Faith Davies, MD of the University of Miami shares historical perspective about innovation in myeloma, how innovation can and should happen, more about the phases of clinical research and how we can accelerate research in myeloma towards a cure. 

Jenny: Welcome to today’s episode of the HealthTree Podcast for Multiple Myeloma, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom. We’d like to thank our episode sponsor, GSK, for their support of this program.

Now, before we get started with this show, I'd like to share a little about what's coming for HealthTree. In the past 11 years, we've used innovative technology to build three pillars of support for myeloma patients. Our first pillar is personalized education support to help you learn more about myeloma, because when you're more educated, you get better outcomes. That pillar includes this podcast, our webinars, and lots of other educational programs that we have. Our second pillar is the creation of meaningful patient-to-patient connections, like through our Coach program, our social media HealthTree Connect program, and other apps that have to connect you with one another. Our third pillar is this powerful data portal called HealthTree Cure Hub. Now, this tool doesn't exist for any other disease today, and it helps you navigate your myeloma while helping advance research for investigators using real-world evidence.

We built all of that technology to facilitate those programs internally, and we call our first decade HealthTree 1.0. Next week, you're going to hear a little more about HealthTree 2.0, our vision for our next decade. So we invite you to watch for announcements during Blood Cancer Awareness Month that will lead up to a major event on October 23rd that we'll be hosting here in Utah, and we'll be live streaming that as well.

So on the topic of innovation and research and accelerating the cure, we have with us today Dr. Faith Davies of NYU Langone's Perlmutter Cancer Center who will be helping us understand the essential research and processes that need to happen to get us to that myeloma cure.

So Dr. Davies, welcome to the program.

Dr. Davies: Thank you so much for having me. It's great to be here.

Jenny: We’re delighted you're here. Well, let me give a little introduction for you before we get started.

Dr. Faith Davies is the Director of the Center for Blood Cancers and Director of the Clinical Myeloma Program at the Perlmutter Cancer Center. She is Professor of Medicine at NYU's Grossman School of Medicine. Dr. Davies leads NYU's clinical and translational research efforts for blood cancers and treats myeloma patients. Her research focuses on the biology and treatment of myeloma and related conditions. And through clinical trials, she's identifying new drugs and technologies to advance the science towards a myeloma cure in addition to finding new and easier ways of testing or the whole process of having myeloma.

Dr. Davies has published more than 350 peer-reviewed articles and leading journals and is an active member of the American Association for Cancer Research and the American Society of Hematology. She was a former medical director at the Myeloma Institute at the University of Arkansas for Medical Science and received her education at the University of Wales College of Medicine, Royal College of Pathologists, American College of Physicians, and the University of London.

Dr. Davies has focused for nearly two decades on the biology and treatment of myeloma and throughout her extensive career has done significant work to bring new drugs to myeloma patients. We're so excited that you're here to join us. We're just thrilled.

So with that, let's get started on this more broad look at research that will lead us to myeloma cure.

Dr. Davies: That was quite a long introduction, Jenny. But thank you.

Jenny: It's your history, so we have to celebrate you because you're amazing, totally amazing. Now, when I was diagnosed in 2010, I never heard a myeloma expert mention the word "cure." I think it was kind of like socially unacceptable to hear people say that. But now I hear experts stating that a functional cure is potentially possible. We may have achieved it for a certain subset of patients. Maybe we know who they are or who we don't, and we're just getting closer to that myeloma cure. So can you share your perspective on the progress made over the last decade or two even?

Dr. Davies: So when I first started doing myeloma, I guess, as I say, 25 years ago now, I think, we were very much really, although we could give treatment to try and get on top of the disease a little bit, we weren't really making a big impact and patients had a lot of problems with infections, with bony disease, so fractures and bone pains, and unfortunately didn't survive very long. And not only did they not survive very long, their quality of life was really quite poor. And I think over the last 25 years and particularly over the last 15 to 10 years, a number of big things have happened.

So there's generally a better awareness of myeloma. We're still not there with everybody, but you know, at least does come on people's radar when patients present with back pain or something like that. We have better tools to diagnose it and to monitor it. We have better treatments, not only for the disease but also for supportive care, so trying to stop bony problems. And also, we've got a better understanding of the whole biology as well about the science behind it.

So I think all of these things have added up to of making tremendous progress in learning how to use new drugs, how to get patients into deep remissions and to really get it so patient's quality of life and activity gets back to normal. And what this is doing is that to some extent I think myeloma is one of the cancers with the biggest improvement in survival over the last few years. It's giving us the opportunity now to say, okay, yes, we can potentially cure some people.

Now, to some extent, we have two kind of areas that we really need to concentrate on. One is whether, when we say cure, are we saying cure but we can stop treatment, or are we kind of saying if this is more of a chronic condition where, yes, we can keep it under control, but the patient needs to stay on some form of therapy as we move along? And then the second one is that many, many patients we can get into a good remission and we can expect them to have a good quality of life and a long life, but we've still got a proportion of patients who sadly still do quite poorly and we really haven't quite figured out why that is yet.

Jenny: These are the high-risk patients?

Dr. Davies: Those are the ones, yes.

Jenny: Okay. Well, you gave us lots of great answers about why we're seeing so much innovation in multiple myeloma. I think back in 2015, I remember seeing a Wall Street Journal article that just said there was more development being done in multiple myeloma than any other cancers. So I guess, if this is a club we have to be in that we didn't plan on joining in the first place, it's not about the club to be in with the innovation that's just happening. Are there any other factors of why so much innovation is happening specifically in myeloma that you see?

Dr. Davies: I think so. I never quite know whether to describe it as a club or not, but I think one of the amazing things, if that's the correct expression about myeloma, is that as it is relatively rare, the club is actually really important. I think some of those innovations and that progress we've seen is that we've all been learning from each other. Again, when I first started doing this, we all worked in separate little silos. I think what's been happening over the years, those barriers have been broken down and the scientists are talking to their clinical doctors, and also both the scientists and the clinical doctors are not just looking in the myeloma field, they're also looking to other fields and learning from other fields, so like things that may be happening in breast cancer or colon cancer and bringing that information back.

But I think one of the biggest things is the fact that because we are a small club, we have the patients, the patient advocacy groups, the doctors, the pharmaceutical companies, and also the regulatory authorities, so the FDA and so on, and we're all talking together. I think that that means we actually do make a lot of progress. Clearly, we're not always on the same side, but I think having that discussion and working together is actually making us make a lot of progress.

Jenny: Well, I would agree with that. I think that groups are very collegial with one another, and it's been fun to see. You don't get that feeling of hyper-competition. You get a lot of feelings of mutual collaborations with lots of different projects, so I think that's fantastic. Now, when we talk about getting to a myeloma cure, what do you feel like are the essential research components that need to happen? Can you kind of block those out for us and then maybe we'll take a deeper dive on each one?

Dr. Davies: So I think there's a few things. The first thing is the biology, so that kind of laboratory work, and really trying to figure out exactly what is going on in myeloma, what's happening in the bone marrow. Over the years, there's been a lot of work about the actual myeloma cell itself and how it's wired and how it grows and also about the genetics of those cells. So we've learned a huge amount about that. We've also started to learn how the crosstalk between the actual myeloma cell and the other cells in the bone marrow are important. And then more recently, I think one of the reasons why we've made quite a lot of progress is that we're also beginning to learn a little bit more about how the myeloma cell interacts with some of the immune cells in the body. So how does that myeloma cell manage to hide away from other cells in the body and not get killed off?

So learning, we've made huge strides in that area, but we continue to make lot of kind of discoveries in that area and really learning more about that is going to, number one, help us to use the drugs we already have more wisely, okay? So be that in putting them together more wisely or indeed deciding whereabouts in the kind of treatment pathway a drug should be used. So should it be used at diagnosis, or should it be used if the disease comes back? I think that's one area, but the second area as well is obviously as we learn more and more about the cell and how it kind of survives in its environment, we also learn new ways that we may be able to kill it off. And that section of work on the research side of things is really key because it drives what we do in the clinic.

Jenny: Absolutely. Right. And then it seems like, so when I had the opportunity to interview Jim Allison, and he was the scientist that worked on checkpoint inhibitors, and I actually don't recall the disease that it was for but you probably know. But he just said that understanding of the disease biology is so important, and what you're saying is so important because myeloma seems trickier than a single type of cell in a lymphoma or something like that, or you have that interaction between the cells, the genetics, the microenvironment, and the immune cells in the body that you're saying. So it just seems to be a tricky, like because all myeloma patients are not the same and even inside their body, their myeloma spots might not all be the same genetically and things like that seems to be a little more difficult.

Dr. Davies: You’re completely correct. As you say, we've always known when we're sat in clinic seeing patients that every patient is different. We know that some patients respond well to certain treatments, others don't. Some patients maybe present with a lot of bone problems, whereas other patients may have kidney problems. And so we know that the myeloma cell is very different. And when we then go and move to the lab and look at the different tests, we can see within that setting that the myeloma cells are very different as well. And so over the years, we now are able to, on a kind of lab side of things, separate the different kinds of myeloma on a genetic basis. But also, what's been happening now as well more recently is being able to do it a little bit more by looking at patients' immune side of things. So some patients may be, I was going to say, very reactive. Their immune system is very healthy and is able to keep these myeloma cells at bay, whereas other patients, their immune system is maybe slightly weaker and these myeloma cells can grow. And we're learning a little bit about the different ways that that can happen.

And you're correct. Jim Allison's work, which has been amazing work, really highlighted one of these kind of markers on the cells that I refer to as Harry Potter's Cloak of Invisibility. It essentially managed to make the cells hide away and not be recognized by the immune cells. And what he discovered was that if he was to block this molecule, it kind of took off this invisible coat, and then the immune cells could see the cell. And that really worked for some of our solid tumors, so particularly lung cancer and kidney cancers. And what we have to try and do is to find what the equivalent of that is in myeloma. And there's lots of work going on with that, but we're maybe not quite there yet.

Jenny: I thought just to get that understanding, like you're saying, of disease biology is kind of step number one is really important. I think maybe you want to talk about clinical trials because to me they seem to be the ways and means to this myeloma cure. How do you determine which treatments are best for which type of patients in which condition? So maybe first you can just kind of help us go over the phases of clinical trials and how a drug goes through that clinical trial process.

Dr. Davies: I'm going to say what I'm going to call the traditional way of drug development because I think one of the innovations that we desperately need and which is starting to happen is to shake this up a little bit. But in the first instance, what tends happen is that we tend to, when a drug has been shown to work in the laboratory, the first area where that drug will often go into the clinic is the patients who have seen nearly all of the other drugs we use. So those patients are often described as relapsed and refractory patients. And often what will happen is in that first phase of the clinical trial, which we call phase one, we will be looking at a small number of patients and really trying to determine whether the drug does what it says on the tin. So does it actually inhibit the cell's growth in the way that we're expecting it to do?

There's lots of blood tests and what we call pharmacokinetics and pharmacodynamics tests which are done. We also, in those first studies, are trying to determine what is the best dose. Clearly, we have some ideas from the different tests, but we have to make sure that the drug is metabolized correctly by the body, by the kidneys, and by the liver. And we take a little bit of a look at the different side effects of the drug.

Assuming that that drug is doing what we think will be doing, then the next step is the phase two portion of the study. And that is really where we start thinking about efficacy. So there we're looking to see does the drug actually work and to gain a little bit more information about the side effects of the drug and its safety. And then again, assuming that study undertakes and does okay, then we go on to what we call the phase three study, and that is usually where we can compare the new drug to one of the old drugs in that same kind of disease setting. And we tend to randomize patients. So we toss a coin and decide which arm they might go in, new drug or old drug. And then again, we're looking to see how efficacious the drug is, what its side effects is, what's happening with quality of life, and comparing it to that old drug.

It's quite a process, and invariably, as I say, the phase one studies are in patients who are maybe relaxed and refractory. I've had seen lots of other drugs before, but then often the phase two studies might be in an earlier line of therapy, so maybe a patient that's failed two or three lines of treatment before, and then we'll go into the randomized studies. We tend not to, at the moment, treat a new patient with many of these drugs for the very simple reason we don't always know the side effects, and so there's some discussion that maybe it's better for brand new patients to receive the therapies that we know will work and we know what to expect.

Jenny: We're seeing that right in the CAR T trials right now, right? Everybody was in relapsed/refractory after maybe four lines, three or four lines, and then the clinical trials began to move that up in earlier lines, and now I know both companies are going for earlier approvals in earlier lines.

Dr. Davies: Yes.

Jenny: It makes sense that they do it that way. You mentioned this is kind of the standard way of doing it or the old-fashioned way of doing it. What are you seeing as new methodologies or better ways of speeding up the clinical trial process?

Dr. Davies: As you say, it can take quite a long time for those kind of things to happen.

Jenny: Right.

Dr. Davies: And all of patients and doctors want to try and speed all of this up. And there's a number of different things that we probably need to talk about within this kind of thing. I'm just going to say them out loud first, and then I'll come back to them, okay? So one is about the actual trial design and how we think about these studies. But the second one is also what we call the endpoints, what we're looking for when we do one of these studies. So maybe we'll tackle the endpoint one first. So when we usually do a clinical study and we're usually saying, right, okay, when we do this study, yes, what's the safety? But the second question is, how long will a patient stay in remission for? How long does it take to relapse? And potentially as well, how long will the patient survive? And those are two, I was going to say, what we call endpoints, which are relatively easy and set. So it doesn't matter whether you're a patient in North America, a patient in Australia or Europe, all doctors would be able to work out what those kind of end points are so we can put all of the data together.

Now, one of the interesting conundrums for myeloma patients nowadays is that patients may have a remission for five years, for 10 years. And so if that's the case, do we really want to wait five or 10 years if we've got a new drug coming through to say, hey, this drug is going to be okay and it's going to be good, okay? So what the patient organizations, the advocacy organizations, the FDA and the doctors are all trying to work together to look at other ways of doing this. One of the tests that is kind of up for discussion that might be useful for this is the minimal residual disease test. So that's the test where we can measure how the response to the drug and how low the myeloma burden or the myeloma tumor response is. The question is, is that what we call a surrogate marker? So if we were to measure that, would we get the same answer to the study if we were to measure as if we were to measure the relapse rate or the survival rate?

So there's lots of kind of discussion and studies going on at the moment where we're saying, right, okay, well, let's see. Let's see if we measure that rate and then we continue to follow patients for longer and also look at the relapse rate. Do the two things correlate, and do they match up? Because if they were, then what we could say in the future is to say, right, okay, we know or we hope patients are going to do well on this drug. Rather than waiting for five or 10 years' time to confirm that, let's take an early marker at a year. If that's good, then yes, we'll carry the study on, but it also gives us encouragement to move forward. So I think that's one key area that we really need.

The second one I think that we really need is to kind of mix these trials up a little bit and start thinking about new and different ways of doing it. I think there's kind of two good examples of this. There are all sorts of ways that people are looking at it at the moment. But as I say, some of the treatments we maybe want to use may be around using the patient's own immune system to kill off the myeloma cells. As I say, the way the treatments are done at the moment, we usually start off with relapsed/refractory patients. It may well be for those patients that their immune system isn't so good, and we're actually maybe asking too much for the drug.

So there's now a move to try and maybe utilize some of those patients earlier in the disease course. So as you say, like the CAR T cells have now moved up to first relapse and we're kind of hoping because of the patient's immune system is in a better state then that they may be more effective. So there's some discussion about trying to pick out the area where we think that drug may work early on rather than going through this very formal process of doing things.

Jenny: Can I ask a question, if you see that happening for bispecifics too? Like is that kind of what you see happening for all immunotherapies?

Dr. Davies: There's a movement there that clearly it has to be done safely and carefully, but there's a general movement to try and do that, yes. I'm going to say I'm just going to go off a little bit of a kind of tangent here. I think that particularly myeloma, it's kind of important within this that obviously the regulatory authorities are very key in our ongoing discussions with this is really important because I think we all recognize the need for quick access to drugs. But if you think about myeloma, we're actually a good disease area where we have some history for this. So I'm sure many people know that the IMiDs, so pomalidomide and lenalidomide, are actually based on thalidomide, which is the drug that had that dreadful history back in the '60s with the abnormalities in babies.

I think that certainly for the older doctors like myself, that's very much at the forefront as we move forward in the fact that for myeloma, it came out of a good thing. Something good came out of that bad history. But we have to make sure that when we do this drug development that we really do think sensibly about the best place for the drug because the last thing we want to happen is to harm any patients in any way. So when we're doing this, we have to be really, really careful.

But going back to the other thing we talked about earlier as well is I'm trying to pick the right patients. So it used to be that we would just look at a particular drug in all patients, but now there's a movement to say, right, okay, well, I think the drug may only work in this particular group of patients, so I'm going to design my study just to look at this particular group of patients. So an example would be the current studies that are going through with Venetoclax that we think would work very well for patients with an 11;14, and those are the studies that's just that group of patients now that we're looking at. So if you don't have an 11;14, we're not particularly expecting the drug to work in that area. Therefore, we're not going to include those patients in that study.

So there's some movement into how we may think about doing these studies. There's also lots of kind of movement in statistical kind of ways of doing studies as well to speed the process up, which I think is important too. So it's under a little bit of a shakeup, I think, at the moment.

Jenny: I think that's great. I've also seen different types of ways that the FDA is offering different approvals. There's like the fast-track designation. Can you explain some of those ways, and do you see that continuing? Because to me it felt like we didn't have those tools and then the FDA introduced some of those tools and now maybe they're pulling back on some of those tools. I don't know if that's true or not, but from a researcher's standpoint, what do you think?

Dr. Davies: So clearly, the key role of the FDA is to make sure that we are bringing safe and effective drugs onto the market in a timely fashion so that patients can have access to them. So you're right. If we head back kind of 30 years ago, all drugs would have to actually show that there was an overall survival benefit. As I say, now that times have changed and patients are living longer, that's not really a feasible endpoint. So then they've changed it to what we call progression-free survival or how long it takes for a patient to relapse. And then there's also some about response, how well patients respond.

In the kind of fast-track approach, we don't need to demonstrate that the drug is better than a standard-of-care drug. We do have to show how efficacious it is and what its side effect profile is. They will then give a fast-track designation, and so patients can access it and doctors can use it. But the key bit is they still are expecting more studies to be completed. So although they've said yes, they know that that's an early yes and actually what you then need to do is to go on and do the other studies and say, is it better than the standard of care and find out more information about the safety and so on.

There have been a couple of drugs in myeloma and in other diseases which looked initially extremely promising, but then when they went on and did some of the further studies, the actual promise maybe wasn't as much as everybody had hoped. So there's a look around that whole process again. And again, this is another moving part going on behind the scenes, really looking about is the current way the best way of doing this, or are there more ways that we could look at to do this? So other good examples is -- I can say you probably remember this. When we first used to give bortezomib or Velcade, we used to give it twice a week.

Jenny: I did that.

Dr. Davies: You did that? That's actually the way the drug is approved by the FDA, but doctors and patients now tend to receive it just once every week because we found out that that's a better way to give it. It has less side effects that still maintains its efficacy. So there's a whole look at the process to ensure that when we're doing the clinical studies, that yes, we come out with the right answer, that we get drugs through that process as quickly as we can but also that we don't end up with a drug where actually in the long term we're going to use it slightly differently to how it was originally used. As I say, I've been fortunate to be involved in a couple of discussions now with the FDA, just kind of talking these things through and trying to come up with some ideas about how we can be innovative in the way that we do our myeloma drug development but also so that we can ensure that the drugs reach the market that are safe and effective.

Jenny: Yes, of course. Now, when daratumumab was first introduced, it seemed like that and some other drugs have been approved kind of after the phase two study. And interestingly, in last year's IMS conference, there was the whole readout of the GRIFFIN trial, which was testing dara-Revlimid-Velcade-dex versus Revlimid-Velcade-dex. It seemed like there was a little bit of a fight between the United States doctors and European doctors, with the European doctors saying, no, we need a full phase three study, which, in my opinion, it's multi-year, it's another five years, it's many millions of dollars to run that type of study. And you had the United States doctors kind of saying, look, we can see the results. Are there any other ways that we can go for maybe an FDA approval after a phase two without running a phase three? Maybe that's using real-world evidence in the phase, instead of running a phase three trial because you're just comparing it to standard of care. If you have all that data, then maybe you don't need that, or I just want to get your thoughts on that because that, I mean, running a phase three study is hundreds of patients.

Dr. Davies: You're right. One of the differences is actually with the regulatory authorities in the fact that you're correct, the US regulatory authorities will often take this phase two data and then ask you to compare to standard of care, so give this early approval, whereas the European authorities definitely require a phase three. So again, and amongst all of these discussions, there are discussions between the different regulatory authorities trying to come up with some harmonization there, because you can imagine it causes confusion and angst for both the doctors and the patients as to having different things approved in different areas. So that's an important area.

But you're correct. One of the things that the FDA particularly are looking at and the European health authorities, I think, are also looking at it but maybe not quite so ready to embrace. It is what we call a, and the word has now escaped me, a kind of a control arm that is we've derived from real-world evidence. So rather than doing a randomized study where we take patients, give one the new drug and the others the old drug, we go into our real-world data and we pull out groups of patients that would have been eligible for the clinical study who were treated with that standard treatment. So we use them as our control arm and we say, hey, how would have the new patients done compared to this? It's been used in a number of areas. To date, it's mainly been used in areas where the cancers are very, very rare, and it would be incredibly difficult to run a randomized study because there's just not enough of those patients. So it's being used in those areas, but there's a general movement now to start thinking about using that for some of the approvals.

Jenny: I think the next one used real-world evidence to get their approval.

Dr. Davies: Yes. I was going to say the other key area for me where we use real-world evidence is, as I can say, many of our listeners may know, is that sometimes patients to be in a clinical trial, potentially either you need to have pretty good kidneys, pretty good blood counts, live somewhere close to the trial center, et cetera, et cetera. The other very useful thing for real-world evidence is to say, okay, I've got a patient in front of me who looks great, but maybe their kidneys are maybe not working quite as well as the patients who were in the clinical trial. If I go to my real-world evidence, can I look and see how that patient may do compared to the clinical trial? I think that, like the HealthTree kind of database, having that data there really helps both the clinicians and the regulatory authorities to understand how patients respond to therapies better.

Jenny: That might be some of the eligibility criteria too, right? So every trial has what you can have and whether that's your creatine count or your platelet count or your M protein or whatever, because I know some clinical trials for a Black patient sometimes on a kidney function, the kidney function measurements are different than White patients. But sometimes Black patients are excluded from trials just because the criteria is set the way that it is. So I think you could use real-world evidence to like say, well, maybe we shouldn't design our trial like that.

Dr. Davies: That’s a really great example because African American patients, Black patients will also often, as you say, have a slightly different creatine clearance but also potentially often will have a little bit more hypertension and/or a little bit more diabetes. And so that kidney function is maybe not often as good. So they will often get excluded from these studies, and we really need to know how those patients are doing with the drugs. Just as an aside, it's another area that patient advocacy, doctors, FDA, and the pharma companies are all working together to actually try and improve and ensure that our entry criteria to studies are more equitable. So that's another piece of work that is going on in the background as well.

Jenny: And then can you talk to multi-arm trials? I was looking at one company and it seemed like they did a really great job of saying, okay, we're going to have six arms in this trial. That's a lot of patients to try to recruit for a trial, but one arm is going to look at it in this combination, and one arm is going to look at it in earlier diagnosed patients, and one arm is going to look at this drug in a variety of scenarios. So in the same timeframe, you kind of get a lot done at one time. Is that kind of a newer thing? It seemed really smart to me that they would run that and then have their thoughts come out of that, that data come out.

Dr. Davies: So again, I completely agree. It's one of those things that we were saying earlier. It used to be that we took a very standard approach, which was look in A, look in B, look in C. And now there's again this movement to trying to do things, if possible, in parallel rather than in a stepwise progression. The key is to have a well-written clinical protocol. So when we do any of these clinical studies, we have a protocol, a book that we follow that explains every single step. So the key is to make sure that that protocol is well written and very self-explanatory.

As you say, in the old days, it used to be that we would run a separate study in each area, and you can imagine, not only as far as trying to recruit patients, but just for the infrastructure required. So every study has to be reviewed by the FDA. It has to have a whole set of paperwork attached to it. The clinicians have to be trained on it. So there are all sorts of, I was going to say, administrative things and costs associated with opening a clinical trial. So on a practical basis, if you can have a multi-arm clinical trial that's obviously going to be much easier to run and much cheaper to run, then it would be to run six single clinical trials. That's also another advantage of putting these things together. But as you say, running it in a stepwise fashion is really important.

To some extent, you have to have really important, I was going to say, safety steps in there. So for example, I know there's another study that has been running with these multi-arms and they noticed a slight safety signal and so they had to put the whole study on hold for a wee while to kind of make sure that they've addressed that and make sure that the other arms of the study are going to learn from the arm that had the safety signal in. So there has to be a lot of, as I was going to say, oversight when you do it like that, but it does potentially save time and save money.

Jenny: Well, it seems smart. I would think there would be a blessing and a little bit of a challenge, because in myeloma, we have a blessing of all these new drugs. I think what's happening in my myeloma is stunning, completely amazing to have this many trials running, and we're now trying to test which combinations and in what order, kind of like what you were saying earlier. But that gives you a little bit of a challenge too because you're trying to recruit patients for all these different competing clinical trials, right?

Dr. Davies: It's also tough for a patient's perspective as well because often when you're presented with these clinical trials, it's an anxious time anyway because usually your disease either just being diagnosed or your disease is relapsed, and so it's an anxious time. And then you're bombarded with an awful lot of information to take on board and to decide which is the best approach for you. I think it's also a key time from a patient's perspective is to include friends and family in that discussion, discuss it with advocacy groups, and so on, to help you come up with whether that is an appropriate option for the patient as well.

Jenny: Wonderful. Can you address distributed clinical trials? Because you have patients in rural areas that can't go to an academic center. What are you seeing happening in terms of the ability to run more distributed clinical trials? Is that happening? Do you see that?

Dr. Davies: It is happening. It's a difficult one to put into practice. There's been a lot of thought about how you do it. The reason it's difficult to put into practice is that in order to ensure that the results we see from the clinical trials are completely correct, you have to try and control all environments. So you have to make sure that the doctors and the nurses are trained on the drugs appropriately, that you can get the drug to the different sites and that if it's, for instance, it needs to be kept at minus 20 degrees, that the drug is kept at minus 20 degrees and that it's handled properly, that the data is collected properly.

So there's a whole lot of administrative work that goes on, and that's why up till now many patients have had to go to a big center. But clearly, again, making sure that everything is equitable, what we're learning is that that is maybe not the most appropriate model and that trying to move care closer to the patient's home is going to be important. So there are a number of different ways that people are thinking about how to deliver this care, be it using telemedicine. So obviously, COVID taught us an awful lot about these things. And then also deciding potentially which tests maybe need to be done in a larger center and which tests could be actually maybe done in a smaller center. So it's really ensuring that we can continue to control it properly and really trust the results whilst maintaining that the patient can benefit from having that drug.

There's lots of work going on there. I'm not sure we're completely there yet. I think that as kind of informatics improve, there's going to be a big movement in this area, but it's getting there slowly.

Jenny: Well, it's a challenge because the facility has to be prepared to run the trial. When you look at things like CAR T or bispecifics that have certain side effects that are unusual or sort of alarming sometimes, I mean, not if they're managed properly, but if they're not managed properly, then yes. So a lot of that is challenging, how you do that.

Dr. Davies: And a lot of it is going to be around education, yeah.

Jenny: Right, and preparation.

Dr. Davies: Yes.

Jenny: Do you believe that we will be able to kind of go from the down up or top down? When I was first diagnosed, most of the researchers, it seemed to be, were focusing more on more standard-risk myeloma and kind of working their way up to, if we can cure standard-risk myeloma, then maybe we can get brave enough to cure high-risk myeloma. As you said at the beginning, the high-risk myeloma patients are still quite a challenge even though the standard-risk patients are doing really well like 10, 15-plus years when that wasn't happening 10 or 15 years ago. Do you still see that as being the approach, or do you see – I know there's some work being done on these tougher genetic features and learning specifically about deletion 17 or other ones you gain or those types of things that make it a little more challenging. So which direction do you think it's going to go?

Dr. Davies: So this has got my bias in there, so I apologize. Not that any of it hasn't been without my bias, but there we go. I think you're right. People used to concentrate on the standard-risk patients because the idea is that they're potentially, in inverted commas, easier to cure. So if you're going to introduce a new therapy, then the chances are that you're going to get better results in those patients, okay? But I think you're correct. As we've had such advances, it's actually going to be incredibly difficult to start developing new drugs in standard-risk patients for the very simple reason it's potentially going to take a long time until you see whether the drug works or not. The converse of that argument is that high-risk patients, they have much more complex disease. But if your drug is really going to work, you are going to see it in the high-risk patients. You will probably see more activity in the standard-risk patients, but you would definitely see it in the high-risk patients.

So there was a meeting of the International Myeloma Society a few weeks back really aimed at trying to work with the FDA to tighten up the diagnosis of high-risk myeloma because the FDA would be very comfortable for us to do clinical trials in this specific area with a group of patients with high-risk myeloma where we have the potential to see results quickly because we know that often their treatment isn't so effective, but what they want to know is exactly what that group of patients looks like, so what color spots does that group of patients look like. There's been this meeting really trying to ensure that we have a very standard diagnosis for high-risk multiple myeloma patients. So that if we were to do a trial today, say in New York, and then do a different trial in San Diego and a different trial in Spain, that each of those groups of patients designated as high-risk would actually all be the same kind of patients and we'd then be able to look across those studies.

So my personal kind of thing is that I think the high-risk patients are certainly a group of patients with what we call an unmet need where we really need to be innovative and to look at new ways. So I would see that as one of our key areas moving forward.

Jenny: That seems really smart to me because I didn't even think about the faster results, but it makes total sense now with patients just living longer on regular therapies. Yeah, what an efficient way. And you think about it too because patients pick up these genetic mutations over time and with treatment, so you're just starting out with the higher risk thing to see will this work and will it not work? Really smart. Yeah, I think I share your bias.

Well, we've talked about a lot of different types of innovation that can shave time off to a myeloma cure. Patients should be joining clinical trials. I'd like you to talk about that a little bit. And then is there anything else, in your opinion, that patients can do? Because we are willing and ready to help you in your research and your academic work to find a cure for us faster. So whatever we can do for you, we would love to do for you. So what are your thoughts about that?

Dr. Davies: As you say, I think it's often scary, potentially, for a patient to be asked to join a research study. I think that it's always important to kind of take the information, read it, ask your family and friends about it. It's very rare now that we will use a drug where we know very little about it, and usually we'll know something about it. So it's rare to, in inverted commas, be a guinea pig, if that's the right expression. So I think it's important to kind of, if possible, take part in research so that your experience can be, you know, we can learn from your experience. It's also obviously important that you personally may not benefit from that clinical study, but other people may benefit from knowing about your experience. There is some evidence to suggest that patients take part in clinical studies may actually do better, whether that's because they're a slightly different patient or whether that's because they get, I guess, looked after maybe a little bit different and monitored a little bit different, but I think that's certainly in there. Often, if you are in a clinical study, you may have the opportunity to get a new drug that's not available yet.

I would encourage patients to take part in clinical studies. They don't necessarily need to be treatment studies. We also do a lot of studies about quality of life and about patient experience and potentially if you're not close to a hospital that does clinical studies for myeloma, I would really encourage patients to partake in some of these real-world databases like the HealthTree database because having your data there and being able to research as to access it in a controlled fashion, to look at different questions and to look at things is really important. So for example, I've been very fortunate to work with you, Jenny, and the health team, looking at the role of vaccinations and how important that is and who maybe gets off of them and so on. So I think that's kind of really key and that was all from patients giving their data.

I think the other area that's really key is not to forget how important a patient's voice is and for the role of the patient in educating the doctor. That's an awful thing to say, I know that, but many doctors maybe don't see as many myeloma patients as others do. So I think that making sure that as a patient, you understand the different kind of areas you may go down to. The different needs for some of the tests I think is really important to try and be your own advocate as well. I think that's great.

Jenny: I know your job is to be conservative and things like that. I participated in a CAR T clinical trial. And looking back on it, I was able to access that CAR T years before I could have, like right now I would not qualify for the FDA-approved drug because of what the indication is after fourth line and I hadn't had four lines of therapy. So sometimes patients can gain early access to treatments and maybe it's already through the phase one and maybe it's through the phase two already. So you have some indications of the data that's coming out. And yes, you need to do your homework as a patient and kind of ask your team about their clinical trials. But to your point, there are 80% of patients getting treated in the general oncology clinics. The doctors probably are not talking about clinical trials in those clinics because they probably don't offer them. So they're not going to bring up something that they can't offer potentially. So you do need to do your homework.

We have developed a clinical trial finder. We hope in the next, I keep saying several weeks, we'll have an AI-based personalized clinical trial finder, so you will just be able to see clinical trials you're personally eligible to join. But this is an important way that patients can participate, not just for the general community but also for your own care. So we just support you in all the research that you're doing. We want you to have the data that you need to make these incredible discoveries that you and other myeloma researchers are making. I think it's always a great option to talk to your doctor about clinical trials.

Dr. Davies: Yes, I couldn't agree more. If your doctor doesn't have, exactly as you said, if your doctor doesn’t have the clinical trial, they are not going to mind, I cross my fingers that they are not going to mind if there is a hospital somewhere close by that does have a clinical trial that might be appropriate for you. I think that's important.

Jenny: Ultimately. Well, I want to open it up for caller questions. So if you have a question for Dr. Davies on this topic, you can call in at 347-637-2631 and press one on your keypad. Our first caller, go ahead with your question.

Caller: Hi. I was wondering what the process is to talk to my doctor about a clinical trial? How do I get the conversation started?

Dr. Davies: I think there's a number of ways. If you're brave enough, if that's the right expression, just literally say, "Hey, I've learning about clinical trials. Do you have any that are appropriate for me?" So if you don't feel that comfortable having that conversation, then often there will be one of the nurses may be able to help you. But also, as Jenny was mentioning, there are a number of kind of web-based search engines to help find patients the most appropriate clinical trials but also often the actual hospital itself, so your local hospital, probably somewhere on their website will have, it's often hidden, but somewhere on the website under the clinical trials office tab, they will have a list of what clinical trials are open at your center.

Caller: Okay, what if there's one I want to join that's not at my center?

Dr. Davies: How do you do that? If that's the case, then usually they will be, or hopefully there will be a contact number for you to phone or to email. My suggestion would be that you phone and email them and find out what their entry criteria are. And then when you're armed with the information, usually, I'll flip it back to what happens with me, is that somebody would email and say, "Hey, I've heard about your trial. Would I be eligible?" I would write back and ask them a couple of questions. And if it seemed as if they might be eligible, I would then say, okay, either make an appointment to see me, or go see your own doctor and say, "Hey, what do you think about the trial Faith has got going? Could I get referred for it?"

Caller: Okay. Thank you.

Dr. Davies: No problem.

Jenny: Okay. Perfect. Okay. We have another caller. Go ahead with your question.

Caller: Hi. This is a fairly specific personal question. Obviously, we're all hoping to be cured on the way there, hoping for MRD negativity. I just wanted a perspective on having received a result off of a bone marrow biopsy from next generation sequencing that the original clonal sequence is no longer detected. Where is that patient? Is that patient cured? Is that patient still waiting for relapse? What does it mean that that, you know, is the clonal sequence caused by the disease, or does the clonal sequence cause the disease? What does it mean that it has disappeared?

Dr. Davies: No, that's right. So yes, so that MRD test by the NGS, that essentially means that when they look now, they cannot see any myeloma there, any disease there. Now, we know that that's something around about looking for one cell in a million. So they've sort of looked at a million cells, and they cannot see a myeloma cell in that number of cells. Our tests are getting better, but clearly there's that little bit at the back of our mind is what would happen if we looked at 20 million, would we find a myeloma cell? So the way we're thinking about it now is that we tend not to say a patient has what we call a functional cure based on one MRD test. We probably need at least two MRD tests, and we need them to be separated by a timeframe. So another bone marrow, for instance, in a year's time or something like that to see whether you're still MRD negative, whether we can still detect it.

As I say, what's happening at the moment is that we know that patients who become MRD negative have a tendency to have a longer disease-free interval and to live longer. It's potentially a good place to be, but we need to know that that's a stable phase, that it doesn't suddenly just pop back up again. So that's the need for that longer thing. At the moment, we're studying lots of patients to find out exactly, as you said, is if you have a sustained MRD negativity, does that equal a cure, or does it not equal a cure? We don't know the answer to all of those questions yet.

Jenny: Okay. Great.

Caller: Thank you.

Jenny: Thank you. Okay. We'll just do one more question. Caller, what's your question?

Caller: Well, hi, Dr. Davies. Thank you so much for your podcast. I have a question. Sometimes there are several clinical trials, especially in cellular therapies, that may be available at an academic center. How does one decide, let's say, between different bispecifics versus CAR T, other than trial and error or what –

Dr. Davies: Yes, that is a great question. I'm loving that question.

Caller: Where I'm going with that is, are there sort of assays or tests? NGS, next generation sequencing, that most academic centers offer only actually test a panel, I believe, of like 120 mutations. However, we are at a point where doing a full genome sequencing is possible. We can even do single-cell sequencing. Some academic centers in the United States and Europe offer that. Can we also do a T cell vitality test? What is the state of the art in terms of testing with a view to choose the optimal treatment?

Dr. Davies: So absolutely great question and that's exactly what the doctors are struggling with at the moment is in this setting, are we better with the CAR T? Are we better with the bispecific? Are we better going after BCMA, or should we do GPRC5D, for instance? I'm really looking forward to the big medical meeting in December of this year and to the myeloma meeting in the end of September because we're going to be, or we're hoping that there will be lots of new data there looking at exactly what you were saying.

So we know that in many of the clinical trials that have already run, both the academic centers and the drug companies have been looking at single-cell work, looking at T cells, looking at other cells such as macrophages, et cetera, et cetera, of ways of trying to predict who might respond to which therapies. We don't know the answer yet, and I think that some of that data will be coming out towards the back end of this year. I was going to say, I'm going to give Jenny a heads up here that she should have one of these podcasts about something like that next year. Because I think we're all looking for, you know, when we choose our therapy moving forward, do we do it based on whether the patient has the target? Are we looking at the genetics? I suspect, to some extent, we'll maybe be wanting some form of immune test, be it the T cells, be it macrophages or whatever. We don't know the answer yet, but I think we're going to get some early hints later this year.

Caller: If you're a center in real life, do you, you're on a research basis or on a clinical trial basis, perform such vitality tests for T cell or macrophages and/or single-cell sequencing for patients?

Dr. Davies: Not in real life, no. At the moment, we do it in the research setting, and we're in the midst of correlating all of this data with treatment response and so on. We can't do it outside of the research setting yet. And also, one of the main reasons for not doing it outside the research setting, if that's the right expression, is that we don't know what the results mean yet, and we need to figure out what those results mean.

Caller: Thank you.

Jenny: Okay, makes sense. Great questions. Well, Dr. Davies, we are so thrilled that you joined us today, and we just want you to continue doing the amazing research work that you're doing as well as treating patients. So thank you so much for taking your time today to talk to us about research and what it's going to take to get to that myeloma cure. Thank you so much.

Dr. Davies: Thank you for having me, and thank you for everybody who's been listening. Yeah, this is a team sport, so thank you for all of your involvement.

Jenny: Well, thank you. And thanks to our listeners for listening to the HealthTree Podcast. Join us next time to learn more about what's happening in myeloma research and what it means for you.