text:
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.
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 email@example.com. InfoLine hours are 9 am to 4 pm PT. Thank you.
]]>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 email@example.com. InfoLine hours are 9 am to 4 pm PT. Thank you.
]]>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 firstname.lastname@example.com. InfoLine hours are 9 am to 4 pm PT. Thank you.
]]>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 firstname.lastname@example.com. InfoLine hours are 9 am to 4 pm PT. Thank you.
]]>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 email@example.com. InfoLine hours are 9 am to 4 pm PT. Thank you.
]]>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.
]]>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!
]]>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
]]>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;
with renal impairment (#2112)
, African-American (#2030),
obese (#2048),
long-term survivors (#2019),
and those with co-morbidities (#1301;
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;
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;
and the anti-CD 38 agents daratumumab (#84;
and SAR 650984 (#83;
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
Critical Issues Need Answers:
Providing Best Options for Myeloma Treatments in 2014
Friday, December
5, 2014
12:00 pm PT
(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:
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
The International
Myeloma Working Group (IMWG) Conference Series
Monday, December 8
8 pm PT
(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.
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.
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.
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
During this era of novel therapies, salvage transplant has become an overlooked option. Presentations at the recent meeting, held under the auspices of the American Society of Blood and Marrow Transplantation (ASBMT), the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Workshop, the National Marrow Donor Program, and the International Myeloma Foundation, suggest that it is time to take a second look at the uses and recommendations for salvage transplant--both the name, perhaps, and the process.
We know that transplant has clear benefits as a high dose consolidation therapy for patients in the frontline setting, as described in the 2011 publication in the journal Blood, International Myeloma Working Group (IMWG) consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. The Minnesota workshop provided a wonderful opportunity to re-examine of the merits of second transplants as well.
The workshop was co-chaired by Dr. Sergio Giralt (Memorial Sloan Kettering Cancer Center) and Dr. Ed Stadtmauer (University of Pennsylvania School of Medicine, Abramson Cancer Center) representing the Center for International Blood & Marrow Transplant Research (CIBMTR) and the BMT CTN, and myself, representing the IMF and the IMWG. Other organizing committee members were Drs. Hari Parameswaran, Phillip McCarthy and Marcelo Pasquini.
Two of the key presentations during the workshop were:
Dr. Stadtmauer's excellent overview of the role of salvage ASCT. The data from the International Bone Marrow Transplant Registry (IBMTR) were compared with other reported studies. Outcomes correlated with the length of the first remission with ASCT, as well as the depth of response with both the first and second (salvage) transplants. To put the results in perspective with regard to other potential therapies for relapse patients, average remissions were about 1 year and subsequent overall survivals approximately 2-4 years.
Prof. Gordon Cook's (University of Leeds, UK) presentation of the results of his Myeloma X Trial. Salvage transplant with melphalan 200mg/m2 (ASCT) was compared with simply Cytoxan by mouth (400 mg/m2 once/week for 3 months). Starting in 2008, 174 patients were randomized. The full results were published recently in Lancet Oncology. It was very helpful to see the benefit of salvage ASCT in this randomized setting. The data also confirmed the importance of length of prior remission and depth of response.
After breaking into four work groups, workshop participants presented their ideas and recommendations, which included:
With priorities agreed upon by all of the workshop participants, the meeting concluded with a commitment to prepare guidelines promptly under the auspices of the IMWG and also to set up several planned studies. The IMF team of Lisa Paik, Diana Wang and myself were very pleased to be in attendance and will be working closely with the transplant team members to ensure rapid progress to achieve the planned outcomes. In addition, follow up meetings will occur as feasible at the Annual Meeting of the American Society of Hematology (ASH), the IMWG Summit and other venues.
So, as always, stay tuned.
Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to email@example.com. InfoLine hours are 9 am to 4 pm PT. Thank you.
]]>Today's Oncologic Drugs Advisory Committee (ODAC) hearing convened in an optimistic fashion with many in the myeloma community expecting there would be a recommendation for approval of panobinostat, an HDAC inhibitor used in combination with Velcade and dexamethasone. Publicly available data indicated a 3.9 months progression-free survival (PFS) or remission duration benefit with the three-drug panobinostat combination in patients who had been treated with 1-3 prior therapies. Note was made of significant toxicities, including low blood platelet levels (56.7%), diarrhea (25.4%), and fatigue (24.6%). However, going into the hearing, it was felt that the benefits outweighed these types of toxicities. From the myeloma patient perspective, there was the hope that panobinostat--representing a new class of drugs, the HDAC inhibitors--would be added to the myeloma treatment armamentarium. IMF staff and team members were at the ODAC hearing to affirm the continued unmet need for new drugs to treat myeloma.
Unfortunately, the presentation by Barry Miller, FDA Senior Clinical Analyst, dashed these hopes and expectations rather quickly. Miller pointed out that "missing data" was the main reason the FDA staff asked for the ODAC review. A large amount of data was unavailable or "censored," often because patients withdrew from the trial. The question was "Why?" Did the patients withdraw for incidental reasons (minor problems, trial logistics, etc.) or major toxicities, or even unexpected on-trial deaths?
As pointed out by Dr. James E. Liebmann (ODAC panelist from University of Massachusetts Memorial Medical Center), there was a disparity in "on-treatment deaths" in the panobinostat arm of the trial. The uncertainties about "censoring" apparently had led to four separate estimates of the PFS duration: 3.9 months (the duration reported); but also 2.2. months; 3.7 months, and 1.9 months. The FDA's own analyses gave a PFS difference of 2.2. months (9.9 months versus 7.7 months): rather disappointing compared to the 3.9 months provided by Novartis and their IRC (Independent Review Committee). IRC member Dr. Paul Richardson was unable to explain the reasons for the censoring to the satisfaction of the ODAC reviewers. Dr. Richard Pazdur (Director of the FDA Office of Hematology and Oncology Products) himself raised the issue of censoring as an important concern.
Ultimately, Dr. Richard Pazdur summarized what appeared to be the prevailing opinion of the ODAC reviewers.
"PFS is not the question, there's clearly some benefit. ... The question is what is the magnitude of benefit and does it warrant the toxicity."
This perspective reflected the vote of 5-2 against a recommendation to the FDA to approve panobinostat. Dr. Liebmann also summarized the difficulties faced by the panel when confronted, as they were, by patient advocates (Robin Tuohy, Michael Tuohy and Diane Moran) including a woman who had benefitted for five years on panobinostat. He said, "First, this is a very difficult decision... this agent does have some activity ... and can be useful in this disease. But, "I think the toxicity outweighed the marginal benefit in PFS."
He went on to say that we should not give up on the drug or class of drugs, and certainly this is the case. Although it seems very unlikely that the FDA will go against the ODAC recommendation, it may still be possible that Novartis can answer the questions that were raised.
This is certainly a wake-up call for the myeloma community. What are the expectations for new drugs moving forward? Do we need to set the bar higher and try to achieve a much greater benefit, especially in the setting of important toxicities? My sense is that all involved will be recalibrating and setting their sights on longer remissions and lesser side effects - key needs for myeloma patients everywhere!
tuned and we will keep you posted as many new drugs move forward in trials and
hopefully give the benefits we all want to see.
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 email@example.com. InfoLine hours are 9 am to 4 pm PT. Thank you.
]]>For some time, members of the International Myeloma Working Group (IMWG), the IMF's research division, have been trying to identify and describe a group of patients without CRAB features. Finally, Dr. Vincent Rajkumar, my co-chair in this project, has succeeded in bringing together the data, plus ideas and opinions from the IMWG members, to create new diagnostic criteria for myeloma. The criteria define a new "Pre-CRAB" group of patients who need treatment. A paper detailing the IMWG's updated criteria was published today in the journal Lancet Oncology.
This step forward has many important implications, not the least of which is the expectation that earlier treatment will lead to better outcomes! This is the central idea of the IMF's signature Black Swan Research Initiative, in which early treatment is combined with close assessment of low levels of residual myeloma--minimal residual disease (MRD) testing--to push for therapy to achieve an MRD negative status that can lead to a cure.
IMWG's updated criteria represent no less than "a paradigm shift in myeloma,"
said Dr. Rajkumar in a video
interview. "We are now willing to
treat myeloma before symptoms happen. This is a big deal." To read the IMF's announcement about the
IMWG's updated criteria CLICK
In a recent paper in the journal Blood, Dr. Bart Barlogie and his team at the University of Arkansas in Little Rock claim they are "Curing myeloma at last: defining criteria and providing the evidence." This is a bold statement. I would argue that while the paper provides a statistical/computer model, achieving and documenting true cure demands a follow-up of individual patients and cannot be predicted by a computer model.
But let's examine the approach taken here more closely to see why. In order to comment intelligently on this paper, one must search through the details of the methods used to define cure and provide the "evidence." The term "cure fraction" is used in the paper. It is derived from a combination of relative survival estimates (myeloma patient survival versus a patient without myeloma) and a complex computer model derived from a statistical approach used in 1982 for breast cancer. Is this a valid statistical approach to derive a "cure fraction"? The authors of this statistical paper emphasize the constraints of the approach. Two risk groups are required for the statistics to work. Dr. Barlogie divides his patients into "high" and "low" risk so that this approach can be applied, but as readers are probably aware, the Mayo Clinic mSMART approach divides patients into three risk groups. Which is correct or better? We don't know.
After careful review, it appears that the "cure fraction" from the Little Rock "model" is considered to be: patients with "high risk" disease by gene expression profiling (GEP) who remain in complete remission (CR) for > 5 years and "low risk" patients by GEP who stay in CR for > 10 years. Are such patients cured? Clearly they are doing well, but the risk of relapse is not zero. The label of "cure" is still just a statistical prediction, which is treatment and model dependent. The outcome for each individual patient is determined by individual staging and prognostic factors, as well as non-myeloma related co-morbidities. Although calculating a "cure fraction" using the proposed model does allow comparisons between the different "total therapy" regimens used in Little Rock, it does not affirm that individual patients are actually cured.
What is more helpful is to offer criteria that can predict a likely very good outcome at the start of therapy and/or early in the disease course. This is the strategy of the IMF's Black Swan Research Initiative. Using MRD assessment as a primary tool, it is possible to predict likely long remissions with complete remissions, especially with CR or stringent CR for patients with initial stable response. Without claiming that patients are necessarily "cured" (meaning that there will never be a relapse even after 10 years), one can predict chronic disease control, which is most helpful to individual patients. Thus, for example, in a young patient with good risk features--(ISS Stage I), normal F.I.S.H. testing (no t[4;14]; 17p-; 1q+ ), and normal LDH at baseline who achieves stringent CR and flow MRD-negative status--a very good outcome can be predicted.
The total therapy regimens clearly produce excellent outcomes for some patients. But in 2014, most patients and investigators are looking to novel therapy/transplant regimens that can be successful without the automatic double transplant approach plus other elements of the total therapy program. The pioneering value of total therapy has triggered the search for other ways forward that can occur within the Black Swan Research Initiative, which allows use of MRD assessment to achieve the best outcomes.
Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to email@example.com. InfoLine hours are 9 am to 4 pm PT. Thank you.
]]>On October 3rd and 4th, in conjunction with Slovak Myeloma Society (SMS) & Patient Club, the myeloma patient association of Slovakia, the IMF co-hosted the second annual Slovak Patient & Family Seminar in Liptovsky Jan in the beautiful region of Low Tatras in northern Slovakia.
It was my pleasure to attend the seminar and have the opportunity to continue to expand the IMF's relationships with patient organizations throughout the world that share the common goal of supporting and improving life for myeloma patients.
Mr. Hrianka Miroslav, a representative of SMS, moderated the seminar and did a fantastic job organizing a highly informative and enjoyable meeting. The seminar, which welcomed 130 patients, family members, and physicians from different cities across Slovakia, was a great success.
seminar began with a patient forum, which included an uplifting testimony from
a Slovak myeloma patient who focused on the idea that "every day is a new
beginning." This presentation was quite moving and was followed by
presentations on activities of several myeloma patient associations in Central
Europe. These included presentations from:
The second day of the Patient & Family Seminar began with my presentation. I shared an overview of the IMF, our mission, goals, achievements, and the IMF's international initiative: the Global Myeloma Alliance (GMA). Mr. Hrianka Miroslav, meeting organizer, is representing Slovakia in the GMA.
During my presentation, the IMF's message was well received and understood by the Slovak patients. I enjoyed sharing information about the resources and support the IMF provides to patients worldwide.
Following my presentation, Dr. Roman Hajek of the Czech Republic shared information about new myeloma drugs, treatment side effects, and clinical trials. He also provided personal consultations for patients. The participants paid great attention to this crucial presentation.
One of the things I will take away from this seminar is an appreciation for the remarkable relationship between the Czech and Slovak people. These two countries used to be one, Czechoslovakia, until a political split happened smoothly in 1993. This peaceful divorce is still called the "Velvet Revolution." However, as independent as the countries are now, Czech and Slovak people have an excellent relationship and strongly support each other, which I have seen in their fight against myeloma. I could see this relationship in the very well received presentations from Dr. Hajek and the Czech Myeloma Group. It is an inspirational relationship that should be taken as a great example all over the world.
Back to the seminar! Day two also featured the following interesting presentations: "Integrative Myeloma Treatment & Logotherapy" from Dr. Pavel Kotoucek of Homerton University Hospital in London; "Physiotherapy and Spa Treatment" from Dr. Eva Kmetyova of University Hospital in Bratislava; "From Diagnosis to Ambulatory Monitoring of the Disease" from Dr. Zdenka Stefanikova of University Hospital in Bratislava; and "the Art of Healthy Living, Separate Diet" from Prof. Katarina Horakova, DrSc, of Slovak Technical University in Bratislava.
I am very grateful to Mr. Hrianka Miroslav--who is a caregiver to his very brave wife Milada, who has been fighting myeloma for nine years--for organizing such an informative and enjoyable meeting. I am looking forward to attending the 2015 Slovak Patient & Family Seminar!
Nadia Elkebir
IMF Director of Europe and the Middle East


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subset: commoncrawl


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A Forum For Modders Of The Farming Simulator Games
Free forum : A forum meant for discussions of all sorts.
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Shadowrun Online is a Shadowrun play by post (PbP) site where running the shadows is a way to survive. Shadowrun 4th Edition RPG.
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Welcome to the official forums of Zephyr Faction.
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A place for fans of anime and video games to hang out.
A video gamer website to share your gamertags, ID's, and friendcodes. See inside for more details.
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Are you a fan of videos from Giddyfish on Youtube? Here's the place you can discuss them, as well as other topics such as your favourite games!
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Anime, Rp, Roleplay, games, music,
It's a far-out game. Two games, to be precise.
Free forum : A forum dedicated to various player-created simulation games, ranging from Star Wars, Warhammer 40k and Babylon 5, to Find the Murderer and Paranoia. A gaming-exclusive forum, free of t
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We talk about Newgrounds, Flash, Music, Video Games, and pretty much everything else.
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This forum is for fans of Sandlot Games and the games they made.
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A place for creative European gamers to hang out.
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Covering the newest iphone/ipod games with reviews, photos, and more. Get a look into todays hottest games and peek into the future games. Mingle with developers, get latest info, and conversate with fellow gamers.
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TripAdvisor Reviews H8 Oslo
Travel Blogs from Oslo
Why Does Everything Close So Early?!?!
... and started removing my sweatshirt, socks etc. We did have more luck this time though, as the train wasn't as full. At first I was afraid more people would be getting on, so I avoided moving to another seat, but at around 1:30 in the morning, I finally decided it was worth it. We each had two seats to ourselves, making it easier to sleep. While I didn't sleep great, compliments of the extra room and sleeping pill, I slept better than the first ...
Maritime Heritage and Public Spaces
... Pacific islands.
From there, we went to yet another Viking Ship museum – this one presenting four Viking burial craft from the early Viking period (800s). These ships, discovered in 1904, are the best preserved Viking relics even though the graves were raided around 1000 and that the preservation methods employed in the early 1900s is not sufficient to preserve the artifacts into the future. One of the universities in Oslo is investigating how ...
Oslo, Norway
... br>
Remember, you can click on any picture to see it enlarged.
That's the end. As you can probably see, we really had an enjoyable walk through this park.
But now we're off to western Norway. We're off to the fjords. Join us in the next Travel Times. My double will be there. Hope you are too.
Second Day in Oslo
... arts museum.
On the walk back to the hotel, we saw the building that's the opera house and ballet theater. Kind of a unique place. There was a show of some sort outside the building. People were sitting on the slopes, watching, cheering. The building was by the water. There was a modern glass sculpture in the water which resembled a crumbled glass building (or ship).
There were a lot of constructions going on in Oslo which sort of ruined some of the nice ...
Heat wave in Oslo - Day 8
We had to wait for train to arrive in Myrdal for Oslo. It was really late, 1.5 hours late. We were due to arrive Oslo just before 11pm. Apparently train came and stopped just before Oslo city and waited. We were frustrated and tired. Then I had to ask the train conductor for assistance. It appeared Oslo has suffered bad heat wave, causing tracks to buckle or/& snap. Thus delaying arrival, the tracks had to be replaced on the spot. Conductors said ...
Other places to stay in Oslo
Grand Hotel
Sentrum, Oslo | 4 star hotelfrom $228- Charming and with great location, but could need some upgrading
- Didn't like it that much
- Great hotel, great location
Thon Hotel Opera
Sentrum, Oslo | 4 star hotelfrom $179- One of the best
- Above the average
- Great Hotel in Central Oslo
Radisson Blu Plaza Hotel, Oslo
Grünerløkka - Sofienberg, Oslo | 5 star hotelfrom $167- Good & central business hotel
- Money well spent
- Great Hotel
Radisson Blu Scandinavia Hotel, Oslo
Sentrum, Oslo | 4 star hotelfrom $150- Ok hotel
- Great views and good location
- Loved this place
Clarion Hotel Royal Christiania
Sentrum, Oslo | 4 star hotelfrom $187- Rather Disappointed
- Great location, good value
- Good Hotel, Excellent Location
Hotel Bristol
Sentrum, Oslo | 4 star hotelfrom $190- Old School Atmosphere
- Lovely Hotel (if you dont mind sleepless nights!)
- Would stay there again
Thon Hotel Slottsparken
Uranienborg - Majorstuen, Oslo | 3 star hotelfrom $139 -
Quality Hotel 33
Bjerke, Oslo | 4 star hotelfrom $135 -
Scandic Edderkoppen
Uranienborg - Majorstuen, Oslo | 3 star hotelfrom $146 -
Rica Holmenkollen Park Hotel
Vinderen, Oslo | 4 star hotelfrom $163 -
Comfort Hotel Boersparken
Sentrum, Oslo | 3 star hotelfrom $112- Highly recommended
- Great location, free internet access
- Good value
Scandic Byporten
Sentrum, Oslo | 4 star hotelfrom $159- Excellent location!
- Wonderful hotel
- Very convenient hotel, well managed
Soria Moria Hotel
Vinderen, Oslo | 4 star hotelfrom $173 -
Scandic Solli
Bygdøy - Frogner, Oslo | 4 star hotelfrom $146- Nice hotel nasty cheese/bar prices
- Lovely hotel, good location
- Excellent value for money
Thon Hotel Europa
Sentrum, Oslo | 3 star hotelfrom $136 -
Rica Helsfyr Hotel
Helsfyr - Sinsen, Oslo | 3 star hotelfrom $155 -
Rica Victoria Hotel
Sentrum, Oslo | 4 star hotelfrom $163 -
Anker Hotel
Vinderen, Oslo | 3 star hotelfrom $111- Mixed feelings
- Great Rates, Great Location
- So-so hotel
Scandic Sjolyst
Ullern, Oslo | 3 star hotelfrom $134 -
Thon Hotel Munch
Sentrum, Oslo | 1 star hotelfrom $114 -
Rica Oslo Hotel
Uranienborg - Majorstuen, Oslo | 3 star hotelfrom $152 -
Hotell Bondeheimen
Sentrum, Oslo | 3 star hotelfrom $142- Late arrival means a smoking room....
- Pleasant accomodation in Oslo: to be suggested
- Disappointing
Radisson Blu Hotel Nydalen, Oslo
Vinderen, Oslo | 4 star hotelfrom $124 -
Thon Hotel Gyldenlove
Uranienborg - Majorstuen, Oslo | 2 star hotelfrom $143 -
Thon Hotel Stefan
Uranienborg - Majorstuen, Oslo | 3 star hotelfrom $175 -
Hotel Continental Oslo
Sentrum, Oslo | 5 star hotelfrom $223- Excellent
- If this is a great Norwegian hotel - they're in trouble
- Outdated and Overrated....


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The name says it all: At this monthly party, the Home Alone star spins danceable songs from a well-stocked MP3 player. This month's theme: "Hulk Hogan's Slutty New Year's Eve in June Dinosaur Prom Night." Of course.
Macaulay Culkin's iPod
Venue name: | Le Poisson Rouge | Contact: |
Address: |
158 Bleecker St New York |
Cross street: | at Thompson St |
Transport: | Subway: A, C, E, B, D, F, M to W 4th St |


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Article Preview
Duluth airport hits temperature record while Park Point keeps it cool
Published 05/18/2012, Duluth News Tribune
According to the National Weather Service, the high temperature at the Duluth International Airport was 87 degrees, setting a record for the date.
Word count: 263Log In
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Brent extended losses on Monday after Iran said a deal on its nuclear program could be agreed this week, which could boost the country's oil exports.
CNBC's Rick Santelli looks ahead to Thursday's ECB meeting, and oil prices going lower.
The "Squawk on the Street" crew dissect the play on oil companies including EOG Resources after the company posted a great third quarter.
Saudi Prince Alwaleed Bin Talal, has called on authorities to create a sovereign wealth fund to help reduce the state's reliance on oil.
CNBC's Jackie DeAngelis discusses the day's activity in the commodities markets. Crude bounced in the morning after reports of an explosion at a Saudi pipeline. That and a bullish inventory report drove the price up a bit.
Oil futures spiked Wednesday on unconfirmed rumors of an oil pipeline explosion in Saudi Arabia and data that showed U.S. crude inventories rose less than expected.
CNBC's Jackie DeAngelis discusses the day's activity in the commodities markets. Oil fell to $75 today but ended up a bit above $77. Strength in the dollar continues to drive oil prices lower.
Oil has fallen very far very fast but one research analyst believes crude prices may be close to its bottom.
Oil prices could have a hard time finding a floor after Saudi Arabia trimmed prices in the face of growing North American oil production.
In light of the midterm election, CNBC's Dominic Chu looks at stocks and sectors to watch.
The oil price plunge has not pushed energy shares to new lows, as much of the damage "has already been done" according to asset managers.
Falling oil prices have always been somewhat of a double-edged sword. But some say the negatives to the economy are taking on added concerns.
CNBC's Jim Cramer discusses the huge flood of domestic oil hitting the U.S., and Alibaba's earnings.
West Texas Intermediate bounced back and forth between positive and negative territory just around the $80 level for most of the session.
CNBC's Jackie DeAngelis discusses the day's activity in the commodities markets. Crude had a volatile day until Saudi Arabia was cutting the price of oil to the US.
Oil dived more than 3 percent on Tuesday to multi-year lows, as Saudi Arabia's sharp cut in export prices to the U.S. looked likely to deepen a supply glut.
CNBC's Bob Pisani dissects the pop in the energy ETF midday, and move in energy and big oil stocks afterwards.
Philippe Dauba-Pantanacce, senior economist for Turkey, Middle East and North Africa at Standard Chartered Bank is bullish on oil prices and claims data shows there is no real oversupply.
Global oil prices spiked at midday on Monday, with benchmark Brent turning positive after a big hike in Saudi Arabia's monthly export prices.
Governments can manage climate change but will have to cut greenhouse gases to zero by 2100 to limit risks a U.N. report said on Sunday.
Andy Lipow got it right when he predicted $3 gas by Halloween. Here are his predictions for Thanksgiving and beyond.
Get the best of CNBC in your inbox


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She Said It, We Didn't
She Said It, We Didn't
by GiggleSugar
Like us on Facebook
"I think I get in more trouble just because of who I am. The cops do it all the time. They'll just pull me over to hit on me. It's really annoying. They're like, 'What's your phone number? Want to go to dinner?' They won't even give me a ticket. They just pull me over...I have so many cops' business cards." - Paris Hilton
7 years
Maybe she should've gone out with them. Now they all think she's a tease and they'll write those tickets. Payback's a bitch, sweetheart.
Link Love
- Why casual sex could actually be beneficial — xoJane
- How keeping family secrets can literally make you sick — The Frisky
- The most underrated chick flicks ever — Her Campus
- Slam poems that pack a serious feminist punch — HuffPost Women
- Tips and tricks for making the first move — Dear Wendy
- How to get the perfect online dating photo — College Candy
- The top 10 male body parts women love — AskMen
- Introverts, rejoice! Here are the emoji of your dreams — POPSUGAR Tech


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Home » A&E / Life&Style » Charlotte Pride Band celebrates 'Heroes'
Charlotte Pride Band celebrates 'Heroes'
Updated: April 24, 2014 at 4:05 pm
ENGAGE: Write a letter to the editor | Comment on this story
The Charlotte Pride Band will present their final concert of the season in May. The concert, "HEROES" will celebrate and salute all the individuals who provide inspiration.
The band promises to have the audience "soaring with Superman and swinging with big-band style with America's greatest generation."
Formed in February 2010, the Charlotte Pride Band is now in its fourth year. It's one of three or four dozen LGBT-inclusive community bands nationwide. In Charlotte, they've been gracing audiences with big sounds and fun a plenty — all with volunteer players.
The "HEROES" concert is scheduled for May 10, 5 p.m., Heaton Hall at Myers Park Baptist Church, 1900 Queens Rd. Tickets are $13 for individuals, available online or at the door. A family pass is available for $22.50 and includes admission for two adults and children under 12. For more information or to purchase tickets, visit charlotteprideband.org. : :
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Give a one-time gift or sign up for ongoing voluntary online subscription to support qnotes' nearly three-decade long community service and keep our publication's dynamic, hard-hitting and insightful news and entertainment coverage alive. Click here to support us today.
About the author: Matt Comer is the editor of QNotes, first hired to serve in the role in October 2007. He can be reached via email at email@example.com or via phone at 704-531-9988, ext. 202. Follow him online at facebook.com/matthew.mh.comer or at twitter.com/themattcomer.
Charlotte LGBT Protections
On March 2, Charlotte City Council rejected LGBT-inclusive non-discrimination ordinances. Click here to full and continuing coverage.You can support QNotes
You can support independent, local LGBT media! Give a one-time gift or sign up for an ongoing, voluntary online subscription to support qnotes' nearly three-decade long community service and keep our publication's dynamic, hard-hitting and insightful news and entertainment coverage alive. Click here to support us today.On Stands Now
QNotes is ready for spring and all the fine arts and entertainment that will come with it. Take a look through our Spring A&E Guide, with theatre listings, events, concerts and more, plus our cover story with local performer Tyler Smith. Also: local, regional and national news of note.
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Time Out Youth to celebrate new cyber...
A local LGBT youth services agency is expanding their outreach to transgender youth and partnering on a new program for those youth who have... more
The Charlotte that is, not the...
We tell ourselves we are a progressive, can-do, forward-thinking city that comes together to amicably solve our problems. It is the Charlotte Way, we... more
Charlotte rejects LGBT-inclusive...
Charlotte City Council passed several proposed LGBT-inclusive non-discrimination ordinances, approving an amendment proposal that exempts restrooms,... more
Anti-LGBT activists confront...
As City Council hears tonight from a list of nearly 120 speakers on a contentious LGBT non-discrimination ordinance proposal, anti-LGBT activists are... more
Community Events
Wednesday, March 4, 2015
Women's HIV Group at Different Roads HomeWednesday, March 4, 2015
Thursday Line Dance Lessons at Cathode Azure ClubThursday, March 5, 2015
Charlotte Pride Band - Spring Concert Band PracticeSaturday, March 7, 2015
Chapel Hill: 'An Enemy of the People' by Henrik Ibsen adapted by Arthur MillerSaturday, March 7, 2015
Charlotte Pride Band's 'Music That Moves You' Concert recent discussion


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National Sleep Foundation (NSF)http://www.sleepfoundation.orgNSF is an independent nonprofit organization dedicated to improving public health and safety by achieving understanding of sleep and sleep disorders, and by supporting education, sleep-related research, and advocacy.
Nationwide Children's Hospital 700 Children's Drive Columbus, Ohio 43205 614.722.2000


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Different furniture needs different furniture cleaning ... more
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High Quality Renderings
Closed - This job posting has been filled and work has been completed.
Job Description
We are an Architecture & Interior Design Firm. We recently lost our portfolio that was saved in our hard drive and we're now looking to buy high quality for renderings for use on our website portfolio.
All renderings must be original and will need high resolution preferable 4k pixels by 4k pixels (or similar).
We are looking for all types of renderings:
Exterior Views (single-family homes, multi-family home, high-rises, town homes, apartments, villas, and commercial projects- restaurants, hotels, retail, office buildings, etc)
Interior Views (modern kitchen, dining room, patio area, interior design details)
Elevations (front and side views)
*** We are not looking for renderings designed to specific measurements, this is more to capture the concept and "look and style" of a space or home. We need a lot of different style renderings in a short amount of time so we can have our website running again***
This job is perfect for someone who has experience in 3D renderings, AutoCAD, Revit, etc...
Since we lost most of our work, we are not in a position to pay for all new renderings. We want to be fair to the designer so we will pay you per rendering. Each rendering will be $75.00. They can be old renderings from your portfolio, or you can change an old design to make it slightly different and new.
What we want are renderings that are already complete. If you have renderings in your portfolio, you can show them to us and if we like them we will agree to pay the $75.00 per each rendering...
We will be attaching a few documents showing the quality of work we're looking for. Some of these images are projects we've completed, others were pulled off the internet because they are similar to our jobs and they are up to our standards...


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Countdown: Top 10 Giants of all time
How do you shrink more than 85 years as a flagship NFL franchise into a top 10 list of all-time? Not easy when you're talking about the Giants, who started up in 1925 and have produced a ton of great players who have given the team plenty to celebrate over the decades. Newsday's Bob Glauber gives his take on the best of the best.
Matt Harvey at Mets spring training
By the numbers: Manny Pacquiao
USA at Algarve Cup
Brandon Marshall
43 NFL players who became pro wrestlers
WWE's Bella twins
Islanders vs. Predators
Mets spring training games 2015
Who can stop the Kentucky Wildcats?
Five free agents the Jets could target
Five free agents the Giants could target
Anthony Mason public viewing


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Show 2 replies
1. Re: How to view the text of the trigger
Paul M. Oct 11, 2006 3:00 PM (in response to 520411)You can use USER_TRIGGERS dictionary view, e.g.SQL> set long 100000
<YOUR TRIGGER> must be uppercase.
SQL> select DESCRIPTION, TRIGGER_BODY
2 from user_triggers
3 where trigger_name = '<YOUR TRIGGER>'; -
2. Re: How to view the text of the trigger
520411 Oct 16, 2006 7:33 PM (in response to Paul M.)Thanks a lot. I worked.
Again thank you so much.


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La Dolce Vita Posters
La Dolce Vita Posters is quite exceptional and makes a perfect wall decoration, the item dimension is 11 x 14 inch and the price is $17.99. If you're trying to see top recommended La Dolce Vita Posters with reasonable price, the poster is the luxury deals for you.
La Dolce Vita Posters is a bewitching painting, you can see the details of the paint strokes and the color is a mass of more realistic than in some of the prints. The poster itself is standout, but the image does not show that there is an off-white border around the painting. This product measuring , these are also printed on cardboard. The unit is a self-help organization poster that is general enough to be emption to your life, but specfic enough to decidedly make a lasting impact. La Dolce Vita Posters is a cool size -and it looks famous on the wall and in a frame. This product is a highly cool poster, well printed and speedy shipped in a protective poster case. The poster is in wonderful condition with pleasant characteristic. The product is huge, resplendent and absolutely terrific, the inexpensive price $17.99 is wonderful. La Dolce Vita Posters affords competitive pricing to clients.


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HA! Jenna Jameson Responds to Lefty Haters With "Your Mom" Quips
When it comes to responding to despicable left-wing trolls on Twitter, Jenna Jameson certainly knows how to deal with them. : Yesterday, Jameson, a successful businesswoman and entrepreneur, simply tweeted that former President George W. Bush didn't destroy her industry. Well, that caused a conniption fit on the left. : With a torrent of hate tweets directed at her, she simply responded with a litany of "your mom" quips. : It was genius and: Twitchy, as always, reported on the incident.
She doesn't stop there. : She asked a couple of proggie trolls what the inimitable Barack Obama has done for the country in the past four years. : The responses were interesting.
One thing most folks seem to forget is that Ms. Jameson can hold her own in these political exchanges. : Does anyone remember her invitation to debate if pornography was harmful at the Oxford Union? : Many forecasted her to sink in the deep end, but, her argument won 204 to 27! : Talk about a Dewey vs. Truman moment. : While I'm sure Twitter isn't nearly as an incisive or respectable forum for debate in the likes of the Oxford Union, it just shows that Jameson can easily fend off the proggie drivel. : This usually happens when facts are on your side. : Therefore, these trolls should just stop embarrassing themselves. : Oh and November is coming!
(H/T Twitchy)
Also see...
The latest feminist obsession with rape has reached the point where false accusations are now being thrown around loosely. It has resulted in a negative stigma toward men on college campuses, and...
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Matt Vespa is a conservative blogger based in Virginia. Besides contributing to Right Wing News, Vespa writes for RedState, PJ Media, Independent Journal Review, and his personal blog Noodle Pundit. He's also the 2013 recipient of American for Prosperity Foundation's Andrew Breitbart Award For Excellence In Online Activism and Investigative Reporting
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I leaned into a sitting position when I saw a shadow in the corner. It shifted and grew taller, and I saw it was not a shadow, but a man. 636 more words
Tags » Albert Camus
Moving through
Flocks of birds drew my eyes to find the clearing in the overcast February sky in-between 2 concrete city buildings. My body lured, as hope leaped up into my heart. 330 more words
Discovering the Desert of My Soul
( This is a repeat of a previous post but I believe it could be helpful in your Lenten Journey.)
I don't exactly know why, but a few years ago I felt a real spiritual unction to study Christian Mysticism. 884 more words
Vient Ensuite
"Il n'y a qu'un problème philosophique vraiment sérieux : c'est le suicide. Juger que la vie vaut ou ne vaut pas la peine d'être vécue, c'est répondre à la question fondamentale de la philosophie. 37 more words
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"In the program 'The Millennial Pope' Germaine Greer speaks movingly about suffering and God, and I was asked to respond to her cry. Although a self-proclaimed atheist, Greer, with tears in her eyes, movingly expressed her deep appreciation for religious music as a human cry toward a Presence that was 'just not there.' Then, in face of the sufferings of children in Africa, she added, 'If God exists, I hate him.' What could I possibly say in response?" 1,262 more words