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Myeloma Voices

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In recent weeks, you may have seen full-page newspaper ads signed by 160 award-winning scientists from around the world pleading for funding to help save the planet in the face of climate change. This week, the United Nations convened what the New York Times called "the largest gathering of world leaders ever devoted to climate change."  The need is clear, but momentum  to take action has been strangely lacking.

Toxic chemicals not only affect our planet, they affect the humans who inhabit it. On September 10, the IMF held a congressional briefing in Washington DC that presented information about the link between chemicals at the 9/11 sites and cancer. There are clear links between exposure to certain environmental toxins and myeloma, but the cause of myeloma has typically been listed as unknown. There is no momentum to investigate further or try to prevent myeloma.

We have knowledge about environmental toxins that could help make myeloma a preventable disease; there is a long list of chemicals that cause cancer, and there are thousands more--equally or more toxic--in widespread use that have never been tested to see if they cause cancer.

Where is the motivation to use energy and chemicals wisely, and to begin de-contaminating our planet and its people?

Ever so slowly, the tide is beginning to turn. The Rockefeller Brothers Fund announced this week it will sell assets in fossil fuel companies and invest in cleaner alternatives.  Germany is building massive wind farms off shore to make a meaningful contribution to cleaner energy generation. The European Commission now requires toxicology testing for all new chemicals, and older chemicals are under much tighter review. Reduced use of chemicals is now on the agenda.  And innovative, environmentally sensitive companies such as Pylantis are working to replace petrochemical plastics with non-toxic, recyclable and compost-ready alternatives. Even China has announced a multi-billion-yen program to reduce and shift away from pollution.

study published recently in the journal Nature illustrates the need to eliminate toxic chemicals, not just in the environment, but in our diets as well. According to NPR, the study suggests that for some people, diet sodas may alter "gut microbes in a way that increases the risk of metabolic diseases such as Type 2 diabetes." The change in gastrointestinal microbes leading to diabetes and obesity is also linked to myeloma and other cancers (breast cancer and certain pediatric cancers), again demonstrating that there is a multi-system, multi-step disease causation process. In the case of diet soda, it is potentially a reversible process.

Reversing our exposure to toxic chemicals requires recognition of their effects: agricultural run-off leaks into rivers, lakes, and oceans, and then into fish and into food, causing DNA damage and reducing the strength of the immune system. Inflammation triggers the growth of damaged plasma cells in the case of myeloma, or of other cells, causing other types of cancer.

Cancer prevention requires a multifaceted approach that focuses on eliminating ALL toxic chemicals. Safe chemicals, real food, clean water, and clean energy are critical elements for insuring our good health.  

Is it too late? Let's hope not! We really need our planet--one on which myeloma is decreasing, not increasing.

I invite members of the myeloma community who have an interest in raising awareness about pollution and toxic chemicals to think about what might be done to change the momentum and get rid of the lethargy! I welcome your thoughts!

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 InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine 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 InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to infoline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.

5 Comments

I was diagnosed with Stage III-b Multiple Myeloma, type lambda, with 90% marrow plasma cells in March of 1993. I took part in a conference in Hamilton, Ontario, in 2002 in Hamilton, Ontario, Canada that dealt with the pervasive use of synthetic organic compounds since WWII for cosmetic and agricultural use as weed killers, and as industrial degreasers, particularly in the then-burgeoning automobile industry. The point was made very strongly that this class of chemicals is NOT water-soluble, but is instead fat-soluble. The meaning of this is that human exposures are not excretable, with the exception of lactating mothers, who thus provide a lifetime of exposure to their infants; they accumulate in the human body (and in the bodies of grazing animals, for example, which are then eaten by humans, increasing the accumulation) making the concept of 'maximum allowable exposure' meaningless. Yet our government health agencies continue to establish these 'maximum exposure' standards. This is an area of public policy that must be addressed by our societies by educating the public and of course, the legislators and public-policy makers. I would expect that those who have a financial interest in the continued use of fat-soluble chemicals will strongly oppose putting restrictions on or eliminating the use of these pollutants, but the people must ensure that their representatives in government are not influenced by the corporate interests.

As a New Yorker, we recently had a first responder fire fighter come to our MM support group. He now is in search of a donor match for an allo transplant. The suffering he has endured is awful. Who would have thought his good deed of helping with the 9-11 cleanup would result in his exposure to toxic chemicals, leading to his diagnosis of MM.

Today, 9-25-14, three firefighters, also first responders passed away due to Cancer, yes, three in one day. Could not agree with your article more....where are we headed without serious change?

Here is a long standing resource about chemicals' impact on our lives.

http://healnatl.org/

Thank you for this fine article. I live in a town called Forest Knolls where the Bay Area Air Quality Board (SF area) states that our little town has the worst pollution due to wood burning stoves. Even though this has been declared, it is an uphill battle to get people to change their burning habits to something more clean. Some people even have stated that they like the smell or it makes them cozy. I spent 45 yrs. running, biking, etc. in our community only to realize that this may have caused my MM. Thank God that we have a small group that are involved in trying to make change. Probably won't be in my lifetime.

In our private lives, toxic chemical for cleaning are inexcusable, as well as applying toxins to your yard to make it a golf "paradise." Why not try white vinegar as a purifier? Baking soda has its uses.

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So much has been written and said about myeloma this year. But what is the bottom line for important changes in 2014 versus 2013 and before? Here are the high points in the context of the IMF's 10 Steps to Better Care, comprehensive guidelines with diagnostic and treatment information designed to ensure patients receive the best care.

Step 1: Know what you're dealing with. Get the correct diagnosis.

Early diagnosis is the new theme. Now we can start to treat myeloma before anemia or bone and kidney damage emerge.

As a result, quality of life for myeloma patients will improve forever. Triple therapy with KRd (Kyprolis, Revlimid, low-dose dexamethasone) in high-risk smoldering myeloma is producing MRD-negative status (no residual disease as shown using the new flow method) and is undoubtedly the pathway to cure for some patients.

Step 2: Tests you really need.

Sensitive imaging techniques detect very early active disease. Whole-body, low-dose CT should be considered if there is a question of bone disease at diagnosis or relapse. PET-CT picks up active myeloma inside and outside bone.

Step 3: Initial treatment options.

Revlimid/dexamethasone (Rd) on a continuous basis is a new, simple option for ongoing disease control, especially for the elderly and/or unfit/frail patients. Triple therapy with Revlimid/dexamethasone and a proteasome inhibitor gives superior outcomes for fit patients with or without initial auto transplant. FISH testing has become more complex--but we still do not know how to treat high- and low-risk patients differently, beyond individual, careful discussion with your doctor.

Step 4: Supportive care and how to get it.

Despite recommendations to the contrary, I believe it is still very important to limit the use of bisphosphonate therapy (Aredia and Zometa). Osteonecrosis of the jaw is a concern with long-term use. Since novel therapy combinations produce deeper response than in the past, ongoing bone destruction is less often a concern, and any survival benefit with very long-term Zometa use remains questionable.

Step 5: Transplant: Do you need one?

Autologous stem cell transplant (ASCT) is still an important treatment option. About 20% of patients have sustained remissions beyond 3 - 4 years with ASCT. ASCT with high-dose melphalan should be looked at as a consolidation that can provide benefit. It will be some years until we know which patients benefit the most.

Step 6: Response assessment: Is treatment working?

The new flow cytometry MRD test provides important pathways forward both for drug development and to achieve cure. When a new therapy leads to MRD-negative status for a patient, it can indicate that one therapy is decisively better than another. This can save millions of dollars and years in drug development time. As noted above, achieved MRD-negative status is the pathway to cure for the individual patient. You can read my blogs explaining this in more detail here, here, and here.  

Step 7: Consolidation and/or maintenance.

Consolidation and maintenance are both ways to achieve a better response, either within a few months or with ongoing therapy. The clear benefits still need to be balanced against quality of life issues and costs--and discussed with your doctor on an individual basis.

Step 8: Keeping track of the myeloma: Monitoring without mystery.

The HevyLite test provides a new blood (serum) test to accurately measure response at a very low level. It is a more sensitive and precise test for low-level monitoring versus the IFE (immunofixation electrophoresis) test, especially for IgA myeloma.

Step 9: Relapse: Do you need a change in treatment?

It remains important to assess possible relapse very carefully. Maybe one lab test is just a mistake? Double check. Are there CRAB features?  Is new treatment really needed? If new treatment IS needed, can a prior successful therapy work again? Discuss the options with your doctor.

Step 10: New trials: How to find them.

It is exciting to see truly new types of therapy having an impact! Anti-CD38 antibodies will definitely have a role. The striking response with measles virotherapy is a breath of fresh air in thinking about myeloma. If virotherapy really works, could a single shot cure the disease despite all the mutations and risk features we keep hearing and reading about? Perhaps. And wouldn't that be amazing? So let's see what happens with the new virotherapy trials Dr. Stephen Russell and the Mayo Clinic team are starting this fall. The first patient who received the massive dose of measles virus is still doing well.

As always stay tuned for updates: we have ASH 2014 to come!

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 InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine 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 InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to infoline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.

9 Comments

Very helpful article .Thank you Dr Durie. My observation relates to good practice and the management of side effects. Bortezemib has proved a very effect agent but for many of us causes severe PN even if administered SQ. Also many patients do not respond to conventional therapy and are increasingly resorting in desperation to homeopathy....infra red socks being the latest. We seem to understand little of the processes at work with PN. Would It not be possible to start to look at this and develop best practice guidelines for its management. Not as sexy as a new drug but would have a considerable impact on Q of L for many of us.

have been diagnosed for 2-3 years with smoldering multiple myeloma. Dr. Pierce with the Salem Hospital, Salem oregon is my physician. Currently am being seen twice a year for testing. Just monitoring. Is there a tretment now or just do as I am instructed - monitoring only?

Which HevyLite chain test should be ordered?

There are 3 heavy light chain tests.

Do you order, IgA, IgG, & IgM to be comprehensive?

Or if you are IgG do you only order the IgG test?


thank you

Please will you clarify if Fosamax is listed in the bisphosplonate therapy with Aredia and Zometa? thank you

Thanks for info... its good to read articles about myleoma

Hi Dr. Durie, My wife is deadly afraid of Aredia. The doctor keeps insisting she take it once a month because of high and low calcium and bone lesions. She has had about 6 infusions. Her calcium today, Sept 18, was 8.0 in a range of 8.4-10.2 mg/dl. She wears two large partial dentures and has a history of loose teeth and weak gums. That is why she is so afraid. She is 81 years old and I am doubtful that Aredia is going to strengthen her bones at this point in her life. If you need more information, I will gladly send it. Thanks much for any input you can make about this. Edward Palumbo
P.S. We had the pleasure of hearing you speak at a conference in Paris 4 years ago.

I heard that the woman who was successful with the measles vaccine has relapsed.
Is that true or just the tumor on her forehead reappeared that was radiated and mitigated.
Thank you for all of your insightful information and opinions on upcoming treatments.
Best of luck with your research and information gathering.
JMZ

Revlimid with CLL Lymphoma and MM?

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Recently there has been discussion among some myeloma patients concerning the need for fully personalized myeloma treatment. Is there a benefit to this type of approach? Intuitively, the answer is "yes."  But I would argue that "no" is the better answer.

Let me explain. Yes, there are many variants of myeloma which could be considered individually and personally. These include secretory myeloma (IgG, IgA, IgD: Kappa/Lambda only --- ) ; non-secretory myeloma, plasmacytoma, plasma cell leukemia, extramedullary disease and more. But there is a fundamental similarity in biology. Immunomodulatory drugs (IMiDs) (e.g. Revlimid and Pomalyst) combined with proteasome inhibitors (e.g. Velcade and Kyprolis ) produce excellent responses for most subtypes of disease. Even in the relapsed/refractory setting, Kyprolis/Pomalyst/DEX produces responses (>/= PR in 70%), including in patients with high-risk 17P- disease. Long remissions occur for many patients.

Thus, although it is now known that myeloma cells have hundreds of mutations in different subclones, most of these are wiped out by newer novel combinations. The subclones which persist or recur are the ones which require special attention.

Fortunately, a new Flow MRD test, which is highly sensitive and can be used to identify and sort residual clones, is ideal for studying such resistant subclones. A vital element of the IMF's Black Swan Research Initiative is studying the patterns of resistant disease--which are already emerging--and using this knowledge to guide treatment selection.  Figuring out how to mop up disease that remains after initial therapy is much more manageable, in my view, than attempting to individually tailor treatment at the outset.

It appears that broadly applicable relapse therapies can be developed. Studies from single cells or clones from individual patients provide clues for successful approaches that can be applied broadly to others with similar subclones.

The opposite approach of attempting to target each of many, many individual mutations is truly challenging and, I believe, ultimately not feasible. There are too many individual mutations and too much time and expense needed to develop multiple targeted therapies.

If key so-called "driving mutations" can be found, this will be the answer for new drug development. But, again, these therapies will be broadly applicable to treat patients with resistant disease and/or combined with current treatments to start curing patients! The anti-CD38 antibody therapies are examples of this type of more broadly applicable agent that can significantly contribute to better outcomes.

So, although studies of individual patients are extremely helpful, the goal is to have broadly applicable therapy--to "lump and not split" and learn more from treating larger numbers of patients together, not separately. Myeloma can be divided into apples and oranges and maybe even pears, but not a complete fruit cocktail, which would be counter-productive from the standpoint of both diagnostics and treatment.

The argument against fully personalized therapy is therefore very important in the way that myeloma research moves to achieve the best results for all patients in the most rapid fashion.

Stay tuned as the Black Swan Research project moves research in this direction!

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 InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine 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 InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to infoline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.

5 Comments

I disagree. If you are the patient who needs personalized therapy I am sure you would want this therapy in order to survive. Also, being a mathematician, I have seen individual cases in math which led to generalized theorems which then become very useful. Just my opinion Thanks Bob Withelder

Although I do understand your argument here, I wonder if a particular approach for any given patient might at least have an expected response based on blood type?

Please write to the stockholm commitee for medicine to nominata Dr Durie for the Nobel Prize in Medicine .

His work and dedication have saved thousand of lives and may eventually bring about a cure for a cancer that affects hundred of thousands of young people

Thank you

Dan List

Dr. Drurie
Thank you for your generous time and support.
I met you at the ASH convention in New Orleans after I gave the presentation at the IMf grants? It was my pleasure.
Thanks again,
Dan List

We read that Revlimid cannot be used if the patient has both CLL Lymphoma and MM. Is this true?

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The IMF Strengthens International Relationships in Europe

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The IMF continued to strengthen its international relationships with patients, advocacy groups, and biopharmaceutical companies focusing on myeloma research with meetings in Europe this month.

On September 5th and 6th, the IMF, in conjunction with Czech Myeloma Group Foundation and KPMM (Klub Pacientu Mnohocetny Myelom) hosted a Patient & Family Seminar in Lazne Belhorad, Czech Republic.

I attended the seminar and shared with the more than 110 patients, family members, and physicians in attendance information about the resources and support the IMF provides to patients worldwide.

The meeting marked a special occasion for KPMM - the organization's 10th anniversary. The two-day seminar opened with a well-received video from IMF President Susie Novis congratulating KPMM on its success over the past 10 years.

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The seminar was educational, lively, and enjoyable for all who attended thanks to the tremendous hard work and professionalism of Iveta Mareshova and Alice Onderkova of KPMM. From the medical presentations and patient interactions to the beautiful location of the Tree of Life Resort, complete with a lake, the meeting was a huge success.

The first evening of the seminar also welcomed lively local entertainers: a magician and ballroom dancers. The entertainment and welcoming atmosphere put patients at ease and encouraged them to socialize with one another.

The educational program began during the second day of the seminar. Dr. Roman Hajek presented news about myeloma research and treatment developments, while Dr. Petr Hylena described the accomplishments and activities of KPMM over the past year. 

Dr. Miroslav Hrianka, president of the Slovak Myeloma Society, also attended the meeting and spoke about his group's activities and the treatment landscape for patients in Slovakia. The myeloma communities from the Czech Republic and Slovakia have a close relationship, supporting each other and working together.

Patients living with myeloma told stories about enjoying their lives and experiencing new things no matter the heaviness of the disease, which provided inspiration to all in attendance. We heard about and saw pictures of the exciting life of a myeloma patient who decided with his wife not to allow his myeloma to run his life. He and his family travel the world to hike, walk, swim, and enjoy other physical activities. It was very touching and definitely inspiring.

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The rest of the afternoon included a presentation on changes in social security in the Czech Republic, presented by Lea Janku; a panel discussion that included lively questions from the audience; and breakout sessions for more concentrated Q&A discussions. With beautiful weather, the afternoon Q&A sessions were conducted outdoors by the lake. Dr. Roman Hajek led a session on clinical trials, Dr. Vladimir Maisnar led a session on the management of side effects, and Dr. Petr Pavlicek led a session on alternative treatment approaches.

The meeting ended with an enthusiastic "thank you and see you next year" from all of the participants. This very successful meeting was a wonderful way to celebrate KPMM's 10th anniversary.

I also visited Boudry, Switzerland this month to meet with myeloma researchers at Celgene Europe's headquarters. Celgene is a developer of important myeloma therapies that have made an impact on many myeloma patients around the world. The company's therapies include Thalomid (thalidomide), Revlimid (lenalidomide), and Pomalyst/Imnovid (pomalidomide). Celgene scientists continue their commitment to myeloma with research on additional therapies.

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During the trip, I visited Celgene's Boudry research laboratories, which were impressive and very well organized. I was happy to see the space where the exciting work is being done.

I then shared with 15 researchers and Celgene Europe employees in the meeting room--and many more on video--the important work the IMF is doing with myeloma patients in Europe and around the world. In addition to learning about the IMF's patient education, support, and advocacy efforts, the audience was very interested to learn about IMF-led research projects, including the Black Swan Research Initiative.

I look forward to continuing to expand the IMF's relationships with researchers and patient organizations throughout Europe that share the common goal of supporting and improving life for myeloma patients. 


Nadia Elkebir
IMF Director of Europe and the Middle East


Czech Patient & Family Seminar photos courtesy of KPMM member Mr. Pavel Skarka.

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A Whole New World: Becoming a Patient Advocate

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What does it mean to be a patient advocate? If you asked me that six years ago I would have no idea how to answer that question. Six years ago I was newly diagnosed with myeloma and struggling to learn about this heterogeneous disease and all the treatment options that would be available to me. Six years ago I was quite a different person. Six years ago I didn't have discussions with my healthcare team or ask them questions when things didn't seem right. Six years ago I thought I would offend my doctor if I sought a second opinion. Six years ago I was an uneducated, uninvolved patient who blindly followed doctor's orders. BUT six years ago I had the good fortune to attend my first IMF Patient & Family Seminar in Short Hills, New Jersey and things began to change.

The IMF quickly taught me that "Knowledge is Power." Being a teacher I liked acquiring knowledge so I began educating myself about myeloma. I attended IMF Patient & Family Seminars, listened to webcasts and Living Well with Myeloma teleconferences, participated in online communities like ACOR.org, which is now smartpatients.com and read countless publications. Gradually I became a more active participant in my healthcare. I was asking questions, engaging in discussions, requesting tests and seeking second opinions. I was becoming my own advocate and an "e-patient."  I shared what I learned about the importance of being an educated, empowered and engaged patient with members of my support group, the newly diagnosed myeloma patients I mentored, family and friends. 

I thought I was a "patient advocate;" boy did I have a lot to learn! In 2011 I was to asked to represent the Philadelphia Multiple Myeloma Networking Group at the IMF's annual Support Group Leaders Summit. While registering at the summit, two young ladies from the IMF Advocacy team approached me about participating in an upcoming advocacy training webinar. They were so nice and passionate about what they were doing, I couldn't say no.

I was trained by the IMF on how to become a political advocate. The IMF Advocacy team helps guide individuals to advocate for critical health issues that affect the myeloma community. I learned how to arrange a meeting with my representatives to Congress, how to conduct an in-district meeting and what the appropriate follow-up should be after a meeting. I was also educated on the current critical issues facing myeloma patients. Soon I found myself sitting at an in-district meeting with the legislative health aide from my district in New Jersey, asking for support for the oral chemo parity bill, the Cancer Drug Coverage Parity Act. I'm happy to say days after that meeting, Rep. Rush Holt, my representative to Congress, signed on as a co-sponsor of this bill. I would like to think it had something to do with my meeting and how well the IMF Advocacy team prepared me for it.

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This year I attended the American Association for Cancer Research's (AACR) Annual Meeting. I was selected to be part of the AACR's Scientist-Survivor program. This is a very competitive program, but thanks to the training and opportunities the IMF has afforded me I received one of AACR's coveted scholarships. While at the meeting I discovered an entire new area of advocacy- research advocacy. Research advocates provide the unique patient perspective in the research process, working with investigators, companies and government agencies to accelerate progress against cancer. As part of the AACR's Scientist-Survivor Program I learned that the National Cancer Institute (NCI) and the Department of Defense (DOD) use research advocates. I also learned that research advocates must demonstrate an understanding of cancer and the research process, have a familiarity with how the scientific community works and be able to work as a member of a scientific team.

Many of the other participants in the Scientist-Survivor Program were already research advocates serving on IRBs (Institutional Review Boards), participating in advisory boards, speaking on panel discussions at scientific meetings and refining cancer research education materials. They were very willing to guide me on how to become involved in this new avenue of advocacy. Once again I felt prepared to undertake this new endeavor because of the IMF. I learned a lot about clinical trials and research by attending the American Society of Hematology's Annual Meeting as a patient advocate representing the IMF.

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Upon my return from the AACR's Annual Meeting I created a research advocate profile on the NCI's newly designed Office of Advocacy Relations (OAR) website. But I felt I was at a stand-still. I was in the NCI system, but I only would be contacted if they needed a research advocate that matched my profile.

Once again I was asked to represent my support group this year at the IMF Support Group Leaders Summit. Part of this year's training was a session on.... you guessed it- research advocacy. Research advocates Jack, Jim and Mike presented to the group and encouraged us to get involved. They suggested we start our advocacy efforts at the local level at our own cancer center. I took their advice and contacted my local cancer center and asked if I could observe one of their Institutional Review Board (IRB) meetings. IRBs are groups of experts who review plans for clinical trials before they begin, seeking to protect the safety and rights of people who will participate in the research. My local cancer center was very accommodating and invited me to sit in on an IRB meeting a few weeks ago. After the meeting I wrote a thank you note and asked how I could become involved as a patient advocate on an IRB. In response to my question they invited me to observe another IRB meeting and then start the training process to join an IRB! I am now on my way to becoming a research advocate.

Why am I sharing this? Because anyone can become an advocate! You can be a support advocate, a political advocate, a research advocate or a fundraising advocate. The IMF is there to support you and provide you with the tools to be successful. Join the IMF ACTION team, start/participate in an IMF support group, work with Suzanne Battaglia to organize a fundraiser or try your hand at research advocacy. I have evolved as a patient and an advocate over the last six years and I have to credit the IMF with being instrumental in my metamorphosis.

Cynthia Chmielewski
@MyelomaTeacher on Twitter 

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After more than10 years of progress in myeloma treatment due to the introduction of the novel therapies, researchers now need to know how to eliminate the myeloma cells that remain after current therapies. Today, we are on the brink of having a test that will help us have a clear plan to eradicate residual disease.

The new highly sensitive and extremely accurate flow cytometry test developed with the support of the IMF's Black Swan Research Initiative by Spanish researchers is that test.

It is proving itself to be the most affordable, most sensitive, most easily accessible MRD test yet, and earned near-unanimous acclaim from researchers at a flow workshop co-hosted by the IMF at Memorial Sloan Kettering Cancer Center (MSKCC) in July, as I reported in my blog here.  Asked by an audience member, "Can one of the fluorescent dyes (fluorochromes) used in the FLOW MRD test be changed or improved?" Dr. Alberto Orfao, the FLOW MRD test developer from Salamanca, Spain, said, "Of course - possibly yes!" But these types of tweaks can be never ending, added Dr. Orfao.

 "Do we have a test right now which is working very well? The answer is: YES," said Dr. Orfao. "It is standardized, reliable and sensitive enough at the 10-5 level. Nothing more is needed. It is time to stop tweaking and move forward with full validation in patient trials!"

As readers of this blog are no doubt aware, some in the myeloma community argue that we need a DNA sequencing [molecular] test for MRD in the bone marrow. The main potential advantage of the molecular test, they contend, is greater sensitivity versus flow. However, the new flow method is now equally sensitive and provides excellent prediction of very good patient outcomes. I would add that a more sensitive test might encourage overly aggressive, unnecessary treatment, causing more harm than good!

To be sure, careful comparisons of molecular and flow testing are essential. But after careful consideration of all the pros and cons of each method, the IMF's Black Swan Research team has chosen Flow MRD as the primary MRD detection method--as the benchmark for comparison with other methods.

On the pro side, an important benefit of the new flow method is that it utilizes a stored computer database of all possible myeloma clones or subclones for instant comparison and classification. All myeloma clones or subclones can be identified by flow methodology at any point during the course of the disease. Conversely, the DNA "dominant clone" approach risks missing minor subclones, which take over later in the disease. If residual subclones are identified, these can be characterized and sorted one by one with the flow method for detailed studies, including full sequencing of the DNA.  Applying DNA technology in this combined flow/ molecular fashion is simple and very informative.

The new flow method allows careful measurement of myeloma at the very low levels of disease needed to predict excellent outcomes and enhance treatment for some patients to achieve an MRD-Negative status.

Since the flow test is standardized, widely available and cheap, there is no longer a need for another method such as the molecular method, which has a number of disadvantages. One limitation of the molecular method is that the bone marrow from the time of diagnosis (or a new relapse) is needed to identify the "dominant or main clone" for future monitoring. In my opinion, the molecular method has other disadvantages. It is more expensive--estimates range between $750 and $1,000 (compared to between $100 and $150 for the new flow test)--and cannot be performed at the local center. To those who would argue for using both the molecular and flow tests, a practical point to keep in mind is that "splitting" bone marrow samples into two parts, one for flow and one for molecular, is not ideal. For the best results, the flow test needs the maximum number of myeloma cells from the "first pull" from the bone marrow aspiration sample to give the most accurate results.

Thus, although it is important to compare the flow and molecular methods in some trials, it seems likely that flow is all that we need! Moving forward, there can be some "fine-tuning," with the addition of the Hevylite ratio test as a quantitative replacement for immunofixation (IFE) and whole body PET/CT to directly evaluate myeloma disease outside the bone marrow.

So stay tuned as the Black Swan Research Initiative moves rapidly forward to achieving chronic disease control and 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 InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine 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 InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to infoline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.

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new update from the World Trade Center Health Program (WTCHP) at Mount Sinai Hospital combined with data from the New York City Fire Department indicates that 2,518 first responders have now developed cancer. Myeloma is, unfortunately, among the top four cancers reported, along with prostate and thyroid cancer, and leukemia. This is more than a doubling of the number of cancer cases since last year at this time. If the numbers continue at this pace the burden of cancer, including myeloma, will become enormous--costly in terms of both lives and dollars.

Studies have shown that 9/11 workers have developed myeloma at a higher rate than expected in the normal population. Research has also shown a relationship between myeloma and exposure to carcinogens located at the World Trade Center site, as I've written about here. There is an important "proof of principle" regarding the development of myeloma among 9/11 first responders. The myeloma has been attributed (by the experts reviewing the exposures) to exposure to 1-3 Butadiene, an industrial chemical used to produce synthetic rubber (for example in automobile tires, but also in styrene compounds). The chemical is a known cancer-causing agent which, in the 9/11 setting, is now clearly linked to the causation of myeloma.

Cancer patients--including those with myeloma--can receive awards through the September 11th Victim Compensation Fund (VCF). Although patients are obviously grateful to have a VCF available to help cover lost earnings, plus $250,000 for each patient for "pain and suffering," there are many ongoing concerns and questions. For example, as of June 30, 2014, only 881 claims for cancer have been deemed eligible for compensation. The rest are still under review. A particularly perplexing point is why only 10% of the claim is paid out initially, with the rest of the payment deferred until 2016 (i.e. 2 years from now). This is a long time for patients whose lives are threatened by cancer. So far, the award amounts for 115 cancer claims paid have been between $400,000 and $4.1 million. This is a total of $50.5 million to date. It is not clear how many cancer patients have died.

There are some deadlines that 9/11-related cancer patients should note. Individuals who were diagnosed with a 9/11-related eligible cancer on or before October 12, 2012 and who have not already registered or filed a VCF claim must register with the Fund by October 12, 2014 for review this year. According to the VCF website, "Registration preserves your right to file a claim in the future (before the VCF ends on October 3, 2016). Registration is not the same as filing a claim and you are not required to file a claim even if you have registered." If an individual is diagnosed after the October 12 deadline, he or she can register any time up until the October 3, 2016 deadline.

Myeloma patients are strongly urged to submit claims absolutely as soon as possible. This tragic occurrence is both debilitating and complicated to deal with. The IMF is here to help. Let us know if you need help with paperwork and/or the details of managing the myeloma in the best fashion possible. Let the IMF know if you might need help in any way by contacting the InfoLine team, infoline@myeloma.org.

In addition, the IMF is keeping a spotlight on this important subject by hosting a briefing in Washington, DC, Wednesday, September 10 at 11:30 am. Speakers will focus on the link between agricultural and 9/11 toxic exposures, and myeloma. 

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 InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine 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 InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to infoline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.

 

9 Comments

Thank you for identifying the causative carcinogen. I worked in lower Manhattan for one of the first companies to open after the attacks. We returned to work on Monday,
September 17. A fire smoldered at the WTC site until December or January. The smell in the Nassau subway station ( the stop before the WTC) was so unbearable, I changed commuting routes. The air was hazy and the sky was grayish. I remember that we were assured by the head of the EPA and the Mayor of NYC, that the air quality was ok. I was present in lower Manhattan, at least, 5 days a week for 8-10 hours a day until August 2008. My office was on the fifth floor of a building facing Broadway and, I had an entire wall of air conditioning vents facing Broadway. When I returned to work, I remember cleaning dust and dirt from my office furniture and window sills.

In 2012, I was diagnosed with Myeloma and, had a large plasmacytoma in my sternum and lesions. I have no family history of Myeloma. I have undergone induction therapy and had a stem cell transplant. I am in remission and see my oncologist every three months and visit my stem cell doctor at MD Anderson every 6 months. I have complications from the cancer and treatment. I have very troubling short term memory problems and cognitive impairment; chronic sternum pain; periodic upper back pain; eye problems, shoulder issues; osteoporosis; fatigue issues; joint pain; and, I wear hearing aids because I have unrelenting tinnitus from chemo medications.

I filed an application with the WTC Health Program. It has certified my Myeloma eligible and is a 3rd party insurance payor. I commend the WTC Health Program staffers as they have been of great assistance. After an evaluation, I was told that I am at risk for post traumatic stress syndrome. I also filed a complete claim with the VCF and, am awaiting a decision. I assure you there is no amount of compensation that will suffice. I am grateful to be
alive.


I strongly encourage other Myeloma patients who believe they are eligible to contact the World Trade Center Health Program and to register and file a claim with the 9/11 Victim Compensation Fund.

I was a responder at the Pentagon. It is my understanding that four individuals from my agency was diagnosed with the disease, to include me. In my team, three of us was diagnosed with cancer. I was diagnosed with multiple myeloma. Another individual was diagnosed with non-Hopkins lymphoma and another with a stomach cancer. My agency required annual physicals. From a review of the physicals, blood markers clearly indicated the advancement of my disease. Although I was receiving physicals, my disease was not discovered until 1/8/2008 and I was a Stage 3A (advanced stage of the disease). Fortunate for me, it appears my cancer is slow-growing and it has little or no impact on my kidneys and bones. Unfortunately for me, like all myelomiacs, the disease keeps rearing its ugly head, so treatment is a ongoing thing.

Hi
My name is Clara Russell I was not in
the New York 9/11 tragedy but was
recently diagnosed with Multiple
Myeloma in January 2013. It first
started with pain in my left shoulder
while working as a custodian and I'm
eager to know why, how and where
this disease came from. If you have
any info please let me know?
Thank you, Clara Russell


Is there also a connection to Diethylstilbestrol exposure in utero and multiple myeloma?

Please keep us informed on the date , place, speakers, and other information concerning the briefing in DC on toxic exposures. This is an extremely important topic.
Thanks for all the IMF does!
Mickey DeTemple

Hi Mickey, please see our briefing page here: http://cqrcengage.com/myeloma/sept10. It should give you the information you're looking for. If you have other questions please contact me at rwezik@myeloma.org.

Is there a way to watch/read this briefing on September 10 in Washington? Thanks

Hi Franklin,
Please see our briefing page here: http://cqrcengage.com/myeloma/sept10. It will give you information on the briefing, power points from our presenters and a video of our patient advocate. Contact me at rwezik@myeloma.org if you need help.

Getting our politicians or anyone else to promote the World Trade Centr Health Fund has been a mission of mine since January 2012. I have Multiple Myeloma and I worked in the area. I am certified under the World Trade Center Health Fund.

Finally, I got the attention of John Owens, Editor of Anton News to run a story about 911 and the World Trade Center Health Fund. You can read the article in The Port Washington News, The Weekend july 30-August 5 edition.

You discuss in your article about the first responders. What about the victims. Those of us that worked or lived in the area. Do you have numbers on us?

I will be leaving for vacation tomorrow and will return on August 25. I would be happy to contribute to getting the word out any way I can.

Scott Matty
e-mail- sbmatty@msn.com

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A recent study illustrates just how useful minimal residual disease (MRD) testing by flow cytometry is to predict excellent outcomes with new highly active combination therapies. A phase II study from the Intergroupe Francophone du Myelome (IFM) is reported in the July 14th issue of the Journal of Clinical Oncology. This study served as a pilot protocol for the ongoing IFM/Dana-Farber Cancer Institute 2009 phase II study assessing lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone frontline with or without autologous stem cell transplantation (ASCT). In the phase II study reported in the JCO, 31 patients with newly diagnosed symptomatic myeloma all received RVD followed by ASCT plus RVD consolidation and one year of Revlimid maintenance.

The results with this protocol were extremely good. Very good partial response (VGPR) or better was achieved in 58%, 70%, and 87% of patients after RVD induction, ASCT, and RVD consolidation, respectively. What was especially exciting is that 68% of patients achieved MRD-negative status as measured by flow cytometry. MRD negative by flow is an extremely helpful category as a one-time test measured at the point of maximum response. When MRD negativity is confirmed by subsequent serial testing (i.e. sustained MRD-negativity) and supported by additional testing, such as a negative pet/CT scan and normal HevyLite test, one can use MRD-Zero as a new category indicative of potential cure status.

With a median follow-up of over 3 years (39 months), patients achieving MRD-flow negative status are still in remission. The overall survival is obviously 100% at over 3 years. Thus, as we await the results of the phase III comparison study, the impact of induction, ASCT, consolidation, and maintenance is quite impressive, especially with regard to the MRD-negative status and stable remission status of the patients.

These findings strongly validate the key principle of the IMF's Black Swan Research Initiative. Monitoring with sensitive MRD testing at very low levels of disease both predicts exceptionally good outcomes and can be the basis for additional treatment decisions to achieve the sustained deep responses noted above, which can translate into cure.

It is important to emphasize that these new data support considerable prior data, for example utilizing Velcade plus thalidomide rather than Revlimid with dexamethasone (VTd) for induction, followed by transplant, consolidation, and maintenance. The new RVD results are clearly more promising, but the pattern of benefit throughout the four treatment phases is comparable. For the RVD regimen, it was notable that 13% of patients achieved MRD-negative status during the maintenance period.

The clinical benefit of achieving MRD-negative status documented using the Spanish flow methodology has been recognized for more than 10 years. Two sequential studies by the Spanish team in 2008 and 2012, and one from the UK team have shown that patients achieving MRD-negative status by flow have longer remissions and overall survival. What is remarkable about the new data is the sustained value of the deep responses in the IFM trial: no relapses after more than 3 years.

Thus, with the even more sensitive and standardized new flow method now available and use of increasingly effective novel combinations of therapy, it seems very likely that it will be easily feasible to reliably predict unusually good outcomes and define a patient population potentially curable with comprehensive frontline treatment. This new IFM study thus points the way to incorporation of MRD testing by flow cytometry into tailored approaches to achieve the very best results with therapy throughout the course of disease.

As always, stay tuned for further exciting developments! 


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 InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine 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 InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to infoline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.

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On July 18-19, 2014, the IMF co-hosted the US Myeloma Flow Workshop at the Zuckerman Research Center at the Memorial Sloan Kettering Cancer Center in New York City. There were 24 participating medical centers from across the country plus representatives from the National Cancer Institute (NCI) and US Food and Drug Administration (FDA) in attendance. Attendees included key myeloma experts from the centers as well as technical staff responsible for the running of flow cytometry laboratories. US myeloma experts present included Drs. Vincent Rajkumar, Shaji Kumar, Ola Landgren, Ken Anderson, Saad Usmani, Suzanne Lentzsch, Jonathan Kaufman, Phillip McCarthy, and Andrzej Jakubowiak.

This educational workshop was structured to inform participants about the role of testing for minimal residual disease (MRD) and currently available testing procedures. The main focus was the new automated, highly sensitive flow cytometry method developed by the Spanish team for standardized detection of MRD in myeloma.

The establishment of a reliable MRD test is a key first step for the IMF's Black Swan Research Initiative. The Black Swan Research approach focuses on the use of the best MRD testing to track myeloma at the lowest levels as a basis for treatment decisions to achieve cure. It was therefore very exciting to have the top experts in flow cytometry in the room to assess the value of the new flow test for MRD.

During the workshop's morning session, Dr. Bruno Paiva (University of Navarra, Pamplona, Spain) summarized the importance of MRD testing in assessing treatment outcomes - much as he had done in March at the Salamanca, Spain, Flow Workshop before an audience of 70 global experts waiting to be convinced of the role of MRD testing using flow. After the Spain meeting, the flow cytometrists went home to set up the new method in labs from Germany to Australia. Would it be the same in the US?
Next, Dr. Alberto Orfao (University of Salamanca, Salamanca, Spain) presented to a hushed room. It was clear everyone wanted to hear all the details of the new flow cytometry method he and his team had worked for years to develop, a project that has received IMF support as a key element of the Black Swan Research Initiative.

Afterwards, the usual technical questions emerged and were answered in Alberto's typical calm, complete fashion. An interactive session followed to determine what barriers may exist to the adoption of the new flow method in the US.

As workshop presenter Dr. Brent Wood (University of Washington, Seattle, Washington) would later ask, "What is more important for us? To do our own thing? Or to come together and standardize in a way that is good for our patients?"

The consensus among workshop participants was "Yes, we want to standardize. But how?" Among the practical questions and concerns voiced were the following:

  • Do samples need to be processed in 24 hours?
  • When is the best time to get samples for response assessment?
  • How can we find the time to set up a new method in a very busy laboratory?
  • What about the costs? 
  • We have contracts for the old antibodies--how about the new antibodies?
  • What about the new software which standardizes the analysis and results?

The software for this cutting-edge test is a very important aspect because the cytometer uses eight colors and the results consist of clusters displayed in eight dimensions! If this sounds mind-bending, it really is.  Sophisticated software is required to accurately sort or "gate" the cells and determine which are myeloma cells and which are not! This is the fundamental question the new flow method can answer: are there any myeloma cells left or not--and ARE WE REALLY SURE?

Clearly everyone who attended the flow workshop was eager to have the means to answer to this question, and to be really sure. That left the matter of whether or not the practical laboratory implementation issues can be resolved in order to begin using the new flow method. The workshop participants asked the IMF team to help. There was immediate agreement that every effort will be made to assist labs that are anxious to start the new method, but which face challenges doing so.

After much excellent discussion, a dinner, and a morning session with further questions answered, participants left well informed and highly motivated to implement a new highly sensitive flow MRD method.

In the coming weeks and months, Dr. Bruno Paiva, Dr. Alberto Orfao, their teams, and the IMF team will be at the ready to assist. There is a strong sense of optimism that a reliable MRD test will be available very soon for US patients.

Stay tuned and updates will be posted along the way!

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DurieBlog_antimalaria.jpg

In the early 1980s, I was testing anti-malarial drugs such as quinine against cultured myeloma cells in the laboratory. We had developed drug-resistant myeloma cells specifically for this purpose. Several lines of research had revealed that resistance to drugs such as Adriamycin (an anthracycline), a key component of the "VAD" (Velcade, Adriamycin, dexamethasone) chemotherapy regimen popular at the time, was mediated by a cell membrane protein called P-glycoprotein, which conferred an MDR (multi-drug-resistant) phenotype. What P-glycoprotein does is pump drugs such as Adriamycin out of the cell - a protection mechanism against cell toxicity. However, in the case of Adriamycin, we want the Adriamycin to stay in the cell and kill the myeloma.

This can be achieved by giving drugs which block P-glycoprotein! I became interested in this because of another drug called verapamil (a cardiac drug which can slow the heart and reduce blood pressure), which blocks P-glycoprotein. I showed that giving verapamil to patients resistant to VAD chemotherapy produced new responses and remissions at the safe doses of verapamil.

Another drug studied was the anti-malarial drug quinine, which had similar effects, but more challenging side effects. SWOG (Southwestern Oncology Group) study #9210 was conducted to evaluate the efficacy of quinine along with the VAD regimen. I was co-chair of the SWOG myeloma committee at that time. Unfortunately, we had to discontinue the quinine/VAD study because of the unacceptable toxicities.

Meanwhile, a much more promising and safe drug called cyclosporine (an immune suppressive agent) proved to be effective in laboratory studies, and a clinical trial was initiated in collaboration with the HOVON group in the Netherlands. Results were published in the journal The Lancet in 1992, with my friend and colleague Dr. Pieter Sonneveld as the first author. Patients completely resistant to VAD chemotherapy had remarkable sustained benefit with remissions lasting nine months or longer in this relapsed/refractory setting. Although a number of other agents were subsequently tested, these results remain the best utilizing this anti-P-glycoprotein strategy. However, with the advent of novel therapies in the later 1990s, we moved away from this MDR-targeted approach.

But be assured the anti-malarials were rigorously evaluated as part of this strategy. Like many other agents, such as alpha interferon (anti-viral agent), there is always the potential for important anti-myeloma therapy in the appropriate setting in the future. These agents are not neglected, only superseded by much better novel agents. Nonetheless, it may be that one of these agents will provide the solution to the complex puzzle which is myeloma and lead to a cure. I still have my P-glycoprotein files and publications - now stored in the cloud somewhere! Stay tuned for any updates, whenever they occur.

 

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 InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine 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 InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to infoline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.

1 Comment

Dear Dr. Durie,

It is very interesting you mention the role of antimalarial compounds in the context of multiple myeloma. My research group is interested in getting a better understanding of the molecular mechanisms behind a number of neoplastic processes, one of them being MM. We have recently published an article describing a quick and non-invasive method for diagnosing and monitoring MM patients using metabolomics:

"Multiple myeloma patients have a specific serum metabolomic profile that changes after achieving complete remission", Puchades-Carrasco et al., Clin. Cancer Res., 19: 4770-4779, 2013.

Furthermore, we have been working on the development of structure-based approaches against several therapeutically relevant targets. One of them is heparanase, a protein highly expressed in MM. In fact, compounds that interfere with the biological activity of heparanase have been linked to the inhibition of myeloma tumor growth:

"SST0001, a Chemically Modified Heparin, Inhibits Myeloma Growth
and Angiogenesis via Disruption of the Heparanase/Syndecan-1 Axis", Ritchie et al., Clin. Cancer Res., 17: 1382-1393, 2011.

Interestingly enough, in the course of a project focused on the identification of heparanase inhibitors carried out at my lab, we did find that amodiaquine, an antimalarial compound, does bind to heparanase and could be a potential inhibitor of its activity, perhaps providing a complementary mechanism to the one you described in your blog on the effects of antimalarial drugs on MM:

"Hit identification of novel heparanase inhibitors by structure- and ligand-based approaches", Gozalbes et al., Bioorg. Med. Chem., 21: 1944-1951, 2013.

Best regards,

Antonio

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