By Jennifer Ahlstrom | Posted - Aug 13th, 2020





Full Show: Rapid Drug Screening to Find and Repurpose Other Drugs for Multiple Myeloma with Keith Stewart, MB, ChB, MBA, Princess Margaret Cancer Centre

Keith Stewart, MB, ChB, MBA
Princess Margaret Cancer Centre
Interview Date: July 28, 2020

Thanks to our episode sponsor



What's the fastest way to find new drugs that can be used in myeloma treatment? Because the typical drug cycle is 17 years from the time an idea becomes a new drug, it may mean rapidly screening existing drugs being used for other diseases. The thalidomide story is a perfect example of that. Now, with robotics, this type of screening is possible. Dr. Keith Stewart (now at Princess Margaret) and his Mayo Clinic Scottsdale colleagues performed deep research to screen over 400 existing drugs to see if they worked against myeloma with some interesting findings. Proteasome inhibitors worked well, immunomodulators worked only inside the patient's body and other drugs like selinexor and panobinostat worked well in more sophisticated myeloma. The research identified a new class of drugs called PIKfyve inhibitors that could also be effective. We applaud this effort and believe it could lead to a faster myeloma cure. 

Dr. Stewart on Myeloma Crowd Radio


Full Show

Jenny: Thanks for joining us on today's episode of Myeloma Crowd Radio this afternoon. I'm your host Jenny Ahlstrom. We'd like to take a minute to thank our episode sponsor, GlaxoSmithKline, for their support of Myeloma Crowd Radio. 

Now, before we get started today, I'd like to mention that the topic we'll be discussing today with Dr. Keith Stewart has a great deal to do with the genetics of myeloma. Last Saturday, we hosted a Myeloma Crowd virtual Round Table with Dr. Sikander Ailawadhi, Dr. Faith Davies, and Dr. Brian Van Ness to discuss myeloma genetics. We also have an entire course inside of HealthTree University dedicated to myeloma genetics that's taught by myeloma experts. You can access those resources on the website and on website because we should all understand our own type of myeloma. 

We're excited to have Dr. Keith Stewart with us on the program today. Welcome, Dr. Stewart.

Dr. Stewart: Well, hi Jenny. Great to be here. 

Jenny: Let me just introduce you before we start in with questions and the topic that we're here to talk about today. 

Dr. Keith Stewart is Professor of Medicine at University of Toronto, Vice President of Cancer at the University Health Network, Medical Director at the Princess Margaret Cancer Center, Vice President of the Toronto Central South Regional Cancer Program of Ontario Health and the Richard H. Clark Chair in Cancer Medicine. Prior to this recent appointment, Dr. Stewart was Medical Director of the Clinical Cancer Research Unit at the Mayo Clinic in Arizona, Professor of Medicine and Consultant in Hematology and Oncology at the Mayo Clinic in Scottsdale. He's returning to his roots at the University of Toronto having started there in 1992. He serves on the Scientific Advisory Board of the MMRF of Myeloma UK and the National Cancer Institute's Cancer Therapy Evaluation Program. Dr. Stewart received the Vasek and Anna Maria Pollack Professor of Cancer Research at the Mayo Clinic for ten years, has been listed in America's top doctors and was in Canada's top 40 under 40 List of Physicians in 2002. 

Dr. Stewart is an Editorial Board Member of the American Society of Hematology or ASH Clinical News and has performed editorial service for blood, current gene therapy and targeted therapies in oncology. Additionally, he's reviewed articles in over 19 additional publications. Dr. Stewart has research specifically supported by the NCI with a very coveted SPORE grant as well as other grants on the topic we'll be discussing today -- clonal evolution in myeloma and high throughput drug screening and correlations with mutational status in myeloma cell lines. He has also performed significant research funded by the NCI on overcoming drug resistance. 

Welcome again, Dr. Stewart. We're so excited about your work and this topic today. 

Dr. Stewart: Well, thanks, Jenny. That guy sounds great. 

Jenny: He is great!

Dr. Stewart: Thank you for the introduction. 

Jenny: Let's talk about this new research that was done while you were at the Mayo Clinic that I'm sure you're continuing your work there at Princess Margaret. What was the hypothesis to create a new test to screen drugs against different types of myeloma? 

Dr. Stewart: Well, Jenny, we had been working on trying to develop our own drug, some work we had done with the Leukemia and Lymphoma Society. We started partnering with a group of medicinal chemists or people who make drugs for a living actually in California. At some point in our efforts, one of them who had decades of experience making drugs for pharma said, “Keith, the quick way to success in this business isn't what you're doing. It's drug repurposing.” Drug repurposing, it’s the notion of taking drugs that are used for different indications and using them to treat cancers or other diseases, the classic example, of course, being thalidomide, which turned into Revlimid and pomalidomide, which is obviously probably one of history's greatest examples of how this can work properly. 

We thought about what they said and decided that we would try and explore drug repurposing. So we took out of their fridges and freezers that they had not only the old and known drug that works in myeloma, which in some ways would be a positive control, but also some drugs that we thought might be active but had never really been tested. So that's how we started. We quickly recognized that there were some opportunities to take the system we built and to try and use it to personalize therapy for patients. 

Please interrupt me if I keep going on too much. 

Jenny: Oh, no. Sure.

Dr. Stewart: What we had built was using robotics. We would take a bone marrow sample from a patient with myeloma. We would sort out from the total bone marrow, the tumor cell, the myeloma cells. Then we would place those into tiny little wells with only one or 2,000 cells per well. We would use plates with 96 wells on them or even smaller plates. Then we would use a robot to deliver drugs, different concentrations into the wells to see if they were able to kill off the myeloma cells in that system. During that, we realized that this might be a way to personalize care. We ended up selecting about 80 drugs which, in our studies, both known drugs and some that weren't known to work in myeloma, would be suitable for this kind of tests.

So the idea when we started was, “Now, we have this robotics. We know how to do this. It seems to work. Can we build a test that when I take a bone marrow from a patient, within a few days, we can come back to the patient and tell them that certain drugs would work in their condition and certain drugs would not. So that was the premise of how we started. The important thing were we wanted it to be something that would be quite quick to turn around, quite simple to perform and that would be something that's compatible with getting approval for this to be a clinical test one day. So that’s how this started.

Jenny: Did you start this process a long one ago? 

Dr. Stewart: We probably started maybe -- I'm going to guess about four years ago. It took us a while to establish the system, to do the drug libraries, the library of drugs to screen, not to see which drugs might be suitable, to refine the conditions. One of the interesting things we found is that you could tell within 24 hours of adding the drug to the tumor cells that this drug was likely to be effective. And if you waited longer, it would just be more obvious. So that was quite important because for your listeners, myeloma cells, when you take them outside of the human body, they die quite quickly actually, they're simply very highly dependent on substances in the body that keep them alive. So they only really survive at best for three or four days, sometimes five days. So we needed something that worked quite quickly and that is reliable. 

Jenny: I think there's an interesting finding we'll talk about later about some of the IMiDs that they take a little bit longer to work. 

Dr. Stewart:  Yes. We’ll come back to those because they're a strange breed. 

Jenny: You also talked about this as primarily a research tool, but it could end up as a clinical tool. I think patients are just curious about that. Maybe it's just for research because if you can do high throughput screening on hundreds of drugs, that's a lot faster than guessing, even if it’s not a clinical tool.

Dr. Stewart: Right. Our work initially set out to do exactly that, which was to build a clinically relevant test that we might apply to patients. I don't know that we will take it forward as a clinical test for some reasons. Maybe we can discuss later. But there are companies out there that are doing this now, particularly in -- there are some companies doing this in the leukemias. I think there are even one or two companies if you search hard enough that might offer something similar in myeloma. But I think for a variety of reasons, we're going to probably keep this in the research arena for now. You'll probably go into a little bit of detail some of the things we found, but it probably – this part is important to mention that we ended up studying, in our paper, about a hundred myeloma patients but now through our SPORE grant, the National Cancer Institute, which is to look at drug resistance. We have studied about 160 patients as well as about 14 myeloma cell lines, which are of course immortalized cells that we can use and are replenishable. 

The thing that you started off mentioning was the genetics of myeloma. We decided we would not only work to see what drugs worked in an individual patient, but we would also do genetic studies to see if we can link the responsiveness of a patient to a certain drug to the type of genetics that were driving the tumor to grow in the first place. And that in some ways, became just as interesting as the concept. 

I'll tell you that when we sent grants and papers for review, one of the criticisms -- which is a valid one -- of what we've done is that myeloma cells, as I mentioned already, are quite highly dependent on the natural environment of the bone marrow for survival. There are many groups quite right where you say, if you take that natural survival away, you're probably biasing your drug library screening in favor of killing the cells because that natural support system, the gas and electricity, water to the host if you want, that doesn't exist anymore. So that was true. We acknowledged that weakness. On the other hand, to create that environment in a way that would be compatible with the clinical test is almost impossible. So that is why we chose to do something simple and efficient. We thought because we could see a result within 24 hours, it fulfilled those criteria. 

Jenny: And the speed of death is probably indicative too, right? I mean that's what you're looking at. To be able to do such a broad set, I think it’s just fascinating. You were testing also individual drugs, right? It wasn't like you were doing combinations of drug therapies or you were just screening a big panel of drugs. 

Dr. Stewart: We started off with about 300 drugs. We picked 80. So all the drugs you've heard about and some that you haven't. What we do for each patient is we test all 80 drugs one at a time against the patient cells. What we did -- because sometimes you don't have enough cells to do all 80 drugs. What we did is we put what we thought were the most interesting drugs on the first plate so that cells were limiting. At least we could study maybe only the first 14 or the – I think we could fit 14 drug tests on one plate. So we would go in batches of 14, 28, et cetera. 

For each patient, we’d be able to tell the physician of the 80 drugs we tested, “These drugs killed myeloma cells quite effectively. These did not at all. And some of them are in the middle,” and then provide that result back from that. Because it was research, we could provide it as a clinical test and they could take action on it. But it was more to try and understand whether it would be helpful or not in a real life situation. 

Jenny: Plus, it might uncover a whole new class of drug just like the thalidomide accident essentially.

Dr. Stewart: It actually has. We think we found a class of drugs that we had not expected to find. When you talk about what are we going to do in our research moving forward, you've already hit on the two things we're going to focus on. The first is combinations of drugs. We don't think -- and history teaches us a single drug is unlikely to be effective against myeloma -- even in a single patient. There are many flavors of myeloma. We don't think a single drug is going to capture all of these at the same time. Also, sometimes one and two equals four in chemotherapy world and we wanted to see if we could find drugs that work more effectively together, which we've done in some instances and I can talk about that later. 

Then the second part of our research was to explore these new drugs that we found that we think should be effective in myeloma and should be pursued in the clinical trials. 

Jenny: Okay. Now, you have me very curious. I'm making a note that we talk about these new classes. And I'm grateful that you're thinking about all the genetics as well. I've heard other myeloma experts say sometimes that they are surprised at how aggressive what might be considered standard risk myeloma can behave. Then alternatively, some patients have these high risk features but don't behave as high risk. 

The Mayo Clinic Scottsdale group was really well known for the genomics of multiple myeloma. Are there any thoughts that you have around that before we jump into some of the findings? 

Dr. Stewart: Yes. I think what the audience, the myeloma patients listening, need to understand is the type of genetic testing we do today as a routine clinical test is not particularly sophisticated. It only gives a fairly coarse estimate of risk. To get to the full estimate of risk, one needs to do much more sophisticated testing, sequencing of the genome, looking at the RNA, which is the product of DNA and what actually is the machinery driving the cell. It's not the blueprint, special workhorse.  So you can do those tests. Some of them are commercially available. There's a company called Skyline Diagnostics in the Netherlands that offers testing for the RNA. It's been quite good at showing prognosis, less good at predicting what therapies you should receive. 

Then when you do genomic sequencing, you actually find that there are many, many more genetic changes present in an individual myeloma patient than with the number of copies you are testing for.  Groups like the Myeloma Research Foundation’s CoMMpass Study, which studied over a thousand patients and continues to be an ongoing study, has found for example that you require sometimes -- you can then say going to very fine detail what is a very bad myeloma versus an okay myeloma, even all the FISH testing which most people have done, which is the standard clinical test that indicates lower high risk and that it may not be correct. One of the shocking findings actually is -- some of your audience would have heard about deletion of chromosome 17 or the gene is p53. Now, if you have loss of that part of chromosome 17, then you are a high risk patient. That's been 10% of all patients with diagnosis. With each subsequent relapse, it becomes more frequent. 

What we learned in the CoMMpass studies is in fact – hopefully, your audience will know you have two copies of every gene. It turns out you have to damage both copies, not just one, which was what we're testing for, to be truly high risk. So part of the implication is a lot of patients that we're telling are high risk are probably not. On the other hand, maybe some are standard risks who, as you pointed out, do badly and clearly are higher risk genetically than we first suspected. It would be naive, however, to say that we understand everything. I think even with genetic testing, it's still imprecise. I think this is why people are beginning to explore things beyond genetics, to look at the chemicals and the proteins that ultimately make the clock run in the cell and try and decipher better what's a high-risk patient, what’s not and what makes them drug resistant and what makes them sensitive, which is why we combine genetics with the drug screening. 

Jenny: Right. Nowadays, are you suggesting that your patients get into the gene expression profile like the SKY92 test or the next generation sequencing like the Foundation Medicine test when you do genetics? 

Dr. Stewart: Well, the Foundation Medicine test would be halfway there and try to – you can go much deeper than that even. So it's like many things. That's where the science is ahead of the funding. Today, it's hard to get funding for anything except the basics on a routine basis. But the science is telling us that we should be taking deeper and that overtime, that will gradually become part of our routine work. But for today, it's usually in the next stage, we do FISH testing. Usually, in most cases, you're able to get the genetic sequencing if you want it done. First, the myeloma panel, we developed one, Sloan Kettering I think has one. Then, of course, there's Foundation Medicine and commercial labs that will offer this kind of testing as well. 

If I were a patient with myeloma, I'd want that done. The question is whether the insurance company will pay for it. 

Jenny: Yes and sometimes, you have to ask your care team for it specifically.

Dr. Stewart: Yes. Sometimes, it can be done on a research protocol even if it's not a clinically valid test. It can be done on a research basis. So certainly, if you point out, it’s something our group in Scottsdale and across the Mayo Clinic really focused on for many years. It’s how to develop these tests and to bring them up as clinically diagnostic.

I will say that much of the reason that sequencing hasn't caught on is that this time, much of the information you learn is interesting, but it doesn't terribly alter treatment. The one place where I saw recently that it does offer treatment was some data that the Skyline group had generated where they suggested just using their test changed the type of treatment people got almost half the time so that some patients who were thought to be standard risk became high risk and high risk patients became standard risk and their physicians took that information and altered -- not necessarily the drugs the patient would get but perhaps how long they stayed on them, whether a second transplant would be used -- because this was done in Europe -- whether maintenance was with one drug or two drugs. So they made some alterations to therapy based on that test. And I think that will gradually pick up steam. Right now, that test isn't FDA approved. It is available at some centers around the country. Certainly, you should be asking your physician if it's available or if similar genetic tests are available at your center. 

Jenny: I think especially if you’re newly diagnosed or you're relapsing and trying to decide what to do. 

Dr. Stewart: I think information is power. So it never hurts to have more information about your disease. Certainly, sometimes, it's not what you want to hear, but it's usually better to know that for many reasons. So one, it might change your treatment; two, new drugs might come along that aren't available today and venetoclax is an example of that; three, sometimes it's just better for life planning to know what side of the fence you sit on. 

Jenny: Yes. I completely agree. When you were mentioning the test, you talked about it running it in 24 hours and being within 24 hours, you could tell. Is that the normal turnaround time? Was there a different turnaround time? How long did you let it go? You mentioned you know that myeloma cells are dying outside the bone marrow.

Dr. Stewart: We tried 24 hours, 72 hours and five days. What we saw is if you take it five days, we lost a lot of cells. So it was a bit noisy. If you look at 72 hours, it was probably the cleanest time point for analysis. However, we realized that at 24 hours, you could already see that patch emerging, not much change over the next two days except it was more cells dying. So we ended up -- because there are more cells alive to study and because it was a faster turnaround using 24 hours as our metric.

Now, you mentioned the immune modulating drugs earlier, Jenny, which are, again, thalidomide or lenalidomide or Revlimid and pomalidomide or Pomalyst and iberdomide, which is the new one that's coming. And they all work the same way essentially. It’s that one after the other, they become stronger. One of the things that I'm always puzzled about and we studied these drugs for decades now and which this test really brought home to me is they are pretty horrible trying to kill myeloma outside of the body. They really don't do a very good job. One of the reasons our test turns out, I think, not to be as clinically useful as we thought it might be is you couldn't really tell if the IMiD drugs, if these four drugs -- because we studied them all -- were working or not. And even if you waited for -- you could kind of tell it five days which ones were responding, which one won’t. 

But the other thing that people I don't think has fully explained yet is you need huge doses of the drugs. I mean thousands of times higher doses of the drugs than you need for other more effective drugs. For example, proteasome bortezomib or carfilzomib, the proteasome inhibitors, you need what we call nanomolar concentration, which is tiny amounts of the drug versus micromolar, so a thousand times more drug to get the same effect. So why that is true, I have no idea. Today, I think it suggests that some of the action of those drugs might not be directly related to killing the cells but more to activate an immune system or are causing some arrest of cell growth. The assay we use measures the inability of -- it measures cell death. It doesn't measure very well if the cell just stops growing. That doesn't help as much. 

So that's one of the mysteries of life that we have figured out yet. Why are these drugs so powerful in humans and yet, if you were to take a lab-based test to try and decide what drugs to use, you would never pick these ones? Fortunately through serendipity they turned out to be a very powerful and probably one of the most useful drugs we have in this disease. But had you started where we are looking for drugs that look good in a test tube, you would never have picked those three drugs. So that's a very curious thing and one that we still don't really understand. 

Jenny: Hence the name immunomodulator, right? They’re modulating the immune system, which is maybe why they're only good inside the body.

Dr. Stewart: Well, I think that maybe, it'd be very aptly named because – they were named that because of the effect they have on some of the proteins that stimulate the immune system, particularly the block one of them. Secondly, they increase one of them called interleukin-2. But for many years, I don't think any of us thought that's how we were working until the discovery that CAR T-cells were so effective. I think having us re-examine the skill these drugs have to kill cells in humans that it may actually do to their immune activation as much as directly killing a myeloma cell. 

Sorry. But diverging a little bit, these are sort of theoretical things right now. The important thing for patients is they work extremely well. 

Jenny: Well, let's talk about what else you learned because I was blown away at all the detail that you learned from this study. I was just amazed by it. 

Dr. Stewart: Well, it was many, many years of work with the talented team. I should give credit to my lab and to Dr. Nathalie Maurice who did all the drug work and her husband, Dr. Joachim Petit, who did all the drug screening and the staff who analyzed it. Just to summarize for the audience a little bit some of the things we learned, first of all, the drugs we thought would work really well worked really well. So the proteasome inhibitors, bortezomib and carfilzomib, were consistently at the top of the list of most effective drugs. The immune modulators which we talked about already were disappointingly not among that top list. 

The second thing we learned, there was about ten drugs that we studied that were completely inactive, some drugs which were even at the time in clinical trials for myeloma. For example, we studied a drug called ibrutinib. Ibrutinib is approved and used in other leukemias, particularly chronic lymphocytic leukemia. I was in clinical trials in myeloma when we started this study. We saw no activity of that drug at all in myeloma. One of the things we point out is if you did this kind of screening, you could probably reject drugs more quickly. Or I think more importantly, you could select in the lab patients who are most likely to respond to the drug and enrich your clinical trial for those patients so you would see faster evidence of activity and hopefully get to faster drug approvals. 

The next thing we found, Jenny, was that by this time, the drug Venetoclax had been discovered to be very powerful – and I'm sure you've talked with this on your show before -- in one particular genetic type of myeloma. Just in case other people haven't heard this from other places, it's a type of myeloma. It's 20% of myeloma patients. They have broken chromosome 11 and it's joined to chromosome 14. So a good reason to get genetic testing done today is to find out if you have that type. That particular type turns out to be exquisitely sensitive to the drug Venetoclax, which is approved by the FDA for a number of cancers, not yet myeloma but approved for a number of leukemia. It’s really changing how that's treated. Chronic lymphocytic leukemia, it’s changed how that's treated. 

The point of my story is that in our system we went to look to see, number one, does Venetoclax work? The answer is yes, but only 30-40% of the time. Then did it mimic what we're seeing in humans that it mostly worked in these translocation 11;14 patients? And the answer was yes. So it was a positive validation of part of the assay that this drug was working in the test tube just like it did in humans and in the same genetic subgroup of patients. 

Conversely, when we looked at Selinexor, which as you know was recently been approved, we found that rather than being active in good risk patients like translocation 11;14, Selinexor turned out to be most active in the higher risk patients, those with, for example, loss of chromosome 17 that we discussed earlier. 

We were also able, Jenny -- because we randomly took bone marrows from any patient that was willing to share with us some of their precious tissue, we had patients who were newly diagnosed. We had patients who were on the first relapse. We had patients with had had many prior therapies. We were able to then correlate what stage of disease were you at when the drug worked. Again, we found that Venetoclax, for example, work better if you treated people earlier in their disease course. And Selinexor, conversely, works better in people with more advanced disease. So just the Selinexor has been approved for now. At more heavily pretreated high risk patients, we were able to see that as well in this assay. 

One of the global questions we asked was if you just put everything together on one picture and said, “Where is myeloma more sensitive to these drugs?” it was the opposite of what you would expect. You would think, “I’ve got new cancer. It should be more sensitive to the most drugs.” We found the opposite. We found that in newly diagnosed myeloma, less of the drugs were active. And in people who had late stage myeloma, more of the drugs were active, particularly classes of drugs we don't usually use in myeloma therapy. The thinking there is that as the myeloma is progressively more drug resistant, it's growing a bit faster. It got more genetic mutation. It opens itself up to sensitivity to drugs that don't exist when the myeloma is slow growing and not particularly genetically disrupted. That was another surprising finding, but I think maybe explainable. 

So those were some of the other things we found. 

Jenny: Yes. It seems like it would be opposite. It'd be much more sensitive. Did you find which drugs were the most sensitive for newly diagnosed myeloma samples? 

Dr. Stewart: The most sensitive drugs were the proteasome inhibitors, carfilzomib and bortezomib. There were some other drugs in there too. Selinexor was also quite -- it may still work quite well in newly diagnosed patients. It was just more evident in late stages. There's a drug called Romidepsin, which was used for T-cell lymphoma. That worked very well in our assay. But we don't use it in myeloma so it might be worth exploring some more. 

I’m trying to think off the top of my head what was in that top five list. Then Venetoclax, if you have that particular translocation, corticosteroids of course, dexamethasone, more active in newly diagnosed patients as you would expect. Apart with the exception of the immune modulators, that sort of fit the pattern of what we've seen. 

We did not have daratumumab. We just didn't have that in the panel at the time. We weren't sure it’ll work in our assay. So we have never gone back to look at any of the immunotherapies like daratumumab or the CAR T or BiTEs to activate T-cells because they wouldn't be likely to work in our assay. 

I think drugs like GlaxoSmithKline’s drug that’s worked its way throughout the FDA…

Jenny: Yes, the antibody-drug conjugate.

Dr. Stewart: Yes. It probably would work in this assay, but we didn't study it at the time. The other drug we found that was very powerful in newly diagnosed patient was the drug Panobinostat. Many of you may not have heard of Panobinostat, but it was FDA approved for multiple myeloma, particularly when combined with a proteasome inhibitor. We found it to be extremely important in this assay. So both Panobinostat and Selinexor are both approved for treatment of myeloma, both very powerfully active in these assays. The challenge is they're also somewhat toxic to humans. So they're also hitting the right things. They're doing their job. They were brought forward as drugs. They're doing their job in all these models. But the problem is when you get them to humans, they do other things as well. So both drugs cause diarrhea and fatigue, will lower blood platelets. So for that reason, they haven't perhaps had the -- either we haven't explored the right doors or combination of those drugs that can be given more safely yet or because they do hit all the right notes when you look at them in an assay like this and are probably very powerfully effective if you could give enough of the drug, safely. 

Jenny: Is that why Panobinostat isn't used as often, just the side effect profile?

Dr. Stewart: Absolutely. It’s the main reason it's not used that often. In the groups of patients that was studied, it was effective but not hugely effective. But if it was less toxic, I think we'd use it a lot because it does work quite well. 

Selinexor, and the company Karyopharm is doing the right things. They're exploring lower doses less frequently in combination with other drugs. We learned recently that when you give a much lower dose with bortezomib, it's very, very effective. And the side effects are more manageable. I actually don't like that term manageable, but they are a bit less. So I think it's still a difficult drug for patients to take. But as we explore how to give it more safely, I think there's still opportunity there. 

Jenny: You went over deletion 17p. What about the Selinexor? It might be better in those patients. Did you find anything else for deletion 17p? Then what about the 1q gain or 4;14 or the other or maybe even 14;16 that are considered to be more high risk features? 

Dr. Stewart: I think that's already described, the two main findings, which were the 11;14 and the deletion 17 patients. We still have a lot of data to go through and analyze because we did look at all 20,000 genes that are in the human genome and to try and decipher whether there were patterns of those genes that link to whether the drug worked or not. The problem you get into a little bit, there's so many different types of myeloma and so many different mutations that that despite the fact we went to 150 patients, it gets down to quite a small number quite quickly. For example, there's MBTH. There’s something called IDH, which happens to about one to 2% of myeloma patients. And those drugs, you can target that with. But of course, we only had maybe three or four patients in our whole group. So it's not very much to work on because they're just such a rare thing to see happen. Unless there’s something else that I've forgotten about, those were our main findings with respect to genetics, but more work to be done.

Jenny: Then did you see similar things for what you call double hit myeloma – and you might need to explain that -- or triple myeloma?

Dr. Stewart: Double hit myeloma is what I was talking about earlier -- sorry, it's not really. We worked with Gareth Morgan and his team in Arkansas. Then they moved to New York. Well, what Gareth did really -- I shouldn’t take a credit for this -- and his team did -- they looked at large numbers of myeloma patients, maybe 1,500. Then they looked at all the different genetic changes. They looked at the age and the kidney function and the hemoglobin and the performance test of the patient and tried to decide that what was the most high-risk patient population. They discovered there were three things that predicted for very high-risk disease. One of them was double hit myeloma because there were two genetic changes that defined what that would look like. It could be you have one of the chromosome translocations. So the chromosomes have broken and rejoined. That we know is high risk. You could have one of those, but you had a second change, too, which might be deletion of chromosome 17, for example. We stole the term “double hit” from the lymphoma doctors because they had already used this to describe lymphoma patients who had two genetic changes and were very high risk for early relapse. So we came up with this term “double hit” myeloma. And triple hit myeloma means you have three bad genetic changes in yourself instead of two bad hits, which was the double hit. 

The good news for myeloma patients is only about 6% of all patients we studied had double hit myeloma, so 94% of patients did not. So studying this population is going to be tricky in trials because it's not that common, which is good. 

Jenny: Yes, interesting. Then triple hit is just having three different genetic mutations?

Dr. Stewart:  Yeah, so something like translocation 4;14 and deletion 17 and amplification of chromosome one, all of which are individually associated with high risk. If you put all three together, that's going to be a difficult case. The connotation for the physician is you've got to treat that aggressively or look for new ways to treat it like CAR T therapy. There's not a guarantee that anybody with those changes will do badly, but just on average, they will do less well than other patients and because everybody still remains a bit unique, so not to despair if you find those things, but rather just look for perhaps alternative therapies or a more aggressive approach to therapy. You may still do very, very well with those changes. But overall, if you took a hundred patients with them, a hundred patients without, those with them would not do as well.  

Jenny: Let's talk about precursor conditions. Did you have smoldering myeloma samples in addition to the myeloma samples? Then what were the difference in responses to these drugs? 

Dr. Stewart: We had some but not very many because we tried not to have them because it was a different question. We ended up with about eight of the 150. To make this analysis simpler, we just decided to treat those as newly diagnosed myeloma. So I don't have anything impactful and meaningful to tell you about the differences that we found on our studies. I think generally, we would expect the smoldering myeloma cells would be slower growing and still quite very sensitive to the drugs we know to work in myeloma, but as I mentioned already, probably less sensitive to the broader panel of drugs which are less specific, I think. So not much to say for that.

The treatment of smoldering myeloma is a bit controversial right now as you know. I think my opinion is a bit different from others. I don't think treating a myeloma with a single drug like Revlimid or daratumumab for that matter is a terribly good idea. Others have shown in studies that your myeloma doesn't -- it takes you longer to develop myeloma if you're on those drugs, which is for sure. And that could be a good thing just to allow more drugs to become available. I just worry that essentially, what you're going to do is create drug resistant cells before you need to and that the best way to get a drug resistant cell in the lab is to grow a myeloma cell or another cancer cell in low doses of a single drug for a long time. They’re on these guarantees that you'll get drug resistance. So I just worry a little bit that unless you're really, really clearly going to going to get myeloma in the next 18 months, I would personally not recommend therapy. I think if you are going to treat myeloma and you decide it needs treatment, then you should treat it properly. You should give all the same drugs you would give to a newly diagnosed patient. But that's probably a minority opinion these days. Certainly, if your physician feels otherwise, you should talk to him about it and go through the pros and cons.

Jenny: Well, that makes a lot of sense, I think. If you have it, just treat it. And if you can wait it out, wait it out. Not being on anything might be better. You don't make the cells more sophisticated. 

I had a question, too, on cyclophosphamide. I find that a lot of people use cyclophosphamide later on in therapy when things start not working. I just didn't understand the findings in your study. 

Dr. Stewart: No, it's quite simple really. Cyclophosphamide is a good drug in myeloma. We use it a lot back in the old days. It's of the same class of drugs is Melphalan. They’re called alkylating agents. It's a very good drug. It's also quite easy to take, very few side effects, can be given orally. In fact, it's probably better orally once a week. It can play an important role in people's therapy. In fact, as you know, many of your patients will know we used Cyclophosphamide in newly diagnosed patients for many years and still do when sometimes, for example, Revlimid isn't available and the patient's in the hospital and they can’t get access to Revlimid. There's still a lot of cyclophosphamide to use, so it’s a very useful drug. 

Cyclophosphamide is metabolized. So you take what is essentially a pro-drug. And it's not active until it's metabolized in the body and it becomes active. We forgot this when we set up our screen. We use the pro-drug or the stuff you would swallow, but has now been metabolized. You will be surprised at first to see there was no activity. Then we realized, of course, that that's actually a good thing. It proved that our assay was correct because there's no way the drug could work without metabolism. So it was a negative control. That's what we said in the paper. As expected, the negative control of cyclophosphamide, which has now been metabolized, doesn't work. It's useful in some ways to show that the assay wasn’t just totally nonspecific and just any old poison would kill the cells. 

Jenny: Earlier in the show, you hinted that you found these new classes of drugs that were active, that have not been tested in myeloma. We can’t get to the end of the show and not cover that because that's really important. So what new classes of drugs did you discover? 

Dr. Stewart: Well, we published a paper on this now. In our very first screen where we took 300 or 400 drugs and looked at them – and they were sort of drugs that this chemical company had on the shelf. They’re called Madison. Great scientists, they are great colleagues and partners. I don't know quite why they pull this one off the shelf because the thing they had it was convenient. The really fascinating thing about this class of drugs is they were developed by drug companies to treat totally different diseases, essentially to treat inflammatory bowel disease and psoriasis because they were shown to be able to turn off some of the proteins in the bloods or the genes that are making the proteins in the blood that were driving the inflammation associated with those diseases. So inflammatory bowel disease, inflammatory condition. There are things called cytokines which are proteins, which usually stimulate the cells of the inflammation system to grow faster and to proliferate. These drugs were developed because they inhibited those cytokines. 

In our assay, quite amazingly, they were extremely powerful and extremely potent. But not all examples, only about 40% of them, for reasons we don't fully understand yet. Subsequent work on this class of drugs, they're called PIKfyve inhibitors. And that's spelled P-I-K-F-Y-V-E. There were three of them that had all been developed by a drug company, so you buy it off the shelf now. All three of them were very powerful. I’m somewhat surprised, it consistently only in about 40% of patients. It turns out that these drugs or inhibitors of inflammation were doing so by blocking this gene called PIKfyve kinase. We went on to publish a paper just last year to show the details of that result. 

All three of these drugs in this class were very active in about half of the patients, 40% of patients and that since they'd already been in clinical trials before and were relatively nontoxic in the trials, that these are drugs that were potentially repurposable and could be used in humans. So part of our ongoing work now is to try and make slightly different molecular versions of the drugs and then take those into clinical trials. That's something we're working on now. We're at the stage actually of looking to go to animal studies to see if they're toxic or not in animals, looking at other types of cancers to see if, “Is this just myeloma or other cancers affected?” So far, it seems to be pretty specific to lymphoma and myeloma and not so much of the cancers. 

We think we're onto something here. The drugs that we use are generic chemicals you can buy out of a catalog today. We think it's important to develop slightly modified versions of those and then take them forward to one day go into clinical trials. We thought it was quite an exciting discovery. Hopefully, it will lead to more investigation from other people and maybe a resurgence of use. But it's one. One of the three drugs is called Apilimod. There is a company that is studying that in early stage trials in lymphomas. Certainly, hopefully, we got their interest and they want to study their drug in myeloma as well because it's already in clinical studies. It wasn't the strongest of the three, but it certainly was the most readily available. A company, unless they changed their name, is called LAM, L-A-M, Therapeutics. I haven't spoken to them in 18 months, but I think they're still studying the drug in lymphoma. 

Jenny:  Well, I think it's fascinating to be able to find a whole new class of drugs that could be working. Yeah, go ahead.

Dr. Stewart: The way they work is kind of curious actually. When you treat a cell, the cell fills up with what looks like a bunch of sacks of fluid or balloons. We call it vacuolation, so these big kind of fluid filled sacks develop in the cell. Then the cells spontaneously died. It's not something you see with other drugs when you treat myeloma. So it's something quite unique. So just even understanding how they're doing that and why that's important in myeloma cells, life is going to be an interesting area to study over the next few years. 

Jenny: I think it's fascinating. I also saw something there about -- before we open it up for caller questions, I just had a couple more -- that there were hyperdiploid patients. I guess these are patients that have extra copies of chromosomes. But what did you see that worked potentially best for those patients? 

Dr. Stewart: Jenny, off the top of my head, I can’t even remember.

Jenny: No, I will have to go back to look too. I’ll include it there. 

Dr. Stewart: Hyperdiploidity, we will consider a low risk disease. It’s about 50% of myeloma patients. It's very odd because it's the odd-numbered chromosomes. It's chromosome 1,3,5,7, which nobody will be able to explain to you why that is very strange. We classify those as lower risk, so some of the -- again, a little bit more sensitive to the usual drugs and less sensitive to the more potent drugs. Selinexor was a little bit last effective in that group.

Dr. Stewart: I think what people need to know is that class, that type of myeloma is the one honestly that has the best prognosis. Therefore, it's usually quite exquisitely sensitive to the drugs that we use. It's one of the types that we feel most confident we're going to get a good outcome for. Fortunately, it’s 50% of patients. It's a little bit more common in older patients than younger ones and a little bit more common in IgG myeloma as opposed to IgA. If you didn't know this, the audience, IgA tends to associate with the higher risk genetic changes. Again, we have no idea why. So IgG, generally, hyperdiploid disease, a little bit better prognosis. 

One of the curious facts I often tell people when I'm lecturing this to families and patients, the worst bone disease is in hyperdiploid patients often. And the theory there is that -- so paradoxically, if you're actually so terrible, it may not be such a bad thing in the long run. The reason for that is we think this disease is around for longer. It has more time to do damage before it is picked up because it's more slowly growing and it's causing less problems initially until the bones get quite damaged and then you start to notice it. 

Jenny: Yes, I've heard that too -- higher bone damage but lower risk. Interesting. 

Dr. Stewart: Exactly. 

Jenny: My last question, I guess would be, is this a methodology that you can use to work with pharmaceutical companies to rapidly find new opportunities? I mean I would think that you could do really rapid drug screening and save them a lot of time and money and effort to see if something like this would even be workable in myeloma. 

Dr. Stewart: I think that that's exactly probably the biggest take home message from this. We even like, for Venetoclax for example, rather than doing a trial in a hundred patients to show that it works 20% of the time, which is what the data end up showing, if you took that same drug and made sure it works first, you could probably double the response rate or triple it and have a much faster readout that your drug is effective. It may not work for all drugs. We already talked about the immune modulators and how that didn't work and the cyclophosphamide because it wasn't metabolized, didn't work. Then some drugs like bortezomib work almost 100% of patients, so it would really help there to find good drugs. For drugs with that more targeted nature, like the new ones we discovered or like Venetoclax, it could be a very powerful tool.

Jenny: I agree. I mean whatever we can do to save time and money and get to answers faster about what potentially could cure myeloma, that would be terrific for everyone. 

Dr. Stewart: Exactly. 

Jenny: Amazing. Well, Dr. Stewart, I want to open it up for caller questions as well. So if you have a question for Dr. Stewart, you can call 347-637-2631 and then press 1 on your keypad. We'll start with caller one. Go ahead with your question. 

Caller: Hi, Jenny. It’s Jack.  

Jenny: Hi, Jack. 

Caller: Dr. Stewart, it’s always good hearing from you. 

Dr. Stewart: Hi, Jack.

Caller: I had a question on the assay. Myeloma patients always go to presentations and one of the first graphs we see is that the deeper the response you get, the longer progression free survival and overall survival one typically has. Are you able to measure depth of response in this assay? 

Dr. Stewart: No, Jack, we can't measure that. It actually tells you two things. It tells you what percentage of the tumor cells die. So 30% die or sometimes, it was quite interesting. We saw that 20% or 30% of the cells would die. The other 70% were just quite happy to keep living, suggesting that there were two different flavors of tumor in the sample or myeloma in the sample. The second thing it tells you is what concentration of drug is required to do the killing. So we use something called the effective concentration, 50%. So what we would read out to the physician is “This is the concentration of drug to kill 50% of the cells in 24 hours.” So that doesn't really tell you much more than that. It doesn't tell you whether in an individual patient, that drug’s going to get rid of 99% or 10%. 

Part of the reason is also we all metabolize drugs differently. So you give drugs, the same drugs to two different people, different sizes, different weights, different genetic makeup. It's not always better liver function, worst kidney function. You're going to get different concentrates to the drug and they will do different things. So that's why we can't really tell what the depth the response would be. We're just trying to predict where there's going to be some response or no response. 

Caller: Thank you. Enjoy the maple leaf. 

Dr. Stewart: Oh, thanks. Well, that'd be a long thing coming. But it's sad as a Canadian - I don't even like hockey that much. But there you go. 

Jenny: All right. Thanks, Jack. 

Dr. Stewart: Don’t tell them 

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

Caller: Yeah. Dr. Stewart, it's your favorite patient, Chad. No, I don't know if you remember me from Phoenix. 

Dr. Stewart: Hi, Chad, how are you?

Caller: I’m doing good. Hey, two questions. One, you and Jenny had talked at the beginning of the show about getting more accurate genetic testing. Is that something that you can just ask your doctor to order for you or how do you go about getting that? 

Dr. Stewart: I think you should discuss with your doctor and say you've heard that might be useful and that you'd like to pursue that if you can. I think there'll be a couple of questions that might come up -- if you're willing to pay something out of pocket, whether you want to join a research study or just to find out what your insurance will cover in the first place. So I think we're very variable depending on where you are. I think if you're in a major center, you're going to be able to get that testing quite easily. If you're in a smaller community setting, it may require a referral, some major center to get that kind of testing done. 

Chad, by the way, you need to call me afterwards because I know you had some issues recently. I'm glad to hear your voice actually. So give me a shout. 

Caller: I will, for sure. Second question just real quick, as you know, I was supposed to go into a CAR T trial in March and that got derailed because of COVID. How is it looking for FDA approval of just commercially available CAR T?

Dr. Stewart: Great question. The only one that's been filed with the FDA so far is from Bristol-Myers Squibb, which used to be Celgene, of course. It's a BCMA-targeted CAR T. My understanding is when they filed initially, there were some issues with the manufacturing portfolio they submitted. They had to go back and fix that and resubmit it again. The last I heard -- and it may not be completely accurate so don't hold me to it -- was they have refiled and it's in the works. We used to tell our patients we expect to see this. Personally, I think there's absolutely no doubt it will get approved. We expected to see approval this summer. I think because of that manufacturing delay and perhaps because of COVID slowing everything down, it may be into the fall before we see a commercial product. 

We're all waiting anxiously because there's huge pent-up demand for this. Right now, it's not only not commercially available but the clinical trials also got completely disrupted by the COVID pandemic. Manufacturing problems -- not problems but inability to manufacture during the pandemic slowed down availability. The drug companies couldn't come in and study the charge of patients in the hospital. So a lot of the trials were just halted and stopped. It's been a bit of a difficult situation for everybody. 

But for commercial product, I think -- by the way, I want to just tell your audience that FDA approval doesn't automatically mean the drug’s on your doorstep the next day. Once they approve it, then there is a period of time during which the insurers have to catch up. The supply chain has to kick into action to deliver across many countries. The experience in lymphoma is to some degree that even the pharma companies themselves are having a little bit trouble manufacturing enough of the product to satisfy the demand. So there are lots of reasons that this might be a bit slower to roll out than everybody had hoped. 

In the meantime, a lot of clinical trial is going on, if not with CAR T, with things called BiTEs. They seem to be pretty active as well. And if you can't get hold of CAR T, I would suggest you talk to your doctor about whether a BiTE therapy on a clinical trial may be of interest. Unfortunately, those are still pretty early stage testing, which means there's, again, more demand than supplies. So you have to persevere, I think, to trying one of those studies. But they do seem to work quite well in some patients for quite a long period of time. 

Caller: All right. Thank you. 

Jenny: Thanks. Thanks for questions, Chad. Thank you, Dr. Stewart, for answering. We have one more question. Caller, go ahead with your question. 

Caller: Hi, Dr. Stewart. My question is how do you use this test panel to test future immunotherapies? Where do you from here? Do you test immunotherapies now or more drugs in different classes or anything else? 

Dr. Stewart: I didn't know if I heard all that correctly. But we haven't really used this assay to test immunotherapies because there is no immune system in the wells. The T-cells that are activated by CAR T therapy are not present, so we wouldn't expect to see an activity. So we haven’t really -- it actually doesn't actually lend itself to studying the immune system. I think there are other groups out there trying to do that where they are trying to study that in the tester, but it's still ways out from being clinically impactful. 

Small molecule wise and new drugs coming along, nothing I've really heard about to get excited about. We certainly are looking forward to getting Venetoclax approved by the FDA. We think that the CAR T and the BiTEs will get approved over time. So it's more coming, but new classes completely out of the blue and very active or maybe some -- if there are, I'm not aware of them. 

I mean the good news I think is every two years, we got a new drug in myeloma. That's been consistent since 2000. So 20 years on, we have ten drugs now. There's no sign of that slowing down. There's dozens of drugs in the clinic. There's at least four or five that should get FDA approval in the next few years. So they keep coming. 

Jenny: Yes. It's amazing. Thank you so much for your question. 

Dr. Stewart, thank you so much for joining us today. What an informative body of research you've been working on. I think it's truly moving the field forward in knowing how to treat, which kind of patient, how to personalize medicine. And I’ll just say keep going with this assay. 

Dr. Stewart: All right.

Jenny: Thank you for joining us today! We're excited for your research and excited that you're at Princess Margaret and just appreciate everything you do for patients. 

Dr. Stewart: All right. Take care, everybody. Thank you. Bye-bye. 

Jenny: Okay. Thank you so much. And thank you for listening to another episode of Myeloma Crowd Radio. We invite you to join us next time to learn what myeloma research means to you. 

Jennifer Ahlstrom
About the Author

Jennifer Ahlstrom - Jenny A - Myeloma survivor, patient advocate, wife, mom of 6. Believer that patients can help accelerate a cure by weighing in and participating in clinical trials. Founder of Myeloma Crowd, Myeloma Crowd Radio, HealthTree and the CrowdCare Foundation.


Add a Comment



Thanks to our site sponsors: