into clinical trials so that the testing may be validated prospectively in a standardized fashion. 

Dr. Rajkumar predicted that within two to three years the software will be able to be run anywhere globally. "It's why the Black Swan Research Initiative can change the world." 

To some of the investigators on the team, it already has changed. Jesus San-Miguel asked a provocative question during the discussion of this new testing protocol at the meeting in New Orleans: "My question is--how many patients are already cured?" He was referencing the concept espoused by BSRI that finding the pathway to a cure requires systematic evaluation and validation every step of the way. 

The new cytometry test may soon identify patients who have indeed been cured - which in turn would pave the way for successfully replicating their particular portfolio of treatments. Cross correlations will prove very important in establishing a more finalized MRD testing panel. A key aspect of MRD testing and validation is to compare the flow and molecular methods, such as the Sequenta DNA method. Imaging and molecular testing will round out BSRI's testing protocol.

Five Major Objectives to Achieve Our Goals

There are five major objectives to achieve our goals: 1) Establish a standardized definition for MRD-Zero accepted by the International Myeloma Working Group (IMWG); 2) Standardize the new MRD tests themselves; 3) Validate MRD-Zero in retrospective datasets; 4) Integrate standardized/automated/validated MRD-Zero testing into trials at different disease stages; and 5) Use MRD-Zero for treatment decisions to achieve cure.

Our timeline to accomplish all of this is approximately three years. But progress may be swifter than we imagine. Leading up to the next BSRI investigator meeting in spring 2014 the team is working to establish a chain of publications that will introduce the new definition of myeloma, including ultra-high risk. 

We must also better understand the nature of resistant sub-clones to achieve MRD-Zero.

And, of course, alongside our scientific efforts we are cultivating the financial support for the costly clinical trials and labor-intensive research required to find answers to our questions. This is crucial if we are to accelerate BSRI's efforts to find a cure for myeloma.

Fortunately, support has been forthcoming--a sign we are on the right path.

Multi-Year Collaboration with Onyx Pharmaceuticals

Last December, the IMF was thrilled to announce the start of a multi-year collaboration with Onyx Pharmaceuticals, Inc., an Amgen subsidiary  Onyx is BSRI's inaugural industry partner and we are grateful for their early and enthusiastic support. 

The IMF is equally appreciative of the support given by generous individuals such as IMF Board of Directors member John O'Dwyer and his wife Dorothy. The couple are BSRI Founding Donors and, taking his commitment a step further, John has kindly agreed to serve in the important role of Chairman of the BSRI donor campaign. The O'Dwyers are also joined by Andrew and Laurie Kuzneski in the BSRI campaign.  

We are indebted to Loraine Boyle, whose Peter Boyle Research Fund--named in honor of her late husband--turned its focus this year to Black Swan at the 2013 IMF 7th Annual Comedy Celebration. Private donors have committed more than $625,000 to the initiative so far.  And local member fundraisers have begun earmarking their contributions for BSRI. The proceeds from October 2013's Miracles for Myeloma 5K run in New Jersey, for example, will fund Bruno Paiva's study of Minimal Residual Disease in myeloma.  

This is all great. We want as many members of the myeloma community as possible to participate--researchers, patients, caregivers and friends. Anyone who can contribute whatever they can, be it research, financial support, or raising awareness of our work, is welcome. By pulling together, collaborating, and expanding our minds to consider possibilities never thought of before, I am certain we will find a pathway to achieving a cure. 

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF Hotline staff instead. Specific medical questions posted here will be forwarded to the IMF Hotline. Questions sent to the Hotline are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF Hotline, call 800-452-CURE, toll-free in the US and Canada, or send an email to hotline@myeloma.org. Hotline hours are 9 am to 4 pm PST. Thank you.