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Myeloma Voices

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After more than10 years of progress in myeloma treatment due to the introduction of the novel therapies, researchers now need to know how to eliminate the myeloma cells that remain after current therapies. Today, we are on the brink of having a test that will help us have a clear plan to eradicate residual disease.

The new highly sensitive and extremely accurate flow cytometry test developed with the support of the IMF's Black Swan Research Initiative by Spanish researchers is that test.

It is proving itself to be the most affordable, most sensitive, most easily accessible MRD test yet, and earned near-unanimous acclaim from researchers at a flow workshop co-hosted by the IMF at Memorial Sloan Kettering Cancer Center (MSKCC) in July, as I reported in my blog here.  Asked by an audience member, "Can one of the fluorescent dyes (fluorochromes) used in the FLOW MRD test be changed or improved?" Dr. Alberto Orfao, the FLOW MRD test developer from Salamanca, Spain, said, "Of course - possibly yes!" But these types of tweaks can be never ending, added Dr. Orfao.

 "Do we have a test right now which is working very well? The answer is: YES," said Dr. Orfao. "It is standardized, reliable and sensitive enough at the 10-5 level. Nothing more is needed. It is time to stop tweaking and move forward with full validation in patient trials!"

As readers of this blog are no doubt aware, some in the myeloma community argue that we need a DNA sequencing [molecular] test for MRD in the bone marrow. The main potential advantage of the molecular test, they contend, is greater sensitivity versus flow. However, the new flow method is now equally sensitive and provides excellent prediction of very good patient outcomes. I would add that a more sensitive test might encourage overly aggressive, unnecessary treatment, causing more harm than good!

To be sure, careful comparisons of molecular and flow testing are essential. But after careful consideration of all the pros and cons of each method, the IMF's Black Swan Research team has chosen Flow MRD as the primary MRD detection method--as the benchmark for comparison with other methods.

On the pro side, an important benefit of the new flow method is that it utilizes a stored computer database of all possible myeloma clones or subclones for instant comparison and classification. All myeloma clones or subclones can be identified by flow methodology at any point during the course of the disease. Conversely, the DNA "dominant clone" approach risks missing minor subclones, which take over later in the disease. If residual subclones are identified, these can be characterized and sorted one by one with the flow method for detailed studies, including full sequencing of the DNA.  Applying DNA technology in this combined flow/ molecular fashion is simple and very informative.

The new flow method allows careful measurement of myeloma at the very low levels of disease needed to predict excellent outcomes and enhance treatment for some patients to achieve an MRD-Negative status.

Since the flow test is standardized, widely available and cheap, there is no longer a need for another method such as the molecular method, which has a number of disadvantages. One limitation of the molecular method is that the bone marrow from the time of diagnosis (or a new relapse) is needed to identify the "dominant or main clone" for future monitoring. In my opinion, the molecular method has other disadvantages. It is more expensive--estimates range between $750 and $1,000 (compared to between $100 and $150 for the new flow test)--and cannot be performed at the local center. To those who would argue for using both the molecular and flow tests, a practical point to keep in mind is that "splitting" bone marrow samples into two parts, one for flow and one for molecular, is not ideal. For the best results, the flow test needs the maximum number of myeloma cells from the "first pull" from the bone marrow aspiration sample to give the most accurate results.

Thus, although it is important to compare the flow and molecular methods in some trials, it seems likely that flow is all that we need! Moving forward, there can be some "fine-tuning," with the addition of the Hevylite ratio test as a quantitative replacement for immunofixation (IFE) and whole body PET/CT to directly evaluate myeloma disease outside the bone marrow.

So stay tuned as the Black Swan Research Initiative moves rapidly forward to achieving chronic disease control and a cure!

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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new update from the World Trade Center Health Program (WTCHP) at Mount Sinai Hospital combined with data from the New York City Fire Department indicates that 2,518 first responders have now developed cancer. Myeloma is, unfortunately, among the top four cancers reported, along with prostate and thyroid cancer, and leukemia. This is more than a doubling of the number of cancer cases since last year at this time. If the numbers continue at this pace the burden of cancer, including myeloma, will become enormous--costly in terms of both lives and dollars.

Studies have shown that 9/11 workers have developed myeloma at a higher rate than expected in the normal population. Research has also shown a relationship between myeloma and exposure to carcinogens located at the World Trade Center site, as I've written about here. There is an important "proof of principle" regarding the development of myeloma among 9/11 first responders. The myeloma has been attributed (by the experts reviewing the exposures) to exposure to 1-3 Butadiene, an industrial chemical used to produce synthetic rubber (for example in automobile tires, but also in styrene compounds). The chemical is a known cancer-causing agent which, in the 9/11 setting, is now clearly linked to the causation of myeloma.

Cancer patients--including those with myeloma--can receive awards through the September 11th Victim Compensation Fund (VCF). Although patients are obviously grateful to have a VCF available to help cover lost earnings, plus $250,000 for each patient for "pain and suffering," there are many ongoing concerns and questions. For example, as of June 30, 2014, only 881 claims for cancer have been deemed eligible for compensation. The rest are still under review. A particularly perplexing point is why only 10% of the claim is paid out initially, with the rest of the payment deferred until 2016 (i.e. 2 years from now). This is a long time for patients whose lives are threatened by cancer. So far, the award amounts for 115 cancer claims paid have been between $400,000 and $4.1 million. This is a total of $50.5 million to date. It is not clear how many cancer patients have died.

There are some deadlines that 9/11-related cancer patients should note. Individuals who were diagnosed with a 9/11-related eligible cancer on or before October 12, 2012 and who have not already registered or filed a VCF claim must register with the Fund by October 12, 2014 for review this year. According to the VCF website, "Registration preserves your right to file a claim in the future (before the VCF ends on October 3, 2016). Registration is not the same as filing a claim and you are not required to file a claim even if you have registered." If an individual is diagnosed after the October 12 deadline, he or she can register any time up until the October 3, 2016 deadline.

Myeloma patients are strongly urged to submit claims absolutely as soon as possible. This tragic occurrence is both debilitating and complicated to deal with. The IMF is here to help. Let us know if you need help with paperwork and/or the details of managing the myeloma in the best fashion possible. Let the IMF know if you might need help in any way by contacting the InfoLine team, infoline@myeloma.org.

In addition, the IMF is keeping a spotlight on this important subject by hosting a briefing in Washington, DC, Wednesday, September 10 at 11:30 am. Speakers will focus on the link between agricultural and 9/11 toxic exposures, and myeloma. 

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

 

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A recent study illustrates just how useful minimal residual disease (MRD) testing by flow cytometry is to predict excellent outcomes with new highly active combination therapies. A phase II study from the Intergroupe Francophone du Myelome (IFM) is reported in the July 14th issue of the Journal of Clinical Oncology. This study served as a pilot protocol for the ongoing IFM/Dana-Farber Cancer Institute 2009 phase II study assessing lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone frontline with or without autologous stem cell transplantation (ASCT). In the phase II study reported in the JCO, 31 patients with newly diagnosed symptomatic myeloma all received RVD followed by ASCT plus RVD consolidation and one year of Revlimid maintenance.

The results with this protocol were extremely good. Very good partial response (VGPR) or better was achieved in 58%, 70%, and 87% of patients after RVD induction, ASCT, and RVD consolidation, respectively. What was especially exciting is that 68% of patients achieved MRD-negative status as measured by flow cytometry. MRD negative by flow is an extremely helpful category as a one-time test measured at the point of maximum response. When MRD negativity is confirmed by subsequent serial testing (i.e. sustained MRD-negativity) and supported by additional testing, such as a negative pet/CT scan and normal HevyLite test, one can use MRD-Zero as a new category indicative of potential cure status.

With a median follow-up of over 3 years (39 months), patients achieving MRD-flow negative status are still in remission. The overall survival is obviously 100% at over 3 years. Thus, as we await the results of the phase III comparison study, the impact of induction, ASCT, consolidation, and maintenance is quite impressive, especially with regard to the MRD-negative status and stable remission status of the patients.

These findings strongly validate the key principle of the IMF's Black Swan Research Initiative. Monitoring with sensitive MRD testing at very low levels of disease both predicts exceptionally good outcomes and can be the basis for additional treatment decisions to achieve the sustained deep responses noted above, which can translate into cure.

It is important to emphasize that these new data support considerable prior data, for example utilizing Velcade plus thalidomide rather than Revlimid with dexamethasone (VTd) for induction, followed by transplant, consolidation, and maintenance. The new RVD results are clearly more promising, but the pattern of benefit throughout the four treatment phases is comparable. For the RVD regimen, it was notable that 13% of patients achieved MRD-negative status during the maintenance period.

The clinical benefit of achieving MRD-negative status documented using the Spanish flow methodology has been recognized for more than 10 years. Two sequential studies by the Spanish team in 2008 and 2012, and one from the UK team have shown that patients achieving MRD-negative status by flow have longer remissions and overall survival. What is remarkable about the new data is the sustained value of the deep responses in the IFM trial: no relapses after more than 3 years.

Thus, with the even more sensitive and standardized new flow method now available and use of increasingly effective novel combinations of therapy, it seems very likely that it will be easily feasible to reliably predict unusually good outcomes and define a patient population potentially curable with comprehensive frontline treatment. This new IFM study thus points the way to incorporation of MRD testing by flow cytometry into tailored approaches to achieve the very best results with therapy throughout the course of disease.

As always, stay tuned for further exciting 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 infoline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.

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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.

6 Comments

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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