Dr. William Matsui, MD
Johns Hopkins School of Medicine
Interview Date: May 6, 2016
Dr. William Matusi of the Johns Hopkins School of Medicine wants to understand why myeloma patients almost always relapse. His study led him to understand the difference between myeloma B-cells (stem cells) and more mature myeloma plasma cells. He noticed that the B-cells could generate more tumor cells while the mature plasma cells could not and also noticed that they were different in their sensitivity to chemo. Additionally, proteasome inhibitors target the proteins on the myeloma cells’ surface, but these early B-cells don’t make a lot of protein.To add more complexity, as a patient relapses, their M-spike number becomes less informative as to how their disease is or is not progressing. Because these B-cells can be counted in a patient’s blood, Dr. Matsui is measuring levels with a special flow cytometry test. He shares his research of borrowing B-cell treatments like rituximab from lymphoma, but found that the CD20 target typically used for this type of blood cancer didn’t work in myeloma. When he used a new CD19 target, however, he saw dramatic impact in multiple myeloma and he believes that the recent UPenn success further validates the idea that CD19 could be present on myeloma stem cells. To learn more about joining this exciting study, click here:Johns Hopkins MEDI-551 Clinical Trial
Dr. William Matsui on Myeloma Crowd Radio
Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom.
We’d like to thank today’s episode sponsor, Takeda Oncology, for their support.
Now, we’ve wrapped up the first portion of our Muscles for Myeloma campaign and we’re going to keep that program open indefinitely. We had a lot of requests for people who wanted to do different activities. So we have people that are riding bikes, doing bike races and are organizing co-worker teams. We are so thankful that you joined — and I hope you will continue to join — because fitness still matters for myeloma patients and the treatments they can receive and their outcomes.
Also, before we get started, many of us have myeloma experts as part of our healthcare team, which we highly recommend. The Myeloma Crowd is now hosting live patient meetings to help you connect with myeloma experts who can help you understand your treatment options, especially at relapse and for high-risk patients, because these patients need it the very most.
Now, our first Myeloma Crowd Roundtable on High-Risk Disease will be tomorrow, May 7th in Salt Lake. And the second will be held June 18th in Saint Louis with another coming shortly in Boston. So we will have experts at these meetings and it’s an opportunity for you to learn about immunotherapies, high-risk genetics, effective strategies for relapsed/refractory myeloma so that we can prepare for our best myeloma care.
Now, onto today’s show. We’ve heard a little bit about myeloma stem cells and how they can mature into myeloma plasma cells. And one doctor, Dr. William Matsui has been working on the study of these stem cells for over a decade, and has exciting insights to share with us. Quite possibly, hitting myeloma earlier in the process may eliminate the challenges that myeloma currently gives us. So we are completely thrilled that he is joining us today. So, Dr. Matsui, welcome.
Dr. Matsui: Thank you.
Jenny: We’re so happy to have you here. Let me introduce you before we get started. Dr. Matsui is the Head of the Myeloma program at Johns Hopkins. He’s also Professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center and is a Member of the Department of Oncology, and Member of the Graduate Program in Pathobiology and Cellular and Molecular Medicine. He is on the editorial and review boards of Haematologica, Immunology, and Immunogenetic Insights, is a SPORE recipient award researcher in lymphoma in the past, and has won multiple teaching awards in the Johns Hopkins Department of Medicine and Oncology. He has received the Kimmel Foundation Scholar, Sidney Kimmel Foundation for Cancer Research Award, as well as the LLS Scholar in Clinical Research Award. Presently and for the past six years, he’s been serving on the NCI Investigational Drug Steering Committee and is Co-Chair for the Cancer Stem Cell Taskforce.
So, Dr. Matsui, welcome again. Maybe you want to begin by helping us understand what is the difference between a myeloma stem cell and a myeloma plasma cell, and then how you came to discover this in your research.
Dr. Matsui: Sure. So first off, thanks so much for having me. I think it’s a wonderful opportunity for me to shed some light on the research that we’ve been doing. I think that really, there are couple of ways to think about cancer and to think about cancer stem cells. For sure, cancer stem cells are not an exclusive concept to myeloma. They were initially identified in acute leukemia, and around the same time, we had data in myeloma and there were findings in breast cancer and in brain tumors.
So really, what we wanted to study in the beginning, and this is very early on in my career, I wanted to try to figure out the answer to one question. And the question was, why do patients with myeloma relapse? And myeloma is emblematic of many chronic hematologic malignancies where you can achieve disease control through many different routes. But there’s an inevitability of relapse for the majority of patients. So even though you can clear all of the tumor out, there’s something there that makes the tumor come back.
For me, this is the question I wanted to answer is: what is driving relapse? If we could understand that process, then maybe we could prevent relapse and we could have patients live longer. So, the way I started thinking about it was that there must be some cell, there must be some part of the myeloma that does two things: one is that it survives. It’s able to survive whatever the treatment is because it would stay there. It has to be there through the therapy, and it’s got to have the ability to grow.
So if you look at many different tissues and organs normally, and one good place as an example is your bone marrow, your bone marrow has stem cells in it and those cells are responsible for making all of the cells in your blood. So they are very specialized set of cells. The minority of cells, stem cells are only probably one in a million cells in your bone marrow but they have the special property of being able to produce blood cells.
Most organs and tissues are like that where there are stem cell compartments, and then the majority of cells in that organ or tissue are differentiated cells or more mature cells. So in normal tissues, you have compartmentalization. You have stem cells that are responsible for making mature cells, and then you have the mature cells that actually go and do things like red blood cells to carry blood, white blood cells to fight infections.
We thought that maybe there’s this compartmentalization that happens in myeloma that maybe the plasma cells were one component but maybe there were other components there, and could we sort of figure out what was there? With this question of relapse, the one property that we thought was very, very special was to have the cells be able to grow and make new cells. So if you take myeloma from a patient sample, if you try to grow it in the lab, it’s actually very, very difficult to do. If you use a lot of myeloma cells, then maybe you can get some of the cells to grow, but the vast majority of cells don’t have that property.
One way we went about it is that we thought to ourselves just like in the bone marrow, you have young cells and you have more mature or differentiated cells. So in myeloma, myeloma is an end-stage cell, a plasma cell. So a plasma cell is at the end of the line. It is responsible for making antibodies that are useful for our immune systems. But a plasma cell is not responsible or capable of making more plasma cells. Its job is to make antibodies. Its job normally is not to make itself.
So, where do plasma cells come from? They come from this other compartment called B-cells, and B-cells are a part of many different lymphomas and some leukemias. So we thought that since normally, B-cells make plasma cells, well, maybe B-cells in myeloma patients actually make myeloma plasma cells. So we ended up taking patient samples and dividing them up into plasma cells, and dividing them up into B-cells and we tested their growth ability both in the lab in a petri dish and then in animals. So we would inject the cells into specialized mice and see if they would get myeloma.
What we found was that even though B-cells are maybe one in a million tumor cells, most of the myeloma cells are plasma cells. That’s what we see when we do a bone marrow on a newly diagnosed patient. It ends up being that those cells are not capable of generating tumors either in the lab or in an animal.
Jenny: And these are the plasma cells?
Dr. Matsui: Exactly. But if you take the B-cells and try to do that, it ends up being that you can get an animal to get something that looks like myeloma. It takes about six months for that to happen, and you can get growth in the lab. So we basically knew that there was this feature of growth. The whole point of the cancer stem cell concept really is that there are tumor cells that look different in pretty much all tumors. And can you match up what they look like, which is the B-cell with a function, which is growth? So in that way, we decided to now start focusing our energy on B-cells and on stem cells. That’s really how we got started was just to define those two cellular types.
Jenny: And I know that the bone marrow microenvironment, from what you were saying earlier, myeloma is hard to grow alone in the lab. So part of that is because it’s out of the bone marrow microenvironment or there’s something just unique to these B-cells you think, or both?
Dr. Matsui: I think that there’s both, actually. So if we use the bone marrow microenvironment, you can get these cells to grow better. You can also do it independently of that microenvironment to some extent for some patient samples, but not for all patient samples. I think that for us, the biggest sort of achievement early on was just the ability to get myeloma to grow. And we tested a bunch of different systems. We found one where you could see myeloma growth, and that allows us, that gives us an assay that we can test all these different cell types to see which one grows.
And one thing I forgot to mention but I think is very important is that we did not discover that there were B-cells that were related to the plasma cells of myeloma. That has been done, actually, about a decade before and it had been done by about over a dozen different laboratories. So this idea that there were B-cells in this plasma cell disease myeloma was not a new concept. All we showed was that those B-cells have this one particular property, which is the ability to grow.
Jenny: That’s a great explanation about the difference between the two types. In your early research when you were separating this out and seeing the difference between the B-cells and the plasma cells, what else do you learn about the difference between these types of cells and how myeloma behaves, I guess?
Dr. Matsui: We actually found that after we identify these different cell populations, one of the first sort of tests, this idea that if they were the entity, if they were the cells that were responsible for relapse, then what they had to do is they also had to survive the chemotherapy that will be used to treat patients with myeloma, because if they were susceptible for the chemotherapy, then they would never linger to or stay around to grow.
One of the initial things we did was show that the B-cells and the plasma cells have different sensitivities to different, at the time, myeloma agents. So at that time, we tested four different drugs; we tested dexamethasone, we tested lenalidomide or Revlimid, we tested bortezomib, and we tested Cytoxan or cyclophosphamide. It’s similar to Melphalan.
So we found in each instances that the plasma cells were very susceptible at a specific dose to all of those agents. And that makes sense because those are the agents we used to get rid of plasma cells in patients. But the B-cells were not necessarily killed by those agents. And so we were able to identify some reasons why that’s the case, and I think that the most recent one is that the way that proteasome inhibitors like bortezomib and carfilzomib work is that they work best in cells that are making a lot of protein because if you inhibit proteasomes, then the protein gets all messed up in the cell and then the cell wants to kill itself.
So if you use proteasome inhibitors, they actually work the best against cells that are making the most protein. Plasma cells are really good at making immunoglobulins. They make a lot of it. And I think that’s a major reason why proteasome inhibitors are so great in myeloma. But B-cells, actually, don’t make very much protein. So they’re naturally resistant to a proteasome inhibitor because they don’t depend on the proteasome inhibitor to make sure that all of the protein is clean and doesn’t accumulate and all of this stuff because the cells just don’t make that much protein. So that’s sort of a natural way that the cells are resistant to one specific kind of agent.
And most recently, what we’ve shown is that if you actually increase, try to speed up or make more protein in the B-cells, then now, they start to become sensitive to proteasome inhibition. So we’re trying to figure out strategies to make that happen.
Jenny: Interesting. That’s so interesting that you can just measure the protein levels and manipulate it like that.
Dr. Matsui: Yes. And I think that one way to think about it, another example is that patients, as they advance, oftentimes, their M proteins don’t reflect how much plasma cells are there, like there tends to be less secretion of protein. So patients will have lower M spikes even though they have more plasma cells, and that’s because in general, the plasma cells start making less protein after a while. And we think that that drives them to be more like stem cells, and the more stem cells you have, the worse things get.
Jenny: So you could have a lower M spike, is what you’re saying, and still have worse disease because you have more?
Dr. Matsui: Yes. So when I follow patients, oftentimes, you’ll see their M spikes going down or being stable, yet the symptoms of this disease are actually getting worse. That’s because the disease itself, the cells, the plasma cells themselves are not making that M protein. So you can’t use that as much as an accurate way to follow the patient’s course.
Jenny: And then if that’s the case, then the proteasome inhibitors might not work as well because you’ve got lower protein levels, right? Is that what you’re saying?
Dr. Matsui: Exactly. You’re totally right. So we think that the amount of protein that’s made is somewhat tied to sort of this property of growth. So the less protein you made, the better you are at actually growing, and there’s this weird relationship there.
Jenny: Wow, that’s fascinating. I’ve never heard that before. Okay. That’s really, really important. You said these cells have different sensitivity to different drugs. So you’re talking about the proteasome inhibitors and how if the B-cells don’t have a lot of the protein, some of those may not work. What about the others like dexamethasone or the IMiDs like lenalidomide and then chemos like cytoxan or melphalan? What did you find on those?
Dr. Matsui: So we don’t know for dexamethasone and we don’t know for lenalidomide. For IMiDs, there’s been great data recently that shows how iMiDs work. They bind to this protein called cereblon and sort of do all the stuff in the cell. That was not known for a long time and that was just recently discovered. And we suspect, I suspect that the cereblon levels are different between plasma cells and B-cells, but that’s something we are just testing now. So we’re not definitively, we don’t know why there’s a resistance to sensitivity between these two cell types. The other is with steroids, we have no idea with melphalan and with Cytoxan.
There are specific enzymes that are actually really good at degrading chemotherapies. So they sit inside the cell where the molecule of chemotherapy comes in that neutralizes and digests it right away. And stem cells tend to have much more of those enzymes than do plasma cells. So they are protected because they have more of an ability to clean out all the chemo that’s around.
Jenny: Which is why the chemo might not be touching the B-cells. I mean that might kill some of it but not all of it.
Dr. Matsui: Yes, exactly.
Jenny: Interesting. So I was reading your recent paper that you just announced at the conference, and I can’t remember the name of the conference. But in your study you’re comparing lenalidomide and dex and then adding this third agent. So, do you want to give us some history about that — and how you decided to run that and what that’s all about? Because your results are really so fascinating.
Dr. Matsui: Yes. So we had found that there were myeloma drugs like proteasome inhibitors and IMiDs that didn’t seem to affect the B-cells, right? But a lot of lymphomas consist of these B-cells. So there are lymphoma-specific agents. There are a lot of agents we use in lymphoma that we don’t use in myeloma because they’re specific for B-cells. They’re not specific for plasma cells.
So one of the drugs that we tested pretty early on, and it was a drug that’s universally used for patients with non-Hodgkin’s lymphoma is an antibody called rituximab. And rituximab binds to a specific protein on the surface of B-cells. It is not on the surface of normal plasma cells and it’s almost never on the surface of myeloma plasma cells.
So early on, and this was a number of years ago, we decided, “Well, what we should do is we should try to target these cells, right, because if we get rid of these cells then our hypothesis would be that we should delay relapse.” So we did a trial where we gave a high-dose chemotherapy regimen. We gave cyclophosphamide, and then what we did is we gave this antibody, rituximab. And the reason why we chose rituximab is that because we knew it was safe, because it’s been given to thousands upon thousands of lymphoma patients. So we knew what to expect as far as safety.
So we did that. The regimen was well-tolerated. We gave people chemotherapy. Their M proteins went down. We started giving them the antibody, and we would give that once a month. And it ended up being that in that trial, it was a trial of 21 patients, the relapse rate was quite high. It was quite high and it was pretty short.It was on average about a year and a half from when you got the chemotherapy to when you relapse.
That was not a great success clinically by anyone’s measure. But what we did was we did studies during that whole period of time on the patients and they allowed us to get bone marrow and check blood. So what we’re doing is we are seeing whether or not we could count the number of myeloma stem cells in a person as they went through treatment. And what we found is that in some patients, the number of stem cells, myeloma stem cells, went down over time. That was in about a third of the patients.
But then in the other two-thirds, the number would go up. So for whatever reason, even though we had this antibody, the number was going up. We found two things. One is that in the patients where the number was going down, those patients were in a remission for about four times longer than if the number was going up. And then the second thing we found was that we looked for the antibody. Did the antibody, actually, get rid of the cells? To our surprise, the antibody was not getting rid of those myeloma B-cells, which was a total surprise because when you do this in lymphoma patients, it clears out all of the normal B-cells and all of the cancerous B-cells, right? So there is something about the antibody —
Jenny: It’s the wrong target or something
Dr. Matsui: Exactly. We said, “Look. I think that we’ve hit the right target, but I think we’ve probably not used the right drug, because we have not cleared those cells out.” So we had looked for other ways of targeting the cells, their B-cell characteristics. And at one point, we had thought about doing a trial with something called radioimmunotherapy. It’s the same type of antibody. It targets this one protein, CD20, which is on B-cells and it’s linked up to some kind of radioactive molecules. It’s used in lymphoma, and we were going to do a trial where we tried that because we said, “Look. If we can stick an antibody to the cell, then what we need to do is we need to put something toxic on that antibody to try to kill the cell, and we will do it by radiation.”
So we had that planned and then the interest in radioimmunotherapy, in general, was waning and the sponsor we were working in decided that they didn’t want to do the trial. So we had to find something else and we looked for other antibodies. One of the antibodies we looked at is an antibody from a company called MedImmune, and this is the agent that we used in this trial that we presented just recently. And the conference was that the American Association of Cancer Research or the AACR conference. What we found was that that antibody was a little bit different than rituximab. It bound better to the stem cells and it made the stem cells actually go away compared to the Rituxan or the rituximab that we had used many years before.
So we did a trial where we took patients. They were newly diagnosed. They received two cycles of len/dex, and then we would add in the antibody, and patients got three doses of antibody over a space of two months. The antibody had really no side effects at all. And then we just followed people. We followed them clinically, we followed their M proteins, and then the other thing we did was we followed their cancer stem cells.
What we found was that if you are just on Revlimid the first two rounds, we can see that your myeloma stem cells would start going up. And it went up in pretty much all of the patients that we studied, and that sort of makes sense because we had shown previously that lenalidomide really didn’t attack those cells so well. So those were cells that were left and they were starting to expand. Once we added the antibody, in just about all of the patients, we can now see those cancer stem cells going down.
Dr. Matsui: This is the first time in the single clinical trial that we had something where we saw them actually going down in a uniformed way. And the only other time where we were able to see this in a very dramatic way, like we were able to see it in a few of the patients in the earlier rituximab trial, but we’ve done the same assays on patients who have had allogeneic transplantation. Those are transplants I’m sure you know where you use a donor. And in those patients, some of them can be in remission for a long, long, long time. In those patients, those are the ones that we can find on occasion, the myeloma stem cells go completely away.
So there are a lot of like questions about the trial that we presented, and by no means, has it been a definitive trial.
Jenny: Well, do you mind if I ask you a couple of questions?
Dr. Matsui: Sure.
Jenny: First of all, what was the target for rituximab? When you say it was an antibody, was it targeting like CD19 or another number? What was that targeting for?
Dr. Matsui: It’s the CD20, which is like CD19, it is on B-cells but it’s not on plasma cells.
Jenny: Okay. And then so this new one is targeting a different — it’s targeting a CD19, right? So it’s a different target, basically.
Dr. Matsui: It is.
Jenny: Okay. So I think patients should know that because some of the monoclonal antibodies that are out now like daratumumab is targeting CD38, right?
Dr. Matsui: Yes.
Jenny: And Empliciti or elotuzumab is targeting, now I can’t remember what it targets (SLAM-F7). And then another question is how do you count stem cells? How are you counting these and what tests are you using to count these?
Dr. Matsui: We’ve been doing two tests. Originally, we had developed an assay. When we started the whole thing, we developed an assay where we could grow myeloma from patient bone marrow samples. And you can grow them in a way that you can count how many cells have the capacity to grow. So we were able to use bone marrows. We would do bone marrows and then you could put them in the lab and then you could enumerate how many stem cells or how many cells with the capacity to grow were in that sample, and then you just extrapolate back to try to get a percentage. That requires a bone marrow.
That is not something that is easily done time after time after time. So the one thing that’s very different normally about B-cells and plasma cells is that B-cells are in your blood and they are in your circulation. So if you look at your white blood cell count, it has neutrophils and it has lymphocytes. So part of those lymphocytes are T-cells and part of those lymphocytes are B-cells. So B-cells normally run around in your circulation. So we developed an assay about six or seven years ago that we draw a tube of blood and then we can count them from that blood using a machine called a flow cytometer where we look for specific proteins or cells with specific proteins and we can count how many of those there are in a sample.
So we’ve switched from doing it in both the rituximab trial, which is get CD20, and the MEDI-551 trial which is the antibody gets CD19. We tested both bone marrow and blood. And what we found is that they always seem to match up. What we’ve done subsequent to that, and for trials that we are planning in the future, we think that we don’t need to use bone marrows. I would rather not use bone marrows as a way of trying to monitor because because I think it’s too many marrows for the patients.
Jenny: There’s only so much conscious sedation we can take.
Dr. Matsui: Exactly. So what we’re doing now is we can do it from a single tube of blood. I think that that is the way that we’re going to monitor things looking forward, and that’s really the body of data that we had in this trial we just presented. That was from doing blood monitoring.
Jenny: Well, that’s amazing. And that’s just the flow cytometry test?
Dr. Matsui: It is, it’s a flow cytometry test.
Jenny: Oh, interesting. Okay. So you led up to your biggest takeaway and then I interrupted you. So let’s go back to that. You said your biggest learning from the study was…?
Dr. Matsui: What we don’t know is, does the change of stem cells actually correlate with how the patients would do, right? So that’s the biggest question. The question in the field is it’s not whether B-cells that are related to myeloma exist. We did discover that. That was discovered by many groups, many famous groups ten years before we did anything with myeloma. So that’s not a question. The other question is that there’s some cell that has the ability to grow in myeloma.
So the controversy is that, is it B-cells that have that capacity? And do those B-cells, even though we can show this function in the lab, the ability to grow in the lab, is that something that actually happens with people? So we’re counting these cells and the question is that, does that correlate with how patients do? Because if we make them go down, then it should take longer for patients to progress or relapse.
In this trial that we just reported, we didn’t follow the patients for long enough. What we found was that after we gave them the three doses of the antibody, they were still on Revlimid and Decadron throughout this period of time. You could see that the number of stem cells go down but then since they only received three doses of antibody, you could see subsequently a couple of months later that they would start to rise again. So what we’re trying to do now is match up — well, if the number stayed down, if the patients remain and have a response for longer or eventually get to complete responses, so we’re following the patients now. We just don’t know because we haven’t followed them for long enough.
Most of the patients on that trial have not progressed, which is great, but we don’t know whether there’s this correlation that exists. So right now, we’re trying to think of strategies built upon this idea of targeting CD19, not targeting CD20. Can we do it in a more definitive way and do it sort of in the context where we can maybe see that giving something that targets CD20 will actually make a difference? Because I think in this early trial, it’s great that we see the numbers go down, but we were limited in the amount of antibody we could give even though it was totally safe for the patients. They didn’t have any side effects from it.
The trial itself was designed to just see whether we could change that number of stem cells. It wasn’t designed to see whether or not it was going to really impact over very long periods of time, whether patients remained in a remission or had a complete response or how long it would take for them to relapse. We’re following our patients for that but it’s a pretty small trial, so I don’t know if we’re going to be able to make too many claims about us giving the drug. That cell is going down and it did this to the disease in an individual patient.
Jenny: So a few questions about that. If the myeloma stem cells can be tracked, why aren’t more of the myeloma researchers tracking them? Because then you’d be able to know for whom is this applicable. You know, you had that question earlier. We don’t know if it correlates. So why aren’t checking it if it’s just a flow test?
Dr. Matsui: It’s a specialized flow test. It requires sort of different reagents than what people use. It’s not like you can’t do it. It’s done not using the standard techniques of flow that you would do in sort of any kind of clinical lab. It’s interesting because I think that even though we have these findings, not everybody thinks that this is true. I get a lot of questions about, do you know that they’re B-cells? Do you know that they’re actually important in patients? I think we’re trying to address that through our early clinical trials.
But there’s a lot of skepticism and I think that that’s okay. I think that as long as there’s like scientific openness, and I think that as long as people allow us to sort of ask these questions, I think we’ll get to it. I think we’ll get to that stage where we can prove or disprove that the B-cells matter. You know, it’s funny because the question I will get time and time and time again is that, “how do you know that these cells are important in people?” And what we’re trying to do is to do these early clinical trials where we match up how does the stem cell number change and how does that affect outcomes.
It was actually not us. It was actually another group, a group at the University of Pennsylvania that I think really showed that there is potential in this idea. They did a small study where they didn’t use an antibody, they used something called a chimeric antigen receptor T-cell or a CAR T-cell. These cells are cells that T-cells or immune cells that you take from the patient, you engineer them to recognize CD19, and then you put them back in the patient and they go and they attack any cell that has CD19 on it. There’s been pretty amazing results in B-cells leukemias and in some lymphomas, that you target CD19, CD19 is on the cells, so you can get rid of those cells.
So they did a trial with a limited number of patients where they gave these CD19 targeting T-cells to patients with myeloma. And it’s a crazy thing to do because the myeloma cells don’t express CD19, right?
Jenny: Right, that’s why I was asking about CD19.
Dr. Matsui: So they ended up having not everybody responded but some patients responded and they definitely showed that CD19 was not expressed by the plasma cells and they have patients who remain in a sustained remission. So for me, it wasn’t our work clinically that’s proven this, that’s even come close to proving that the concept is correct. But I think that the study of Penn for me is this landmark moment in my career because it’s some demonstration that targeting CD19 (they’re not targeting anything else besides CD19) that this is a viable target, and potentially, that’s because you’re targeting the myeloma stem cells.
So we’re in discussions to do some collaborative things with the University of Pennsylvania to monitor cancer stem cells in their subsequent trials where they’re using CD19 targeting agents. And it’s given us a real boost to pursue CD19 as a potential target in upcoming trials that we’re in these stages of developing right now.
Jenny: Well, I think they are just rocking it with the CAR T-cell stuff. It’s amazing. And I know that they were surprised that they had such good responses with the CD19. So other CAR T-cell trials, one of which we’re funding, is targeting CS1 and BCMA, which are other targets and I know they (UPenn) have a BCMA trial that they’re going to target. And the NIH does too (BCMA), but it was so fascinating to watch because they have that patient who — she had had like nine prior therapies and stem cell transplants that hadn’t worked. And then she got a CD19 CAR T-cell with the transplant, and all of a sudden, voila! It means she’s got the deletion 17 and everything. So she was really high risk. That was super exciting.
Dr. Matsui: Yes. So I think that there are two really important things for me that come out of that University of Pennsylvania experience. One is that I think that CD19 is potentially a target, and then the other is that it’s not all of the patients that responded. So it may not be a target in every single patient, and I think that it’s made us go back and think about looking at other targets as well. So we’re doing some work right now trying to figure out whether BCMA, which is the CAR T-cell targeted at the NIH and Penn, whether that is expressed on some myeloma stem cells or not. We’re going back looking at CD38, if CD38 is expressed because daratumumab targets that.
That experience wasn’t our data. For us, it’s such a reinvigorating piece of news because we had been trying clinically to do something, but we didn’t do it in as definitive a way – as precise an approach and as potent approach as using CAR T-cells, which the Penn folks did. So I think that it’s super exciting. It’s super exciting for us now. Like I said, it’s really reinvigorated our research program to really go ahead and think that we can actually make some headway targeting these things. And hopefully, for some patients, that will make a difference.
Jenny: And just my own personal comment about whether it being controversial or not, if you’re not tracking it, you’ll never know. So if more researchers started tracking it, I mean why are we talking about the controversy? Just track it and then you’ll start seeing patterns that it relates for relapse – whether you see it in some and that’s what makes them high-risk or whatever. It doesn’t make sense. Not just to say “That’s controversial so I’m not going to look at that.
Dr. Matsui: Yes and I totally agree with you. I think that if you could convince other people to do it, we would be happy to help them do it. Like I said, I think that we opened up and thought about a lot of different ways of moving forward clinically. I think we’ll have a nice set of trials coming up on the horizon.
Jenny: I want to talk about a little bit about what you could do it with next. So you talked about using len/dex. So some of the therapies are killing the myeloma cells, the plasma cells, and they’re very effective at doing that. And I know a lot of immunotherapies, some doctors are saying, “Gosh, the ideal time to use these immunotherapies is actually post-transplant.” In your plans that you have coming up, what do you see for the use of other therapies, not just the doublet like len/dex together? Or what else would you want to use with this for a longer period?
Dr. Matsui: Right. So one way to really show that this idea is important would be to have someone in a complete remission. And if the cells are responsible for relapse, if you target those cells and get rid of those cells then the patient should relapse at least as quickly. For us, there are a couple of ways that we’re trying to think about it. One is that we’re thinking about it in the post-transplant situation. We’re thinking about doing a trial where we target CD19 after an autologous stem cell transplant. We thought about a few different approaches that are out there. We could use the same antibody that we used in the len/dex trial. We could think about doing something like CAR T-cells after a transplant, or the other is that there’s sort of a compromise in the middle which are things called bi-specific antibodies.
So there’s an antibody drug called blinatumomab that’s approved for childhood leukemia, and it’s like an antibody. One part of it binds to CD19 and the other part of it binds to CD3, which is on T-cells. So what it does is that this molecule acts as a bridge to bring T-cells directly to CD19 cells. And in pediatric patients with leukemia, their cells express CD19 and you can use this drug to effectively get rid of that leukemia. So we’re thinking about all three of those approaches. Can we use just an antibody alone? Can we use CAR T-cells? Or can we use sort of this bi-specific antibody to try and target after an autologous transplant?
The other thing that we’re trying to do is we’re trying to think about ways of treating patients with allogeneic transplants. Allogeneic transplants are sort of up and down in the history of treatment in myeloma. They were very toxic and very dangerous in the early days. We, as an institution at Hopkins, have done a lot of work in making transplantation a lot safer. For example, one of the things that used to happen is that there’s a side effect called graft-versus-host disease where the donors of immune system would attack you. And that would happen in about a third to a half of the patients, and it can be a very dangerous situation.
So we’ve modified the way that we transplant individuals so that that risk of graft-versus-host disease, of serious graft-versus-host disease is less than 5%. So we’ve brought that way, way down. I think that the transplant itself is much safer for patients. We know that allogeneic transplants can potentially cure some patients with myeloma, although in our hands, it’s been the minority of patients have been cured. Most of them relapse. About a third of patients will remain in a remission.
One thing we can do is we’re getting a whole new immune system, which is a pretty exciting thing. So can we modulate that now to go after myeloma so we can lower the chance that you relapse? And we have thought about using, here again, targeting CD19 after an allogeneic transplant using the approaches we talked about before. But what we would like to do here at Hopkins is build upon our ability to do allogeneic transplants more safely. We do many of our transplants now where we use — they’re called haploidentical transplants where you need to be half matched with an individual. So you don’t need a sibling who’s fully HLA matched. What you can do is you can use a parent or a child and they are going to be at least half matched because they get half of their genes from you or they gave you half of your genes.
So we do a lot of those haploidentical transplants so we can find donors for about 95% of patients. We do the transplants now, all these mini-transplants and they’re at Hopkins done primarily for a portion of patients. They’re done entirely as an outpatient. So what we’re trying to do is build upon that success and now work on how do we prevent relapse after an allo transplant, because there, you’re using something very powerful which is a new immune system to try and get rid of your myeloma. I think the age has come where I think that we can do the transplants themselves safer. Now, that gives us the opportunity to focus on measures to try to prevent relapse. And it’s been fascinating in the field of transplantation because many therapies that are not curative, when you give them without a transplant, there’s been Gleevec in CML, Gleevec in this disease, ALL. And those medicines are now seemed curative if you give them after the transplant.
So what we’re going to try to do is give things after the transplant. We thought about a lot of things besides CD19. We can think about things like proteasome inhibitors as well on combination or other antibodies like CD38. And I think that we have a lot of interest to do that. That’s part of the program. We’ve been trying to build up protocols. We generate protocols that we now carry out allogeneic transplants on patients with multiple myeloma.
Jenny: It’s so interesting. So you are saying that CD19 is your ideal target. Are you seeing any other indicators on those B stem cells that you could go after? I know you talked about a few like BCMA and things like that. I guess you’re looking at other targets.
Dr. Matsui: Right. You know, it’s easy for us to look at specific B-cell targets that are used in lymphoma because the lymphoma people do all the heavy lifting and generate all these things that target B-cells. And then we just sort of co-op them and see if they’ll work in myeloma against the cells that we’re interested in. I think that beyond that, certainly, I have a lot of great collaborators who, besides myeloma collaborators, I have a lot of great collaborators who work on cancer stem cells and they work on them in other diseases like pancreatic cancer and leukemia and breast cancer.
What we’re finding is that cancer stem cells from a variety of different tumors, they share some things in particular that they don’t share with the mature tumor cells. So there are sort of these certain factors that may be important for cancer stem cells and they may be important for cancer stem cells across a bunch of different diseases. So we’ve thought about trying to not just target B-cells but to target things that are affecting stem cells. One example is a trial that we’ve been working on where there are these molecules at the end of your chromosomes called telomeres. They’re there to protect like sort of the ends of your chromosomes. There is an enzyme that makes those. And that enzyme is turned on in pretty much all cancers.
So what we had is we have a molecule that actually targets that enzyme to try and see if we can weed away those telomeres, make them shorter, and then that will induce the cell to die. So besides B-cell things like CD19 and CD20, we’re looking at sort of signaling pathways that we believe are important in stem cells regardless of where they come from.
Jenny: That’s fascinating. Well, you have a lot of work ahead of you. It’s so exciting that you’re doing this.
Dr. Matsui: I have such great people in the lab and I have such wonderful collaborators. When we set out to do something, I think that we’re a pretty determined lot and I think that we get things up and running. Without that, I think it would be much, much harder. I have a very dedicated group, individuals that I work with.
Jenny: Wow. It’s so exciting doing what you’re doing and we’re so grateful that you’re doing this. So I want to open it up for caller questions, and I know I have a question for — an additional question. So if you have a question for Dr. Matsui, please call 347-637-2631 and press 1 on your keypad. I would have a caller at 204-6956. Go ahead with your question.
Caller: Hi. Thank you for taking my call. What a great show and so hopeful. I was wondering what you would tell someone like me. So I did a stem cell transplant and auto in December and knock on wood I have no residual disease. But right now, we’re kind of putting me on a very minimal maintenance therapy are Velcade and dex. But is there something that tells that maybe I should be looking into? Do I have to wait for relapse? And if I do relapse, will I be looking at another stem cell transplant in order to be able to do some of these treatments with therapies?
Dr. Matsui: Yup. I think that one thing to keep in mind is that there have been many, many advances in myeloma and it’s a very different disease in how it’s being treated than a decade and a half ago. You know, even though we are [0:55:36] [Indiscernible], we still utilize all of those same approaches for our patients. And I think that if you’re on maintenance now, the question is that how much is they’re going to improve and prevent the relapse versus how much is it hurting you, because that is the balance.
So if you’re tolerating it well, I would say I would stay on the maintenance personally. I think that if you are having problems with it and the treatment is becoming worse than your disease, then I would say you have to rethink what one is doing. I think that with maintenance strategies, they’ve been incredibly transformative, I would say, in myeloma. We used just treat patients for a small period of time and then we would just follow them. And I think that more often than not, now we continue patients on treatment, and that’s really a testament to how tolerable the medications have become.
So I think that the strategy you’re on is a very, very, very reasonable one. I think that the hope for the future are things like stem cell based therapies, and also, immune-based strategies that I think control the disease. And I think that those are not going to be too long before they get into the clinic. So I think right now, you’re doing exactly the right thing. I’m hopeful that there are many options like if and when you relapse. But at this day and age, I think that you are getting optimally what you used to be getting. I think that if there’s a clinical trial that you wanted to think about doing something else. I think it’s always important to figure out what else is out there in clinicaltrials.gov, or the MMRF or IMF websites are great places to look.
Caller: I also would like to put in a plug for sparkcures, because it’s awesome and it’s only myeloma based. I am watching those intently. So right now, I’m handling the maintenance therapy like a charm and hopefully I stay in remission for a very long time. But thank you very much. I love this radio program. It’s just awesome. Thank you.
Dr. Matsui: Good luck.
Jenny: Okay. Thank you. Thank you so much for questions. Okay. We have another question at 889-4902. Go ahead with your question.
Caller: Hi, Dr. Matsui. What I just wanted to know is, do myeloma stem cells have the same genetic features as mature myeloma plasma cell?
Dr. Matsui: So it’s interesting because we’ve looked into this and some of them do and some of them don’t. So if you look at a patient’s myeloma and you look for the genetic mutations, even in the plasma cell, there are may be different mutations in an individual patient. And what we find is that in some patients, the stem cells have exactly what the plasma cells have. And in other patients, what we find is that there are different mutations in the stem cells. One of the ones that we see quite often is mutations in a gene called Ras, which is a gene that pops up as a mutated gene in pretty advanced disease.
So what we think is that there’s a stem cell hiding out with that mutation in the beginning. And for whatever reason, it can be controlled, and then at some point, it starts to expand and take over everything. So we see both patterns and we’re trying to figure out if one pattern is more favorable than another, and we haven’t figured that out yet.
Caller: Okay. Thanks for answering my question. I appreciate it.
Jenny: Okay. That’s so fascinating, that answer. Completely fascinating. It’s so complex, this disease. It is. It’s so difficult. We’re glad there are experts like you. Okay. Our next caller is at 983-6757. So go ahead with your question.
Caller: Hi. Good afternoon, Dr. Matsui. My name is Dana Holmes and I’m a smoldering myeloma patient. I’m listening to your presentation and I’m fascinated by it but I’m also very unsettled by it, and I’ll explain why. I’m looking into potential clinical trials for early treatment for smoldering myeloma. And I’m wondering if any of them that are potentially out there now available to a smoldering myeloma patient would even be able to, I guess, corral these myeloma stem cells at this early stage. What are your thoughts?
Dr. Matsui: I think that there are some potential strategies that are out there that can work against both plasma cells and the stem cells. I think that one of the things that we thought about is things that change a process called epigenetics, and one of the drugs that’s approved that modulate epigenetics is a drug called panobinostat. So that may target both plasma cells and stem cells. I think that a big component of smoldering disease is what is your immune system doing. I think that your immune system plays a pretty big role at keeping everything in check, and we’re trying to figure out now whether or not that immune modulation is driven by stem cells. It’s very early days but stem cells regulate the immune system in many, many systems. So we’re trying to figure out whether that’s the case in myeloma.
Caller: So which smoldering myeloma clinical trials that are presently available to someone like myself? Are any of them worth my while now to pursue or do I hold back and hold on to my smoldering shoes for a little bit longer hoping that something better will come along? Because I think what I tend to worry about is if I treat too early, am I opening up the playing field for these more aggressive clones that might be hiding out?
Dr. Matsui: I am totally with you. I think that smoldering disease in some patients can be smoldering forever, and I think that if you sort of stir the pot, there may be issues I think we don’t really know. We have very little understanding of smoldering disease, from cancer stem cells or from even basic myeloma biology. Unless there’s a clinical trial, and I talk to my patients about trials, if that trial makes sense to them, then I think that they should go on a clinical trial.
Otherwise, I tend to have patients. I just watch them very, very carefully. I almost always treat them before they run into any CRAB criteria. But I am afraid of stirring the pot because I’ve had patients just do so well where you — I could swear that I’m going to treat them in six months but it never happened. And if it’s not hurting them, then I don’t want to hurt them by giving them any medications.
Caller: So what is your threshold then, if I may ask, for your particular set of patients for smoldering patients as far as ringing that treatment bell because obviously, you’re preventing the CRAB criteria from settling in and taking hold, but how do you actually do that as a myeloma physician? What tools are you using to establish that?
Dr. Matsui: I think that there are better criteria when to treat patients earlier and sort of label but not label them smoldering but label them actual myeloma. So one is that if your serum free light chain levels or the ratio is greater than 100, I think that’s one. I think that if you have an access of plasma cells of 60%, 70%, I think that would be one. And then the other is that if you have focal bone lesions more than one, that is now considered myeloma and you should treat under those conditions.
Caller: Okay. So then those are the new IMWG guidelines.
Dr. Matsui: Exactly. I think that’s one way, and then the other way I do it is, oftentimes, I just sort of get an idea of what is the slope of the changes in their myeloma lapse because if you see a very steep rise, then I think that you have to be a lot more vigilant. I think that if everything is sort of puttering along or stable then that’s what I want to see. I don’t care how high it is necessarily but I want to see that if it’s rock stable then I’m just going to keep watching.
Caller: So then you would actually treat them as newly diagnosed myeloma patients, obviously.
Dr. Matsui: Right. I think that I am not so much a grey area person.
Caller: Well, you know, that’s actually very nice to hear because I feel like I’m just being swallowed up by the grey zone.
Dr. Matsui: Yeah. And I think that you have to figure out what side of it do you want to be on. And I would not necessarily stick a toe or a foot in the water. I would just sort of check out treatment. I think that if the time is to get treated, then exactly like a newly diagnosed patient, you have to think about their induction, what you’re going to do after that. Maintenance strategies, clinical trials, all of those things come into play.
Caller: And you really set out a long-term plan at that point.
Dr. Matsui: Yeah. I think that I would to the extent that you feel comfortable doing that. This idea of just giving someone some Revlimid, I’m not necessarily so comfortable with that because even though we did that in this one clinical trial, because we started the clinical trial a while ago, we give more than one or two drugs now to just– all of our patients, and I would not use single agent therapy. If the patient needs treatment, I’m going to try to make all of their myeloma go away and I’m probably going to use three drugs.
Caller: What are your thoughts about the new International Myeloma Foundation, the Black Swan Research Initiative’s ASCENT trial? Which is in my thoughts, it’s similar to, I guess the UAMS total therapy but for smoldering patients because the proposal is to treat with carfilzomib, Revlimid and dex with daratumumab and then it randomizes to either a stem cell arm or just continued therapy, and then followed by maintenance which includes the monoclonal antibodies. And perhaps, even a checkpoint inhibitor. I mean it’s really like throwing the kitchen sink at the smoldering myeloma population.
Dr. Matsui: Yes. And I think that after a while, you can figure out whether a patient is someone who wants to get treated or someone who wants to wait. Necessarily, I don’t like deciding that the first time I meet someone, but you’ll figure that out. And I think that if they decide that they want to be treated, then it’s more than likely that they want to go a pretty aggressive route. But that’s what it sounds like. I think that if people are reticent to be treated, there’s no way I would put the mono-trial like that because that is like their worst nightmare. But I think that it’s individual for the patient and for me. I’m trying to help you make the decision and educate you but you have to live with that decision.
Caller: Right. But do you, as a myeloma physician, see it as potentially curative at least in the subset of patients? Because again, they’re presenting it that perhaps 50% of the patient population or that cohort will be cured. Again, I struggled with what exactly is cured, what’s the definition of cure three years, five years, ten years. I don’t think there’s a real established definition yet. So what are your thoughts on that?
Dr. Matsui: I think that they’ll certainly get people into remission because it’s pretty easy to do that with smoldering disease. I don’t know —
Caller: I know I’m putting you on the spot —
Dr. Matsui: I don’t know whether you could cure someone with smoldering disease just because they have smoldering disease. I think that the potential is there. I think that the right way to do it is on a clinical trial rather than making it up yourself. But I think that there is potential there, and I think that if someone wanted to be treated, I would recommend something like that.
Caller: Okay. So what trials do you have at John Hopkins for smoldering patients at this point?
Dr. Matsui: So we actually have not had a smoldering trial in a little while. We’re going to open up one with the panobinostat. And we’re thinking of, perhaps, participating in some of the other cooperative group trials, but we have really focused more on advanced disease. We’ve not been working so much on smoldering disease but it’s something certainly that we all, as a community, have a great interest in.
Caller: Yeah. I’m wondering if we hold the key to the cure, you know, quite frankly with the lower burden of disease. So I thank you for your work. Are you taking on new smoldering patients if a patient were to call your office and set up an appointment? Would you take on new patients or you would –?
Dr. Matsui: We would and I think that we would definitely feel much better about it if there are clinical trials that we could send people to. But now, I think that just having conversations with people about their smoldering disease is something we do quite often.
Caller: Okay. Excellent. Dr. Matsui, thank you so much for your time and your brilliance and how you shared this so readily with the myeloma community. I very much appreciate your time. Thanks again. And Jenny, thank you for this forum. It’s absolutely terrific for us.
Jenny: Oh, thank you so much, Dana, for your question. Great question. Okay. We have one more question that I want to get to. It’s 663-1227, and go ahead with your question.
Caller: Yes, doctor. My husband had Stage 3 multiple myeloma two years ago at 71 years old, and they started him on Velcade, which he was ultrasensitive to or sort of like an allergy. So they had to take him off. And then the rev and the dex, the rev made him real sick. So right now, he is on no chemotherapy and he has the IgG type, which I understand is the less aggressive maybe. And what I wondered was, is that the most significant, the M protein? Because when he was not on the Revlimid, it went from — well, not observed in the beginning to 0.5 to 0.2 to 0.1, which is without any meds. I’m just wondering if — and it kept by kappa/lambda ratio, those two. Are those the two most significant ones they check besides the urine and everything?
Dr. Matsui: I think that those are the standard ways to follow patients. I think that using those tests, the light chains and the M protein, I think that the major issue is not necessarily the number but what effect does the myeloma have on your body; are you having problems with kidney failure? Are you having problems with anemia? And I think that if you have a number that’s positive, yet you don’t have any of those other issues and you’re not tolerating chemotherapy well, I would say it’s probably better to not be on chemotherapy and to watch very closely. Like I have a number of patients who, just like your husband, they couldn’t tolerate anything. They got small round of therapy. They didn’t tolerate it but they responded, and I’ve been watching them for a number of years. Their myeloma has never gone away. You can see it on their M protein but they’ve never run into any other problems.
Caller: Well, in the beginning, in the first six months or so, he did get kidney failure and his BUN was like 112, which is off the chart to me, and his creatinine was up. But now, his creatinine is good but his BUN is up to 21, which I know sometimes 8 to 18, they use. But otherwise, the only thing he probably is really having without the chemo is tiredness and still the neuropathy I think from the Velcade. I’m not sure.
Dr. Matsui: Yup. So I think that if his kidney function is maintained and if he’s not severely anemic, then —
Dr. Matsui: Yup. And that’s a reasonably good level of hemoglobin. I think that in this situation, you don’t want to make the therapies worse than the disease. And I think that —
Caller: That’s [1:14:57] [Indiscernible] as a nurse myself. Would you say that it would be up to the patient how he feels whether he can go on like a trip on a plane for a week someplace at this age?
Dr. Matsui: I think that you ask your physicians. I think that if he’s not been on any therapy and he’s been totally stable, my guess is that there’s less of a chance something is going to happen over the next week. So I think that if things are stable, I think that patients can do a whole, whole lot.
Caller: Well, are they working actually when you say you’re working on the CAR T like immunotherapy? Is that if those are in clinical trials from what I understand, but does the clinical trial take about two years? And if it comes out positive, can they use that on any multiple myeloma patient or do they have to be a certain stage or do they have to be certain criteria for that?
Dr. Matsui: Right. I think that it depends on where CAR T-cells go because none of them are approved by the FDA. They’re all done on clinical trials and I think that it sounds like there might be some possibility that the first ones are approved, maybe even as soon as later this year. So I think that once that happens, and that’s going to be in things like lymphoma and leukemia, I think that once that happens, then it becomes much, much easier to look at CAR T-cells as a therapy for myeloma because it’s very clear how you sort of generate that into something that’s usable for many patients. Right now, it’s still very restricted because they’re in trials, but hopefully as they get better, technology gets better and you can use it in many patients with leukemias and lymphomas, I think that that will naturally expand to myeloma as well.
Jenny: Well, just a suggestion because I know we’re overtime and we’re going to let Dr. Matsui go, but there are two resources I think that the caller, you will need a specialist in your corner — second is you can take [1:17:27] [Audio Glitch] website because we are partnering with Smart Gears, which is a tool that was created specifically to find myeloma clinical trials. So that’ll tell you all your inclusion criteria, which trials might be open based on your husband’s stage of disease and all of that. I think that would be really, really helpful for you. But I also think that having a myeloma specialist in your corner is really, really important.
I know we’re overtime, so Dr. Matsui, I’d like to thank you for participating on our show. We’re so excited about what you’re doing and we’re just very grateful that you took time and overtime to help us out today.
Dr. Matsui: Well, thank you so much for having me.
Jenny: And thank you so much for your questions.
Caller: Well, Jenny, thank you so much for all your help. It’s really appreciated.
Jenny: Thanks for your question. We so appreciate that.
Caller: Okay. Thank you. Bye-bye.
Dr. Matsui: Thank you so much for having me on. I think it was a great opportunity to present what we’re doing, and hopefully, we can move forward.
Jenny: We’re looking forward to your next steps. So we’ll be watching you carefully. Thank you again. Okay. Thank you so much for listening.
Thanks for listening to another episode of Myeloma Crowd Radio. You can join us for our future shows to learn more about the latest in myeloma research and what it means to you.