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A significant event in the evolution of the IMF's Black Swan Research Initiative occurred this past weekend in Salamanca, Spain. On March 21-22, the IMF-EuroFlow Workshop - co-organized by Lisa Paik (Senior Vice President of Clinical Education and Research Initiatives at the IMF) and the Salamanca-based flow cytometry team - focused on a breakthrough in the standardized detection of minimal residual disease (MRD) in myeloma. 

This new technique is an automated and highly sensitive flow cytometry for the standardized detection of minimal residual disease (MRD) in multiple myeloma. Excited to learn about the latest advance in this method, approximately 70 participants from 13 different countries attended the workshop. There, they learned in a "hands-on" fashion the full details of the new myeloma detection antibody panel and the computer software, which provides results in a standardized automated fashion: identifying each single cell (myeloma or not) in the bone marrow and/or blood samples.  

I am thrilled to report that the workshop was a success! Attendees left ready and enthusiastic to introduce the new methods in their home laboratories.  Professor Alberto Orfao (Head of the Flow Team in Salamanca) and Professor Jacques van Dongen (his colleague from the EuroFlow team at Erasmus in Amsterdam) did a fantastic job in constructing and implementing an intense and detailed program that more than fulfilled the educational needs of the attendees.

From there, Dr. Bruno Paiva (a key Black Swan investigator from Pamplona in Spain and expert at analyzing patient outcomes) and I traveled directly to the FDA in Silver Spring, Maryland to participate in the FDA-NCI Roundtable: "Symposium on Flow Cytometry Based on the Detection of Minimal Residual Disease in Multiple Myeloma." The bottom line for this roundtable was also tremendously helpful and important for the Black Swan Research Initiative. There is a strong consensus evolving that MRD assessment is both required and recommended for response assessment in clinical trials, and that the new flow methodology is the most promising current approach.

Thus, MRD testing is becoming mainstream and flow is the method of choice. So the Black Swan Research Initiative is definitely "going with flow" right now and we have high expectations that new trials including MRD assessment will lead to better outcomes for all myeloma patients.

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF Hotline staff instead. Specific medical questions posted here will be forwarded to the IMF Hotline. Questions sent to the Hotline are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF Hotline, call 800-452-CURE, toll-free in the US and Canada, or send an email to hotline@myeloma.org. Hotline hours are 9 am to 4 pm PST. Thank you.
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A recent editorial in Leukemia authored by doctors Shaji Kumar and Vincent Rajkumar of the Mayo Clinic in Rochester, MN, provides a thoughtful overview of the current status of minimal residual disease (MRD) assessment in myeloma. In it, the authors raise three questions: What are the implications of MRD negative status? What is the best method to measure it? And what do the results mean for treatment?

In introducing answers to these questions, the authors identify key aspects of the IMF's Black Swan Research Initiative, including how to interpret MRD test information; which tests to use; and most importantly, how to use MRD test results to improve outcomes and achieve true cure for myeloma patients.

From the patient perspective, it is important to realize that a negative result (MRD-Zero) does not automatically mean a patient is cured. We are learning that sustained MRD-Zero combined with other test results such as stringent CR (sCR) plus negative imaging and/or scan results can indeed translate into cure for a subset of patients. But there is more work to be done.

A Promising MRD Testing Method

The first project of the Black Swan Research investigators team was to identify the most useful MRD method. Flow cytometry was identified as a promising technique, and a collaboration was established with EuroFlow and the University of Salamanca (now also Pamplona) to develop a very sensitive, reproducible method with a computer software readout to truly standardize the method. 

Within the last year this research project has been highly successful and the results will be presented to the myeloma scientific community at a workshop in Salamanca, Spain March 20-21. Groups from the US, Europe and the Asia-Pacific region will participate in this IMF-co-sponsored meeting to reach consensus on this new flow cytometry method for MRD testing. It is strongly anticipated that this can become the new standard test which be both widely available and affordable (approximately $100 per test). The full educational rollout of this test will occur in the coming months.

Development of this test is not the end of the story, but it provides an immediate benchmark for ongoing trials and comparisons with other methods. In the short term, MRD testing is complementary to other methods of response assessment and trial endpoints.

MRD Testing and Treatment Strategies

The important third point is how to change treatment strategies based upon MRD test results? Should treatment be stopped if sustained MRD-Zero is achieved? Is it more prudent to consider some consolidation and/or maintenance therapy? Obviously trials are needed and are in development now. If MRD is positive in the setting of high-risk disease can specific back-up therapy be recommended?

Again, a key area within the BSRI is to determine the sensitivity/resistant patterns of residual clones and initiate appropriate clinical trials. Another scenario is if the residual MRD has an "MGUS signature" pattern. Interestingly, this is probably the most secure situation right now in which we can recommend careful follow-up "off therapy" to see if the residual MGUS is sustained--indicating a functional cure state.

So it is obvious that much exciting work needs to be done--BUT having a reliable test and interpretation strategies are key steps in moving the search for a cure forward!

Stay tuned on this...there is definitely much more to come soon.

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF Hotline staff instead. Specific medical questions posted here will be forwarded to the IMF Hotline. Questions sent to the Hotline are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF Hotline, call 800-452-CURE, toll-free in the US and Canada, or send an email to hotline@myeloma.org. Hotline hours are 9 am to 4 pm PST. Thank you.
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This week there are several interesting items in the news that help us understand how and why monoclonal gammopathy of undetermined significance (MGUS) occurs, and when it may or may not turn into active myeloma.

Matthew Drake and the Mayo Clinic bone research team worked with a group from Sheffield University in the UK to illustrate that the bones in MGUS patients are not normal. MGUS patients have weakened bones versus age and sex matched controls. There is increased porosity ("more holes") in surface bone and reduced bone strength. This is important and at the same time quite puzzling. It is important since we now need to be looking more closely at this to assess if bone treatments, such as we use in active myeloma, need to be considered also for MGUS patients. But the puzzling part is that we associated bone problems with the "B" in "CRAB," features characteristic of active myeloma. 

So we need a new level of scrutiny about the type and severity of bone damage that indicates transition to active myeloma. These indicators are: a positive PET/CT scan; definite lesions on a whole-body low-dose CT scan, and or/multiple lesions on an MRI scan. Just reduced bone density is not specific enough or sufficient. This is certainly not the end of the story in terms of understanding what is happening in MGUS versus the major change that occurs with serious bone destruction in active myeloma.

Another interesting story that caught my attention is the report of the full genetic sequencing of sharks that have cartilage, but no true bone like humans. It turns out that sharks are completely missing all the genes needed to make bone. It also turns out that they are also missing genes linked to the immune and blood system which are part of the same complex. What you may not know is that sharks rarely develop "bone" cancer (such as myeloma). It was thought that this was because cartilage blocks cancer formation. 

I carried out research years ago which revealed that there is some evidence for this idea. If you add cartilage components to myeloma cultures, growth of the myeloma is slowed - a little, but not a lot. Despite this there was a phase of great enthusiasm about "shark cartilage" treatments. And some short-term benefits were seen. But now it is clear that sharks lack hard bones and also lack the cells that can link in with myeloma cells to increase myeloma cell growth. Having hard strong bones is excellent. But these bone cells, if triggered the wrong way, can lead to bone destruction, immune defects, and ultimately myeloma in some cases.

Our old ideas have been turned upside down! It is not the presence of cartilage which makes the difference, it is the absence of bone cells.

Triggering the activity of the myeloma cells is the key aspect of myeloma and true bone destruction. A study from the Swedish team shows that increased Freelite levels are still a reliable indicator of disease progression to active myeloma. Yet another study looking at the overall cell genetics shows that many genes are involved in the activation of MGUS and the predisposition to MGUS in the first place.

So, lots of things in the news. Always many new things to learn. Every new detail allows us to understand better and guide patients with critical decisions for recommended diagnostic testing and treatment choices. 

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

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

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

We Can Analyze Hundreds of Thousands of Events

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

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

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

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

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

Five Major Objectives to Achieve Our Goals

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

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

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

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

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

Multi-Year Collaboration with Onyx Pharmaceuticals

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

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

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

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

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

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In the current issue of the journal Science there is a special section called "Single-Cell Biology" (cells go solo). It is now technically feasible to study individual cells in great detail at the molecular, metabolic and functional levels. What is being discovered is that a reading of the "average" from 100, 1,000 or a million cells as has previously been done disguises the great diversity at the individual cell level. 

This raises the question: Are there high-risk genetic features in myeloma cells? 

The answer turns out to be yes and no! Some do and some don't have really abnormal genetic profiles. Discovering the ones that do can guide us to the next phase of therapy for myeloma patients. 

This is significant for the International Myeloma Foundation's signature project, the Black Swan Research Initiative, which is directed towards finding a cure for myeloma. If a myeloma patient's treatment produces an excellent result, with achievement of Minimal Residual Disease (MRD) Zero (no detectable myeloma), follow-up monitoring is required. Although it is hoped and assumed that many patients will have sustained MRD-Zero and may be cured, some will not be cured with the first attempt. These patients will start to have single cells of myeloma detectable by flow cytometry on MRD testing. 

Studies of these single residual myeloma cells will provide the clues needed to eradicate the cells with new alternate and/or higher dose therapy. Checking cells one by one, as BSRI team members Dr. Alberto Orfao and Dr. Ola Landgren are now able to do, will illustrate the diversity and need most likely for a combination approach  to eradicate all these residual myeloma cells. This new technology for single-cell analyses can be key in coming up with the answers to achieving cure! And it is just another piece of the puzzle that is the BSRI, a multifaceted approach to cure myeloma. 

To learn more, stay tuned as we update with blogs, teleconferences, and reports in 2014. 

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF Hotline staff instead. Questions are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate. To contact the IMF Hotline, call  800-452-CURE, toll-free in the US and Canada, or send an email to hotline@myeloma.org. Hotline hours are 9 am to 4 pm PST. Thank you.
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This year's annual meeting of the American Hematological Society (ASH) was truly exhausting, but especially exciting. So many abstracts, so little time!  One had to be a magician to cover major sessions running in parallel. Add to that the cold weather in New Orleans, travel delays, a vast, maze-like, conference center, and you end up with multiple 18-hour days.

But there was much to learn and the IMF's goal is to see the research results through the language and lens of science and point the way forward for patients towards better outcomes and a cure.

On the final evening, the IMF's Conference Series debate, "Making Sense of Treatment" went a long way to capturing the key outcomes from this year's ASH. Four topics were covered: Best Frontline Options; the Role of Maintenance; Minimal Residual Disease: Is This Important?; and New Drugs: Which Will Make an Impact?  The panel from our Stockholm Conference Series --- Doctors Antonio Palumbo, Ola Landgren, Joseph Mikhael and myself--returned to do battle again!

Best Frontline Options

The impact of novel therapies is clearly evident in the improved outcomes in the frontline setting. The panelists grappled with two main questions: How many drugs should be used in an ideal combination? And is carfilzomib (Kyprolis) now preferred over bortezomib (Velcade)? An important ancillary question  was whether or not treatment should change based upon the age or "fitness" of the patient, which is an important research interest for Antonio Palumbo.

Two drugs (Revlimid/low dose dexamethasone (Rd)) prevailed in the MM-020 trial presented at the plenary session. Rd as continuous therapy was superior for patients over age 65 years versus Rd for 18 months and MPT (Melphalan, prednisone, thalidomide) for 12 cycles- which is the standard, approved MPT protocol. So there was a clear vote for 2 drugs (Rd) in this elderly setting. But what about transplant eligible patients? 

Results with both Velcade and Kyprolis combinations as 3 drug combinations are really good. It was generally agreed that 3 drugs are enough (versus 4 or even 5 drug combinations) unless possibly one of the new monoclonal antibodies adds an important new mechanism of action.

Results incorporating either Revlimid (VRd or CRd) or Cytoxan (VCd [Cybord] or CRd) into the combinations are really excellent. But even higher percentage and deeper responses are clearly occurring with the Kyprolis combinations. 

So what did our experts have to say about all this? 

Joseph Mikhael felt that the longer term results with Cybord (Velcade/Cytoxan/dex), with, for example, 81% survival at 5 years in standard risk patients, justifies use of this regimen as a first step, especially since it is cost effective and well tolerated. Conversely, Ola Landgren indicated that CRd (carfilzomib/Revlimid/dex) gives higher and deeper responses, is well-tolerated even in the elderly and works well for both standard and higher risk patients. His perspective is that CRd can be an option across the board for all frontline patients. 

Antonio Palumbo is very much focused upon the need to assess the "fitness" of patients at diagnosis including the presence or absence of so called "co-morbidities"--other medical problems and other needed medications. Antonio's protocol results also support the value of multi-drug combinations and even high dose therapy for "fit" elderly patients. So there was a sense that the Rd two drug combos is a simple excellent option, but in fit patients it is certainly reasonable to explore the value of more aggressive combination therapies.

The Role of Maintenance

The greatest controversy emerged over the role of maintenance. The controversy at ASH this year was triggered by the presentation by Michel Attal from the IFM team, who presented the longer-term results of Revlimid maintenance following autologous stem cell transplant. As had been expected, the presentation showed improved length of remission with Revlimid maintenance, but no overall survival benefit. There have been many speculations about reasons for the lack of survival benefit, including use of 2 months of Revlimid consolidation after transplant given to all patients (including those with no maintenance). 

But what brought a flood of myeloma experts to the microphone for questions at ASH was an analysis which showed dramatically better outcomes for patients on placebo (no Revlimid maintenance) at the point of first relapse. As pointed out by Dr. Shaji Kumar from the Mayo Clinic, this was a flawed analysis in an already flawed study. But many issues were left unresolved at the time of the presentation. Other abstracts strongly affirmed the value of Revlimid maintenance (in addition to continuous or extended use in the frontline setting) using meta analyses of available trial results. 

Joseph Mikhael said he does not routinely recommend maintenance because of the confusion surrounding the data. Conversely, Antonio Palumbo, Ola Landgren, and I said we feel that the preponderance of data supports the use of maintenance, which we feel comfortable recommending, certainly from the standpoint of efficacy. 

Minimal Residual Disease -- Is It Important?

There was unanimity on the subject of the importance of Minimal Residual Disease.  MRD is important. We need to now measure MRD in a standardized fashion and use the information to compare results in randomized trials and to direct treatment to achieve MRD-Zero in trials designed to seek a cure.

Thus the central concepts of the Black Swan Research Initiative® are being enthusiastically endorsed by the myeloma expert community. 2014 is indeed going to be exciting as we see the research results and the rapid process to achieving a cure.

New Drugs -- Which Will Make an Impact?

I listed 8 drugs which are most promising from the 2013 ASH presentations: anti-CD38 monoclonal antibodies (daratumumab and SAR650984); MLN 9708; ARRY 520; ACY 1215; Selinexor; anti-CD138; panobinostat; and bendamustine. There were interesting discussion points about all 8 compounds. However, everyone agreed that the anti-CD38 compounds are both the most exciting and most likely to add a new mechanism of action to our current combination approaches.

Joe, for the first time, presented the more detailed results with SAR antibody as a single agent. About half of the patients responded, some with very deep responses (greater than VGPR).

Follow-up results with the daratumumab antibody were also presented showing substantial benefit. There is great anticipation that even more promising results are to come with anti-CD38 trials moving forward rapidly in 2014.

The IMWG Conference Series at ASH closed with a follow-up from Joseph Mikhael about the new acronym, "Lobster" that he proposed at our last debate. He now suggests that the new acronym will be "CRAB-LEGS" to identify patients with early active myeloma who do not yet have "CRAB" features. So stay tuned to hear more details about this. 

And finally, it was realized that if progress in treatment continues at the current pace, myeloma experts are in danger of putting themselves out of a job. It was agreed that if both doctors and patients end up on permanent vacation in Hawaii, it will be fine!

So here is to further improved outcomes in 2014 and an improving future for all myeloma patients everywhere!

A more comprehensive overview will be provided on the "Post-ASH" teleconference scheduled for January 16, 2014. Register here: http://bestofash2013.myeloma.org/ 

To view the archived video of the IMWG Conference Series: Making Sense of Treatment click here: http://bit.ly/1bHvql7

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF Hotline staff instead. Specific medical questions posted here will be forwarded to the IMF Hotline. Questions sent to the Hotline are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate. To contact the IMF Hotline, call  800-452-CURE, toll-free in the US and Canada, or send an email to hotline@myeloma.org. Hotline hours are 9 am to 4 pm PST. Thank you.
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Last week, in Part I of my overview of abstracts released by the American Society of Hematology (ASH) in advance of the group's annual meeting in New Orleans, I focused on combinations using the approved novel agents. Hearing more details and follow-up about these novel combinations at the ASH meeting, Dec. 7-10, will be very important.

In this segment, I start by summarizing where we are with new agents in earlier trials at the Phase I-II or preclinical stages. There are eight agents which are of interest. 

  • anti-CD 38 monoclonal antibodies (MAb) daratumumab (abstracts #227 and #1986) and SAR 650984 (#284) 
  • MLN 9708 (ixazomib citrate: abstracts #535, 1944, and 1983)
  • ARRY 520 (abstracts #285 and #1982) 
  • ACY-1215 (abstracts #759 and #3190)
  • selinexor (also known as KPT-330, abstract #279)
  • anti-CD 138 monoclonal antibody (BT062, abstract #758) 
  • panobinostat (abstract #1970)
  • bendamustine (abstract #1971)

As was the case last year at ASH, the most promising single-agent activity against a new target is with anti-CD 38 monoclonal antibodies. The single-agent activity of the Sanofi compound (SAR 650984; abstract #284) is illustrated in a dose escalation study involving 32 patients which produced several greater than or equal partial responses. With daratumumab in combination with Revlimid/dexamethasone (anti-CD 38 MAb; abstract #1986) all 6 patients had greater than or equal partial responses with 3 having greater than or equal VGPR. Laboratory studies using a human-mouse hybrid model  (abstract #277) have shown strong synergy with lenalidomide (Revlimid). 

With ARRY 520 (a kinesin spindle protein [KSP] inhibitor), a 16% partial response rate was noted in a study of 32 patients incorporating weekly dexamethasone (#285). Combined with carfilzomib, a small study showed a 58% response rate (#1982). There were again several reports about MLN 9708, the new oral proteasome inhibitor. Results in the newly diagnosed (#535), relapse (#1944), and maintenance settings (#1983) all showed promise and good tolerability. 

Results with ACY- 1215 and selinexor are still early. ACY-1215 (selective HDAC 6 inhibitor) is an oral agent being evaluated in combination with Velcade (#759) and Revlimid/dexamethasone (#3190). Although the combinations are well tolerated, only a few higher-level responses have been seen thus far.

The preclinical results with the XPO 1/CRM 1-dependent inhibitor (selinexor) are reported and show good synergy with carfilzomib (abstract #279). Results with panobinostat (abstract #1970) again show some promise in combinations with Velcade and dexamethasone. Rather surprisingly, the combination of bendamustine with Velcade plus dexamethasone shows really excellent results in the relapsed/refractory setting, with PFS median results of 10.8 months and overall survival median of 23 months (abstract #1971).

And there you have it!  Not a lot dramatically new to add, but it is quite encouraging that several agents are continuing to move strongly forward in clinical trials.

As we move towards 2014, the ASH abstracts that will have the biggest impact are those which provide a better understanding of underlying biology and how to test for minimal residual disease (MRD) and risk factors, and those which provide insight into trigger factors and disease subtypes such as extramedullary disease and plasma cell leukemia.

Testing for Minimal Residual Disease (MRD) and MRD-Zero

Over 25 abstracts deal with minimal residual disease testing, monitoring, and risk assessment. Abstract #402 from the Salamanca/Pamplona team with Bruno Paiva as the lead author characterizes minimal residual disease at the immune and molecular level. In abstract #531, Paiva extends these observations by identifying and characterizing subclones which emerge during the course of treatment. This understanding of subclones which persist or emerge despite current novel therapy is key to developing more successful treatment and achieving MRD-Zero--the primary goal of the Black Swan Research Initiative (BSRI)

Quite a number of abstracts touch on the comparison of various methods to most accurately assess MRD-Zero. Another key abstract from Spain on this topic (#1848) compares flow and molecular techniques. Different aspects of risk and response assessment are covered in abstracts #762, #1841, #1842, #1868, #1878, #1902, #1936, #3126, #3152, #3223, #4290, #4647. Although DNA methods may be slightly more sensitive, a new flow technique may prove to be equally, if not, more sensitive, and has the advantage of allowing identification and molecular study of any residual clones. Hearing all the details at ASH will be very important. So much more to learn!

An important report (abstract #1936) from the Bologna team shows that 29% of patients who appear to be in complete response by other methods of assessment have positive PET/CT scans. Thus, follow-up imaging is essential to confirm the residual disease status. Another abstract (#762) shows that early improvement in the serum heavy/light chain ratio (HLCR, Hevylite) predicts for a high likelihood of subsequent development of MRD-Zero.

Understanding the Biology of Myeloma

In the category of understanding the biology of myeloma better, I draw your attention to a few abstracts. A collaboration between Washington University and Mayo Clinic researchers (abstract #397) has revealed that in mice predisposed to myeloma, one particular gene (Samsn 1) is missing in all cells (called a germline mutation), which results in both B cells (precursors of myeloma cells) and microenvironmental cells such as macrophages and osteoclasts being primed for activation. Another abstract (#3116) also suggests that we take a closer look at predisposing and triggering factors for MGUS and myeloma. 

The team of French researchers from Nantes shows that in 22.7% of patients with MGUS and myeloma, the monoclonal protein reacts against infection: specifically hepatitis C, Epstein-Barr Virus (EBV), and the stomach infection H. Pylori. This raises the possibility that infection can trigger initial disease and possibly relapsing disease. Clearly further studies are required. Another aspect is obesity, which is known to be linked to the onset of both MGUS and myeloma. A large epidemiologic study (abstract #1872) shows a strong association between increasing body mass index (BMI) at age 20 years and a younger age at diagnosis in African-Americans with multiple myeloma. Definitely food for thought!

Subtypes and Categories of Patients

Considering different subtypes and categories of patients with myeloma and related diseases, there are several abstracts: young patients (< 40 years: abstract #3226); older patients (abstract #687); IgD myeloma (#s 1880 and 1935); IgM myeloma (#1881); plasma cell leukemia (#761); extramedullary disease (EMP; #s 1896, 3141, and 3188); central nervous system involvement (abstract #3118); patients susceptible to very early death in ≤ 2 months (#3195) and those patients in remission for ≥ 6 years (abstract #3366). A small, but important point in abstract #3195 is that patients at risk of death within the first 2 months of the myeloma diagnosis are those with unrelated serious health issues. With the advent of novel therapies, it is only months to years later that the impact of high-risk myeloma features is seen as a challenge in controlling progressive or relapsing disease: a reassuring point.

As far as molecular risk features, there are fewer than the usual number of abstracts dealing with this topic at ASH 2013: abstract numbers 399, 529, 530, 1846, 1855, 1856, 1992, 3092, 3108, 3111, 3114, 3121, and 3147. There are two key practical points. In abstract #529, it is noted that poor risk features (such as FISH t(4;14) or -17p) will prevail even if there is hyperdiploidy (extra chromosomes: normally considered to be a good-risk feature). Thus the presence of hyperdiploidy does not counterbalance poor-risk features. A related, and somewhat frustrating point (in abstract #1992), is that the 1q21 FISH abnormality does confer poorer risk, but is not part of the standard FISH testing panel!  So, back to the drawing board again to have a new recommended FISH testing panel.

And there you have it for now: many interesting abstracts, some which I predict will prove to be very important, and others where we are waiting to hear more at the time of the ASH meeting in New Orleans in December.

Please remember the IMF's various educational programs at and from ASH: live-streaming of the Satellite Symposium on Friday, December 6th, and the Conference Series on Monday, December 9th, blogs/Twitter ongoing, interviews with lead investigators immediately after ASH, and post-ASH highlights in January 2014!

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

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The ASH 2013 abstracts were released on November 7th.  As usual, there are a staggering number of myeloma abstracts: this year, 830. The IMF team has been reviewing them studiously, trying to identify what is new, interesting, and important. We have identified 131 abstracts worthy of specific comment: 38 oral presentations and 93 posters.

The first key point is that a myeloma abstract is one of the top "plenary session" abstracts for ASH overall this year. Abstract #2 (I believe this may be its priority ranking for 2013 ASH) will be presented by Dr. Thierry Facon of the Intergroupe Francophone du Myelome (IFM) and details the results of a Phase III trial involving 1,623 patients over age 65 years (a huge study) which compares lenalidomide (Revlimid® [R]) low-dose dexamethasone (d), given until disease progression (ARM A) with Rd give for 18 cycles (ARM B) with the combination of melphalan, prednisone, andthalidomide (MPT) for 12 cycles (ARM C).  

This study thus compares two drugs (Rd) - with and without maintenance - with three drugs (MPT).  According to the abstract, there is a 28% reduction in the risk of progression with the Rd (ARM A) versus MPT (ARM C), which is statistically significant. There was also a trend toward survival benefit: 22% reduction in the risk of death.  A topic of keen interest is also the rate of second primary cancers (SPMs).  The question has been whether SPMs are more linked to Revlimid use versus melphalan, as for example, in the MPT regimen. The hematologic SPMs were 0.4% with Rd in ARM A versus 2.2% in ARM C, which certainly trends toward more SPMs with melphalan exposure versus Revlimid. The solid tumor SPMs were 2.8% in both arms, which is now considered to be an expected rate for myeloma patients. I am sure we will hear more at the ASH presentation. Of added importance, it is widely speculated that these results can lead to the approval of the Rd doublet as frontline therapy both in Europe and in the US. This approval is particularly important outside the U.S., where drugs can only be prescribed strictly within the labeled indication.

Of the 131 interesting and important abstracts we have identified this year, 43 involve the approved novel agents thalidomide, lenalidomide (Revlimid), bortezomib (Velcade), pomalidomide (Pomalyst) and carfilzomib (Kyprolis). For thalidomide, aspects presented will include thalidomide consolidation (#537), which improved both progression free (PFS) and overall survival (OS), and thalidomide combined with dose escalation of carfilzomib (#688), which proved to be a rapidly effective regimen for newly diagnosed myeloma. For lenalidomide, there are multiple aspects presented and discussed in numerous abstracts.  

An overarching topic, already touched upon with abstract #2, was the benefit of lenalidomide for maintenance and/or as ongoing continuous therapy. Data include the follow-up of the IFM lenalidomide maintenance trial post autologous stem cell transplant (#406), which again showed PFS but not OS benefit, and a meta analysis of lenalidomide maintenance (#407), which assesses PFS, OS, and SPM rates overall. An additional concept explored in the maintenance phase of the MM-015 update (#405) from the Torino team is the value of lenalidomide maintenance considering "PFS 2," which refers to the length of the second response in patients relapsing, with or without prior lenalidomide maintenance. The PFS 2 was markedly improved in the melphalan prednisone Revlimid arm (MPR-R) with Revlimid maintenance versus the melphalan prednisone alone (MP) arm. This added piece of information is now being considered as part of the drug approval process, especially by the European Medicines Agency (EMA). 

For bortezomib (Velcade), there are several important observations.  First, in abstract #1968, the cumulative dose of administered Velcade in the VMP (Velcade, melphalan, and prednisone) arm of the Phase III VISTA trial is directly linked to improved overall survival outcomes. This is a key educational point in the use of Velcade, which has become much better tolerated with the subcutaneous (SQ) route of administration. Another important abstract (#3187) evaluated cardiac issues (such as heart failure) in myeloma patients in a retrospective analysis of bortezomib (Velcade) trials. Use of Velcade was associated with a low rate of severe (grade ≥ 3) heart failure in both newly diagnosed (2%) and refractory (1.9%) patients. This rate is not statistically different from the expected background rate. 

Other interesting abstracts include numbers 1940 and 1969, which report upon the combination of Velcade with pomalidomide and dexamethasone in relapsed myeloma. This is clearly a very active and well-tolerated regimen. Follow-up data are reported on other Velcade combinations, including Velcade/Cytoxan/dexamethasone [CyBord] versus Velcade/Revlimid/dexamethasone [VRd] (#3178), CyBord long-term follow-up (#3192), VTD long-term follow-up (#3221) and Velcade combinations in the elderly with or without autologous stem cell transplant (#3344).  Key points here include the impressive efficacy of CyBord (versus VRD: #3178) with a substantially lesser cost and the sustained longer-term benefit of the CyBord regimen (#3192).

Pomalidomide is covered in several abstracts, basically confirming the efficacy in the relapsed/refractory setting (#408, 686, 689, 690, 1979, 3185, 3191, and 3198).  Points of note include efficacy with high-risk features, such as 17p- on FISH testing (#689) abnormal cytogenetics (#408) or high-risk GEP (#3191). The combination of pomalidomide with carfilzomib also continues to show considerable promise (#690).  Of interest, the combination of Biaxin (clarithromycin) with pomalidomide plus dexamethasone is also remarkably effective (#1955).

Carfilzomib (Kyprolis) was a part of many trials reported this year at ASH. Combinations showing great promise are carfilzomib/Revlimid/dexamethasone (CRd; numbers, 538, 1939, and 3220), Carfilzomib/Cytoxan/dexamethasone (CCd: #585), carfilzomib/MP (CMP: #1933), and carfilzomib along with Biaxin plus Revlimid/dexamethasone (#3216).  Response rates are high and deep: prolonged benefit is being achieved. It will be very helpful to learn the full details of these exciting combinations at ASH.

Next week: In part two of this ASH preview, I will cover new drug updates as well as a diversity of other topics, including many details about testing for minimal residual disease (MRD) and new molecular/genetic research findings. So 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 Hotline staff instead. Specific medical questions posted here will be forwarded to the IMF Hotline. Questions sent to the Hotline are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate. To contact the IMF Hotline, call  800-452-CURE, toll-free in the US and Canada, or send an email to hotline@myeloma.org. Hotline hours are 9 am to 4 pm PST. Thank you.