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In a highly anticipated decision announced this week, the US Food and Drug Administration (FDA) approved the use of Revlimid® in the frontline setting based upon the results of the FIRST trial (which I have discussed in the IMF's presentation on news from the 2014 American Society of Hematology meeting here). Ongoing Revlimid/dexamethasone was clearly superior to a previous standard of care, Melphalan/Prednisone/Thalidomide (MPT), as well as shorter-duration use of Revlimid/Dexamethasone (Rd).

This approval consolidates what has been widespread off-label use of Revlimid in the frontline setting in the US for several years. Practitioners and patients in the US are very fortunate that the off-label mechanism has allowed flexible use of Revlimid, including its use in the popular Velcade®/Revlimid/dexamethasone combination for induction therapy.

The FDA has also added much more detailed guidance than in the past, recommending stem-cell harvesting after the first four cycles of therapy, if possible, and much closer blood-count monitoring. There is also a particular caution about the potential risk of second primary malignancies (SPMs) in the post-transplant Revlimid maintenance setting. With these caveats it is important to note that ongoing use of Revlimid (so-called continuous therapy) is supported by this decision.

The likely approval of frontline Revlimid in Europe* in the coming weeks is much more significant for European patients and physicians. Right now, frontline use is not possible. The pending approval will allow use specifically of Revlimid plus low-dose (weekly) dexamethasone exactly as used in the FIRST trial. This is a key point--the triple combination of VRd will not be immediately approved. Use is restricted to the FIRST trial protocol schedule only. This restriction is becoming an increasingly troubling problem because of the difficulty of completing multiple trials to encompass all the potential treatment combinations. Regulators use the lack of data to restrict the expense of broader use. This is an artificial constraint in that the efficacy and safety of many other combinations is widely known and well documented in the medical literature.

Implications of drug approvals in 2015 and beyond

What is frequently not so clear is the exact comparative efficacy and safety of different combination regimens. For example, how does VRD (Velcade/Rev/DEX ) compare to VCD (the CyBorD regimen) as a primary induction treatment?  Without a direct head-to-head comparison, one can say that the percentage and depth of responses and overall outcomes are rather similar. Both three-drug regimens are also safe, well tolerated, and more active than the two-drug combinations of Rev/dex (just approved) or Velcade/dex, also previously approved. Regulators, however, can point to the substantial cost savings of using VCD versus VRD, as well as the benefit of saving Revlimid for use in an approved relapse setting after VCD.  How best to combine and sequence drugs is a legitimate question without an immediate, clear answer, for sure!

In the US,  selecting among available therapy options falls into the realm of the treating physician working within NCCN guidelines and currently allowed off-label use, neither of which requires validation based on clinical trials of direct comparators. In Europe and elsewhere around the globe, the American scenario  cannot occur. Regulators require trial comparisons.

Thinking about the number (and potential cost) of trials needed to resolve all these questions is mind-numbing! In the interim, cost and regulatory control become the final arbiters limiting new drug use to the exact trial schedule(s) - IF the cost can be justified using trial endpoints and quality-of-life indicators.

Layered on top of comparative drug efficacy are safety concerns in particular circumstances. In the FIRST trial, ongoing Revlimid use as a frontline approach is both safe and very efficacious. But does this mean that similar ongoing use of Revlimid as post-transplant maintenance can be viewed equally? Lingering concerns remain about how best to use Revlimid as post-transplant maintenance. Is Revlimid maintenance recommended for many patients, but not all? Should maintenance be indefinite or for a defined period to maximize benefit? Revlimid used along with oral melphalan or as consolidation and maintenance immediately after high-dose intravenous melphalan, as in the IFM trial, may carry an extra risk of SPMs, including otherwise unexpected lymphoid malignancies such as ALL. It is thus difficult to give blanket approval for the use of any drug in all circumstances--no matter how efficacious and safe overall. 

Should treatment decisions fall within the realm of the primary physician, as they do here in the US? Or should options be left to the discretion of regulators, as is the case elsewhere in the world?

There is much to celebrate as Revlimid is fully available in the frontline setting, but many issues that will limit ideal global access and use remain to be resolved.

*February 20, 2015 UPDATE:

The anticipated frontline approval of Revlimid by the European Commission has occurred today (press release here), just two days after the FDA ruling in the US. This rare rapid approval by both agencies reflects the strength of the submitted packages indicating the value and safety of ongoing Revlimid/low-dose dexamethasone in the non-transplant population. The ability to achieve long-term disease control is an important step forward, especially for unfit or frail patients for whom transplant is never an option. It is hoped that broad access to Revlimid throughout Europe will follow. -- Brian G.M. Durie, MD

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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Cases of measles have been very much in the news: 121 cases (as of today) reported in the US this year. To assess how much myeloma patients might need to be concerned or not, it is helpful to put this number of cases in perspective.

Since 2001 in the US, there have been up to 220 cases a year, according to the Centers for Disease Control and Prevention. During January through August 2013 (a year from which data have been analyzed), there were 159 cases, of which 157 were linked to exposures occurring outside the US (in particular, from Europe). Of note, since October 2014, there have been more than 300 measles cases in Germany linked to visitors and immigrants from Bosnia and the Middle East. In 2001, there were over 6,000 cases of measles in Germany. Other sources of measles are from China and the Philippines. The controversy in the US is that although the measles vaccination rate overall is 91%, "pockets" of unvaccinated children can lead to local clusters of cases.

As for myeloma patients, the vaccination rates are high. In fact during assessment for the measles virotherapy trial at the Mayo Clinic, in which a massive dose of engineered measles vaccine is administered to treat the myeloma, it was noted that a majority of myeloma patients have robust measles antibody levels in their blood and definitely do not need revaccination.

Cases of measles among myeloma patients are actually extraordinarily rare: I have never seen or even heard of a case. It thus seems that although the immune system of myeloma patients is compromised, measles is not a particular risk.

Anyone born in the US (or most developed countries) before 1957, which is the majority of myeloma patients, will have had the standard two or more doses measles vaccination. There is a 90-95% likelihood that myeloma patients will have 95-99% protection against measles. Since the measles vaccine is a live virus vaccine, revaccination is not recommended especially for patients on active therapy for myeloma. Anyone taking prednisone or dexamethasone should definitely not have measles revaccination.

So what is recommended? The main thing is to limit exposure right now in crowded places and also avoid visiting or spending time at any day care center where unvaccinated children can contribute to local clusters. The risks are very low for myeloma patients overall. So, be vigilant as always with regard to fever and any indication of infection - but most likely it is not going to be measles!

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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There has been some discussion lately about an alternative method of funding myeloma research known as crowdfunding. Crowdfunding is the act of raising money from a large number of individuals on the internet for a specific project or venture.

Is this something which might be helpful for the myeloma community? Perhaps.

Fortunately, many mechanisms currently exist for myeloma research funding through the government-funded National Institutes of Health (NIH), National Cancer Institute (NCI), and private foundations. The question is: what types of research are not receiving adequate early or "pilot" funding (the typical type and level of funding that comes from crowdfunding)? The answer is funding is available. If there is promising new drug activity for the treatment of myeloma, a rather robust venture capital marketplace has emerged to move testing forward.

So, where does crowdfunding fit into the myeloma-research scheme?

Investigations into more basic scientific questions require substantial ongoing funding (from the NIH, for example). Velcade ® is a case in point. As I explained in a previous blog, its development was the result of many years of research into the mechanism of cell action, at a cost of hundreds of millions of dollars.  Crowdfunding might not be a good fit for this type of research since the payoff comes many years in the future. For simpler translational-type research projects, which might benefit patients in the shorter term, there are several mechanisms in place, both private and corporate.

In this arena, it is important to prioritize and not squander resources. I believe that the most critical source of prioritization at the present time is the IMF's research division, the International Myeloma Working Group (IMWG). Through the IMWG workgroup activities, top-level projects are identified--those that can have the greatest impact upon the myeloma community, based upon the collective input from the top investigators in the field. Those projects include: clarifying the nature of high-risk disease; comparing X-rays with whole body low-dose-computed tomography (WBLD-CT) to assess bone disease; determining outcomes for relapse/refractory patients and of course, the Black Swan Research Initiative ®.

Articulating the need for and importance of these projects has led to substantial funding and has allowed them to proceed. Are there other projects which deserve funding? Possibly. But to avoid wasted efforts and conflicts, it is best that these be evaluated and discussed, with crowdfunding as one possible mechanism of pilot funding if needed.

Donors and patients are now highly informed and need to know the value of projects as a basis for decision-making. There is also a need to know if alternate sources of funding are actually available and, if crowdfunding is a "last resort," where does it fit in the scheme of overall funding?

Time will tell how crowdfunding for myeloma research will evolve. But as yet it is unclear if there really is an urgent need for this type of funding and how effective or valuable it can become.

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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Access to new drugs outside of the US is frequently delayed by several years following FDA approval in the US. For example, lenalidomide (Revlimid®) received US FDA approval in June 2006, yet is still not fully approved and available globally. This lack of access has a significant negative impact for myeloma patients. At the point of relapse, patients who may have been treated frontline with VTD (Velcade®, Thalomid®, dexamethasone) or CyBorD, only relatively recently and in some cases have been able to turn to Revlimid®.

In the case of pomalidomide (Pomalyst®), the most recently approved IMiD (approved in the US for relapse/refractory disease in February 2013 and in Europe in August 2013), global access is currently very limited. Pomalidomide is not available for relapsing patients in Asia.

The IMF's Asian Myeloma Network has therefore negotiated with the Celgene Corporation to establish an individual or "named" patient access program for pomalidomide. Utilizing a treatment protocol very similar to the trials conducted in the US and Europe, eligible relapsing patients can now gain access to pomalidomide through the main Asian treatment centers. After overcoming numerous regulatory and logistic hurdles, the protocol was activated in December 2014 with Dr. Wee Joo Chng as the principal investigator. Dr. Chng, an IMWG and AMN member, is based at the University of Singapore where the data management and coordination center is housed and funded.

Accruals started rapidly in Korea with Dr. Jae Hoon Lee, who enrolled four myeloma patients in December. He is excited to report that at first follow-up, all patients showed evidence of response and excellent tolerance. Patients are now enrolling in Singapore, to be followed by Thailand, Hong Kong, and Taiwan. Unfortunately, it is not yet feasible to open the program in Japan and China, the other two AMN members.

The successful launch of this pomalidomide access program is very exciting for both patients and physicians in Asia. This is a model through which patients can gain early access to new drugs which can be literally lifesaving! It is hoped that it is just the beginning of programs to enhance global access to new FDA approved drugs, which are so desperately needed to improve myeloma patient survival.     

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 preparing for my "Best of ASH 2014" presentation, I noted there were plenty of new drug presentations, but not as many as were presented at the American Society of Hematology (ASH) annual meeting in 2013. This raised the questions: "What is the driving force behind new drug development in myeloma?" and "Where exactly are the new ideas coming from?" Do we expect new drugs to keep coming?

We have been fortunate to have FDA and ongoing global approvals for five novel agents in myeloma: thalidomide, bortezomib (Velcade®), lenalidomide (Revlimid®), carfilzomib (Kyprolis®), and pomalidomide (Pomalyst®/ Imnovid®). How did this happen and what does this tell us about what to expect in the next 5-10 years?

It is helpful to think back to 1995 when pamidronate (Aredia) was approved for the treatment of bone disease in myeloma: the first drug approved specifically for myeloma in many years. Aredia is a bisphosphonate, a class of drugs developed to clean clogged pipes because it binds to calcium deposits. Aredia was approved by the FDA for treatment of high blood calcium in 1991. Since pamidronate binds calcium, researchers realized it could also be helpful in areas of myeloma bone damage, as well as in osteoporosis and other types of bone damage. This is typical for drug development. Uses evolve over many years. A more potent bisphosphonate, zoledronic acid (Zometa®), was approved for use in myeloma in 2002. The common trend is to improve drugs which are known to work. In addition, a completely different drug, denosumab (high-affinity antibody for RANK-Ligand,) is now being assessed for its value in treating myeloma-related bone disease.

If we turn to bortezomib (Velcade), we find a similar pattern. Bortezomib is a proteasome inhibitor. Much of the early research leading to its use as a myeloma treatment occurred in the 1970s and 1980s when proteasomes were discovered and the impact of blocking the elimination of damaged proteins was first appreciated. It was felt that inhibitors could be useful in the treatment of viral diseases. Discoveries related to proteasome chemistry led to the 2004 Nobel Prize in Chemistry for Avram Hershko, Aaron Ciechanover, and Irwin Rose. An important paper showing that proteasome inhibitors are effective anti-tumor agents was published by Julian Adams in 1999. Julian subsequently collaborated with Dr. Michael Kauffman at Millennium Pharmaceuticals in the clinical development of Velcade, which proved to be remarkably effective in myeloma. This final step in the drug development process was both tenacious and skillful. At this stage, many investigators were involved and many brave patients agreed to take the drug, not knowing if it would be effective: true pioneers moving into unknown territory! This subsequently paved the way for another proteasome inhibitor, carfilzomib (Kyprolis), more recently approved for myeloma.

The story about IMiD (immunomodulatory drug) development is particularly fascinating. Thalidomide, developed in the early 1960s as a sedative for use during pregnancy, was found to cause birth defects and was not FDA approved. However, it was subsequently found to be excellent treatment for a type of leprosy and had special limited approval for use in that setting. Fast forward to the late 1990s when Beth Wolmer, the wife of a myeloma patient in Little Rock, Arkansas, desperate to find a treatment for her husband, asked Dr. Bart Barlogie to try thalidomide to "shut down the blood supply" to the myeloma. Since this was a possibility based upon anti-angiogenesis research in Dr. Judah Folkman's laboratory at Children's Hospital in Boston, Dr. Barlogie agreed to try thalidomide. Unfortunately, it did not work for Beth Wolmer's husband. But the silver lining to this story is that another desperately ill myeloma patient had a dramatic response. As the saying goes - the rest is history! Thalidomide was approved for use in myeloma. Its molecular variants, lenalidomide (Revlimid) and pomalidomide (Pomalyst/ Imnovid) have been more recently approved as more effective and better tolerated analogues.

So what does this pattern of discovery and drug development mean for new drugs in 2015 and beyond? Firstly, refinements of prior drugs are the simplest strategy and this will continue to be a useful approach. Revlimid is more effective and has less nerve toxicity than thalidomide. Pomalidomide is the most effective IMiD currently available, and is also the best tolerated. The oral proteasome inhibitors ixazomib and oprozomib, currently in development, have the major advantage of being administered by mouth versus Velcade and Kyprolis, which are given by injection.

Secondly, the value of new types or classes of drugs is less certain. The anti-CD 38 monoclonal antibodies daratumumab and SAR650984 are very promising, and daratumumab even has "breakthrough" status for review at the FDA. But how long will remissions last? How big an impact will these antibodies have for prolonging survival for myeloma patients? It is too soon to know. As I have said in the past, it is important to remember that new drugs are new: there are many unknowns! Fortunately, there are multiple monoclonal antibodies in development and there is thus an opportunity to assess which is best, or which is the best niche for each. In addition, many other classes of agents are in early to midterm development. Thus the relative merits of different classes of new agents can be assessed.

Thirdly, accurate tools and methodologies are required to show precisely if one therapy is better than another. For this aspect of drug discovery and development, the IMF's International Myeloma Working Group (IMWG) has made, and is continuing to make, a major impact. The IMWG Uniform Response Criteria are essential. Assessment of outcomes for relapsed/ refractory patients is key to providing a benchmark for the FDA. Does a new agent meet an "unmet need" - meaning can a new agent really improve the outcomes for patients who have received all prior therapies? Increasingly, this is an all-important yardstick. An expensive new drug must provide significant benefit with acceptable side effects.

The good news is that decades of basic research have created many promising leads. Many basic and clinical researchers have contributed. Only time will tell which leads will pay off. The enthusiasm, expertise, and expectations are in place. Let's hope that accelerated research and development will start to cure myeloma patients in the next 5-10 years!       

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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A new study published in Science magazine and reported in the New York Times this week shows that random mutations in normal tissues are more important than previously thought. The study, conducted by Johns Hopkins Medicine researchers Cristian Tomasetti and Bert Vogelstein, did not analyze myeloma, but developed principles that apply broadly for all cancers. The key finding in this new study, explained in depth here, is that although family/hereditary factors and environmental exposures account for about 30% of the risk of developing cancer, the other 70% of the risk comes from errors in copying DNA, which is required when cells divide to produce new cells.

Copying errors occur in stem cells, the cells that give rise to each individual tissue, such as bone marrow, skin, or lung. In the case of skin and lung tissue, the researchers found that there is still a greater than 30% impact from traditionally known risk factors, such as UV light exposure and smoking. In the case of myeloma, the percentages and risks are not so clear.

According to myeloma data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program, both MGUS and myeloma are 2-3 times more common in African Americans (14.8/100,000 in men) versus other races (7.2/100,000 in Caucasian men; 4.3/100,000 in Asians and American Indian men). Myeloma is also much more common with increasing age: median age at diagnosis 69 years. In addition, several toxic exposures strongly increase the likelihood of developing both MGUS and myeloma. Also some infectious agents, especially viruses have been linked to an increased likelihood of developing myeloma.

The additional factor to consider is the background number of plasma cell stem cells and the tendency for them to divide. Fortunately, although not studied exhaustively, we know that DNA copying errors tend to occur at a low level. Myeloma, in general, is a slowly growing tumor, and recruitment from the stem cell compartment occurs intermittently when the plasma cell response system is stressed. The regulation of such antibody responses is under tight immune control.

This aspect of immune regulation of plasma cells and myeloma cells is of increasing interest. Several new therapies such as daratumumab, the SAR compound, elotuzumab, and CAR-T cells are active against myeloma in part by enhancing the immune system against myeloma. In my recent blog about longevity on the island of Ikaria, I discuss the ways in which diet as well as many lifestyle factors (such as mindfulness) can reduce stress and enhance the immune system, thus prolong longevity and reduce risk of cancer.

So, what does this mean for myeloma? Do these random mutations trump previously known risk factors, such as heredity, race, and potentially dangerous toxic and/or infectious exposures? Since random errors in DNA copying occur over time, early diagnosis is key to prevent copy error mutations. This includes the notion that some mutations can be key or "driving" mutations that cause a switch from smoldering to active myeloma. There can thus be both mutations that accumulate in the damaged myeloma cells as well as driving mutations which should be avoided (or "prevented") by early diagnosis. These driver mutations should become the basis for new genetically targeted therapies.

If this is starting to sound familiar, that is because it is the framework for the Black Swan Research Initiative®: diagnose early; monitor low levels of disease (MRD); study and target residual resistant clones. Only time will tell if the copy error random mutations are truly random, or if particular patterns emerge which allow broader application of curative therapies.

New studies are always food for though and trigger a search for new research and treatment opportunities. 

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In a new book, writer Diane Kochilas explores why "the small Greek island of Ikaria is home to some of the healthiest, most vibrant people on earth." It's a phenomenon I have previously written about here with an emphasis on the Ikarian diet. And although technically Kochilas's new book is a cookbook, the recipes are interspersed with wonderful stories and insights about Ikaria and its people. As we head into the holiday season, we might do well to adopt a few of the characteristics of the Ikarian lifestyle--key among them, finding joy in the here and now.

Identified as one of the "Blue Zones" in a 2008 book by Dan Bueltner, the island of Ikaria has been visited by physician scientists and many other groups attempting to try to understand why so many residents live to a ripe old age, often beyond 100. Diane Kochilas synthesizes this information into a kaleidoscopic patchwork of new interviews with older island residents and family members, as well as wonderful details of island recipes and the ways of life.

The original Blue Zones identified by Dan Bueltner were not quite as magical as the name makes them sound. Blue Zones were simply areas containing a higher-than-average population of residents living to be ≥ 100 years of age, circled in blue marking pen on a map! (If a different colored marking pen had been handy, perhaps we'd be discussing Pink Zones or Orange Zones.)

Although it was tempting for researchers to link the longevity to really healthy food, it was immediately evident that other factors are involved. For example, 100 years ago, life on Ikaria was not a paradise. Quite the contrary! Most older residents describe rather impoverished early lives with food being just the bare necessities. But a pattern emerged of enjoying life and taking advantage of what the land and surrounding seas can offer, without the stresses of modern life emerging elsewhere.

As I have mentioned in my previous blogs on the subject, there are no clocks on the island. People live in the moment, stopping to talk to a friend or neighbor, watching the sun rise or set, arriving several hours "late" for a planned meeting. But there are not really planned meetings. In addition, there are incredible "feasts of life" called panygyria, which occur in the evenings through the summer months. Again, no special start or stop times, and mostly running through the nights.

So what can one say about the food? Kochilas's recipes and photographs make the food of Ikaria sound and appear especially delicious without being especially "healthy" or "health conscious," in the common parlance of today. However, their diet does not include "junk food." In fact, only in the last few years is there any access to fast food on Ikaria. Breakfast can include Greek coffee, linked to reduced heart disease and longevity. Breakfast can also include a little red wine watered down and used for bread dipping. Goat's milk is popular and sometimes sage tea sweetened with pure local honey or petimezi (grape molasses). Foods which caught my attention included a spinach and rice dish, comforting bean and lentil soups, and special Ikarian pasturma or bastirma: air dried goat meat. It is probably important that meat on the island is mostly free-range goat or lamb.

All kinds of greens are widely used on Ikaria. But of note, these are often in the form of pastries or pies, such as Swiss chard plus spinach or onion and leeks. Not only does this enhance the deliciousness of the greens, it multiplies the ways in which they're served - both cooked (in pies) and raw (in salads). Pasta and rice are major food items. Salt used in cooking is carefully gathered from rocky pools at the water's edge. Especially tasty looking dishes include salt cod with tomatoes and onions, pan-fried fish with vinegar and rosemary, and local octopus--sweet-and-sour braised or braised with two wines.

As we head into the holiday season we must not forget the desserts! Ikarian desserts include delicious-sounding honeyed dough puffs, walnut-olive oil cookies dipped in honey, stuffed Lenten cookies and grape molasses chocolate cake.

A degree of indulgence is part of the Ikarian lifestyle. Theirs is not a rule-driven society fraught with deadlines and locked into strict schedules. Enjoying life, spending time with family, cherishing parents and grandparents as they get older, living in harmony with the rhythm of daily life are key aspects of the Ikarian experience. Are the genes of the families living on the island important? Maybe so. Is it something special in the soil and surrounding seas--are they especially healthful? Maybe.

Just living their vibrant lives is definitely key. I was reminded of the importance of "living in the moment" by a recent episode of the CBS news program 60 Minutes, which focused on the life-altering practice of "mindfulness." Undoubtedly the remoteness and quietness of Ikaria help enhance mindfulness a lot.

So over the holidays, enjoy the special moments with your family and friends. Indulge a little: we will regroup in the New Year! 

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Another hectic ASH has concluded. My pre-ASH expectations were largely confirmed with the full oral and poster presentations. But some important changes in philosophy and strategies for myeloma management emerged. These changes were key discussion points at various educational sessions, including the IMF's Satellite Symposium on Friday, December 5th and the IMWG Conference Series Debate program on Monday, December 8th

Considerable attention was focused upon the new IMWG Diagnostic Criteria, with Dr. Vincent Rajkumar as the first author, published in Lancet Oncology in November. This represents a paradigm shift in the approach to early disease. Patients with myeloma-defining events are now considered eligible for treatment. These defining events, which are biomarkers of malignancy, are: bone marrow plasma cells (clonal) of 60% (S = sixty); serum Freelite ratio of ≥100 (LI for light); >1 focal on MRI studies (M for MRI). At the Conference Series Debate, Dr. Joseph Mikhael quipped that we now have "SLIM"-CRAB! Joking aside, this is a major shift to standardize early intervention and improve outcomes for myeloma patients.

The follow-up question is: how should we be managing high risk smoldering myeloma (HR-SMM) patients (excluding the ultra-high risk patients now considered to have myeloma)? This led to an active discussion by the panel on Monday evening. Interestingly, the new aggressive approach to early disease transitioned over to the HR-SMM patients also. There was much more interest in recommending a full myeloma treatment approach to achieve the very best outcomes - within the context of a clinical trial, of course. Options considered included the three-drug carfilzomib/Revlimid/dexamethasone (CRd) approach of Dr. Ola Landgren, as well as a completely new approach of using daratumumab.

The discussions of what options to use for frontline therapy were the most revealing. Based upon the many presentations at ASH this year, some options were clearly preferred. In the transplant setting, a triplet including a proteasome inhibitor was a unanimous choice. Velcade/ Revlimid/dexamethasone was preferred, although Velcade/Cytoxan/dexamethasone (CyBord) was considered an acceptable back-up option. Dr. Landgren referred to the notion of a paradigm shift here, too. Based upon excellent results, many investigators are now using Kyrpolis versus Velcade in this frontline setting, and many were interested to see Dr. Antonio Palumbo's data with one day per week Kyprolis (along with Cytoxan plus dexamethasone) with results equivalent to the twice per week Kyprolis schedule. This makes the Kyprolis triplets so much more user friendly. This shift in thinking (#175 and #4739) was strengthened by the very robust results of the ASPIRE trial in which Kyprolis Rd was compared with Rd in the 1-3 relapse setting (#79). The superior results with KRd here reflected a likelihood of similar excellent results as already seen in the frontline setting.

For non-transplant patients, the choices were also simplified by the ASH presentations. The update of the FIRST trial consolidated Rd (continuous versus 18 months) as a "standard of care choice" in the elderly (#81) including ≥ 75 years of age. For "fit" elderly patients, however, there was a strong preference for a triplet to achieve the best outcomes, with options including VRD-lite (#3454), CyBord or VMP (#178) (in Europe): very similar to the pre-transplant induction options. And what about up-front transplant? Dr. Philippe Moreau at the educational sessions made a very strong case for the need and value of upfront ASCT. Detractors included Dr. Paul Richardson and Dr. Ola Landgren, for example, who indicated that newer "novel combinations" should provide equal benefit. The problem is that despite probably everyone wanting this to be the case, there is no such "novel combination" which has emerged so far. Thus, for now I am still firmly in the camp of offering up front ASCT to all those who are eligible.

The next question was where might a really effective "novel combination" come from? Considering the relative merits of all the new agents in the pipeline, there was strong agreement that the anti-CD38 antibodies (daratumumab and SAR 650984) offer the best hope of truly enhancing depth of response and improving outcomes (#83, #84, #178, #3474, #4729). Although likely to be approved in patients with relapse/refractory disease (to fulfill "unmet need"), the greatest optimism was to incorporate anti-CD38 therapy into frontline strategies. These results will be for a future ASH.

Of the other new agents presented, there were mixed feelings among ASH attendees about the HDAC inhibitors in the wake of the negative ODAC vote for panobinostat (#32#33) There was speculation about whether or not the three-month extension for panobinostat review at the FDA will lead to a reversal with an FDA yes vote. The major benefit with CAR-T cell immune therapy in other malignancies has led to some optimism about use in upcoming myeloma trials. The data on the Karyopharm agent selinexor were also noted (#4773). The 67% response rate using selinexor plus dexamethasone in patients with very advanced disease means that investigators will be watching closely as larger studies proceed.

Note was also made of the results with the oral proteasome inhibitors ixazomib and oprozomib, especially in the maintenance setting. Results presented by Dr. Shaji Kumar with ixazomib were especially promising with extended PFS and improvement in response during the maintenance treatment (#82). With the oprozomib (#34), there were concerns about the formulation of this oral agent, which is now provided with a "stepped-up" version--an extended-release 240 mg/day capsule designed to overcome the GI and other toxicities. Initial results are encouraging with the new formulation.

There was quite a bit of interest in a new approach to new drug evaluation presented by Dr. Philippe Moreau, who combined daratumumab with many of the standard novel combinations to assess efficacy and toxicity. This is a rapid way to screen many different combinations. In this case, it was especially interesting that daratumumab combined with pomalidomide plus dexamethasone was very effective, producing one stringent CR. Tolerance was assessed as well as the ability to harvest stem cells after such combination therapy.

We will touch on a number of other trends in upcoming blogs, but hopefully this will give you a flavor of how "fine-tuning" is leading to clearer decisions and recommendations for better outcomes for patients. So as always stay tuned

1 Comment

Thanks so much, Dr. Durie, for your ASH post. I remain hopeful for my husband who is feverish these days with his MM at 30% and CLL Lymphoma at 50% from a BMB at IU under Dr. Rafat Abonour.

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To prepare for the upcoming 56th annual meeting of the American Society of Hematology (ASH), which will be held in San Francisco Dec. 6- 9, the IMF's Medical Editor Debbie Birns and I poured over 800-plus scientific abstracts related to myeloma that will be presented at the event.  While this year there doesn't appear to be the sort of news that will reset the needle in the myeloma landscape, a few trends stand out.

Targeting specific populations: After years of excellent outcomes with the novel therapies, researchers are now looking to fine-tune treatment protocols to maximize effectiveness in specific categories of patients. Studies presented this year consider patients who are young (#2059), elderly (#178; #81) with renal impairment (#2112) , African-American (#2030), obese (#2048), long-term survivors (#2019), and those with co-morbidities (#1301; #2136). This year there are also data in patients with both amyloidosis (#35) and POEMS syndrome (#36).

Diagnostic testing and monitoring protocols: Numerous studies to be presented at ASH 2014 examine the diagnostic efficacy of myeloma tests, including PET-CT (#3371; #3382), Freelite (#180), Hevylite (#3383), and sensitive Flow-MRD monitoring (#3390), among a total of nine abstracts dealing with MRD assessment.

New combinations: Fine tuning of novel combinations is an important aspect as noted above. Perhaps the most important presentation at ASH this year is the "ASPIRE" trial dataset which compares Kyprolis Rd with Rd alone (#79) in the 1-3 relapse setting. The more frequent and deeper responses with KRd will be discussed. Other novel combinations include Kyprolis given once/week (#175) as part of the KCd regimen (Kyprolis/ Cytoxan/ Dex) and reduced dose RVD (Revlimid/ Velcade/ Dex) so called "RVD Lite" for elderly patients (#3454). A new interesting combination is alternating VMP with Rd which is also very active in the elderly population (#178).      

Pipeline drugs:  A Phase 1-2 study (#82) of the oral proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone shows promise in newly diagnosed patients. Separate abstracts show benefit with Ixazomib used as maintenance (#82) and in patients with amyloidosis (#3450). Also presented will be data on selinexor (#4773), elotuzumab (#4762), ibrutinib (#31), oprozomib (#34), panobinostat (#32; #33) and the anti-CD 38 agents daratumumab (#84; #178; #3474) and SAR 650984 (#83; #4729).

SNAPSHOT OF IMF ACTIVITIES AT ASH 2014

While in San Francisco, the IMF will host several educational events, three of which will be live-streamed for viewing by those unable to attend the ASH meeting. I strongly recommend tuning in to learn first-hand what myeloma researchers are identifying as the most compelling data presented.

Critical Issues Need Answers:
Providing Best Options for Myeloma Treatments in 2014
Friday, December 5, 2014
12:00 pm PT
www.ash2014symposium.myeloma.org (live and archived)

The symposium will have a unique program format that includes "point-counterpoint" presentations and interactive case discussions. Each point-counterpoint session will begin with an initial clinical question followed by the presentation of two alternative views. Topics to be considered:

- When to Treat Patients With Smoldering Myeloma
- Assessing Response and Minimal Residual Disease Following Induction Therapy
- Incorporating Maintenance Therapy into Treatment Strategies
- Best Choices of Salvage Therapy in Relapsed/Refractory Myeloma

News Briefing:
The Latest on Blood Cancers - From Advances to Patient Advantages
Sunday, December 7, 2014
8 pm PT
www.myeloma.org (live and archived)

I will serve as moderator for this event, hosted by the IMF, the MDS Foundation on behalf of the MDS Alliance, the Lymphoma Research Foundation and the National Patient Advocate Foundation. A panel of leading blood cancer experts, advocacy organizations and patients will put ASH data into perspective, showcasing how scientific advances help patients.

Making Sense of Treatment:
The International Myeloma Working Group (IMWG) Conference Series
Monday, December 8
8 pm PT
www.imwgconferenceseries.myeloma.org (live and archived)

I will moderate and join with my colleagues and IMWG members Drs. Joseph Mikhael, Dr. Ola Landgren and Dr. Antonio Palumbo to tackle the key questions currently facing myeloma doctors and patients in light of the latest research presented at ASH.

2 Comments

What your opinions regarding a clinical trial at the James Cancer Center at Ohio State University regarding Pomalyst Capsule 4mg, ACY-1215 12 mg/mL and Dexamethasone. Acy-1215 have not been approved by the FDA.

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The first week of November 2014 saw the IMF co-hosting three Patient & Family Seminars in Norway and Denmark, where leaders from international patient associations came together with acclaimed speakers to discuss the latest in myeloma news and treatments. It was an opportunity for the IMF to make international patients aware of our resources and bring the global myeloma community even closer together. I had the pleasure of attending the meetings, and now you can follow along on my journey with this recap of events.

The Patient & Family Seminar in Trondheim, Norway kicked off on November 1st with Dr. Anders Waage of the Norwegian University of Science and Technology in Trondheim, moderating/translating and Dr. Angela Dispenzieri from Mayo Clinic leading a discussion on monitoring, potentially preventing, and treating complications of myeloma. New treatments for myeloma were also a hot topic during this meeting. The Norwegian patients really appreciated having a speaker from abroad come to their city to speak about myeloma. In fact, there was such a demand for attendance that the meeting actually hit capacity at almost 200 participants, and a few had to be turned away.

Other presentations delivered during the seminar included:

"Pain and Physical Activity with Myeloma," presented by Janne Anita Sundfær, RN
"Awareness and Coping," which was presented by Tone Hansen, Director, Henie Onstad Kunstsenter, Høvikodden. Norway. Tone is also the leader of Blodkreft Foreningen (the Norwegian patient association) and an excellent psychologist. Her talk was uplifting for both patient and caregivers.
"Clinical Studies in Norway for Patients Diagnosed with Myeloma" from Dr. Waage
"Learning and Mastery Groups for Patients Diagnosed with Myeloma," from Turid Almvik, RN
"Emotional and Physical Effects of Recurrence," presented by a Celgene representative

Though many of the aforementioned presentations were medical in nature, designed to educate the participants about various aspects and stages of myeloma, there was much room for individual patients to ask questions and share their stories, as well.

The Patient & Family Seminar truly brought together patients and medical professionals alike.

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On November 4th, a second Patient & Family Seminar was held, this time in Oslo, Norway, with 208 people in attendance. Some of the attendees were newly diagnosed patients who were participating in a meeting for the first time. As such, after Tone Hansen, the leader of the Norwegian Patient Association (Blodkreftforeningen) started the event, the first presentation was on the introduction of diagnosis. Dr. Nina Gulbrandsen, Professor and Chief Physician, Oslo University, Rikshospitalet, shared her expertise in the subject.

The other presentations in Oslo included Dr. Fredrik Schjesvold's "Current Treatment for Newly Diagnosed Pateints and Treatment at Recurrence," Tone Hansen's "Awareness and Coping," Celgene's "Emotional and Physical Effects of Recurrence," and Dr. Waage's "The Norwegian Research Center: Jebsen's Centre for Myeloma." Patient stories were also shared.

Following the second successful Patient & Family Seminar in Norway, I attended two physician meetings.

The following day in Oslo, Celgene held a physician meeting. Approximately 50 physicians took part, including some speakers who were part of the prior Patient & Family Seminar. Dr. Dispenzieri repeated her presentation of "Diagnosis and Treatment of Myeloma," which created a lively discussion during the Q&A section.

A physician meeting held at Odense University Hospital in Denmark followed the next day, on November 6th. This time, approximately 40 physicians attended, many of whom worked with Syddansk Universitet's Dr. Niels Abildgaard. This time, Dr. Dispenzieri presented "Virotherapy in Multiple Myeloma-- The Mayo Experience" and produced yet another lively discussion and exchange of information regarding Mayo Clinic's practices.

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The final event of the week, the Patient & Family Seminar in Middelfart, Denmark on November 7th, drew 210 participants in person but also included a virtual contingent, as the meetings were live-streamed to allow additional patients to sit in.

The attendees started the event by singing a beautiful biblical song, and then Ole Dalriis, Chairman of the Danish Myeloma Foreningen, and Bibi Moe opened the meeting by introducing the IMF, and I carried on by introducing the day's activities.

Dr. Abildgaard acted as moderator and translator for Dr. Dispenzieri, who presented "Monitoring and Management of Myeloma Treatment," which produced a lively discussion. The Danish patients were very educated about their disease, and their questions were thoughtfully formed.

The Patient & Family Seminars I attended in both Norway and Denmark provided supportive feedback and a large outpouring of gratitude toward the IMF. I am very happy to share that relationships are strong. It was a delight to work with both Blodkreftforeningen and the DMF, and I am already eagerly anticipating next year's events! We truly are One Myeloma Nation.

Nadia Elkebir
IMF Director of Europe and the Middle East

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