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Stem Cell Transplant Advances and Use in the Age of Immunotherapy
Stem Cell Transplant Advances and Use in the Age of Immunotherapy image

Sep 20, 2023 / 10:00AM CDT
HealthTree Podcast for Multiple Myeloma

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Episode Summary

Dr. John DiPersio of Washington University shares how stem cell transplant is evolving for multiple myeloma care. As a decades old but tried and true and effective therapy, it is still routinely  used in the myeloma clinic as a way to typically provide an extended remission. Advances are being made in the stem cell transplant process which include a recent FDA approval of a stem cell collection drug called motixafortide (Aphexda) that can speed the time and quality of collected stem cells. Dr. DiPersio will also share how many patients may want to undergo stem cell collection whether they plan to do a stem cell transplant or not and how transplant use is changing in the age of immunotherapies.

Thanks to our episode sponsor, GSK.

Full Transcript

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

Now, before our show this morning, I'd like to let you know that we will be launching what we call HealthTree 2.0 on October 23rd. In the last decade, we've developed over 14 tools and programs to support you in three ways. First, we've built a pillar of lifetime personalized support and education programs. This includes this podcast, HealthTree University, our news website, our webinars, roundtables, patient navigators, and others. Secondly, we've created a pillar of meaningful patient-to-patient connections through our coach program, our social media app called HealthTree Connect, our Moves App, and our upcoming regional chapters that we'll be expanding, and you'll see that happening later in this year. Thirdly, we created a powerful patient data portal called HealthTree Cure Hub. This tool doesn't exist for any other disease today, and it helps you navigate your myeloma while helping advance research for investigators using real-world evidence.

We built all this technology to make that possible, and we called all of that HealthTree 1.0. In our next decade, HealthTree 2.0 will be an expansion of our efforts to help advance a cure in multiple myeloma with greater outreach and with HealthTree regional branches and a focus on more research and partnership with myeloma investigators. As patients, there is so much more that we can do to help these investigators advance their research. So our announcement is live on our website, and we encourage you to register for that and create a watch party.

Now on to our show. Stem cell transplant is considered a core treatment for multiple myeloma and as the original immunotherapy, we'd like to learn today more about how it's advanced, new therapies that are making it easier, and how it should be used with a growing number of immunotherapies in the myeloma clinic.

Dr. John DiPersio joins us as an expert in both cellular therapies and immunotherapies. Dr. DiPersio, welcome to the program.

Dr. DiPersio: Hi there. Nice to hear you and see you virtually.

Jenny: Yes. Thank you so much for joining. Let me give a quick introduction for you before we get started.

Dr. DiPersio is Director in the section of Cellular Therapy, Division of Oncology at Washington University School of Medicine in St. Louis, Missouri. He's also currently the Associate Director of the Bursky Center for the Human Immunology and Immunotherapy Program, and Director of the Center for Gene and Cellular Therapy in a Division of Oncology. He was previously Chief of Oncology at Washington University.

Dr. DiPersio is a reviewer on over 30 major hematology and immunology publications and as an education advisory board member for many cancer centers, including University of Miami, Levine Cancer Institute, University of Michigan, University of Chicago, Memorial Sloan Kettering, Dana Farber, Weill Cornell, and many, many others. He serves as an external advisor to support grants at Dana Farber and Memorial Sloan Kettering, and his awards include the Leukemia and Lymphoma Society Legacy Award, Giants of Cancer Care Award for Leukemia Research, the American Physicians Harriet P. Dustin Award for Science Related to Medicine. He's a former Teacher of the Year, AACR co-chair, and has received many lecture awards and teaching awards.

Your CV is so impressive. It's incredible. As you can tell, you're just so highly esteemed by your blood cancer colleagues and are truly myeloma, leukemia, and immunology global experts. We are so privileged to have you on the show today.

Dr. DiPersio: Well, thanks very much. Very kind introduction. I don't deserve it, but I'll take it.

Jenny: No, you do. Looking at your CV is incredible, just truly incredible. Maybe we want to start with some basics. Stem cell transplant has been highly used in myeloma for a number of decades, but maybe you want to go backwards a little bit and explain how stem cell transplant was really the original immunotherapy.

Dr. DiPersio: So a stem cell transplant was really first developed in the context of transplantation for, believe it or not, both malignant and non-malignant diseases, aplastic anemia and acute leukemia, and really the early transplants were performed by E. Donnall Thomas and in which, and by the way, there's a beautiful recent book published by Fred Appelbaum and the book is called Living Medicine. It just came out a few months ago. It's really I encourage everybody to read it because it does provide you with a really amazing context of how transplant began. Those were really the dark ages in the early '60s, late '50s, early '60s when transplantation was performed mostly from donors into recipients to get rid of leukemia or to fix this bone marrow failure state called aplastic anemia. I think the efforts early on were very, very challenging with almost, I think, 95% of the first 20 or 30 patients not surviving the treatment.

So, obviously, over the years, the approach to transplantation has taken two big directions. One is that the treatment for malignant diseases and bone marrow failure states from donors to so-called allogeneic transplant is associated with a number of unique risks but also some really powerful benefits, and that's what you were talking about, that's the immunotherapy of the infused cells, specifically the T cells, which recognize the host as non-self. So those T cells can actually attack the patient's leukemia or whatever malignancy the patient has and also can attack the host or the recipient's immune system to allow the donor cells to engraft and take over. So the complications really surround this issue of graft-versus-host disease in which the T cells, these immune cells, of the donor can attack not only the malignancy of the host, which is a very powerful effect, but also can unfortunately somehow sometimes have significant off leukemia but on-target effects on normal tissues resulting in things like rash, diarrhea, and liver problems, et cetera, which can be life-threatening.

So over the past five or six decades, we've figured out how to do this much more safely even for older patients. Now we can transplant patients in their 60s and 70s with transplants from donors. We can expect that a large number of those patients will get through the transplant safely with limited complications. What we're really left with now is still relapse of the disease even though a transplant is done because these diseases are pretty tough. That's come an enormous way and now we have ways of really limiting both acute and chronic graft-versus-host disease using various approaches, some of which we've been involved in the development of and some of which have been developed by others in the field.

The other direction is autologous transplant, which relates to myeloma mostly. It was observed early on that high doses of an alkylating agent called melphalan could be associated with prolonged remissions in patients with multiple myeloma. In fact, oral melphalan was used as a treatment for multiple myeloma at very low doses. Some of these patients did very well, and so the thought was could we advance the dose to very high doses and really completely extinguish the myeloma and hopefully have just normal stem cells recover? So that's the principle of autologous transplant for multiple myeloma and that is that high doses of this drug called melphalan, since these myeloma cells are inherently sensitive to melphalan, can be used to eliminate the myeloma and allow the normal cells to survive and grow back so that when they grow back, there's normal blood cells that are being made, but there's no myeloma. So this has become a staple or a standard of care for the treatment of patients with multiple myeloma. And still to this day, even though we have many new drugs for multiple myeloma, it still represents a standard of care approach to the treatment of patients with multiple myeloma, especially those that have had a nice response to what's called induction therapy, which today represents a combination of things like dexamethasone, IMiDs like lenolidamide or pomalidomide and other agents such as daratumumab and et cetera.

This autologous transplant what you do is you collect the stem cells from a patient with myeloma and then freeze them and then give the patient high doses of melphalan so that all the cells are eliminated, including the normal stem cells, and the myeloma cells. The trick is that you infuse the frozen stem cells that have been frozen in advance of the high doses of melphalan, because if you didn't do that, there would be no blood count recovery. Those stem cells magically go into the blood and find their way back to the bone marrow and home to an area called the hematopoietic niche, which is in the bone marrow, and they settle there and they see everything they need to start dividing and making new blood cells. So over a period of just 10 days to two weeks, new blood cells are made. Patients recover and they can leave the hospital with a recovery of their blood counts and hopefully near complete or complete elimination of their myeloma. That's sort of the history of autologous and allogeneic stem cell transplantation.

Jenny: That's fantastic. I'm so happy you mentioned the book Living Medicine. As I mentioned in the introduction, we are having a launch event for our HealthTree 2.0, kind of our next decade. Fred Appelbaum is coming to speak as a keynote speaker at our launch. We will be giving, you know, sharing copies of his book at the event. I am almost finished reading it. It is a fascinating read of the history of stem cell transplant. And I think, had you looked at that idea and that concept five decades ago, you would have just -- and I know people said this probably to him, like you're crazy. How is that? It's like science fiction. How does that even seem possible? Now here we are.

Dr. DiPersio: I think it, you know, with all due respect to even the people that came before E. Donnall Thomas and those early pioneers were a number of stem cell biologists that have been doing transplants in small animals and mice. There was evidence from those studies that transplants could be done, and they could be done across MHC barriers or these histocompatibility barriers. There was some evidence, at least from small animal studies, that this was actually possible. The studies that really launched it into the human setting were a series of experiments done primarily in dogs. That's where E. Donnall Thomas did his early work for which he received the Nobel Prize many years ago.

But I think the most important thing is there always is somebody that's doing something before you do it almost always. Sometimes those guys get a little bit forgotten. In those early prime years where mouse transplant people, I still do a lot of mouse transplants and they provide incredible insights into how to -- and many of the approaches that we've taken with patients and to minimize the toxicity of transplant were first worked out in mice and then now less often in large animals because it's such an expensive undertaking, but obviously large animals were used in the early days, specifically dogs and occasional primate studies. But I think there was, you know, with all due respect to all the people that came before Don Thomas, there was a little bit of evidence that this could be done and could be done safely. So his early studies in the dog were on the shoulders of a number of folks doing these mouse experiments.

Jenny: Well, it's incredible. I think that happens very frequently when people are standing on the shoulders of people who came before who were doing basic research and then moving it to the translational type of research. It's really incredible. I think it's just so impressive. These people are so brilliant, including people like you. It's amazing.

Let's talk a little bit about stem cell transplant, and you talked about how it's being used in multiple myeloma. Patients typically get some kind of induction therapy like daratumumab, like you mentioned, Revlimid, Velcade, dexamethasone in a quad therapy or maybe a triplet, just Revlimid, Velcade, dex or even Kyprolis or something like that. And then the stem cell transplant is given and you give a very nice overview of the recovery, how the recovery works. Could you get your samples back? And then a lot of myeloma physicians will give some kind of consolidation or maintenance therapy. Can you talk a little bit about how the side effect management has become pretty well known and very, you know, facilities don't seem to have any kind of problem with that anymore?

Dr. DiPersio: So the transplantation procedure we use in myeloma patients is called autologous transplant. We use one's own stem cells. So those stem cells engraft after the patient has received high doses of melphalan. The melphalan goes away, gets excreted, and so there's no drug left and then the cells are infused. They're thawed at the bedside and then infused into the patient. As I say, they magically find their way to the bone marrow. From every step along the way, we have spent years and decades honing this down. The process of collecting the stem cells used to be from bone marrow harvest. Now we can actually give drugs that will actually redirect the stem cells that are in the bone marrow to move out into the peripheral blood in large numbers, and then those stem cells can be collected and frozen. The freezing process had to be worked out over a long period of time because when you freeze and thaw cells, there's water in cells and so the water freezes. For any of you who know, if you pour water into a glass and you put a glass in the freezer, the water will expand when it freezes and the glass will break. So the same thing happens in a cell, so you just can't simply collect a cell and freeze it. You need to do something to make sure when you cool it down, the inside doesn't form ice crystals. So there are chemicals that we freeze the cells in so that there's no expansion of the intracellular fluid, so the cells don't burst open. That's called DMSO. Then that is essentially excreted in the patient's lungs when we infuse these cells.

Then the cells, how they get to the bone marrow has been an effort by, in particular, my lab for 20 years, almost 20 years. So I've been very interested in what are all the signals involved and how a stem cell gets into the bone marrow and what tethers or what molecules are actually involved with the attachment of the stem cell to the bone marrow niche and how you actually break those tethers to release them into the peripheral so they can be collected for freezing and then infusion after stem cell transplantation.

Then the management of patients after infusion, you know, the blood counts will go down and they'll go to zero. So the supportive care for patients has undergone a revolution with modern antibiotics, modern blood product infusions to protect patients against infections and bleeding. A number of drugs are used and are being tested even today to reduce the systemic toxicities of the high-dose chemotherapy because that can injure tissues in and of itself, like the GI tract and the liver. So we're looking at new things to try to block that toxicity. And then also the use of growth factors after transplant that might enhance recovery of at least the neutrophil count more quickly. So that's been studied for many years and now it's pretty much standard of care.

Then we know what happens when you engraft and you're not sick, you know, the blood counts usually are stable and the engraftment includes all of the important blood-forming cells, like the white cells that fight infections and the red cells that carry oxygen to the tissues and the platelets which are responsible for blood clotting. So all of those come back in a relatively short period of time and usually quite consistently in those patients that get sufficient numbers of stem cells that were collected before the infusion.

This is all now. It was completely unknown 30, 40 years ago. Now it's a science and a standard of care which most every transplant program follows in some general way. We're all trying to tweak the system every day to try to get more stem cells or better stem cells by using various basic science approaches that we work out again through the mouse and then sometimes through large animal models. Then we're also trying to freeze them better so that they are preserved better. The third thing is we're trying to get them to go to the bone marrow quicker and expand faster and also promote engraftment of all of the lineages more consistently and more rapidly, so the patients don't have any kind of toxicity issues.

Then eventually we'll figure this out to the point where this realistically can be done not only in the outpatient setting, which it can be done now, but in the outpatient setting where there are very few requirements like for transfusions or antibiotics. We're starting to figure out how to really improve the hematopoietic recovery such that those kinds of supportive measures may not be that necessary in the future. It will truly be not only an outpatient procedure but a relatively easy outpatient procedure.

Jenny: Oh, wonderful. Well, for someone who experienced or went through tandem transplants, I appreciate all the work that you're doing to dial this in and as a community to do that, it's incredible. I want to ask you about the stem cell collection process because I know you've been leading a clinical trial focusing on the stem cell collection process, and you mentioned that as one of the steps. Maybe first help us understand how long does it typically take to collect and do patients ever struggle with stem cell collection in that part of the process?

Dr. DiPersio: That's a very good question. Before we could actually, it's so-called in quotations, mobilize stem cells from the bone marrow into the peripheral blood. As I mentioned, we used to bring people to the operating room. In fact, it's still done today with normal donors to bring people to the operating room and collect their bone marrow and freeze their bone marrow away and those are the source of stem cells. It's usually relatively inefficient for autologous transplants, and so we've found that mobilizing these cells into the peripheral blood, we collect many more stem cells and they're very functional and they are responsible for engraftment even faster than bone marrow stem cells are. This has become the standard of care for autologous transplantation in multiple myeloma.

So the process actually requires two steps. Number one, you need to give some drug or drugs to promote this mobilization process. The second is you need to collect these stem cells using a process called pheresis. Let me just mention the first step. So that the standard of care for many years has been to give GCSF, or granulocyte colony stimulating factor, which is something else that I was working on early in my career, cloning this gene and studying this gene and a live gene called granulocyte macrophage colony stimulating factor. Both of these actually induce the peripheralization or mobilization of stem cells into the peripheral blood. We now understand some of the mechanisms.

It's quite interesting actually that one of the tethers that holds the stem cells into the bone marrow gets downregulated by GCSF so that tether starts to disappear, and so the stem cells kind of float out of the bone marrow into the peripheral blood. That's the mechanism of how GCSF mobilizes. But that process takes four to six days, and so you have to get shots every day. During that time also that the stem cell numbers are expanding because GCSF induces a horizontal expansion of the stem cell numbers and also promotes this peripheralization of stem cells out of the bone marrow into the peripheral blood by downregulating this little tether that's actually expressed in the bone marrow itself and therefore, without that tether, the cells are not attached anymore to the bone marrow and float away. And then they're collected by the pheresis.

The second big event that's occurred is that in 2009, we actually made a major effort in the laboratory along with colleagues at a small biotech company in Vancouver called AnorMED and developed a small molecule mobilization agent called Plerixafor. Instead of taking a week to mobilize stem cells into the peripheral blood, this does it in a matter of hours. It blocks that tether instead of downregulating it. While GCSF takes a week to downregulate this tether, this small molecule Plerixafor blocks it in minutes, and so the stem cells just immediately float into the peripheral blood. So it's a rapid mobilizing agent, but it's not as potent as GCSF.

And so there have been two major trials looking at the combination of GCSF plus either Plerixafor or another inhibitor of the same class. This is called the CXCR4 inhibitor called motixafortide, which was just recently published by our group a month or so ago. This drug is also like Plerixafor CXCR4 inhibitor. And both of these studies, the one in 2009 and the one in 2023, showed the same general result, and that is that when you combine Plerixafor with GCSF or this new drug, motixafortide, with GCSF, you get synergistic or robust additive mobilization of stem cells into peripheral blood. Compared to GCSF alone, there was a dramatic difference in the ability to collect sufficient stem cells for transplant.

Now the standard of care for patients with myeloma for the most part is to get either GCSF plus Plerixafor and potentially in the future will be to get GCSF plus motixafortide to harvest the most stem cells. The reason you want to harvest the most stem cells is that some patients require more than one transplant, like you receive tandem transplants for myeloma, and so you need to collect, in a sense, enough for two transplants, not just one transplant. The second is the more stem cells you have for each transplant, the better, faster, and more consistent the engraftment and the lower toxicity and the increased safety of each transplant. The more, the better. So the combination of a CXCR4 inhibitor, which is a small molecule, rapid mobilizing agent, with GCSF, which is a biologic, which takes the five to seven days to work, is synergistic, and this is the standard of care for mobilization in the future.

Now, what's going to happen in the future for mobilization? Well, I don't know, but we're working on a new angle. We haven't published this yet, but we're working on another rapid mobilizing agent that targets a completely different pathway so that instead of giving GCSF for a week and then Plerixafor or motixafortide, we have, at least in mouse models and in primate models, shown that if you give motixafortide or Plerixafor plus our rapid mobilizing agent, you get about the same mobilization as you do with GCSF and CXCR4 inhibitors, but you get it in hours instead of a week. This will be, you know, instead of having to go every day to the clinic to get your shots for a week, it's conceivable that in the future we'll be able to do this the same day. You'll come to the clinic, you'll get both shots, you'll get collected, and you'll be done.

Jenny: Wow, that's impressive. I remember that process.

Dr. DiPersio: The second part of this is the collection process, which is done by a process called apheresis. It's a very nifty process where the blood cells leave one port of a catheter usually and go into a machine where they're centrifuged and the density of the cells results in the stem cells floating at the top of the bowl and all the other cells going to the bottom, the red cells, and the granulocytes, and those cells are returned to the patient. The stem cells which float on the top are siphoned off and they're collected continuously while the patients are undergoing this procedure. Usually, the procedure consists of three to four blood volumes, so between 16 and 20 liters of blood volume, which is four times what you have in your body. But what happens is the one blood volume goes out and almost all of it goes back to you, except the stem cells which are taken out. That process continues until you've had about four blood volumes for each. Those cells are then measured for stem cell numbers by what's called flow cytometry, and then they're frozen in DMSO, like I mentioned earlier, and they're ready for infusion after the patient receives the high-dose melphalan chemotherapy.

Jenny: That's wonderful. Thank you for the explanation. It makes a lot of sense. I know that for the motixafortide, okay, I'm saying this wrong, but I think there was just an FDA approval, right? Aphexda was just FDA approved for multiple melanoma?

Dr. DiPersio: It just got approved, I think, a week ago or so. I think that's exciting. I think it's hard for maybe your audience to understand how hard it is to get drugs approved by the FDA, how much effort and time it takes a team, a village of people, big pharmaceutical effort, oftentimes investors that put their life savings in these, both small and big companies, to make something happen and then, of course, good basic science that gets you to that spot and then good clinical investigators that can execute clinical which show the benefit of the reagent that you're trying to develop. So that process with motixafortide literally took probably almost 10 years from the beginnings. It wasn't simple. It wasn't easy. It took, as I said, a village to do this.

We were fortunate to be involved in a lot of early basic science in the design and execution of the clinical trial. Fortunately, the clinical trial was very positive, and so the difference in the number of patients that were able to collect sufficient numbers of stem cells for a transplant at the end of just GCSF alone was around 16%. After the first apheresis, and it was almost 90% if you got the two drugs together, GCSF and motixafortide. So you can see it represents a big difference. So that's basically and the fact that it was relatively well tolerated and that's why it was approved by the FDA.

Jenny: That's wonderful. Why do patients struggle with collection at some point? Is it because they've received prior therapies that have kind of worn that down, or what's the core cause?

Dr. DiPersio: Very good question. There are three things, I think. One important thing is age and sex-related issues. As you get older and older, especially if you're a female, when you get older and older, the ability to collect stem cells drops slightly. Okay, so that age has impact. And then previous therapies for your myeloma or any other cancer you may have had before you developed myeloma can really, or radiation or anything like that, can diminish your bone marrow reserves. So those patients are particularly difficult to mobilize. Just the number of stem cells that are living in those patients, even though their blood counts may be normal, their reserves are low and you don't know that until you try to mobilize them, and it's very difficult.

Then the third is unknowns. There are a number of people, even normal donors, young allo donors, not many, fortunately, but some, that are very poor mobilizers. So the question is why. We and a few other groups have been looking at that. Do they have some underlying genetic abnormality in their stem cells? Is it inherited? Is it inherited, meaning is it a germline inherited trait in which perhaps some of the tethers in the bone marrow are configured in a different way and hold those stem cells in there, or don't support sufficient numbers of stem cells?

So those are the three things: previous therapy, age and sex, and the unknown. That's why these new agents to mobilize stem cells are particularly important because this allows even poor mobilizers to mobilize sufficient numbers of stem cells to get a transplant, and that's important.

Jenny: You talked about the 10 years that it took to get this particular to market, and it seems like the average might be about 17 years. I've read that somewhere before, that it takes about 17 years to get something to market from the beginning to the end when it's FDA approved. It's just such a long haul. Once it is approved, how do you get the word out to transplanters, essentially?

Dr. DiPersio: Well, I mean, I think the key that we -- the primary focus that we've always taken when we've been involved in the development and FDA approval of three different drugs, which is pretty exciting. In each case, I think the best way to do it, I think, is to do the correct studies and publish the studies in good journals so that the scientific community can read them and assess them. Then we have scientific meetings where the data is presented to all of our colleagues who are actually taking care of these patients. And then they can see what the benefit of these drugs are. And then the drugs, if they're good and they're really worthwhile, they sell themselves, meaning that physicians will look at them and say, you know, this does provide a clear-cut benefit for these patients and then that's why I'll use it.

Every once in a while, you know, there are drugs that look good. But when it's used by the general public after FDA approval, sometimes there are unexpected long-term or short-term toxicities which then kind of result in some problems and sometimes even withdrawal of drugs from the market, which is rare, but also the level of enthusiasm sometimes can either increase substantially or decrease a little bit based on real-world experience with the drugs. So after it's FDA approved, I think if you did a good job and you did the right study and the study was positive and you published it in a good journal and you presented it at scientific meetings in a fair way, these drugs generally sell themselves.

There's one impediment that limits their access to the general population, and that is their costs. In today's world, that's an important fundamental feature of all drugs being used, not being FDA approved so much but being used, because there are options that hospitals have and even outpatient clinics that are often owned by hospitals have, and they want to provide care not only in the best way but also as possible, all else being equal in a cost-efficient way. So they have to look at the cost of new drugs, and sometimes these competitors come off patent and generics are made and they're slightly cheaper. So physicians and formulary committees at hospitals look at the cost of new drugs and the relative additional benefit and the relative increased cost and make decisions about how they would be utilized. But obviously you can, if the drugs are life-saving in monumental, for instance, CAR T-cell therapies, they are phenomenally expensive. But because they have such an amazing impact on disease and the quality of life of patients, we've been able to so far accept the fact that they're very costly and we've been so far able to bring them into the mainstream of patient care

Jenny: Fascinating. You mentioned that some of these drugs can have side effects, obviously. I think every drug does have some kind of toxicity to it. Does this new one come with any notable side effects? Or I know you mentioned that you were working on different combinations also that were different. Are you seeing anything in your studies that are identifying any particular --?

Dr. DiPersio: The paper that we published, it does go into all the detail of all the toxicities, and they're called adverse events that occur during a study, severe adverse events, and so that's all in the publication, but also in the FDA approval of the drug, the label, so-called, that is mandated by the FDA has to list all of those toxicities. So in our hands, you know, it was very well tolerated. The major toxicity was minor skin-related erythema, which is redness, and sometimes a little swelling around the injection site, but that was the major issue. There were no really – every once in a while, a person would have a little bit of itching and then when we used pre-medications, that was gone away. So the systemic toxicities were very limited and well tolerated, and the only thing that was sort of consistently seen was a little bit of swelling and erythema where the injection site is given, the injections are given.

Jenny: Okay. Well, that makes sense. I mean, if you're shorting it down from a week down to a day, that's incredible. Can I ask you a question about this? Because you are working on both cellular therapies or transplant and immunotherapies which are also under that brand, I guess, or that bucket. Should all patients collect -- I'm hearing some CAR T providers say sometimes we're using banked stem cells for post-CAR T recovery. My question is should all patients, whether they're headed to transplant or not, collect and store their stem cells?

Dr. DiPersio: That's a really good question. I don't know how many times we've talked about this. Again, there are issues relating to cost. The issue with prolonged pancytopenia after CAR T cell infusions from myeloma is quite a bit lower than for acute lymphoblastic leukemia and for large cell lymphoma, but it's still an issue. Obviously, when it happens, it's just terrible because you have someone who has no blood counts, and they're obviously at great risk to have something bad happen. So I don't know what the answer is. Obviously, if it could be done cost-effectively for everybody, it might not be a bad idea, to tell you the truth. I think one of the worries is that when you collect some of stem cells, you might be collecting a few myeloma cells at the same time. But I think that's an issue which has pretty much been debunked for the most part.

So I think the issue is should that be sort of a standard of care? And obviously, it would be very hard to do a clinical trial showing the benefit of that approach because the incidence of this, especially in myeloma CAR T's is so low that you'd have to do lots and lots of patients to show a benefit. So who's going to pay for this study? The insurance companies may not want to pay for that extra cost of mobilization. The cost of mobilization and collection is quite substantial, and so it adds another $30,000 to $50,000 on top of the cost of the CAR T cell therapy. So there are lots of issues there, especially if the insurance company is not paying for it, who's going to eat the cost? The patient is not going to pay for it. The hospitals are not going to pay for it. The physicians are not going to pay for it. Ultimately, the insurance companies will have to agree to pay for it. They may not pay for it because there's no FDA approval, or that's not part of the label for CAR T.

Jenny: Right. You'd have to kind of position it as someone's maybe headed to transplant and they're going to collect. If they get to use it later, great. I don’t know.

Dr. DiPersio: What we do and what some other places do, for those patients that come to CAR T cell collection, whether they have myeloma or diffuse large cell lymphoma and they have low blood counts to start with or they have bulky disease, a lot of disease, so the patients that have a lot of disease and low blood counts to start with when you collect their T cells, those are the people that are at the greatest risk of having prolonged pancytopenia. If you say, okay, I'm just going to try to get approval, a one-off approval for this patient, probably 50% of the time the insurance companies will agree to it, but it may not be cost-effective or reasonable to do that in everybody.

Jenny: Well, that makes sense. If you can pre-identify who might be struggling, that might make more sense. Another question that I get a lot asked by myeloma patients is, is stem cell collection and T cell collection possible at the same time?

Dr. DiPersio: Absolutely, but we haven't done this yet. But absolutely, there should be no problem doing both at the same time. That's also for that to be, you know, because the label for each of the CAR T cell products, the label is that you get just an un-mobilized apheresis without GCSF. That's how the drugs were approved. So if you do something different, number one, the insurance companies may deny after the fact. They may find that you use GCSF to mobilize and also the cost, there's going to be additional cost and someone's going to want to know who's paying for it. But if you're asking me one of the safest and easiest ways to proceed would be to do exactly what you're saying and that is to collect both T cells and stem cells at the same time.

With GCSF, it's going to be a little bit tricky, because you have to give GCSF for a whole week. So you'd have to do the process at two different times. But you can imagine, if you had these rapid mobilizing agents, that somebody could come in the morning and get a collection of T cells for their CAR T cell and then get, you know, right after the collection, two hours later, get their doses of motixafortide and another rapid mobilizing agent and two hours later get their stem cells collected in banks. They could all get it done essentially the same day while they were hooked up to the pheresis machine. But, again, that's not how these drugs, these CAR T's were approved, and so the FDA will say, show us that that results in equivalent outcomes. I don't know if anybody has the stomach to do this because that's a big clinical trial. Who's going to pay for it? That's the issue.

Jenny: Right, and the currently approved FDA CAR T therapies are not approved to use frozen T cells potentially either, right? So you'd have to do some kind of storage of those?

Dr. DiPersio: That's right. You know, they're all evolved from fresh products being manipulated. Again, when you actually freeze, thaw, and then genetically manipulate a T cell, you have to prove that those T cells work the same way. Again, I'm not sure if anyone would want to go back and try to prove that because the cost would be enormous.

Jenny: What's the impact of GCSF on T cells? I'm just curious.

Dr. DiPersio: Well, GCSF does skew the T cell population. So it's a very good question and people have looked at the phenotype by staining the surface of these cells. There are some subtle changes that GCSF and also this longer acting PEGylated GCSF has on T cells. There's been some really quite poor evidence in the allotransplant setting that GCSF may alter the T cell function that may result in a slight increase in the number of patients that develop chronic graft-versus-host disease, although most experts like myself really feel that that's most likely due to just the greater number of T cells you get when you mobilize with GCSF in the products compared to a bone marrow harvest or something like that.

There are some subtle differences. And then also, you might ask, well, what does metaphorize or Plerixafor do to T cells? And they also skew the T cell population. The key there is that even though we see these subtle differences in the phenotype of the T cells, it's been difficult to prove that they function differently. That's been the tough part. The bottom line is there are differences in both GCSF and Plerixfor, motixafortide, and do some unique changes in the T cell populations. But proving that that results in any change in outcomes has been either not tested or impossible to determine.

Jenny: That's fascinating. You are also an expert both in transplant and in immunotherapy. As these immunotherapies CAR T bispecific antibodies vaccines come out and are being used in myeloma and other blood cancers, what are you thinking will happen in terms of sequencing with stem cell transplant? Will the strategy be to do an upfront stem cell transplant, save your immunotherapies for second line, or use the immunotherapies first, save the transplant for second or third or fourth line if that doesn't work? What are you thinking?

Dr. DiPersio: You know, I'm looking at what's happened in lymphoma. In the lymphoma world, the number of patients getting autologous transplant now is dropped substantially and that is because these CAR T cell therapies and other immunotherapies have been put in as second line treatments. I suspect that the same studies will be with and are being done actually with myeloma, and so there'll be large randomized studies in patients to get induction and then standard autologous transplant and maintenance versus induction CAR T cell therapy and maintenance in every combination of those things. Yes, I think those studies will be done and those will lead the way forward.

But remember, the reimbursement for an autologous transplant by Medicare is around $40,000. That's obviously a cost more than that because -- but that's the DRG reimbursement somewhere in the $45,000 range, something like that, so very low. The cost of a CAR T is 400 plus thousand dollars just for the reagent and probably closer to $600,000 for the treatment. Again, we might show a slight benefit of giving CAR T cells after induction therapy, but we have to be careful about breaking the bank here. If you give something that shows a little bit of a benefit as opposed to progression-free survival, is that the same as overall survival? For instance, if you do treatment, induction and then auto-transplant and then maintenance and then CAR T, are you going to end up with less surviving patients than if you do induction, CAR T, maintenance, and then an auto-transplant, something like that, or another immunotherapy?

So what I'm saying is that cycling these treatments earlier and earlier, you have to show that there's not only an improvement in progression-free survival but also maybe even overall survival because there are so many other options for treatment and the additional cost to society. You know, there's a lot of patients with multiple myeloma, and there's a lot of people getting autologous transplants from multiple myeloma. If we convert all of those to CAR T cell treatments, the difference in cost is tenfold. Suddenly you increase the cost of care by 1,000%.

Jenny: It's just a question about T cell fitness, right? Are you going to have better outcomes if you use it in earlier line of therapies because the T cells aren't as exhausted?

Dr. DiPersio: I don't know. That's a good question, but I don't know the answer to that. Obviously, there are ways of using off-the-shelf reagents that will become more and more of a potential possibility as we go forward CAR T's and NK cell therapies that may be an off-the-shelf reagent, where the issue of exhaustion is not such a big issue.

Jenny: Is there a difference in responses that you see genetically? I know precision medicine was kind of a huge thing a few years ago, and everyone was trying to find targeted therapies for certain genetic features. It seems like immunotherapies are not considered like that. Patients seem to do well even if they have some of those higher risk features. But have you seen any differences genetically in high-risk versus standard-risk myeloma for stem cell transplant versus the immunotherapies?

Dr. DiPersio: I'm not convinced that there is yet, but I'm suspicious that when -- because not enough patients have been treated uniformly and followed long enough. So I'm going to stick my neck out here and say that there will be, because we see that in every kind of immunotherapy for the most part because, ultimately, the inherent biologic aggressiveness of diseases, if you treat enough patients, will show its ugly head. We see that in ALL, the patients with 4;11 translocations that have B cell ALL, they respond to CAR T cell therapies, but they often relapse afterwards. The same for patients with particularly high-risk genetics in diffuse large cell lymphoma, although you can cure some of them, there is a trend towards worse outcomes in those people with worse genetics. In myeloma, there's just not enough patients that have been treated yet, but I bet I'm just going to stick my neck out that there probably will be some inherent differences in those patients that have really high-risk mutations, including, of course, p53 mutations that get CAR T cell therapy or bispecific therapy and that their outcomes will be not as good. But the data isn't there yet.

Jenny: You would kind of guess that maybe.

Dr. DiPersio: Actually, I'm a guesser.

Jenny: You're a prover. You do the trials and you make it happen. So speaking of that, are there any clinical trials? You mentioned earlier in the show that you're working on your own mobilization solution as well. Are there any other clinical trials you're working on that you'd like to highlight for stem cell transplant or immunotherapy space in myeloma?

Dr. DiPersio: Well, in myeloma, yeah, so I tell you a couple of things we're working on. So we've been interested in, you know, obviously people have identified BCMA as a very good target myeloma. In fact, the two approved products, Abecma and Carvykti, target BCMA. Of course, you know that there are bispecifics that target BCMA. The reason it's such a good target is that it is really differentially and universally expressed in myeloma versus non-myeloma cells versus non-plasma cells. Let me put it that way. That's the first reason. The second reason is when you get a mouse and you knock out BCMA, you actually have a big problem, in that the mice don't develop any B cells, and so they don't survive as long. That means that the gene is less likely to be lost. It can be shed from the surface of myeloma cells, but it's less likely at the genetic level to be lost because it's an important gene for B cell development. It's a good target, and it's really the best and most differentially expressed gene in myeloma.

So we were interested in identifying second generation and third generation targets. What we did is we took the Multiple Myeloma Research Foundation data set and our own data sets here and used the largest data sets in the world and looked at the expression of differentially expressed genes in myeloma, malignant plasma cells versus all the other tissues. We just published this dictionary of all the targets in myeloma in cancer research, I don't know, maybe six months ago. So that is a dictionary of all the targets that are differentially expressed in myeloma and we did it both at the genetic level, at the RNA level, and also at the protein level. This is, I think, the only such really dictionary or compendium of all these potential targets.

There were two other targets that really – there's one other target that we identified that's being pursued by industry, and that's GPRC5D, and that is a target that's expressed in the GI tract and in the skin, and that is in clinical trials right now with a bispecific agent. We also came up with two other targets that we think are really very universally overexpressed in myeloma, and that's CS1, also called SLAMF7. There are two or three groups in the world, including our own, that are working on that. There's a big study in Europe that is being pursued with what's called a mini-gene approach, a transposon approach with a CAR T to CS1. There are two small studies done in the United States. We have our own CS1 that we've cloned, the antibody, and we've made an SCFE.

We have an IND that's pending at the FDA, and we have GMP-grade vector, and we're going to test PS1 as a target in myeloma. Because everybody with myeloma that gets BCMA CARs seems to all recur. So the vast majority of patients, they'll have nice responses, but they eventually recurrence. The recurrence, median and recurrence times can range between 8 months and 15 months, but it's not a permanent treatment. We'd like to get alternative CARs that would target another antigen. We're ready to go with a CS1 CAR. And then there's one other target that we really liked in our study and we've made also unique SCFEs to this target called FcRL5. There is one study using a bispecific target in this reagent called cevostamab. So ours would be the first CAR T cell study targeting FcRL5, and we're making GMP-grade virus now.

Those would be backups for those people who fail BCMA-targeted therapies, either bispecifics or CAR T's. I think that because people live so long, they deserve alternative treatments when they fail BCMA therapy. That's a couple of other things at work.

Jenny: That's fantastic. That's just wonderful. We would love to share your dictionary of targets. So later I will reach out and see if you can email me link to that because we have a news feed and we'll share that on. Wonderful. We actually have a foundation funded, it was the University of Würzburg, right? The work that you were talking about in CS1 and CAR T, maybe in Germany.

Dr. DiPersio: That's exactly right.

Jenny: We funded that back in 2015.

Dr. DiPersio: Exactly. Mike Hudecek.

Jenny: Michael Hudecek, we funded him. It's good to know that we did a good job there to fund some of that work. I am thrilled and it will be fabulous to see what you can do with it. I think in the United States, you can move a little faster than you can in Europe and that will be fantastic. So we will follow you closely on that. But, yes, okay, so we're a little over, but I want to allow just time for one question. If you have a question for Dr. DiPersio, please call 347-637-2631 and plus one on your keypad. We'll just take one because I know we're over. Okay, caller that ends in 8233, go ahead with your question.

Caller: Hi, I was wondering how long after transplant should I wait to have immunotherapy, and does it take a while to recover so that immunotherapy can be effective?

Dr. DiPersio: That's a good question. No studies have been done that specifically look at that. That's, unfortunately, I'm sure that's not what you wanted to hear. But we have recommendations even though no studies have been done. We know a little bit about lymphocyte recovery after transplant and that after myeloma autologous stem cell transplant, the lymphocyte recovery is usually pretty adequate after three months, so 90 days. The recommendation is somewhere between 90 days and 100 days after transplant, you can be revaccinated.

Caller: Okay.

Jenny: Okay, wonderful. Dr. DiPersio, thank you so much for joining us today. You're so knowledgeable, and it's been a wonderful show. Thank you for sharing your transplant and immunotherapy experience with us as myeloma patients. We're just so grateful.

Dr. DiPersio: Thanks for the invitation. I really enjoyed it, and I wish you all the very best.

Jenny: Okay, thank you so much. We look forward to seeing what you do in the future. It's amazing. Thank you for listening to the HealthTree Podcast for Multiple Myeloma. Join us next time to learn more about what's happening in myeloma research and what it means for you.

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