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Myeloma Voices

On July 18-19, 2014, the IMF co-hosted the US Myeloma Flow Workshop at the Zuckerman Research Center at the Memorial Sloan Kettering Cancer Center in New York City. There were 24 participating medical centers from across the country plus representatives from the National Cancer Institute (NCI) and US Food and Drug Administration (FDA) in attendance. Attendees included key myeloma experts from the centers as well as technical staff responsible for the running of flow cytometry laboratories. US myeloma experts present included Drs. Vincent Rajkumar, Shaji Kumar, Ola Landgren, Ken Anderson, Saad Usmani, Suzanne Lentzsch, Jonathan Kaufman, Phillip McCarthy, and Andrzej Jakubowiak.

This educational workshop was structured to inform participants about the role of testing for minimal residual disease (MRD) and currently available testing procedures. The main focus was the new automated, highly sensitive flow cytometry method developed by the Spanish team for standardized detection of MRD in myeloma.

The establishment of a reliable MRD test is a key first step for the IMF's Black Swan Research Initiative. The Black Swan Research approach focuses on the use of the best MRD testing to track myeloma at the lowest levels as a basis for treatment decisions to achieve cure. It was therefore very exciting to have the top experts in flow cytometry in the room to assess the value of the new flow test for MRD.

During the workshop's morning session, Dr. Bruno Paiva (University of Navarra, Pamplona, Spain) summarized the importance of MRD testing in assessing treatment outcomes - much as he had done in March at the Salamanca, Spain, Flow Workshop before an audience of 70 global experts waiting to be convinced of the role of MRD testing using flow. After the Spain meeting, the flow cytometrists went home to set up the new method in labs from Germany to Australia. Would it be the same in the US?
Next, Dr. Alberto Orfao (University of Salamanca, Salamanca, Spain) presented to a hushed room. It was clear everyone wanted to hear all the details of the new flow cytometry method he and his team had worked for years to develop, a project that has received IMF support as a key element of the Black Swan Research Initiative.

Afterwards, the usual technical questions emerged and were answered in Alberto's typical calm, complete fashion. An interactive session followed to determine what barriers may exist to the adoption of the new flow method in the US.

As workshop presenter Dr. Brent Wood (University of Washington, Seattle, Washington) would later ask, "What is more important for us? To do our own thing? Or to come together and standardize in a way that is good for our patients?"

The consensus among workshop participants was "Yes, we want to standardize. But how?" Among the practical questions and concerns voiced were the following:

  • Do samples need to be processed in 24 hours?
  • When is the best time to get samples for response assessment?
  • How can we find the time to set up a new method in a very busy laboratory?
  • What about the costs? 
  • We have contracts for the old antibodies--how about the new antibodies?
  • What about the new software which standardizes the analysis and results?

The software for this cutting-edge test is a very important aspect because the cytometer uses eight colors and the results consist of clusters displayed in eight dimensions! If this sounds mind-bending, it really is.  Sophisticated software is required to accurately sort or "gate" the cells and determine which are myeloma cells and which are not! This is the fundamental question the new flow method can answer: are there any myeloma cells left or not--and ARE WE REALLY SURE?

Clearly everyone who attended the flow workshop was eager to have the means to answer to this question, and to be really sure. That left the matter of whether or not the practical laboratory implementation issues can be resolved in order to begin using the new flow method. The workshop participants asked the IMF team to help. There was immediate agreement that every effort will be made to assist labs that are anxious to start the new method, but which face challenges doing so.

After much excellent discussion, a dinner, and a morning session with further questions answered, participants left well informed and highly motivated to implement a new highly sensitive flow MRD method.

In the coming weeks and months, Dr. Bruno Paiva, Dr. Alberto Orfao, their teams, and the IMF team will be at the ready to assist. There is a strong sense of optimism that a reliable MRD test will be available very soon for US patients.

Stay tuned and updates will be posted along the way!

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In the early 1980s, I was testing anti-malarial drugs such as quinine against cultured myeloma cells in the laboratory. We had developed drug-resistant myeloma cells specifically for this purpose. Several lines of research had revealed that resistance to drugs such as Adriamycin (an anthracycline), a key component of the "VAD" (Velcade, Adriamycin, dexamethasone) chemotherapy regimen popular at the time, was mediated by a cell membrane protein called P-glycoprotein, which conferred an MDR (multi-drug-resistant) phenotype. What P-glycoprotein does is pump drugs such as Adriamycin out of the cell - a protection mechanism against cell toxicity. However, in the case of Adriamycin, we want the Adriamycin to stay in the cell and kill the myeloma.

This can be achieved by giving drugs which block P-glycoprotein! I became interested in this because of another drug called verapamil (a cardiac drug which can slow the heart and reduce blood pressure), which blocks P-glycoprotein. I showed that giving verapamil to patients resistant to VAD chemotherapy produced new responses and remissions at the safe doses of verapamil.

Another drug studied was the anti-malarial drug quinine, which had similar effects, but more challenging side effects. SWOG (Southwestern Oncology Group) study #9210 was conducted to evaluate the efficacy of quinine along with the VAD regimen. I was co-chair of the SWOG myeloma committee at that time. Unfortunately, we had to discontinue the quinine/VAD study because of the unacceptable toxicities.

Meanwhile, a much more promising and safe drug called cyclosporine (an immune suppressive agent) proved to be effective in laboratory studies, and a clinical trial was initiated in collaboration with the HOVON group in the Netherlands. Results were published in the journal The Lancet in 1992, with my friend and colleague Dr. Pieter Sonneveld as the first author. Patients completely resistant to VAD chemotherapy had remarkable sustained benefit with remissions lasting nine months or longer in this relapsed/refractory setting. Although a number of other agents were subsequently tested, these results remain the best utilizing this anti-P-glycoprotein strategy. However, with the advent of novel therapies in the later 1990s, we moved away from this MDR-targeted approach.

But be assured the anti-malarials were rigorously evaluated as part of this strategy. Like many other agents, such as alpha interferon (anti-viral agent), there is always the potential for important anti-myeloma therapy in the appropriate setting in the future. These agents are not neglected, only superseded by much better novel agents. Nonetheless, it may be that one of these agents will provide the solution to the complex puzzle which is myeloma and lead to a cure. I still have my P-glycoprotein files and publications - now stored in the cloud somewhere! Stay tuned for any updates, whenever they occur.

 

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

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Questions continue to pour in about measles virotherapy, which I wrote about in my May 22, 2014 blog here. Myeloma patient and advocate Jack Aiello raised an interesting question: "If the massive 100-billion dose of engineered measles (MV-NIS) virus is destroying myeloma, why isn't it also causing a raging case of measles?"

Dr. Stephen Russell of the Mayo Clinic took the time to provide the highly technical answer, which I will do my best to explain. (I have also created a graphic, FIGURE 1, which I hope will help.)

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First of all, it must be emphasized that the measles virus used as the starting point for these research studies was the attenuated strain, the weakened strain used for measles vaccination. This strain has proven to be very safe with very limited potential to ever actually cause measles.

The next step was to take this weakened strain and "morph" it in a different way by growing it on human cancer cells. Viruses need the machinery of a cell to survive. In this case, the measles virus adapted to growing in cancer cells. A main adaption was to use a surface receptor called CD46 to enter the cell. 

It turns out that myeloma cells have many CD46 receptors, whereas normal cells have very few: a 10-fold difference. Myeloma cells infected with virus also develop a "measles attachment protein" on their surface. This leads to the development of large clumps (called syncytia) of joined and fused myeloma cells which subsequently die. Another factor which helps speed up this myeloma cell destruction is that internal cell defenses are not triggered since the engineered measles virus lacks the critical pieces of C and V proteins which normally trigger the defenses.

So there you have it: selective binding and uptake into myeloma cells, and rapid reproduction of virus because of weakened defenses within the cell. 

The opposite is the case with normal tissues. First of all, measles virus is attacked by antibodies in the blood stream (abundant normally after vaccination, but low-to-zero in half of myeloma patients). Then, there is very limited access to normal tissues which have few CD46 receptors. Plus, when virus does enter, internal anti-viral defenses are high and able to eliminate entering virus.

In myeloma cells, the "Trojan horse" filled with virus enters the CD46 gateway and takes over. In normal tissues, virus rarely makes it through the gate--and even then the cell is armed and ready. And what about the HeLa cells used to grow up massive batches of the engineered measles virus to treat myeloma patients? Well, these HeLa cells are a culture of cells from cancer of the cervix taken from a woman named Henrietta Lacks more than 60 years ago. The cells grow in a liquefied suspension culture. The engineered measles virus is well adapted to targeting cancer cells.

This is why myeloma cells are attacked and normal cells escape unscathed. It always helps to understand. Let's hope that more patients can benefit from this carefully crafted strategy. 

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

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The 50th annual meeting of the American Society of Clinical Oncology (ASCO) is in Chicago from May 30th until June 3rd.  Compared to the hundreds of myeloma abstracts presented at the annual meeting of the American Society of Hematology (ASH), far fewer ASCO abstracts focus on myeloma. Nonetheless, there are more than 50 myeloma-related abstracts in various oral and poster sessions during the meeting.

Most abstracts reflect recurrent themes from ASH 2013, including: updates on the anti-CD38 agents daratumumab (Abstract #8513) and SAR 650984 (Abstracts #8532 and #8512); the value of continuous (versus fixed duration) therapy, especially with lenalidomide (Revlimid®) (Abstracts #8515 and #8516); predictive and prognostic testing for patients with smoldering myeloma (Abstracts #8587, #8595 and #8604); comparison of novel agents (Abstract #8511 - MPT vs. MPR); and updates on pomalidomide efficacy (Abstracts #8593 and #8589). Data being presented for the first time are the data on the HDAC inhibitor panobinostat from the Panorama I trial in relapsed and refractory myeloma (Abstract #8510).

Let's start with the panobinostat abstract - for which detailed outcome results are presented for the first time, with Dr. Paul Richardson as the first author. This trial is a randomized phase 3 study of panobinostat vs. placebo combined with bortezomib (Velcade®) plus dexamethasone in relapse/refractory myeloma. The panobinostat significantly improves the progression-free survival (PFS) and duration of response, plus produces higher overall response and especially deeper responses with higher VGPR and/or complete remission (CRs). Important toxicities were increased fatigue, plus platelet-count reductions and diarrhea, which led to discontinuations of therapy in that arm of the trial. There is great anticipation about these results and the implications for potential regulatory review and approval for panobinostat.

Key aspects of the other abstracts presented at ASCO 2014 include the following:

  • Anti-CD38 results: The daratumumab and SAR 650984 results continue to be very promising. For daratumumab, the single agent ("monotherapy") results are excellent with administration at higher dose levels (13 patients were given 16mg/kg vs. 30 patients given 8mg/kg), which gave an impressive overall response rate of 46% in relapse/refractory myeloma. For the SAR 650984 antibody, both single agent and combination (with Revlimid/dexamethasone) results will be presented by Dr. Tom Martin from UCSF, again with very good results. The single agent study showed an overall response rate of 33% at the higher dose of 10mg/kg dose (18 patients). In a late-breaking abstract excellent responses will also be reported, including deep responses, with the combination of Revlimid plus dexamethasone.

  • There is an interesting study in which continuous therapy is compared to fixed duration therapy. Although ongoing or continuous therapy (such as with Revlimid maintenance) is known to prolong remissions, there has been a concern or question that drug resistance might emerge and negatively impact response to later therapies. In the important study to be reported by Dr. Antonio Palumbo (Abstract #8515), pooled results for 913 frontline patients from two trials (one lenalidomide (Revlimid) based and the other bortezomib (Velcade) based) show outcomes with (452 patients) and without (461 patients) continuous/ongoing maintenance therapy. All outcomes assessed were superior with the continuous therapy, including a key new end point PFS2, defined as the time from start of treatment to the relapse from second therapy (therapy at time of relapse from the continuous maintenance). The PFS2 was 63 months compared to 47 months for the fixed duration therapy patients (P value = 0.0001).

There are two conclusions from this study: 1) The longer first remission (PFS 1) is not cancelled by a shorter second remission (reflected by PFS 2), which is actually also longer; and 2) PFS 2 is an important new assessment tool.

In another abstract, it is important to note that Health Related Quality of Life (HRQOL) in newly diagnosed patients improved along with better PFS and OS outcomes with lenalidomide (Revlimid) maintenance therapy (Abstract #8516: MM020 [FIRST] trial). 

  • For smoldering myeloma, the predictive role of Freelite, cytogenetics, gene expressing profiling (GEP) and imaging are assessed in different abstracts, helping refine the potential utility of these techniques. Two follow-up abstracts indicate pomalidomide (Pomalyst) benefit in one case predicting a 14-month added survival benefit and the other showing excellent results in combination with bortezomib (Velcade) plus low-dose dexamethasone.


So, a step at a time we continue to see patient benefits with new therapies and improved ability to diagnose and monitor the disease. We await hearing full details at the final ASCO presentations. Stay tuned: I will include all updates in my post-ASCO report on July 26th.

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This week I had a chance to talk to Dr. Stephen Russell of the Mayo Clinic about the new measles virotherapy findings and the future of virotherapy for myeloma patients, including a virus that may be an even more potent destroyer of myeloma than the measles virus!

While the news about Stacy Erholtz, a 50-year-old myeloma patient at the Mayo Clinic, may have caught the myeloma community by surprise last week, Dr. Russell, along with Dr. Angela Dispenzieri, have been conducting a trial with engineered measles virus since 2006. In fact, he presented preliminary results at the IMF's International Working Myeloma Group (IMWG) Summit in London in 2011. At that point however, the patients were being treated with lower doses of the measles virus. About three patients per year were entering the study and no responses were seen. 

Then, in May 2013, Stacy was treated with the massive 100 billion dose - equivalent to enough measles virus to vaccinate 10 million people! - and everything changed.

A first patient at the 100-billion-dose level had the intravenous infusion stopped after five minutes because of severe headache. Stacy, the second patient at this dose level, also developed a bad headache, but was able to complete the one-hour infusion. There was a lot of anxiety about possible side reactions. Her temperature spiked to 105°F and she developed shaking chills, which continued over the next two to three days. She also developed surface inflammation at the site of infusion in her left arm. Her blood platelets and white blood cells (lymphocytes) dropped significantly. But dramatically, after 36 hours, the plasmacytoma (myeloma lesion) on Stacy's forehead started to shrink!

A Very Special Patient

Within the first week, her Freelite level dropped. By six weeks, her forehead plasmacytoma had disappeared and the Freelite level plus bone marrow had returned to normal: her marrow was MRD negative according to a flow test. A PET/CT continued to show active myeloma at several sites (in the clavicle, sternum, and T11) but at a much reduced level. By seven months, Stacy's PET/CT was fully negative. As can be imagined, everyone was thrilled.

However, by nine months, her forehead lesion started to grow back. But, there were no other lesions anywhere. This lesion has been treated with local radiation and Stacy is again without evidence of active disease. There will be follow-up testing in June 2014. Thus, a fantastic response, but certainly not a "one-shot cure" yet.

Stacy is a special patient who had myeloma confined to her bones and did not have antibodies against measles in her blood stream. 

How Measles Virotherapy Works Against Myeloma

Of the 31 patients who are part of this measles virotherapy program, about 50% have zero or very low antibody levels. This means that when the engineered measles virus is injected intravenously, it is not immediately destroyed -- as it would be in a patient who had high antibody levels -- and travels to "infect" the myeloma cells. Once in the myeloma cells, the virus "takes over": it divides and divides and divides!! This destroys the myeloma cells (which basically explode), and virus spills into the marrow microenvironment infecting surrounding myeloma cells. 

The virus also activates the local immune system to help "mop up" residual disease in that area. So, this process seems to have worked very well for Stacy and is a tremendous "proof of principle" outcome for her. This type of systemic (whole body) virotherapy can work.

Six patients have now been treated at the massive 100-billion-dose level in two "cohorts" of three each. The second patient in the second cohort also had some response, but to a much lesser degree. This patient also had low measles antibody levels but was rather different in that myeloma was located in muscle tissue outside of the bone marrow.

The toxicities were similar in this second patient, and there was definite uptake of the measles virus into the plasmacytoma tissue documented by nuclear scan. There was also pain at the sites of the plasmacytomas, which seemed promising. But although there was some reduction in Freelite level, by day 45, the level had bounced back up, and the myeloma was clearly progressing again. So quite disappointing compared to Stacy. Of note, this patient has since had an unexpectedly good response therapy using Velcade/Revlimid/dexamethasone.

Next Steps

Treating more patients is the obvious next step. But this is more easily said than done. To produce (manufacture) enough engineered measles virus to treat a patient with the massive dose requires a culture of Hela cells (written about in Rebecca Skloot's bestselling book, "The Immortal Life of Henrietta Lacks") in a 75-liter vat. It takes time to grow up enough virus, then purify, safety check and prepare for intravenous injection. It is estimated that a new larger trial can start by September this year. To treat 100 patients in a trial will require 1,000 to 2,000 liters of cultured cells! For this huge operation a commercial company with a dedicated facility will be used. This is a very expensive project which will cost approximately $50,000 per patient for the massive measles dose. With bulk processing the price will no doubt decrease, and the goal is to achieve a price point of $5,000 per dose.

Dr. Russell openly discusses the magnitude of the project and the commitments which are needed to move this project rapidly forward. The stunning result with Stacy opens many possibilities for further trials.

Other Viruses

Other viruses have been discussed with potential advantages over the engineered measles virus. The measles virus is safe and has been used for many years and thus is very attractive from that standpoint. Another virus, vesicular stomatitis virus (VSV), however, has some attractive features. Since it causes blistering around the mouth, there is no systemic (whole body) antibody response. All patients can be expected to have zero antibodies. In addition, in a model where it is possible to compare, the VSV works faster and is definitely a more potent (in destroying myeloma) versus measles virus. For these reasons, a new protocol with VSV is planned by Dr. Russell and has been submitted to the FDA for review. Feedback is awaited. The clinical lead for this new protocol is Dr. Martha Lacy. Dr. Dispenzieri will continue as the clinical lead for the measles protocol.

Thus, despite many challenges, there is considerable optimism that virotherapy is a dramatic new way forward to treat myeloma using a completely different approach. It may or may not ever be a "one-shot cure" but maybe a "one-two punch" in which follow-up radiation or other therapy can provide a "knock-out" blow. Ideas for further research include ways to increase the number of myeloma cells taking up virus (to 100%, if feasible) and to enhance the local immune "mop-up" process. In addition, as for all novel approaches, combining with/or integrating into other treatments/protocols can undoubtedly improve outcomes.

Dr. Russell will discuss his results at the upcoming IMWG Summit in Milan, Italy. A very lively discussion is expected as the gathered myeloma experts will consider the ramifications of this successful systemic virotherapy breakthrough. 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 hotline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.

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This is such encouraging news..I am in my 60's and was diagnosed with multiple myeloma in June, 2012..It was detected inadvertently. I was experiencing pain in my right groin, thinking I might need a hernia repair..Summarizing events after scan not knowing what was wrong and testing done, it was discovered that I had MM and the numbers didn't look good, although, no organs were involved and I was otherwise, in excellent health. My saintly Oncologist, found me while in hospital and several days after discharge was started on Velcade and Dexamethasone...After the first round of chemo, the numbers dropped dramatically...We thought a possible fluke and wanted the test run again..It wasn't a fluke...The numbers kept dropping and am in total remission. It's been two years now...I have had a couple of surgeries since, unrelated to the myeloma and recovered quickly...I am a nurse and although not working at this time, I get calls from acquaintances that either have cancer or think they might have myeloma to ask me what to do...I am so happy to hear of other treatments that are successful..Thank you for sharing..

Dr. Durie,

Hello, I appreciate your insight into these exciting times with virotherapy. My search continues, and I am most hopeful. My follow up yesterday 5/21 was very encouraging, including my discussion with Dr. Jan Morab, who after soliciting his insight on virotherapy, brought to light his own research. He co-authored "Selective Purging of human multiple myeloma cells from Autologous stem cell transplant grafts using oncolytic myxoma virus" which by his indication Phase 1 is very near. Yes, indeed these are exciting times and a cure will be possible.

All the best,

David Vermillion

Dr. Durie,

Thank you so much for the complete review of the virotherapy breakthrough. Friends have been sending me notes and links but the information has been incomplete, at least until I found the Mayo site. Your review is very much appreciated.

Until Myeloma retired me I was in the soap manufacturing business. Soap making begins in an 8,000 gallon stainless steel tank. Wish I could make one available to grow measles virus.

We've met at two Myeloma patient seminars. I am grateful for the commitment you and Suzie have made to Myelomics.

Michael Lapides

ALRIGHT! Glad to hear our immune systems get to work on this! I am still going up and down with the Thalidomide family of drugs--How do we find out about signing up for a trial on this? Do we need to save up $50K so we can participate???

Thanks so much for clarifying the information about the measles virus. I hope something is found that works while I'm well enough to get it.I really appreciate your blog and Myeloma Minute talks.:-)

Dr. Durie,

I am Kerim Ustunel's daughter, a multiple myeloma patient diagnosed in August 2011. He told me you two met in Istanbul-- his doctor is Dr. Burhan Ferhanoglu and that you even examined him both in Istanbul and Rome back when he was first diagnosed. As time flies, he went through lots of things - his disease turned into secondary plasma cell leukemia last summer and he miraculously overcame a severe pneumonia. After recovery from the pneumonia, Dr. Ferhanoglu had started the VDT-PACE treatment for two consecutive cycles and at the end of the second cycle, which was back in September 2013, we travelled to Rochester, Minnesota where we currently are now.. Under the decisions and guidance of our doctors at the Mayo Clinic, Dr. Rajkumar and Dr. Shaji Kumar, my father underwent an allogeneic bone marrow transplantation from an unrelated donor (9/10 match) in November 2013. The 100 day period was tough, but thanks God he is OK now, presenting some little GVHD signs (skin rash and mouth/eye dryness).. His Freelite levels started to rise a bit couple of weeks ago, so our doctors made him take Velcade once a week for 6 times in total. Dr. Kumar foresees to apply a T-cell infusion (of the donor) but we are in the phase of patience right now, as my father developed some GVHD signs that might hopefully decrease the Freelites to a total cure..

I just wanted you to have an idea of the current situation and my question is if my father would be a candidate for these developing virotherapies, as he underwent a bone marrow transplantation..

Thank you very much for your time and sharing these exciting news!

All the best,
Belis Ustunel

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The IMF is very pleased to see research from Dr. Stephen Russell at the Mayo Clinic achieving success and starting to make a difference for patients. Dr. Russell presented the concept of this approach to International Myeloma Working Group (IMWG) members at our annual summit in London in 2011. I wrote about the "one shot cure" approach in this blog post.

This is a very attractive new approach shifting from chemotherapy and novel therapies to a one-time decisive attack on the cancer, recruiting the body's immune system to do the cleanup job. The measles virus is just one of several being tested for this treatment strategy. This "virotherapy" must be individualized depending upon the patient's prior virus exposure.

In the current report on Dr. Russell's research, one patient has had dramatic benefit--which continues at the present time--the other patient, a temporary response. These patients had limited prior measles exposure. Dr. Russell is looking at other viruses which may be even more effective.

This initial 'proof of principle' is very encouraging. We must have patience--this type of research takes time and must be conducted very carefully to avoid/reduce safety concerns at each step, including safety studies in animals.

Congratulations to Dr. Russell for this initial success--we look forward to ongoing good news.

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

2 Comments

Thanks for tackling this news, Dr. Durie. It's all the rage in raised hope.

Just reading this for the first time, go my news of relapse today, unfortunately. Original diagnosis was may 2012, treatment was dex, velcade, and revlemid, then stem cell transplant. Been in remission until today.was on maintenance for almost 1 you velcade.just had 6 more break from all drugs been great for me but I guess I should not have stopped. Just wanted to know if new drugs since my diagnosis would get me back to remission for a longer period or just use what I was on before, did cause severe neuropathy in the legs.thank you for all the information, back to the fight for life!!

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As a great fan of Julia Child, I was very pleased to read Mark Bittman's Op-Ed in the New York Times on March 26th: "Butter Is Back." Bittman's piece is based upon a new article in the Annals of Internal Medicine assessing the negative impact of fats in the diet. Researchers from the UK assessed 72 different studies using a methodology called "meta-analysis" whereby many studies can be cross-compared and analyzed together.

The bottom line is that there is no evidence indicating that saturated fats increase the risk of heart disease. This means that there is no clear negative impact caused by natural fats such as butter--which is great. But how can this be? And if we translate this into best diet suggestions for a myeloma patient, what can be recommended?

 

As Mark Bittman points out, our attention now needs to shift to the true culprits in diet--sugar  and ultra-processed foods, such as margarine--instead of "Real Food" alternatives like butter or fat in meat or chicken. So-called "low-fat" carbohydrates (snack foods) are key factors in contributing to being overweight or obese.

 

And this is where the focus really shifts to myeloma, for which being overweight is a clear risk factor. An important new article contributes to the growing literature linking obesity to an increased risk of myeloma. This study from the University of Texas shows that a cytokine (growth hormone) called adiponectin can reduce myeloma cell growth. But with obesity the adiponectin levels drop really low, thus releasing the myeloma for more active growth. There is thus a very important feedback loop whereby in the absence of obesity adiponectin can keep potential myeloma growth in check. Thus, trying to stay trim is definitely helpful and healthy. There are even data that show staying fit and active can slow the aging process.

 

A truly fascinating new study suggests that there may be additional ways to slow or even reverse aging: rejuvenating your brain and your body. study from the University of California, San Francisco (lead author Dr. Saul Villeda) shows that giving blood from a young animal to an older animal can counteract and reverse the effects of aging.  Although a variety of effects, including improvements in the immune system, have been noted in the past, this particular study focused on brain functioning. There were definite benefits and improvements. The intriguing question is why? What is it in young blood that can reverse aging?

 

The answer is fascinating because it involves the sirtuin/CREB signaling pathways--the ones impacted by resveratrol present in red wine, which has also been linked to anti-aging properties! Obviously much more work is needed, but the implications extend from the role of blood transfusion, neurobiology, and aging, to what constitutes a health diet, which can help keep your blood and body young!

For now, some simple recommendations remain the same. It is entirely possible to eat better right now, as Mark Bittman said in his May 6 Op-Ed, "Leave 'Organic' Out of It." Eat "Real Food" and natural drinks (include some red wine, if that is allowable in your situation), and be positive about all the new advances in understanding and novel treatments as they become available.

As usual, stay tuned for all new developments.

 

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

3 Comments

I was obese all of my life until 22 years ago when I took off about 145 lb. and have kept it off since, except for one relapse about 10 years ago but have been back in a 107-110 body now for over 9 years. After reading this info I wonder if those 52 years of being overweight and many times grossly overweight, didn't contribute to the Myeloma which was diagnosed only about
2 years ago. at age 71, female, caucasian. Thanks for the info.

Thanks for your translating of this important data.

Are you able to comment on Ingrid Winkler's work on HSCs and her ability to protect normal bone marrow cells during chemotherapy? - see https://www.nhmrc.gov.au/research-highlights/profile/associate-professor-ingrid-winkler

What are the implications for mm, if any, and how soon might those benefits be generally available?

Keep up the good work!

Guy

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DurieBlog_China2014.pngThe IMF Asia Pacific team members just returned from China, where we participated in the annual activities of the IMF's Chinese Myeloma Working Group (CMWG). The team that was in China for the April 9-13th educational events included Dan Navid (Senior Vice President, Global Affairs); Lisa Paik (Senior Vice President, Clinical Education & Research Initiatives); Susie Novis (President) and myself.

The annual the patient seminar this year was held at Zhejiang University 1
st Affiliated Hospital in Hangzhou, about one hour by train south of Shanghai. As in previous years, it was an amazing, heartwarming and heart-wrenching program. The meeting was hosted by Prof. Zhen Cai, a member of the CMWG, and approximately 200 patients and family members participated.

It was wonderful to have a chance to meet the "myeloma doctor team" taking care of patients at Zhejiang Hospital, including graduates of the IMF's Myeloma Master Class.

The meeting began with formal presentations by Prof. Cai, along with the head of nursing services for this 3,000-bed hospital! Ne
xt, the Q&A session began, and with the help of a translator, I launched into a couple of prepared questions. A few hesitant patients began asking questions. That opened the door, and then they really got rolling--it turned into a very lively session! Patients and caregivers were waving their hands, anxious to have their questions answered. It was an avalanche of questions from the audience that went on for more than an hour, until time was called. Off-stage "sidebar" questions continued until I left the hospital about an hour later.

The experience reinforced something I've emphasized many times in the past - "patients are patients" no matter where they li
ve--in China, the US, Europe, or even in Outer Mongolia (where I've actually received questions). In essence from everywhere. Patients want to know: How do I know the treatment is working? Should I switch treatment or continue maintenance? Should I have a stem-cell transplant? Will there be trials for some of the new treatments? Is my father going to be okay or should he fly to the US right away?

The basic treatment available in China is remarkably good. Typical first therapy is CyBord (cyclophosphamide, bortezomib and dexamethasone), followed by a single auto-transplant and thalidomide maintenance. As evidenced in
our recent database report from Asia and discussed in our Asia Myeloma Guidelines, overall outcomes are remarkably good. The major concerns and challenges occur when standard treatments fail. However, the back-up options are limited. Access to trials and the novel agents is definitely limited - as is unfortunately the case globally outside the US. Thus, the IMF is committed to work through the CMWG and our AMN colleagues to enhance trials and access as much as possible.

After a break for lunch we headed to further meetings, the most notable of which was our annual CMWG "summit" meeting. We discussed ongoing activities, presented this year by Prof. Jian Hou from Shanghai, and then I reviewed the opportunities for t
he implementation of the Black Swan Research Initiative in China. There is great interest and enthusiasm about BSRI. A key point is that the new flow cytometry test for myeloma (which I wrote about here) will be feasible in China, since several centers have flow cytometry available. We discussed the rollout and testing plans to incorporate the new flow cytometry method. A meeting will be held in China, similar to the one we recently held in Salamanca, Spain. This will provide a full education in China about the new cytometry method for assessing disease. Similar meetings will be held later this year in the US and Europe.

It was exciting to see how, once again, the same ideas, hopes and expectations are similar in China as elsewhere. Susie is right - we are "
One Myeloma Nation"! The solutions will come from global efforts by the IMF, CMWG, IMWG and colleagues and friends around the world - whether they be in Hangzhou, Heidelberg, Los Angeles, Nantes or who knows where! Networking with local experts is essential. Progress, thankfully, is inevitable and happening every day.

Stay tuned as we keep you abreast of exciting updates as they occur.

 

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

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

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

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

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

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

5 Comments

after the Flow Cytometry test how does one know if the myeloma is hiding somewhere else in the body besides where it was tested. Is it a complete test or only a really really good guess?

Will this flow test need to be approved by the FDA before it can be used on a wide spread basis by all myeloma specialists?
How soon could patients expect to see this in everyday use?

Could the Flow Test Cytometry test be a viable method to track those with Non-secretory Multiple Myeloma?

Is this the same as the MULTI parametric FLOW CYTOMETRY (MFC) used at Mayo Clinic?

The Mayo team is introducing the new method now.

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A recent editorial in Leukemia authored by doctors Shaji Kumar and Vincent Rajkumar of the Mayo Clinic in Rochester, MN, provides a thoughtful overview of the current status of minimal residual disease (MRD) assessment in myeloma. In it, the authors raise three questions: What are the implications of MRD negative status? What is the best method to measure it? And what do the results mean for treatment?

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

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

A Promising MRD Testing Method

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

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

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

MRD Testing and Treatment Strategies

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

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

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

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

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

MRD is interesting but to the layman what is the definition ? I can guess that there is an indication that Multiple Myeloma, which my wife has, no longer shows as a cancer in a treated patient. But there somehow lies the cancer in a somewhat dormant state. So, though the there is no apparent indication of MM Cancer, there lies some residual low level cancer which can be detected through a special test.
Please let me know if this is correct and how MRD is detected in a patient.

Thank You

Is it possible for anyone (aka me) to read the full Kumar-Rajkumar editorial?

I want to share with all myeloma patients that my father is cancer free of myeloma
After taking Alpha lipoic acid. This natural antioxidant is cheap and effective.
He was very close to death. After two weeks of taking two capsules a day the
doctor couldn't find cancer cells on the blood test. We never told the doctor
because he never aloud any suggestion that we ask him. Well this time
my father felt that he had to take a chance. It never interfere with the doctor therapy .
You can't go wrong to try it. Best wishes to all.

Hi Omar,

Good to know about your dad. Can you tell me what stage of Myeloma was your dad in and what treatment he was undergoing? Is it okay to still take Alpha lipoic acid if Velcade is already used for treatment?

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