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May 2014 Archives : Myeloma Voices

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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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.

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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.