TRANSCRIPT
Deborah Borfitz:
Hello and welcome to the Scope of Things podcast, a no-nonsense look at the promise and problems of clinical research, based on a sweep of the latest news and emerging trends in the field and what I think is worthy of your 30 or so minutes of time. I'm Debra Borfitts, senior Science Writer for Clinical Research News, which means I spend a lot of time with my ear to the ground on your behalf and a lot of hours every week speaking to top experts from around the world. Please consider making this your trusted go-to channel for staying current on things that matter, whether they give us hope or cause for pause.
Deborah Borfitz:
In another five minutes or so, I'll be speaking to Dr. Joseph Mikhael, chief medical officer of the International Myeloma Foundation, which has been pulling out all the stops to find a true cure for a rare and often fatal blood cancer. But first, the latest news, including AI for stratifying Alzheimer's patients, a questionable shortcut in rectal cancer drug trials, ChatGPT for determining trial eligibility, a groundbreaking study of a hemorrhage treatment, and a new no-nausea weight loss remedy heading to trials soon. Scientists in the UK report on an AI-based patient stratification model that could accelerate the search for more effective Alzheimer's medicines. The model was used to reassess the results of a completed clinical trial to learn that a drug failing to show efficacy in the total population studied was quite effective at reducing mental deterioration in a subset of patients with early stage slow progressing mild cognitive impairment. The approach is now being translated into the clinical care of dementia patients in hopes of identifying patients most likely to benefit from treatment and thereby lessening some of the cost pressures on the National Health Service. The AI guidance could also make future clinical trials faster and cheaper, as well as better targeted to study participants.
Deborah Borfitz:
A Tulane University researcher has found that a key metric in clinical cancer drug trials pathologic complete response does not reliably predict improvement in long-term survival for patients diagnosed with rectal cancer, raising concerns that some treatments may be fast-tracked for approval without evidence that they help patients live longer. Since 2012, the FDA has allowed treatment success to be measured via tumor-free status post-therapy as a surrogate for overall survival, to cut down on the time and expense needed to get new cancer treatments approved. But the shortcut may end up increasing costs for drug companies over the longer term, suggesting it may make more sense to include a combination of surrogate endpoints instead of just the one. To include a combination of surrogate endpoints instead of just the one. Chat-GPT appears to do a decent job of determining a person's eligibility for a clinical trial, based on a study by researchers at UT Southwestern Medical Center, where chatbots analyzed the electronic health records of 74 patients to see if they qualified for a head and neck cancer trial. GPT-4 proved more accurate than GPT-3.5, though slightly slower and more expensive. Screening times ranged from 1.4 to 12.4 minutes per patient, with costs between 2 and 27 cents. Long story short, while the large language models struggled to identify patients meeting all study criteria, they succeeded in saving time and supporting the efforts of human reviewers.
Deborah Borfitz:
The University of Colorado Anschutz Medical Campus will lead a groundbreaking national clinical trial to evaluate whether early replacement of a critical blood clotting mechanism in the body can improve outcomes for trauma patients experiencing life-threatening bleeding. The investigator-initiated study is being supported by a $29 million grant from OctoPharma, one of the largest clinical trial grants in campus history and potentially among the biggest in the nation. The so-called EFFECT trial will enroll 800 participants across 12 top-tier trauma centers around the country and use real-time testing to guide therapy and assess biological markers of coagulation, inflammation and hemorrhage-inducing factors. European trauma systems already routinely use the fibrinogen concentrate being evaluated in this study, but US guidelines have lagged due to a lack of clinical trial data. The effect trial is designed to close that gap. A nd finally, researchers at Syracuse University and the University of Pennsylvania hope to start clinical trials as early as next year on a potential alternative to Ozempic and Zepbound for the treatment of obesity and diabetes, notably without the usual side effects like nausea and vomiting that force 70% of patients to stop the drugs within a year.
Deborah Borfitz:
The treatment works by bypassing neurons and instead targeting the downstream pathways in support cells in the hindbrain, such as glia and astrocytes, to achieve appetite suppression and weight loss, as demonstrated in obese mice and musk shrews. A new company called Coronation Bio has been launched to turn the discovery into a real-world treatment. You can look for an article I wrote describing the approach in Bio-IT World. As a reminder, links to the published studies and news releases referenced in this month's news segment can be found in the show notes.
Deborah Borfitz:
I am now so pleased to begin my chat with today's guest, Dr. Joseph Mikhael, to talk about the unique strategy being taken by the International Myeloma Foundation or IMF to turn the nitty-gritty of scientific research into a metaphorical black swan event with major impact on the lives of patients living with an incurable disease. Welcome to the show, Dr. Joe.
Joseph Mikhael:
Thank you so much. It's such a pleasure to join you today. I'm looking very much forward to this discussion.
Deborah Borfitz:
Me as well. As listeners may or may not be aware, but we have discussed previously multiple myeloma is quite different than other cancers in several key respects. So, to get us started, could you please elaborate a bit on what sets it apart from the cancers most people are probably more familiar with?
Joseph Mikhael:
Absolutely. In brief, it is a cancer that only accounts for about 1.5% to 2% of all cancers, so it's relatively rare. We see about 36,000, 37,000 new cases per year in the United States, and it's a blood cancer. So people would think of it as of the family of leukemia and lymphoma. But the origin of the cancer is in the bone marrow, the factory of our blood, and the key cell is called the plasma cell. So the plasma cell is the cell that we react to, for example when we take a vaccination, and it makes antibodies. So these are really good cells. We love our plasma cells. These are the cells that are constantly protecting us against infections and things that we get exposed to in the environment. But unfortunately, in multiple myeloma that same plasma cell now becomes cancerous. So instead of making good antibodies or good proteins to protect you, it now makes a bad protein we call a monoclonal protein that can attack the kidney, that can attack the bones.
Joseph Mikhael:
And what really differentiates it is not only that it's less common and it's a less common cell is that there isn't one sort of classic hallmark feature that distinguishes this cancer. So when you think of breast cancer, an individual may feel a lump, or in colon cancer with certain GI symptoms, it's a little bit more predictable. With myeloma, it's less predictable. Most people present with either being just very fatigued, having bone pain or having a low hemoglobin or red blood cell count, if it happens to be tested something called anemia, of course, which is very, very common. So that makes it a bit more challenging to make the diagnosis.
Joseph Mikhael:
Secondly, the other differentiating feature is that because of that, the diagnosis is typically delayed. Most patients have signs and symptoms for over six months. Most people see their primary care provider three times before the diagnosis is invoked, and that is even longer within the African-American, the Latino American population. And lastly, the other feature that I would note is that historically, this disease was really a death sentence. When I started in myeloma 25 years ago, most of our patients lived for one year, maybe two years. Now we expect the average patient to live over 10, if not longer years, and so we've seen remarkable progress in the field, but it is still a very challenging disease to treat and still requires a tremendous amount of collaboration worldwide.
Deborah Borfitz:
Yeah, that is a lot of progress to report, and I'm not sure to what degree. This and I want to talk about this next, the Black Swan Research Initiative that the IMF has underway. I'm not sure how responsible it's been for all this progress or more progress to come, but it effectively, as I understand it, convenes the broader myeloma community in different ways around the common quest to improve outcomes for patients in terms of both their quality and quantity of life, and I know this involves quite a bit of experimentation. So perhaps you can share the nature of these projects by way of an example, including how the idea originated and how collaboration was enabled to make it a reality this Black Swan Research Initiative, okay.
Joseph Mikhael:
Yeah, absolutely. Because, as you describe beautifully, the concept is, you don't really appreciate a black swan event until after it's happened. You don't really not sure that you think of something even as terrible as the pandemic. Right In retrospect we look oh wow, yeah, that really was going to happen at some point with the way things were in the world, but you couldn't have quite predicted it. And so we hope that the major black swan event that we're seeking, of course, is a cure for multiple myeloma.
Joseph Mikhael:
And the rationale and the thinking behind it and I'll just summarize it quickly was to say we have outstanding myeloma researchers and doctors and nurses and pharmacists and incredible patients and their partners all over the world, and very often research and work is primarily nested within academic centers. Often there's some collaborative efforts between centers, and that's very good. But could you have someone way up in the balcony, as it were, who could bring together groups from all over the world and really maximize the benefit of collaborative projects, collaborative ideas? The centerpiece of this was the creation of what we call the International Myeloma Working Group, which is now about 350 true world experts in myeloma all around the world, and they have a tremendous affinity to want to work together. They have allegiance to their own institution, of course, and that's where they're employed and that's where they do their primary work. But by us convening this group together, not just as one massive group, but with subgroups, with different committees, with different working groups and therefore projects, we have been able to advance the science and advance the disease more fully. Sometimes I give this analogy that it's a little bit like the Olympics. Why are so many records broken at the Olympics? It's because the table is set, as it were. The conveners create an atmosphere that brings the best out of everyone, and that's really what we've sought to do within that. So you wanted a couple of quick examples.
Joseph Mikhael:
So in the Black Swan Research Initiative, we recognize that if we're going to cure myeloma, we have to be able to detect the tiniest amounts of it to know that we've eradicated it. And we do that through a method called minimal residual disease. And so the Black Swan Research Initiative, one of its very first projects, was let's make sure that across the world, we have the same definition of both how we do it and what it is. At what level do we say this person is minimal residual disease, negative? What are the tools that we use? Because if every country did it differently, we would, be like with different currencies, not be able to communicate clearly with each other, and so the unanimity, as it were, of MRD was born. Then we said well, for example, more recently we have a project such as our immune therapy registry, which I think is fascinating, which is to say, the reason why we've had such huge evolution and progress in myeloma has been the introduction of these immune therapies, things like CAR T-cell therapy, where we take T-cells out of a patient and train them to attack their own myeloma by specific antibodies.
Joseph Mikhael:
We have drugs that hook on to both the myeloma and someone's own immune system to engage them, to activate it. Each individual center sees dozens, if maybe up to hundreds, of patients, but to best understand the impact of these therapies, to know what are the potential side effects, even ones that can be extremely rare we see things that only happen in less than 1% of patients. If we don't have a way of pulling that information and data together, that sort of big data generation, we may miss that. And so we created this immune therapy registry to say let's capture this data from all around the world and see, and we're now starting to identify trends and side effects and benefits that we might not have seen individually in a certain center. So hopefully you see the theme here right. The theme is if we collaborate all together and share information and share ideas and then now prospectively do clinical trials, we can do much more than the sum of the parts.
Announcement:
Are you enjoying the conversation? We'd love to hear from you. Please subscribe to the podcast and give us a rating. It helps other people find and join the conversation. If you've got speaker or topic ideas, we'd love to hear those too. You can send them in a podcast review.
Deborah Borfitz:
Gotcha and I want to specifically home in on this iStop MM study out of Iceland because I believe that got a lot of attention from the media. It's been well covered but I'm not sure everybody's heard about it and I think it really drives home just how much you can do via collaboration.
Joseph Mikhael:
It's extraordinary. The timing is ironic. Just today I met with the PI of the study and we actually did a podcast together to talk about what the iStopMM trial is. So one of the things that we don't yet do in myeloma but we do, let's say, in breast cancer and in colon cancer is to screen for the disease right. It took us years to determine what is the best way to screen for breast cancer through mammography or for colon cancer through colonoscopy or other means. We're in the midst of that process now because, as I noted before, this disease is insidious and that it is often delayed in its diagnosis. It would be ideal to catch it earlier because we know the earlier we catch a disease, the better patients will do in the long run. And so to really ask the question does screening for myeloma save lives?
Joseph Mikhael:
The iStopMM study was created, and iStopMM is an acronym for Iceland Screens, Treats or Prevents Multiple Myeloma. And what they did is they invited every Icelander over the age of 40 to participate in this study, to have their blood taken to determine if they had the precursor of myeloma something called MGUS or monoclonal gammopathy of undetermined significance and patients are randomized into different groups to determine how intensively they are followed to determine if that screening was actually valuable. It has exceeded expectations by so beyond what we could imagine. They actually stopped collecting informed consents after over 50% of the population consented to this, which is over 80,000 individuals now have had their blood collected for us to understand the true nature of the precursor of myeloma and myeloma itself. The answer as to whether or not we should screen still is going to take a little bit longer.
Joseph Mikhael:
We're about five years into the study now, but even in these five years, the number of learnings, the number of spinoff studies, everything from what is the psychological impact of being screening to, we now better define, actually, some of these conditions, because we've never had that many patients with it in a common database where we could see what is the best range to define it, who needs more testing with a bone marrow and who does not need more testing with a bone marrow.
Joseph Mikhael:
I mean, it is a database that is being interrogated literally on a daily basis to benefit the greater world of multiple myeloma. And so again, it follows that same theme here, although it is in one country, because very uniquely in Iceland, because we have a lot of much more genetic information in Iceland. More people in Iceland have had their whole genome sequenced than in any other country of the world and they have a unified medical system. So not only do we look at the blood test, we know for those 80,000 patients, every pneumonia, every use of antibiotic, every vaccination, if there are trends or patterns that can be determined, but that kind of collaborative effort that we've all worked alongside of our colleagues in Iceland has yielded tremendous results and I suspect, will help us answer the question whether or not we should be screening for myeloma.
Deborah Borfitz:
Perfect, perfect and this kind of segues nicely to my next question, because I know there's many, many countries and many experts in those countries are part of the puzzle. If you will puzzle pieces. Could you speak a little bit to the contribution of you know? What are your colleagues in Spain doing, and Australia in the US and Singapore and Germany you know? Talk a little bit about their and how they collaborate and in what instances?
Joseph Mikhael:
Absolutely. Happy to do so. You know, again, one of the principles of Black Swan and of the work of the International Myeloma Foundation is to recognize that no one center has excellence in absolutely every area. So let's maximize the benefit by encouraging and facilitating research in the areas of excellence in each of these countries. So, for example you mentioned a few of them Spain, Spain, lead the world in what's called flow cytometry. This is the concept of looking at the surface of a cell and the markers on the surface to determine features of that cell. And that's partly how we look for minimal residual disease. And they have developed an incredibly sophisticated technique that can determine one in a hundred million cells if it's a myeloma cell. Because, again, if we're going to cure myeloma, we got to get rid of it all, and that tiny bit that's left is often the most ornery bit. Sometimes I say the last soldier to be killed is Rambo. You don't want to leave that one Rambo plasma cell in your bone marrow to grow back, because it'll grow back with such a vengeance. And so the Spanish group led so much of the work in MRD and in flow cytometry and in supporting them they could share that information of wealth with others so that now other labs could follow that modality.
Joseph Mikhael:
In Australia they had done some tremendous work in trying to detect features of myeloma in the blood instead of having to do it in the bone marrow Now. Doing a bone marrow test may not be the most uncomfortable thing on the planet, but it is not comfortable for patients. It requires a needle that goes into their hip and it can be quite uncomfortable. It would be great if we could replace some of those tests with blood tests, and so they've done highly sophisticated blood testing to look for even tiny bits of DNA or extremely rare plasma cells that circulate in the blood to help us understand the disease a bit more.
Joseph Mikhael:
Our colleagues in Singapore have been the hub of a whole new network that we created throughout Asia over 10 countries, now called the Asian Myeloma Network. Many of these countries were not particularly well known for their work in multiple myeloma but now over the last decade have participated in clinical trials, have participated in educational activities and have created this so-called virtual tissue bank that we have based in Singapore. Across Asia it's very hard to move blood products and we can't create a physical bank of blood, but if each center can retain their own bone marrow and samples that they have, but very clearly articulate it and capture the information from it with a shared virtual database. Then we have this opportunity to learn so much more about myeloma in the region. And the goal, really, of the Asian Myeloma Network was to find ways to bring these great drugs that we've developed across the world to those who, historically, would not have had access.
Joseph Mikhael:
And that's what drives me, by the way, if I can put a personal plea here, this is why I joined the IMF, this is why I'm so heavily involved in this is that I want to help those in tremendous need.
Joseph Mikhael:
We've just created, for example, a Latin American myeloma network, and when I travel a lot in America and I see the slums in Sao Paulo and the challenging areas in Santiago and other places, it makes me so thankful for what I have. And yet these doctors, these hospitals work in very challenging conditions. And if we can find ways to facilitate bringing these new therapies to these poorer patients who have myeloma, like anyone else who has myeloma that need to be treated, then we know we're doing very good. And in doing so, not just, if you will, compassionately bringing a drug, but bringing a whole process of research, of education, engaging the patient community, the care partner community, and that's what we want to systematically do across the planet. So I could go on and on about multiple countries, but hopefully I'm giving a flavor of whether it's a highly sophisticated lab in Salamanca, Spain, or if it's in clinics in the favelas in Sao Paulo. We want to find a way to better understand the disease, commonly treat the disease and provide benefit to every patient on the planet.
Deborah Borfitz:
What about the US? Are we the coordinating center primarily, or do we have some special expertise we're bringing to the table here? Obviously, this is where the International Myeloma Foundation is based, but...
Joseph Mikhael:
Right, we're based here in Los Angeles, and yes, we do more of the coordinating activity and we're actually working to expand more of what we do in clinical trials here. But, yes, the US is really sentinel to all of this, very often being the true convener of these activities, being participants in these clinical trials, being participants in the lab researching this, understanding this. A lot of drug development occurs here, of course, in the United States, and many of our international myeloma working group are based here and they can provide education and understanding to other parts of the world that don't have access to these newer therapies yet. So it really has been. I love the apolitical nature of this, that we want to genuinely be a united nations against multiple myeloma, and it has been one of the joys of my career to truly collaborate with people all across the world, of every background you can imagine.
Deborah Borfitz:
Yeah, well, on a somewhat related note here, to end today's show, I want to talk about the health disparities problem with myeloma, which is the focus of this M-Power project that you lead and I know is near and dear to your heart. Could you share, please, what exactly you're trying to do and for which disadvantaged groups in particular?
Joseph Mikhael:
Absolutely. I'm more than happy to discuss this. As you know, it's both professional and personal for me as an African-American man and physician. This is particularly important to me. When I explained to you the unique features of myeloma, I purposely left out one key feature that I knew that we would come to, and that is the health disparity in myeloma. We could argue that, in fact, myeloma is the most disparate cancer in the African-American community, meaning a Black man or a Black woman diagnosed with myeloma is expected to live half as long as the same aged white man or white woman, and that mortality is not just related to their myeloma, of course, to general health, but myeloma disparity is quite dramatic.
Joseph Mikhael:
Thankfully, we've started to see some changes in this and I wouldn't take personal credit for this, but we believe the work we're doing with M-Power is sentinel to that. So M-Power program that we've created is a bit of a play on words M dash power standing for myeloma power. The idea is to empower the community to change the course of myeloma, to reduce these disparities so that we can see a much greater health equity across the whole of our country and even the world, because the two groups that are particularly where we see this greatest disparities with the African-American population and the Latino American population. So we created this program which is really built on three platforms. One, to engage the community, to go and reach out to the Black community, to the Latino American community, so that they can understand what myeloma is and how it affects their community, so they know the signs and symptoms, to shorten that time to diagnosis. So we do programs in churches and fraternities and sororities. We've had the privilege of being all over the country in multiple cities trying to raise this kind of awareness and empower people.
Joseph Mikhael:
The second platform is to educate the primary care world. That's where myeloma diagnosis is primarily made. And so to educate primary care providers to know that the incidence, for example, of myeloma is twice as high. If you're of African descent, like myself, you have twice the risk of developing myeloma. So to know that epidemiology and therefore be able to ensure that when you're taking care of patients, that you think about myeloma when some of those more vague symptoms or signs are present.
Joseph Mikhael:
And then, lastly, to truly enhance the care of myeloma patients, to find ways directly in the clinic to ensure that patients have access to therapies, because really the disparity comes down to delayed diagnosis and good access to therapies, and part of that is to help a next generation of doctors coming up. We do a program, our health scholars program, where we have medical students from historical Black colleges and universities, who I pair with an expert in myeloma to do a project in health disparities, and we all gathered just last month at the National Medical Association where they shared all of that information together so that we can have another generation of individuals from this community who understand the disparities and can be committed to overcoming them. So it has really been a privilege to be a part of this and I genuinely believe that we can continue to improve this terrible disparity that we see in myeloma.
Deborah Borfitz:
Wow, I really love how you have channeled your concern and passion in this direction to make some real changes, and I hope you get some sleep. It sounds like you don't get much.
Joseph Mikhael:
I do sleep pretty quickly. My wife laughs that it takes me about three seconds to fall asleep.
Deborah Borfitz:
That's very telling. Dr Joe, I cannot thank you enough for being here today and helping everyone to better appreciate how far we've come and have yet to go in caring for people with multiple myeloma. I will be watching and waiting for fresh discoveries and clinical advancements sure to be forthcoming thanks to the efforts of the IMF and its aptly named Black Swan Research Initiative. In the meantime, be well, keep up the good work.
Joseph Mikhael:
Thank you so much.
Deborah Borfitz:
And, as always, a big thank you to everyone out there for listening in. If you're not subscribed to this podcast yet, please consider going to Apple Podcasts and doing so right now, so you don't miss your monthly dose of news and perspectives. You'll be hard-pressed to find anywhere else and, if you're up for it, I'd also be so very grateful if you'd leave a rating and review while you're there. One more thing before we go, if you'd like today's conversation. It is only a glimpse of what you can expect from Scope Europe. Presenters and panelists, please plan to join us October 14th and 15th in Barcelona when clinical operations executives will be exploring the latest trends in clinical trial innovation, planning and operations. Save an additional 10% off any current rate by using the code SOT10. For more information, visit scopesummiteuropecom. Bye for now, thank you.