We are international
Donate

Recently in Dr. Durie's Blogs Category

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.

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.

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. 

DurieBlog_Ikaria.jpg

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! 

ASH2014.jpg

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

ASH2014.jpg

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.

DurieBlog_Stemcellv2.jpgMore than two dozen experts from around the world gathered in Minneapolis, Minn. Oct. 27, 2014 to assess the current landscape for autologous stem cell transplant (ASCT) as an option for myeloma patients who have relapsed. "Salvage" transplant--despite its rather gruesome-sounding name--offers an effective treatment choice for patients who have had a positive prior response to transplant.

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:

  • A need to summarize current knowledge
  • Risk stratification of patients at relapse
  • Assessment of the role of minimal residual disease (MRD) measurement after ASCT in the relapse setting
  • Studies of ASCT at different time points
  • A need for comparative effectiveness research (ASCT at relapse versus other options)

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

DurieBlog_PanaV2.png

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!

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

IMWG+tagline 2014-lyrs_a1_Thumb.jpg

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.

The 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 HERE

DurieBlog_Cure.jpg

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

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

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

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

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

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