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In a recent paper in the journal Blood, Dr. Bart Barlogie and his team at the University of Arkansas in Little Rock claim they are "Curing myeloma at last: defining criteria and providing the evidence." This is a bold statement.  I would argue that while the paper provides a statistical/computer model, achieving and documenting true cure demands a follow-up of individual patients and cannot be predicted by a computer model.

But let's examine the approach taken here more closely to see why. In order to comment intelligently on this paper, one must search through the details of the methods used to define cure and provide the "evidence."  The term "cure fraction" is used in the paper.  It is derived from a combination of relative survival estimates (myeloma patient survival versus a patient without myeloma) and a complex computer model derived from a statistical approach used in 1982 for breast cancer. Is this a valid statistical approach to derive a "cure fraction"?  The authors of this statistical paper emphasize the constraints of the approach.  Two risk groups are required for the statistics to work.  Dr. Barlogie divides his patients into "high" and "low" risk so that this approach can be applied, but as readers are probably aware, the Mayo Clinic mSMART approach divides patients into three risk groups.  Which is correct or better?  We don't know.

After careful review, it appears that the "cure fraction" from the Little Rock "model" is considered to be: patients with "high risk" disease by gene expression profiling (GEP) who remain in complete remission (CR) for > 5 years and "low risk" patients by GEP who stay in CR for > 10 years.  Are such patients cured?  Clearly they are doing well, but the risk of relapse is not zero.  The label of "cure" is still just a statistical prediction, which is treatment and model dependent.  The outcome for each individual patient is determined by individual staging and prognostic factors, as well as non-myeloma related co-morbidities. Although calculating a "cure fraction" using the proposed model does allow comparisons between the different "total therapy" regimens used in Little Rock, it does not affirm that individual patients are actually cured. 

What is more helpful is to offer criteria that can predict a likely very good outcome at the start of therapy and/or early in the disease course.  This is the strategy of the IMF's Black Swan Research Initiative.  Using MRD assessment as a primary tool, it is possible to predict likely long remissions with complete remissions, especially with CR or stringent CR for patients with initial stable response.  Without claiming that patients are necessarily "cured" (meaning that there will never be a relapse even after 10 years), one can predict chronic disease control, which is most helpful to individual patients.  Thus, for example, in a young patient with good risk features--(ISS Stage I), normal F.I.S.H. testing (no t[4;14]; 17p-; 1q+ ), and normal LDH at baseline who achieves stringent CR and flow MRD-negative status--a very good outcome can be predicted.

The total therapy regimens clearly produce excellent outcomes for some patients. But in 2014, most patients and investigators are looking to novel therapy/transplant regimens that can be successful without the automatic double transplant approach plus other elements of the total therapy program.  The pioneering value of total therapy has triggered the search for other ways forward that can occur within the Black Swan Research Initiative, which allows use of MRD assessment to achieve the best outcomes.

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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This past weekend, "60 Minutes" focused on the high cost of cancer drugs. Although the discussion centered on treatments for colon cancer and chronic myelogenous leukemia, it is an across-the-board problem. Lesley Stahl interviewed experts at Memorial Sloan Kettering Cancer Center about the very high cost--$11,000 a month--for a new drug, Zaltrap, to treat colon cancer, versus $5,000 a month for a very similar drug, Avastin. The prolonged survival benefit of 1.4 months did not seem to justify the doubled cost. After a New York Times op-ed that made this point was published, Sanofi, the manufacturer of Zaltrap, immediately agreed to cut the cost in half! This rapid reaction prompted a chain of other reactions revealing the complexities involved in determining current cancer drug pricing.

The basic problem is that many new cancer drugs cost approximately $100,000 a year, and patients may need to take more than one at a time. Few patients can pay such costs directly. This is where the complexity starts. Prices, drug manufacturers argue, are linked to development costs that often amount to several $100 million to as much as $1 billion.

Dr. Hagop Kantarjian from MD Anderson Cancer Center in Houston takes issue with this argument. He examined the costs for the spectacularly successful drug Gleevec, to treat and control chronic myelogenous leukemia with indefinite, continuous use. The cost for Gleevec in 2001 was $28,000 a year. The development costs were recouped within the next decade. The Novartis Corporation has now earned a total of approximately $45 billion from Gleevec alone. The problem is that the cost of Gleevec is now $92,000 a year. What justifies that increasing cost over time? And what justifies the fact that patients in the US routinely pay 40-80% more for their drugs than do their European, Canadian and Australian counterparts?

The major justification offered by a representative of the pharmaceutical trade group on "60 Minutes" is that continued expensive research and innovation are required to develop new and better drugs. Who should pay for that innovation? Certainly not desperate cancer patients who are struggling to pay for lifesaving therapies.

After watching the interviews on "60 Minutes" I concluded that a financial structure that allows pharmaceutical firms to recoup the original investment and rewards them for their risk is fine. The system, however, must price those lifesaving drugs in a way that respects the needs of patients. I believe that the funding of additional and new innovation should be the focal point of a separate dialogue: How can we reduce drug costs and also make drugs available in a more realistic fashion in the global marketplace?

An honest dialogue would require all parties to come to the table - patients, manufacturers, legislators, government entities such as Medicare (which currently, by law, must pay full price for drugs), large hospitals and clinic groups (which negotiate discounts), insurers, and physician care providers (who are largely caught in the middle of complex buying arrangements). This must not be a blame game. Faced with an explosion in cancer drug costs, I believe there is enough momentum to find equitable solutions.

Any ideas for solving this problem will be most welcome and, perhaps, can initiate the necessary dialogue. A starting point for the conversation on behalf of myeloma patients might be our next International Working Group (IMWG) Summit, where we can invite all concerned parties to address this issue. 

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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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.

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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.

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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.

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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.

 

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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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.

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Questions continue to pour in about measles virotherapy, which I wrote about in my May 22, 2014 blog here. Myeloma patient and advocate Jack Aiello raised an interesting question: "If the massive 100-billion dose of engineered measles (MV-NIS) virus is destroying myeloma, why isn't it also causing a raging case of measles?"

Dr. Stephen Russell of the Mayo Clinic took the time to provide the highly technical answer, which I will do my best to explain. (I have also created a graphic, FIGURE 1, which I hope will help.)

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First of all, it must be emphasized that the measles virus used as the starting point for these research studies was the attenuated strain, the weakened strain used for measles vaccination. This strain has proven to be very safe with very limited potential to ever actually cause measles.

The next step was to take this weakened strain and "morph" it in a different way by growing it on human cancer cells. Viruses need the machinery of a cell to survive. In this case, the measles virus adapted to growing in cancer cells. A main adaption was to use a surface receptor called CD46 to enter the cell. 

It turns out that myeloma cells have many CD46 receptors, whereas normal cells have very few: a 10-fold difference. Myeloma cells infected with virus also develop a "measles attachment protein" on their surface. This leads to the development of large clumps (called syncytia) of joined and fused myeloma cells which subsequently die. Another factor which helps speed up this myeloma cell destruction is that internal cell defenses are not triggered since the engineered measles virus lacks the critical pieces of C and V proteins which normally trigger the defenses.

So there you have it: selective binding and uptake into myeloma cells, and rapid reproduction of virus because of weakened defenses within the cell. 

The opposite is the case with normal tissues. First of all, measles virus is attacked by antibodies in the blood stream (abundant normally after vaccination, but low-to-zero in half of myeloma patients). Then, there is very limited access to normal tissues which have few CD46 receptors. Plus, when virus does enter, internal anti-viral defenses are high and able to eliminate entering virus.

In myeloma cells, the "Trojan horse" filled with virus enters the CD46 gateway and takes over. In normal tissues, virus rarely makes it through the gate--and even then the cell is armed and ready. And what about the HeLa cells used to grow up massive batches of the engineered measles virus to treat myeloma patients? Well, these HeLa cells are a culture of cells from cancer of the cervix taken from a woman named Henrietta Lacks more than 60 years ago. The cells grow in a liquefied suspension culture. The engineered measles virus is well adapted to targeting cancer cells.

This is why myeloma cells are attacked and normal cells escape unscathed. It always helps to understand. Let's hope that more patients can benefit from this carefully crafted strategy. 

As always, stay tuned!

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 hotline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.