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The answer is a definite maybe! As myeloma evolves, it does so within the complex immune microenvironment of the bone marrow. The most well-known impact is the reduction in normal plasma cells and reductions in normal immunoglobulin production, causing reduced normal gamma globulins as part of the SPEP (serum protein electrophoresis) pattern. But there are many other effects of the disease which result in reduced or abnormal immune responses. The most well-documented feature of myeloma is the reduced ability to fight infections. Fortunately, this is often not too severe, despite reduced immunity and immunoglobulin levels, while some patients with recurrent infections can benefit from intravenous gamma-globulin infusions, others may benefit from ongoing antibiotic use.

So how can normal immune function be recovered in myeloma patients? This has been extensively investigated for several decades. For example, when it was first demonstrated that interferons (α and β) were helpful in myeloma treatment, chemicals (such as poly ICLC) were developed to trigger the body to produce more helpful interferons. This proved to be of limited value because the immune system became exhausted: only so much interferon could be produced. Likewise, many vaccine approaches attempting to trigger the immune system to reject the myeloma failed because complex inhibitory factors could not be overcome.

Now we have many new immune approaches emerging. One that is the farthest along is elotuzumab (anti-SLAM F7 monoclonal antibody), which triggers natural killer (NK) cells in the bone marrow to attack myeloma cells. This antibody has not worked by itself, but is working well in combination with Revlimid® plus dexamethasone, as well as with Velcade® and dexamethasone (in smaller studies). It seems that increased destruction of the myeloma, which occurs with the combination approaches, is key. This is also what we are seeing with the anti-CD38 monoclonal antibodies (daratumumab, SAR 650948, and MOR 202). With these anti-CD38 antibodies, there is direct killing of the myeloma cell plus recruitment of surrounding NK cells and macrophages to help mop up damaged myeloma cells.

So what we are seeing are new immune methods to reduce the myeloma rather than just modulate the immune response. Reducing the myeloma is actually the key to success. Reducing the myeloma decreases production of all the complex immune inhibitor factors and allows the immune system to bounce back. In patients who have excellent response, after ASCT, we see bounce-back of the normal plasma cells with production of mini monoclonal spikes (called oligoclonal spikes), which is a good sign - actually a very good sign - excellent response and potential long remission. Another feature of the recovering immune system is an increase in T-lymphocytes, which produce interleukin-17 (IL-17): these are called Th-IL-17. This is not something that is normal. This is a reaction to myeloma and successful treatment. Whether this reaction can be usefully enhanced has not been investigated. Whether additional immune enhancement can convert excellent response to cure is a tantalizing but unanswered question.

So is it possible to boost the immune system? Yes, by treating the myeloma and removing inhibitory factors! Whether tweaking, triggering or enhancing the immune system as a sole form of treatment can work remains to be seen. But it is very exciting that immune methodologies are providing a new way forward and allowing us to understand how immune manipulation can help. I am sure there will be many updates to come on this topic! 

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 the current issue of the Mayo Clinic Proceedings, Hagop Kantarjian, MD and S. Vincent Rajkumar, MD discuss the high cost of cancer drugs and propose some solutions. The high cost of cancer drugs is widely known. Unfortunately, this new article does not provide solutions that have an immediate chance of implementation and/or success.

For example, the authors propose government action to allow Medicare to negotiate on drug prices, which is unlikely to occur in the current political environment.

What is needed instead, I believe, is a discussion involving all the stakeholders--pharmaceutical companies and insurance carriers, but also health economists and policy advisors to mediate and guide the discussions. In this setting, realistic solutions can hopefully emerge which transcend finger-pointing. We need specific action items and, since each cancer is different, we need recommendations tailored to the myeloma community. This requires input from both myeloma doctors and patients.

Focus on best outcomes

What constructive suggestions can be made by the myeloma community? First, I would argue, there must be a focus on the best outcomes. It is helpful that we now have a focus on earlier diagnosis, which leads to more decisive treatment choices to achieve the maximum response. For example, triple therapy to achieve VGPR or ≥ CR or even MRD negative status is highly feasible. An optimal treatment package, a pathway or guideline, can be developed incorporating induction, ASCT if appropriate and consolidation and/or maintenance.  We  can lower the cost of myeloma treatment by creating a competitive environment in which physicians see best outcomes, patients can opt for a tolerable and effective approach, and regulators can see a manageable cost structure with clear value.

A drug holiday?

An increasing subset of patients can achieve CR or better and avoid indefinite treatment. We already know that good risk patients achieving excellent responses can be safely followed off therapy. The result?  A treatment-free interval - a drug holiday - a sought-after goal for many patients, which is also attractive to regulators who manage total costs. For now, many patients need and benefit from ongoing therapy. For those patients, a price structure is needed that does not confer a huge burden on the individual or the healthcare system. This is where creative solutions are required.

Another question that must be raised in any discussion of cancer drug costs is: What do we do about drugs that offer only limited increases in survival at significant costs and toxicities? There must be a way to prioritize the search for new drugs that really make a difference - those that achieve improvement in survival of years, not months. It is to everyone's advantage to improve both outcomes and value. Such drugs should receive a competitive edge.

Clearly, costs cannot continue to skyrocket. Good health is not a commodity like a widescreen TV. A widescreen TV can sometimes fit in the family budget. But, healthcare costs must fit within both the family and total healthcare budgets. Yes, profits to recoup drug discovery and development are fair. But there has to be a limit that stops short of bankrupting the whole healthcare system.

How to achieve this in an equitable fashion is the challenge - but a challenge which we can no longer ignore. All parties must work together to come up with solutions which work and can be implemented.

If you have ideas about what can work, let us know. At the IMWG Summit in June, a working group will debate the topic. But there must also be many great ideas out there which can help chart a way forward. So let the dialogue begin!

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.

On Saturday and Sunday, the IMF was honored to chair a workshop in Tokyo, Japan, which introduced Next Generation Flow Cytometry to more than 160 researchers and technicians eager to learn about this super-sensitive automated new myeloma measuring method.

Next Generation Flow (NGF), as I've written about here, here and here, was developed with the support of the IMF's signature Black Swan Research Initiative® and is a crucial step in our ability to chart a pathway to a cure. (Watch IMF's video about the groundbreaking new technology here.)

Susie Novis, IMF president, welcomed workshop attendees on behalf of the organization, and was followed by Hirokazu Murakami (current President of the Japanese Society of Myeloma) and Kenshi Suzuki (Deputy Director of the Red Cross Medical Center), who greeted the audience and thanked the IMF for organizing the workshop. The opening session was co-chaired by myself and Dr. Kazuyuki Shimizu. Dr. Hiroyuki Takamatsu of Kanazawa University set the stage for the presentations to come by describing the perspective of minimal residual disease (MRD) testing in Japan.

Up to now, the key effort in Japan has been to assess NGS (Next Generation Sequencing), which measures MRD using molecular data. As such, Dr. Takamatsu presented a recap of his NGS presentation at the ASH 2014 meeting in December in San Francisco. However, Japanese investigators at the workshop were very keen to hear about Next Generation Flow testing, which can be equally sensitive and much more practical for broad use in Japan.

Throughout the day, Dr. Alberto Orfao of the University of Salamanca in Spain and Dr. Jacques van Dongen of Erasmus Medical Center in The Netherlands examined the current, conventional flow methods of detecting MRD in myeloma as a backdrop to their presentations on the Next Generation Flow technology details, including panel design, data analysis and interpretation, and cross-platform applicability. The day's closing remarks (by myself, Dr. Orfao and Dr. van Dongen) concentrated on the vast improvement in disease detection NGF represents.

It was really heartwarming--and very much appreciated--to hear Dr. Takamatsu, who started the day talking about NGS, tell Dr. Orfao: "I am convinced about the sensitivity and practicality of the NGF method, and look forward to implementing NGF at my center as soon as possible!"

In addition, Dr. Suzuki indicated similar enthusiasm and a desire to adopt the NGF broadly for JMS investigators.

The Japanese were actually the first to hear that based upon the most recent testing, the new NGF method is even more sensitive than originally anticipated: able to detect one myeloma cell in a million or even one in 10 million! In addition, as Dr. Orfao explained, the computer software program for automatic data analysis has been improved since our last workshop was presented in New York at Memorial Sloan Kettering Cancer Center, with a data analysis time of now only 12 minutes--reduced from several hours! This means that samples can easily be analyzed with same-day results, which is a huge advantage.

On the second day of the workshop, participants attended "hands-on" training, courtesy of Juan Flores-Montero of the University of Salamanca. Dr. Suzuki had done a fantastic job in facilitating the "hands-on" session, which went very smoothly and generated tremendous interest from the participants. Especially helpful was a practical, step-by-step video, subtitled in Japanese, which had been prepared in advance by the Salamanca team to demonstrate sample preparation.

Members of IMF's Asian Myeloma Network (AMN) from Japan, China, Korea, Singapore, Taiwan, and Thailand engaged in a spirited discussion of the role NGF might play in their respective myeloma treatment practice and research.

Speaking on behalf of the AMN team, Dr. Wee Joo Chng said that the new NGF method represents a major step forward for the myeloma community and provides a reliable, accessible method for routine MRD testing throughout Asia. According to Dr. Chng, who chairs the AMN Clinical Trials Group, the plan is to integrate NGF into upcoming trials.

The IMF's Tokyo Next Gen Flow Workshop ended on a very positive note, with plans to move forward in the near future. The concrete plans at the end of the workshop were many, ranging from multiple individual contacts with the visiting NGF team as well as broad commitments for collaborations with the JMS. Dr. Kazuyuki Shimizu, past President of the Japanese Society of Myeloma and Chairman for the IMW Congress held in Kyoto in 2013 noted that: "Now I believe most Japanese doctors can understand the importance of NGF... I believe that the landscape of the [use of] flow testing in Japan will be changed." So stay tuned for further developments!

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I continue to receive thoughtful comments on my recent blogabout crowdfunding. This new approach to fundraising deserves careful consideration with an equally thoughtful response to those who have taken the time to write.

Finding a cure for myeloma requires a coordinated effort. It is like solving a complicated puzzle. Although each individual effort helps and every dollar counts, I believe it is better to work together to reduce the possibility of wasted time and effort. What has been an issue up to now is that many investigators have focused on the same part of the puzzle leaving many other parts incomplete. Looking at the whole picture provides the perspective to assign efforts appropriately and utilize the best expertise of individual investigators.

Collaboration makes a huge difference in finding the answer faster. The IMF, the International Myeloma Working Group (IMWG) and the Black Swan Research Initiative® provide a framework within which all interested parties can contribute, suggest new parts of the puzzle to solve or to contribute to ongoing active areas of research.

It has been amazing to learn from open discussions that many parts of the puzzle are completed and to avoid duplication of effort it is important to focus efforts elsewhere.

Collaboration, communication and a team effort bring knowledge and energy to this effort to achieve a cure, which will undoubtedly succeed.

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.

This week's news of interim results from the ENDEAVOR trial, a head-to-head comparison of "real world" schedules of Kyprolis versus Velcade, reveals an impressive benefit of carfilzomib over bortezomib in relapsed myeloma. Indeed, the 929-patient phase III trial showed a progression-free survival (PFS) of 18.7 months for Kyprolis versus 9.4 months for Velcade--basically a doubling of PFS or remission duration.

In the ENDEAVOR trial, Kyprolis was given in the usual schedule of two IV infusions per week for three out of four weeks, with dose escalation to 56 mg/m2. Velcade was also given according to the standard schedule, with subcutaneous (versus IV) administration allowed at the discretion of the investigator. (Sub-Q administration occurred more than 75 percent of the time.)

The results in this large trial follow on the heels of the impressive results in the 792-patient ASPIRE trial, which showed the superiority of Kyprolis plus Revlimid/Dexamethasone (Rd) over Rd alone. A head-to-head comparison of Kyprolis versus Velcade in the frontline setting is ongoing in a trial by the Eastern Cooperative Oncology Group (ECOG). Impressive results with the Kyprolis/Rd combination in the high-risk smoldering myeloma (HR - SMM) setting were presented at the 2014 Annual Meeting of the American Society of Hematology (ASH).

A strong case is emerging to place Kyprolis within the treatment paradigm for myeloma. One must applaud Onyx/Amgen for the direct comparison trials, which allow assessment of both efficacy and toxicity (concerns over which hampered panobinostat's initial approval in 2014). In the case of Kyprolis, although there are some increased toxicities versus Velcade--including cardiac and renal issues as well as dyspnea and hypertension--these certainly do not preclude use of the drug with normal cautions. Although oral formulations of both Kyprolis and Velcade are in development, it seems their primary role will be in the ongoing therapy or maintenance settings.

Kyprolis is already under review by the FDA in the one-to-three relapse setting based upon the ASPIRE trial results. Future reviews will likely consider the other settings in which Kyprolis can add value--from HR-SMM, frontline, and early relapse to the already approved relapsed/refractory situation. The increases in both depth and length of remissions are definitely important. The twice-weekly IV schedule is a challenge for patients and there is much interest in the ongoing once-weekly schedule study results.

Full data from the ENDEAVOR trial will be submitted for presentation at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting. In the meantime, this important emerging option is great news for patients. As always, it takes time to determine the best new treatment paradigm--but head-to-head comparison data help considerably. Stay tuned for what will be many updates to come.

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

In a surprise move this week, the US Food and Drug Administration (FDA) approved Farydak®, despite the 5-2 vote by the FDA's Oncologic Drugs Advisory Committee (ODAC) recommending against approval in November 2014. The approval is obviously good news for the myeloma community. There is an unmet need for new active agents.

It appears that the FDA circumvented the prior controversy regarding less than impressive efficacy and some serious toxicities by focusing on a pre-specified subset analysis of patients treated previously with bortezomib and an iMiD (thalidomide and/or Revlimid ®). For these 193 patients, the median progression-free survival (PFS) was 10.6 months for the panobinostat combination versus 5.8 months with placebo: a 4.8 month advantage. This trumped the prior numbers which ranged from 1.7 to 3.9 months of PFS benefit. The overall response rate was also higher: 59% versus 41%.

The FDA handled the serious toxicity aspect using a "Boxed Warning" approach with a specified Risk Evaluation and Mitigation (REMS) plan for severe diarrhea and potential severe and fatal cardiac events, arrhythmias and ECG changes. The side effect profile is thus acknowledged with warnings about how to best prevent or alleviate these problems.

The willingness of the FDA to consider Farydak® in this fashion is very positive, I think, as it makes agents available that confer some benefit in the randomized trial setting as long as use is accompanied by careful risk assessment. This is preferable to either disapproval or a much looser "compassionate use" protocol prior to adequate efficacy/risk evaluation, such as what is proposed in the so-called "Right to Try" legislation that has passed in some states. So, kudos to the FDA for choosing this middle ground and trusting the treating physician to be aware of the efficacy profile and the "Boxed Warnings." It is certainly hoped that judicious dose reductions of panobinostat as needed will be accompanied by retained efficacy and a reduced side effect profile.

For relapsed patients, each new response is a blessing; each new response is a bridge to further new options. Let's be optimistic that several new agents in the pipeline will likewise receive approval and be available in the most appropriate relapse niche. 

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

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

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

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

Implications of drug approvals in 2015 and beyond

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

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

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

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

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

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

*February 20, 2015 UPDATE:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.