CAR T-cell Therapy for Patients with Multiple Myeloma

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Multiple Myeloma – CAR T Cell and T-Cell Engager Therapy

Wednesday, September 22, 2021

Presenter: David H. Vesole, MD, PhD

Presentation is 45 minutes with 22 minutes of Q & A.

Support provided by Bristol Meyer Squibb and Sanofi.

Summary: CAR T cell therapy is a new type of therapy for patients with multiple myeloma. It is currently available for patients who have relapsed after four or more rounds prior therapy. This presentation describes CAR T cell and related therapies as well as new drugs in the pipeline to treat patients with multiple myeloma

Highlights:

• In autologous transplants, the patient’s cells are removed and returned but are not altered in any way.  In CAR T cell therapy, the patient’s cells are removed, genetically altered to kill cancer cells, and then returned to the patient.
• CAR T cell therapy can cause two major side effects: cytokine release syndrome (CRS) and neurologic problems. There are effective drug treatments for both of these reversible issues.
• Two promising CAR T cell products are Abecma® and cilta-cel. They have shown promising response and remission rates for patients who have had multiple lines of therapy and lack other treatment options.

Key Points:

(00:07:02) Patients who have had an autologous stem cell transplant (using your own stem cells), in general, remain in remission longer than those who have not had a transplant.

(00:08:02) There are many targeted drugs and lines of therapy available for people who relapse including immunomodulatory drugs, monoclonal antibodies, steroids, proteasome inhibitors, alkylators, and HDAC inhibitors.

(00:10:55) BCMA targeted therapies are a newer approach to treat patients with myeloma.  The therapies target and destroy specific proteins on myeloma cells

00:15:38) There are currently 136 clinical trials testing the effectiveness of CAR T-cell therapy to treat patients with myeloma.

(00:19:15) Combining several of these new drugs can greatly improve the response rate and progression-free survival.

(00:23:23) CAR T cells are modified to make them “angry” and armed with missiles to attack  cancer cells.

(00:27:37) It can take four to five weeks to create and ship CAR T-cells cells so bridging therapy may be used for people with aggressive disease.

(00:28:47) CAR T cell therapy is much easier to tolerate than a stem cell transplant and has no age limitations.

(00:40:52) Some patients may be able use “off-the-shelf” donor cells, rather than their own cells, to speed up the process.

(00:42:09) Bispecific drugs use two methods to attack myeloma cells. The treatment is given continuously rather one time.

Transcript of Presentation:

(00:00:01) [Susan Stewart]      Introduction of speaker. Good evening, and welcome to the webinar CAR T-cell Therapy for Patients with Multiple Myeloma. My name is Sue Stewart, and I'll be your host for today's session. I'd like to thank Bristol Meyer Squibb and Sanofi, whose support in part made this webinar possible.

(00:00:20) So now, let me introduce tonight's speaker, Dr. David Vesole. Dr. Vesole is the Director of the Myeloma Program at MedStar Georgetown University, and a Professor of Medicine at Georgetown University. He's also Co-Director of the Myeloma Division, and the Director of Myeloma Research at the John Theurer Cancer Center at Hackensack Meridian School of Medicine, where he is also a Professor of Medicine.

(00:00:48) A nationally recognized expert in multiple myeloma, Dr. Vesole is active in several professional organizations, including the American Society for Transplantation and Cellular Therapy, the American Society of Clinical Oncology, the American Society of Hematology. He previously served as co-chair of the Eastern Cooperative Oncology Group Myeloma Committee, the Center for International Blood and Marrow Transplant Research Plasma Cell Disorders Committee, and as a board member of the New York City chapter of the Leukemia and Lymphoma Society. He's an inspector for the Foundation of the Accreditation of Cellular therapy, and a member of the International Myeloma Working Group. Dr. Vesole has authored more than 250 articles in peer-reviewed medical journals, and over 20 book chapters, and he serves as a reviewer for several journals. Dr. Vesole has presented his research at medical meetings and symposia nationally and internationally, and we're very pleased to welcome him today. Please join me in welcome Dr. Vesole.

(00:02:01 [Dr. David Vesole]       Overview of talk. Thank you very much, Sue. It's quite an introduction. It's almost embarrassing when people go through my resume. I think it just tells you that I'm old, though I'm not sure that means much. It's really a pleasure to speak to the BMT InfoNet attendees. I've had this privilege before in the past, and wearing my dual hat by being a myeloma doctor, but I'm also one of the transplant physicians, and I've been doing both myeloma and transplant for, I hate to tell you, over 30 years. And it really is a pleasure for me to have the opportunity to try and educate people about their disease, options, outcomes, and what they can expect in the future.

(00:02:45) Today, we're going to talk about not exactly only CAR T-cell. We're going to slip in a few other things of new therapy approaches. CAR T-cells are included at Transplant Network talk because it is a form of cellular therapy. Stem cells are a form of cellular therapy when you have a stem cell transplant. Well, CAR T-cells are also a form of cellular therapy.

(00:03:08) And I'm also going to talk about a couple other tangential types of treatments which are monoclonal antibodies. And for those of you who have myeloma, particularly you've had more than one line of therapy, you're probably familiar with monoclonal antibodies but I want to talk about specific monoclonal antibodies, the pathway to improved outcomes for all of our patients in a way that is usually very well-tolerated. So it's a mixed bag, focusing primarily on CAR T-cells therapy, but we're also going to talk about some tangential issues.

(00:03:47) There are many new myeloma drugs for such a relatively rare disease. So, we have been blessed that there is such an active pipeline of myeloma drugs that have occurred over the last 10 to 15 years. One of the reasons people ask me, because I'm old enough to retire, when I'm going to retire. "Why would I want to retire when they keep providing more and more tools to control the disease, and help people live longer and healthier lives?" And if you look at this arrow of a timeline here, you see just in the past five years there's one, two, three, four, five, six, seven, eight, nine new therapies approved.

(00:04:24) This is for a disease that only occurs in 34,000 new diagnoses a year, which there's maybe 140, 150,000 individuals with myeloma in the United States. So it's a rare disease. It's only 1.8% of the cancers. It's the second most common blood cancer, but it's still a very small token of the overall population, since 98% plus of the cancers available are not myeloma.

(00:04:54) So the fact that we have such intense research and such a plethora of drugs available to us over the last few years is really a bountiful benefit of the fact that we have such interested and ardent researchers and clinicians doing the research that's necessary to improve outcomes.

(00:05:16) CAR T cells are only approved for people who have four or more lines of therapy. So these are some of the new drugs. The most recent drugs that have been approved in the past year. Includes isatuximab, so these are important. Actually, let's not talk about isatuximab. I want to talk about the drugs that are approved for the same indication right now as CAR T-cells. CAR T-cells are currently approved, and I've already seen some questions about can you get it earlier than what the FDA indication is? And the answer is probably not. The CAR T-cells are approved for people who have had four or more lines of therapy.

(00:05:47) There are several new drugs that work in different ways. The other drugs that are also approved for that same indication are Selinexor - very unique mechanism of action of how it inhibits transport in the nucleus, across the nuclear membrane; Belantomab, which is an antibody drug conjugate, which I am going to talk to you about, because it was the first antibody targeting the same target as most of the CAR T-cells; melflufen, which is a modification of melphalan, which for those of you who had transplant, you got IV Melphalan. This is a drug that's got a linker to it that helps it get into the cell better, which may or may not be better than the drug Melphalan that you got for your transplant. And then last but not least, which is not on this slide, is the Ide-cel, or Abecma, which was the CAR T-cell that was approved in March of this year. And as we'll find out in a little bit, there's a second CAR T-cell that's probably going to be approved, again, almost certainly for four more lines of prior therapy that's made by Janssen, that should get approved we think end of November.

(00:07:02) With transplant for multiple myeloma, the likelihood of people achieving and maintaining a complete remission for 10 years or more is 25%. So, this is the general schema of the standard of care. Since this is a transplant talk, I'm not going to deal with patients who are not having transplants. I can certainly address question to that approach if necessary., But people get induction therapy. Standard of care is at least three drugs for anywhere between two and six months, transplant standard of care all over the world, and then followed usually by maintenance therapy. Unfortunately, patients are not generally cured, although some of them get prolonged remissions. Indeed, the likelihood of patients who achieve a complete remission, staying in remission for 10 years or more, is 25%. But for those of you who are on the call, who are in complete remission and you've had induction therapy, you've had a transplant, you've had maintenance, the medium time for remission duration is 10 years in 25% of you, which is good.

(00:08:02) For patients who relapse, there are multiple targeted drugs and lines of therapy available. But the time of relapse, there's a whole list of different options here. At the top are monoclonal antibodies, and some of the other ones are other types of targeted drugs. Not going to go over those right now. It's just that there's a whole list. If this is your first relapse or second relapse, it's really up to your doctor to pick which one of these cocktails that they think would be best for you. And I can tell you, each and every myeloma patient is different, and each and every myeloma patient should have the option chosen for that individual. Subsequently though, the second line therapy doesn't work, you have to go to third line therapy and beyond, and what's listed here are some of the therapies that have been used for patients that have more than three, or even four, lines of prior therapy.

(00:08:58) Drug types include immunomodulatory drugs, monoclonal antibodies, steroids, Proteasome inhibitors, alkylators, and HDAC inhibitors. In general, there are a certain number of defined classes of drugs. There's immunomodulatory drugs, of which most of you are quite aware of. I've got the generic names written here. The trade names for them, Revlimid, Pomalyst, are immunomodulatory drugs.

(00:09:16) Monoclonal antibodies, there's Empliciti, there's Darzalex, and there's Sarclisa. For those, Darzalex and Sarclisa are made by different companies, but they're essentially first cousins. Elotuzumab is a different monoclonal antibody.

(00:09:33) There are steroids, the dreaded steroids. Dexamethasone is the most commonly used, although some people get Prednisone.

(00:09:41) There are Proteasome inhibitors, and the ones that you're aware of are Velcade, Kyprolis, and Ninlaro. These are all kind of selected drugs that target specific pathways in myeloma cells.

(00:09:57) But then there's the alkylators. The hammer drugs, if you will, that can't tell one good cell from a bad cell, and the alkylators include Melphalan, which we already alluded to, cyclophosphamide or cytoxan, and most recently, melflufen.

(00:10:10) Selinexor is a unique, recently approved drug. And there are a couple others that I've listed on here. Selinexor is this very unique drug, just recently approved, that affects the membranes of the nucleus, and then there's a drug class called HDAC inhibitors. Panobinostat, not commonly used.

(00:10:28) Most patients get some combination of these different categories of drugs. So in general, you pick and choose one from three categories. Most patients get an immunomodulatory drug, they get a Proteasome inhibitor, and they get asteroid. That's a triplet. There are now quadruplets of giving same group immunomodulatory drugs, Proteasome inhibitors, steroids, and a monoclonal antibody, and those are gaining a lot of interest and a lot of use in front line therapy, as well as relapse therapy.

(00:10:55) BCMA targeted therapies are a newer approach that targets specific proteins and cell types only. But what is new? And what's new is the BCMA-targeted therapies. If you will, if you think of a neighborhood, and in that neighborhood, unless it's a tract neighborhood which many years ago they built just one house after the other, they all look the same. But if you go to a normal neighborhood, you have a bunch of houses, each house is a little bit different. So some houses, just to give you an idea, have red chimneys. Some houses have pink chimneys, some houses have green chimneys. Well, we can mainly make an antibody that attacks a green chimney, and we can make an antibody that attacks any other color chimney you want, or will be in the future. So on the surface of myeloma cells, they have different houses with different color chimneys, and you can make drugs to attack that specific protein. And BCMA is one of the chimneys on the houses that we now have a number of targeted therapies that attack that cell type.

(00:12:02) For patients who are refractory to or relapse after different drugs, new therapies are becoming available. As it turns out, essentially all myeloma cells have some houses with red chimneys that BCMA attacks, which is why we're going to talk a lot about BCMA, with one exception. Unfortunately, over time, patients response rates last for improved periods of time, especially compared to what I did 30 years ago, but ultimately, you become refractory to them, and unfortunately, myeloma ultimately wins. And this is what happens if you're not triple refractory, means you're not refractory to three different of those drug classes. Average survival, I don't like to talk about survivals because everyone is different, and this doesn't include some of the new drugs. But if you're refractory to CD38, which is Darzalex and Sarclisa, but not the other two classes, average survival's a year. In contrast, if you're refractory to five different kinds of drugs, survival's really bad. What do we do with these patients that have such a poor prognosis? And the answer is new and effective therapies to control the disease, so that we can improve their life spans.

(00:13:13) Antibody-drug conjugates attach to myeloma cells to deliver chemotherapy. Well, I already gave you a little spiel about houses with chimneys. This is kind of a medical diagram of it. I don't know if they have a pointer in this thing. But over to the right of the yellow-orange cell there's an antibody-drug conjugate, which we're going to talk about in just a little bit, where you have an antibody that attacks the red chimneys. But attached to that antibody, you put a chemotherapy drug. So the antibody's going to attach to the myeloma cell, and the chemotherapy drug's going to get delivered directly to the myeloma cell, and we call that an antibody-drug conjugate. There's one approved, and we're going to show you some data on that.

(00:14:04) Bispecific antibodies attack myeloma cells and bring in immune cells. You can have bispecific antibodies. Again, we're going to get to this later in the talk. Bispecific antibodies is that you're attacking the red chimneys, but you want to bring in let's say the firemen. So we've got on one side of the protein attacks the red chimney of the antibody, and the other side is a direct system that calls in the firemen. The firemen come in and put out any fires. So you have a duo, bispecific. You've got an antibody that's attacking the myeloma cell, you have an antibody that's bringing in immune cells, so both of those technologies can then kill the myeloma cell. And then the other thing we have at the top of the cartoon are CAR T-cells, which we're going to go into much more detail in just a moment.

(00:15:02) There are several different therapies awaiting FDA approval. So there are a number of different approaches and different mechanisms to attack the houses with the red chimneys. I just mentioned briefly about the antibody-drug conjugates. The one listed at the top, belantomab mafodotin, trade name, which I'm going to again go over this in a little bit more detail in a second s called Blenrep. They are bispecific antibodies. None of these are approved yet. There's a lot of bispecifics, and I want to show you some data on that. You're going to be impressed with the fact that these antibodies, if I'm bringing in the immune cells at the same time, can be very, very effective.

(00:15:38) There are currently 136 clinical trials testing CAR T-cell therapy to treat patients with myeloma.. And then the final category, which is the main focus of this talk, are CAR T-cells. And I should tell you that right now, and you'll see it in one of my slides, there are 136 different clinical trials assessing CAR T-cell activity in myeloma at this point in time. I looked online a couple days ago. There's a website, many of you are probably aware of it, that you can search to see what clinical trials are available, clinicaltrials.gov. And if you search under CAR T-cell, you're going to find 136 different options of CAR T-cell therapies to treat myeloma. There's also about 20 or 30 companies making different CAR T-cells. So of that 136 different trials, there's probably 20 to 30 companies that are trying to focus on different ways to make CAR T-cells to kill the bad guys.

(00:16:30) Drug conjugates, such as belantamab [mafodotin, have a unique mechanism for attaching to cells and delivering chemotherapy. So this is belantamab [mafodotin]. This is this drug conjugate. You've got the antibody attacking the red chimneys. This one is the one that is attached to the chemotherapy drug. So you take an antibody, you attach a chemotherapy drug to it. The antibody attaches to the red chimney, and down the chimney likes it's Christmas comes the chemotherapy drug, gets inside the myeloma, the house, and it helps destroy it. So this is a very unique mechanism of attaching to the cell with the antibody, and delivering a chemotherapy drug directly into the inside of the myeloma cell. So this is a fairly new therapy. This was approved a little less than two years ago. It's not really important, the fact that it's humanized or what the chemotherapy drug, I just want to impress upon you the concept.

(00:17:29) Even modest response rates are significant for people who have had four or more lines of therapy and no other options. So does it work? The trials that use this drug are all called DREAMM. If you give this drug by itself, not in combination with Revlimid, Pomalyst, Kyprolis, Velcade or any other drug, Darzalex, by itself, you give this drug, as you can see on here where it says overall response rate, the response rate's 31%. Is that fantastic? No, it's not fantastic, but in patients who have four or more lines of prior therapy whose outcomes are really pretty dismal, and this really does work. The response rate is not fantastic, but it's certainly better than not having any other options. However, there are no free lunches, as we're going to see with each of these different therapies that I'm going to present to you. And in this particular case, there's no nausea, there's no vomiting, you don't lose your hair.

(00:18:27) Keratopathy or inflammation and irritation of the cornea of the eye can be a temporary side effect of belantamab [mafodotin. This particular drug, for reasons they don't know, temporarily... let me repeat, temporarily... can affect the eye, and it can cause a thing called keratopathy, which is irritation and inflammation, or micro cyst formation in actual corneas. But why is this important? Because of the eye toxicity, the most common symptoms are that you can have grainy eyes, you can have blurry eyes. You can have change in your vision. And these can be very, very disturbing to patients, obviously, but they're almost always reversible. So what if you take this by itself? 31%, not very impressive.

(00:19:15) Combining several of these new drugs can greatly improve the response rate and progression-free survival. This is a small study. They combined it with Pomalyst. Look at the Pomalyst/dexamethasone, just so you have an idea. Pomalyst and dexamethasone by itself only has a 30% response rate. Belantamab, 30% response rate I just showed you. When you take belantamab [mafodotin] and Pomalyst, one plus one equals three because the overall response rate's not 60, it's almost 90%, including complete remissions, maybe you can't detect evidence of disease, and the median progression-free survival - how long they stay in remission - it's beyond a year. So by itself, not so fantastic. In combination with a variety of other drugs, similar data to this is seen when you combine this drug with Darzalex, the anti-CD38 monoclonal antibody. So this drug does work. It works by itself. It works even better in combination. Currently, only approved by itself, but you usually can get by in combining it with some other drugs.

(00:20:20) Eye problems happen to most people who receive belantamab [mafodotin but it goes away with time. These are ocular adverse events, and I believe everyone can have access to the slides. But this just gives you an overview of what happens. To be honest with you, about 80% of the people will have some visual abnormalities on this drug. Again, the vast majority, it goes away. Depending on the severity of it, it ranges from 20 to over 60 days.

(00:20:46) If eye problems are bad or persist, the drug can be temporarily held until symptoms improve. If you have bad problems with your eyes, you hold the drug. This drug, when it does work, seems to hold people at bay, and they stay in remission until you're able to restart treatment. I saw a gentleman yesterday in partial remission. He's had four cycles of therapy. His ophthalmologic examination showed fairly severe keratopathy. We're holding his drug for four weeks. We'll repeat his eye exam. If his keratopathy improves, we'll restart his drug.

(00:21:21) The downside of this, besides the keratopathy, is that before each dose, within a week of each dose of this drug, which is given every three weeks, you have to have an ophthalmologic exam to be cleared before you can get the subsequent dose, or you can't get the drug. So you have to get the ophthalmology exam before the first dose, and then within one week of any subsequent doses, which is kind of an added layer of pain to overall treatment, but necessary because if the visual exam by the ophthalmologist shows that there's significant problems, you need to have the drug held.

(00:22:06) CAR T cell therapy is different from autologous transplants where cells are not altered in any way. So we're going to move on from there to CAR T-cell. CAR T-cells are unlike patients who've had autologous stem cell transplants. [In patients having an autologous stem cell transplant] they take your stem cells [that] you have mobilized with either chemotherapy or white cell stimulating shots. They collect your stem cells out of your blood. They put them in the freezer, and they give them back to you after you've had high-dose therapy. They don't do anything to those cells. Those cells do not have any anti-myeloma effect. All the anti-myeloma effect from an autologous transplant is from the chemotherapy that is administered.

(00:22:42) With CAR T cell therapy, some of the patient’s cells are genetically altered so that they can kill cancer cells before being returned to the patient. This [CAR T-cell therapy]is a different concept. We're taking your own cells, and we're going to give you back your own cells, but we're going to genetically modify them to do two things. And we've got a couple slides to go over what happens with this series of events. We take a virus. We insert it into your white cells, your T-cells, and that virus is programmed to do two things. One, it makes the cells angry so that they kill things, and two, it arms them with missiles. And in this particular case, most of the missiles, with a few exceptions that are being made by the CAR T-cells are missiles against the red chimney.

(00:23:23) CAR T cells are modified to make them “angry” and armed with missiles to attack  cancer cells. So the last slide I showed you with the drug attached to the antibody, that was directed against the red chimney. Most of the CAR T-cells currently in clinical trials are also targeted to the red chimney of those houses. So we genetically engineer them, we give them this virus that gets incorporated into the DNA of the cell, and again, not to be overly repetitious, it makes the cells angry and it arms them with missiles against the red chimneys. And that's what the CAR T-cells are. CAR T-cells, which stands for chimeric antigen receptor because the way the things are made, the receptor, the outside of the cell is directed to the BCMA. Again, that protein, it's directed against the red chimney, and that's why it's called a chimeric antigen receptor T-cell.

(00:24:21) CAR T therapy does not require pretreatment with chemotherapy. So this the general sequence. They just hook you up to a blood processing machine. You don't get chemotherapy, you don't need any pretreatment. They just take you, hook you up to a machine. You stay on the machine four to six hours, they take those cells. They put them in the culture. They bring in the viral vector, it gets incorporated in the DNA, and the DNA does the two different effects that I said, and then they let these cells grow in the culture tube. Now, the growth of these things, as it's shown in this slide, is anywhere between two and a half and four weeks, and we're going to talk about why that's an issue in a little bit.

(00:24:58) The chemotherapy is not to treat myeloma but rather to suppress the immune system and prevent rejection of the altered cells. They then give you chemotherapy, which I think is on the next slide. The chemotherapy is not for myeloma. We've modified your own cells, but because they're modified, we're concerned that you would reject them because they don't look exactly like you anymore because they got modified. So we give chemotherapy to suppress your immune system so that you don't reject the cells that we're going to give you. So the chemotherapy's not meant for myeloma, it's meant to suppress the immune system so these immune cells that we've modified can continue to grow in your body. And it's actually the growth of these cells, they expand rapidly, which we're going to talk about in just a moment. The infusion takes a few seconds, less time than it takes to do a transplant, and then we just wait to see what happens.

(00:25:47) CAR T cell treatment requires multiple specialists in addition to a transplant team. So there's a whole group of people that interact to make this happen. It just doesn't snap your fingers and magic happens. This is done with a whole group of individuals that help assist in getting this done, including coordinators, including insurance finance specialists, including the apheresis people, including the transplant team. One of the reasons that this is being presented in a transplant seminar is that essentially, all the CAR T-cell therapy and effector cell therapies are done on the transplant teams. So if you do transplants, you can do CAR T-cells. So this whole [group] of people interact with each other to make this happen.

(00:26:34) Current hospital stays for CAR T cell therapy are 10 to 14 days. This is what I just told you about. This is a linear diagram. You get your cells collected. Bridging therapy, I've got a slide on that in a second to explain what that is. You get this chemotherapy to suppress your immune system. People are hospitalized after the immunosuppressive therapy. That's [the immunosuppresive therapy] done usually in outpatient, in general Wednesday, Thursday, Friday, weekend off, admit to the hospital on Monday, the CAR T-cells administered that same day. Hospital stays currently are generally 10 to 14 days. 10 to 14 days, and then you need to stay within some type of close proximity to the transplant center or effector cell therapy center so you can be monitored for about another two weeks after that.

(00:27:23) This is leukapheresis, a little bit different than what happened for those of you who had stem cell transplant. Again, you just get hooked up to the machines. They collect your cells, they take them to the laboratory, and then they start doing the genetic modifications.

(00:27:37) It can take four to five weeks to get modified cells back; bridging therapy may be used for people with aggressive disease. Currently, this is approved for patients who've been very heavily treated, and you know what? Sometimes they can't wait four weeks or five weeks to get these cells back, so sometimes we give what we call bridging therapy. Something to tide you over while the cells are being manufactured until you can actually get the cells back. This is necessary sometimes to keep the tumor at bay, sometimes to treat symptoms. It can be anything from radiation, combination chemotherapy, steroids. Something the doctors think will keep this under control.

(00:28:15) For those patients who don't have aggressive disease or those who don't have bulky disease, we sometimes just let them sit for the four to five weeks until we give them their CAR T-cells back.

(00:28:28) In the future, CAR T cell procedures may be done on an outpatient basis. And we already went over this. The CAR T-cells right now are given in the hospital. Can it be done as an outpatient? The answer is yes. When you hear some of the side effects that might occur, you'll see why we're currently doing them as inpatient. But I would anticipate that in the very near future we'll do them as outpatient, just like we can do outpatient transplants.

(00:28:47) CAR T cell therapy is much easier to tolerate than a stem cell transplant and has no age limitation. Just to give you a preemptive information, CAR T-cell treatment is far, far easier for patients to tolerate than a stem cell transplant. There's no comparison. There are toxicities, which I'm going to cover in just a moment, but it's much easier to tolerate then a stem cell transplant, and there's no age limitation for doing CAR T-cell. There's no real age limitation for doing a stem cell transplant [either], but CAR T-cells are generally tolerated [and] can be given to even more frail individuals than you can do with stem cell transplants.

(00:29:23) One side effect is cytokine release syndrome with inflammation, fever and other symptoms. Several drugs are available to treat these symptoms. What's the no free lunch with CAR T-cells? There's two issues. One's called cytokine release syndrome. These cells, when you give them - remember, they're angry and they've got these missiles on them, and they're growing like mad. And when they grow like mad, they release these hormone-like inflammatory proteins, and these inflammatory proteins can do a number on you. The most common thing that happens is shown here, is fever. It can make you feel like the flu. Again, like flu, it can cause low blood pressure. Sometimes it causes low oxygen in your lungs. Rarely can it cause any other permanent damage. It does not cause permanent damage to the heart, it doesn't really affect the kidneys. But fever is very common, usually low-grade, usually easy to control, and there's an Alice in Wonderland drug or drugs available to counteract the fever and these symptoms. Most of these symptoms, which we're going to see in a little bit, are minor, and easily managed.

(00:30:27) But you can get, to just abbreviate this, CRS, depending on which [CAR T-cell] product [you get]. One of the products, the first one we're going to talk about, the average time is one to two days. The second product we're going to talk about is five to seven days. But there are remedies. This drug here, this tocilizumab, we just call it Toci. Steroids can alleviate most of the symptoms that occur from this expansion and this hormone-like inflammatory response from these cells.

(00:30:57) The second side effect can be neurologic problems. They are rare in myeloma patients who receive CAR T-cell therpay but are common in patients with lymphoma and leukemia. There are treatments for these reversible issues. A little bit more disturbing, but also temporary, is it can cause problems with your neurologic system. Show here are some of the things you can do. And I see this happen mainly in people with lymphoma getting CAR T-cells. They have a different target for lymphoma. We really don't see very much neurotoxicity [in myeloma], but it could cause problems speaking, or inability to speak. It can cause seizures, not trying to scare anyone. It can cause problems with writing, it can cause problems with cognitive impairment. Rarely causes motor weaknesses. If any of these happen, there's again a good treatment for this. We're going to talk about specifically what the likelihood of this is, because I know it's scary-sounding, but I'm telling you, it's fairly rare in myeloma, not so rare in lymphoma and leukemia when we do CAR T-cells. It's reversible. No permanent damage.

(00:31:58) Abecma® is one CAR T cell product that has achieved complete remission even in patients with many prior therapies. Now we're going to talk about the first of two different CAR T-cell products. This is the one that's currently available as of March 2021. It's called Abecma, or Ide-cel is the abbreviation, because I can't even pronounce this idecabtagene vicleucel, whatever that is. But this is just the same schema, the leukapheresis. This is for patients who've had four or more lines of prior therapy. They get the lymphodepletion, which, again, that's to suppress the immune system so you don't reject the cells, and then you get the cells back. What they found in some of these patients, just to give you an idea, the average duration [of] prior therapy was six years. The average number of prior types of treatment was six. I can tell you, we had one that had 16 prior therapies. She went into a complete remission after having a CAR T-cell, even though she had 16 different cocktails of drugs over the course of her lifespan.

(00:33:03) One small trial with Abecma®  achieved a 73% response rate. Almost all these patients had previous transplants. They were generally refractory. Whatever the most recent treatment was, they were refractory. And as it turns out, almost 90% of them got bridging therapy, but the way the trial was designed, the bridging therapy really wasn't particularly effective. We didn't know that at the time. This is characteristics. There's 128 patients, not a huge trial, but this is the trial that led to the approval. Response rate. Just by giving these cells, again, the chemotherapy does not affect the myeloma, 73% response rate.

(00:33:39) Complete remission rates with Abecma is 33%.   Complete remission rate, 33%. 33%. This is not curing the patients. For those patients, overall the median time that they stayed in remission was 11 months. For those patients that achieved a complete response, the median time was 22 months, but when you take the whole population, the average time they stayed in remission was 11 months. But most of these patients had absolutely no other options available to them. And that's what's shown on this slide. It shows the curves. Unfortunately, there's no plateau, meaning people continue to relapse over time. Unlike lymphoma, where you'll see a straight line about this 0.4 area. You'll see a straight line. In about 40% of patients with large cell lymphoma are cured when they give CAR T-cells against lymphoma. We don't see any patients that appear to be cured, at least with this particular CAR T-cell product, at this time.

(00:34:45) Most patients who received Abecma® experienced low grade cytokine release syndrome and a few had neuotoxicty that was effectively treated. When you look at cytokine release [inaudible], 84% of the patients had some CRS. The vast majority of these had grade one or two, means they had a fever, 101, 102. Median onset for this product, unlike the next one I present, was one day, median duration five days. It goes away. Good proportion of them got this Toci drug, this miracle reversal agent, if you will. It actually attacks the receptor of one of the hormone-type drugs, and about 15% of the patients required steroids. Neurotoxicity occurs a little bit later. Not a whole lot later, a little bit later than the cytokine release syndrome.

(00:35:34) Neurotoxicity was small. Of the 128, 18 of them developed neurotoxicity. Essentially, all of these went away with appropriate treatment. There's no long-term sequela with this thing. 18% developed neurotoxicity, all of the events occurred within less than a week, and all of them resolved.

(00:36:01) It does cause and can cause long-term low blood counts, because you've got this milieu of cells growing in your body and your bone marrow, so you can have problems with all of your blood counts. If you have problems with low blood counts, you're at risk for getting infections.

(00:36:21) A second product (cilta-cel) has also been tested with people refractory to their prior treatments. This is the second product. It doesn't have a name. We call it just abbreviated cilta-cel. The first one's made by Bristol Meyers, the second one's made by Janssen/Legend. It's, again, for patients with four or more lines of prior therapy. They get the same type of lymphodepletion. They used a little bit lower cell dose than they did for the other trial, and the number of patients treated was a little bit lower than the first one. The first one's the 128 patients, this is 97 patients. When you look at, again, 90% of them had previous transplants, median types of previous therapy was six, up to 18. So some of these patients have been treated forever and ever with lines of therapy, and essentially all of them were refractory to their last treatment.

(00:37:13) Response and remission rates with cilta-cel were high and FDA approval is expected in 2021. Response rate with this one, everybody's going to go, "Wow." The other one's 73%, this one's 97%. I will tell you, it's difficult to compare one trial to another. It's apples and oranges sometimes. But this, I would absolutely agree, is impressive with 97%, including, remember, the other one was 33% complete remission. This one's 67% complete remission. This product will probably, almost certainly be approved the end of November.

(00:37:45) Cilta-cel had somewhat more cytokine release syndrome and neurotoxicity than Abecma. What side effects? Low blood counts similar to the other one, from the cells growing, plus the lymphodepletion chemotherapy causes those side effects.

(00:37:55) Cytokine release, the other one was 84%, this one's a little bit higher, 95%. Most of them grade one, means that it's fairly mild. You may have a temperature of 101. Grade two is a longer temperature, or you may have a little shortness of breath, you may have a little problem with your blood pressure. Very few have severe toxicities associated with this. This one occurs a little bit later. The first one I showed you was day one. This one starts at day four to five. It just happens to be different for this product.

(00:38:29) Neurotoxicity, the other one was 18%. This one is 21%. They did have some patients on this trial that did have some long-term problems from neurologic events. They've now instituted programs to treat people earlier, to not let things hang on, and actually, in the next 100 patients that have been treated, they haven't seen any long-term neurotoxic events. Median time to onset for this is five to eight days. Three to five days to recover is the general time period.

(00:39:12) While cilta-cel appears more effective Abecma, comparing these trials is difficult because of several differences between them. than This one, the data is not as mature, meaning that they don't have patients out quite as far. But it looks like the progression-free survival in the most recent update at the International Myeloma Workshop, which was just a week and a half ago in Vienna, this number looks like it's 22 months versus nine months for the other product. Again, everyone's going to go, "Okay. I want that one," but you really can't directly compare them. But it's 22 months versus nine months it looks like, the remission duration with this product compared with the other one. So this is kind of a comparison of the two products. This one here is the Janssen. The second one's the Abecma. Different cell numbers. We're not sure what to do with that.

(00:40:04) Prior lines of therapy, similar. Refractoriness is similar. Response rate, 98% versus 70-some percent. And complete remissions - this is earlier data - we saw that it was up to 67% versus 33%. The numbers don't all jive. It has to do with the cell numbers that they're showing here, because some of them have different cell numbers. I apologize, it's confusing. Bottom line is that both [are] effective.

(00:40:32) I have to get moving because I have to leave [time for] questions. There's issues that you have to wait usually four to five weeks to generate the cells, and not everyone makes cells. Sometimes they've had so much treatment that even though they put them in culture and try to get them all wound up, they don't grow.

(00:40:52) Clinical trials are testing whether patients may be able to use “off-the-shelf” donor cells rather than their own cells to speed up the process. So how do you circumvent that? Well, you can take cells that are off-the-shelf, we call it, meaning that a donor gave their T-cells. They juiced up a donor cell, and then they give that back to you. You can just order them, and they order them day one, you get them on day two. You don't have the collection of the cells, you don't have to wait until they grow. You can just order the cells and give them to them. And this is very preliminary data, but this is off-the-shelf donor CAR T-cells. They, again, got some type of therapy to suppress the immune system, then they gave the cells to the patients.

(00:41:30) Early data for this approach is preliminary but promising. Very briefly, cytokine release syndrome, a little bit lower. Not as many patients, so it's hard to tell, but they actually had any cytokine release was 45%. They did have 40% infections. Even though they're donor cells, and some of you may have heard of graft-versus-host disease, they didn't see an graft-versus-host disease with these donor cells. When you looked at response rates, again, low, low numbers of patients, but when you see 10 patients, response rate is 60% it looks like with this particular product. So this is very promising, very preliminary data.

(00:42:09) Bispecific treatments use two ways to attack myeloma cells.” Briefly, briefly, what about these bispecifics, the ones that attach to the myeloma cell that bring in the immune cells within the patient? So this is an antibody that has two different arms to it. One attaches to myeloma, one attaches to the immune cells. and then there's actually things called trispecific, attach to the myeloma cell to one immune cell, and actually to another immune cell called trispecific. Very briefly, there's a list of different bispecifics. On this particular one, there's six of them here. These are the response rates, and you look at these response rates and they're ranging. These are small studies, if you look at these numbers. The response rates are 60 to 80% with these antibody treatments.

(00:42:57) Do you get CRS, this release because of what's going on with these cells, and the answer is yes, varying from 20 to 80%. So again, there's no free lunches. These are just giving antibodies. You can give them anytime. It's not one and done. After the CAR T-cells, you're done. These antibodies, these bispecifics, have to be given either weekly, every two weeks, every three weeks, but this is continuous therapy versus a CAR T-cell, where you just give the therapy, you wait and see what happens, and you're done and you get a break from treatment. These are continued. Each one's different. Some of them are IV, some of them are injections into the abdominal area, but the bottom line is that they can be very effective.

(00:43:42) People may be able to have multiple bispecific treatments against different targets and they are available “off-the-shelf.”  There is another bispecific. Those were all against BCMA, the red chimneys. This is a bispecific against a green chimney. And again, very early evidence, but when you look at the overall response rates, small numbers, what you're seeing here is 50 to 70% with this other bispecific that's not against the red chimney. So could you get a drug or CAR T-cell against the red chimney, and then get this one against the green chimney? And the answer is absolutely yes, you could. You could have a series of this type of treatment, of antibodies or cellular therapy, against different targets on the myeloma cell. So these are some of the differences between bispecifics and CAR T-cells.

(00:44:28) Bispecifics, like the donor T-cells, are off-the-shelf. You just order them from the pharmacy. The bispecifics have to be given repetitively, it's either one week or every two weeks, most of them right now. There's les cytokine release, less CRS versus the CAR T-cell. I did not list all the CAR T-cells. I told you, there's 136 trials. They're being moved up earlier, even to front line therapy. Right now the one that's approved is for four or more lines of therapy, the one that's going to be approved in November is four or more lines of therapy. To get it earlier in the disease course will happen, but it's probably going to be two to five years from now before that actually happens. And with that, I will close and open it up to questions.

Question and Answer Session

(00:45:14) [Susan Stewart]   Thank you very much, Dr. Vesole. That was a very exhaustive and very interesting presentation. We have a lot of questions, and we'll try to get to as many of them as we can. First question, several people have asked this. Does health insurance like Medicare, or just general health insurance companies, cover the CAR T-cell procedure yet?

(00:45:37) [Dr. David Vesole ]     The answer is yes, it's FDA approved. It doesn't mean you don't have to jump through hoops to get it approved. Just so you have an idea, and it's all relative, I'll give you a comparison in just a second. CAR T-cells, the production of the CAR T-cells, at least what now, and I'm giving you a ballpark figure, is about $400,000. That has nothing to do with the lymphodepletion we give before it, it has nothing to do with the hospitalization or any care of any of the potential side effects we talked about. Just the product itself is $400,000.

(00:46:11) That stated, for those of you who get Darzalex, Darzalex is $25 to $30,000 a month. I had a patient the other day told me that her insurance was being billed $60,000 a month for Darzalex. So it's all relative, but the answer is yes, it's covered. Medicare, Medicaid, and all private insurance, because it's FDA approved, have to approve it, but right now they're only approving it for those who have four or more lines of prior therapy.

(00:46:40) [Susan Stewart]      All right. Next question is, if you relapse, should you be considering CAR T-cell therapy or a second transplant?

(00:46:53) [Dr. David Vesole]     That's a very, very difficult question. Right now, if it's first relapse, the answer is no, it's not covered. Whether you should have a second transplant, a salvage transplant, really has to do with how long the first transplant lasted. I generally don't do second transplants unless the patient has had a minimum of two to three years duration of their first transplant because with second transplants, rule of thumb, not an absolute, you get about 40% of the time of the first transplant. So if you've got two years after your first transplant, you're going to get about 10 months out of the second transplant. But that stated, if you had eight years out of the first transplant, you may get three years out of a second transplant, so it really depends. Again, the CAR T-cells, what I've shown you right now, the one product was about 10 or 11 months medium duration of remission, the other one's 22 months, so you really have to rely on your myeloma specialist to help guide you through which one you should have.

(00:48:01) [Susan Stewart]      All right. The next person wants to know if you can give any information about what the fatigue level is after CAR T therapy, and how long it lasts.

(00:48:14) [Dr. David Vesole]      I didn't say anything about nausea, I didn't say anything about vomiting, I didn't say anything about hair loss. CAR T-cell therapy, the oldest one we've done I think is 84, without significant problems. The issue with fatigue is because, as I mentioned to you before, some people have low blood counts that can last from weeks to months, and if you're anemic you feel fatigued. So it's not the same fatigue that people get with transplant, because with a transplant their hemoglobin levels actually rise back to reasonable levels fairly quickly, but they can feel fatigued for weeks. This is down and dirty. If you're not very anemic, you really don't have extended fatigue.

(00:48:58) [Susan Stewart]          All right. This individual wants to know how many of the CAR T patients that have been treated have had a dual diagnosis of amyloidosis and multiple myeloma, and what the outcome has been?

(00:49:14): [Dr. David Vesole]          That's a tricky question to answer. If your predominant disease - there's no data on amyloid in CAR T-cell - just pure amyloid. It doesn't exist. Most of the patients who've had CAR T-cells to date may have concomitant amyloid, but that's not their symptom complex that's causing problems. They had to have active myeloma and not have active amyloidosis to be eligible to get a CAR T-cell. So you can have just incidental, you did a bone marrow and the doctor said, "Oh yeah. We saw amyloid in your bone marrow, but we don't have any cardiac problems, you don't have any liver problems, you don't have any kidney problems. You don't have any systemic manifestations of amyloid," that's okay. But if you have any of those organs compromised from amyloid, you would not be eligible for CAR T-cell.

(00:50:04) [Susan Stewart]          All right. Next question, is there any way a patient going to CAR T therapy can prepare for the side effects, such as CRS and the neurotoxicity? Anything we can do to minimize the likelihood that that would happen?

(00:50:20) [Dr. David Vesole]      Not that I'm aware of. And really, I don't mean to scare anyone off. It's truly very mild in the vast, vast majority. And fever's common. You saw those numbers. You get Tylenol, it fixes it. If fevers persist even if you've had Tylenol, they give you this drug called tocilizumab and it almost always fixes it, and it's really not a concern.

(00:50:47) The neurotoxicity can be very challenging, especially because, if it happens, you worry it's not going to get reversed, but it is reversible. It doesn't happen very often, most of it is very early grade. You may sit there and you just can't write a sentence right ,or something like that, for a short period of time. The neurotoxicity's really mild. This is really fairly easy therapy.

(00:51:14) We are going to be moving soon, but not for Medicare and Medicaid, to outpatient. Medicare and Medicaid is a financial issue, as far as reimbursement, so someone has to do that. But in my mind, there's very little reason why we can't do many of these patients as outpatients. I think it's safer than doing a stem cell transplant, although fevers are much higher with CAR T-cells.

(00:51:39) [Susan Stewart]          All right. Next question. Is CAR T-cell transplant considered a one and done therapy, or can it be repeated?

(00:51:54) [Dr. David Vesole]      There's anecdotal data. There's no published data on re-treating with CAR T-cell. I can tell you that we have a very active CAR T-cells trial. The patient I alluded to before that got I think 18 or 20 months out of a CAR T-cell, we treated her again and she only got four months. And the vast majority of the ones that we did, and there's not that many, probably 10, had very, very short second remissions to repeated CAR T-cell. That stated, what if you did a different CAR T-cell? And there are other CAR T-cells being made against different houses with different colored chimneys. There's no reason you couldn't get a CAR T-cell against a different target, or as I've shown you before, one of these bispecifics, particularly the one that wasn't against the red chimneys. And there's more and more of those being developed. There's actually that same one that I told you is not against the red chimneys, I can't remember what color I used, they're actually making a CAR T-cell with that same technology. So the answer is, repeating with the same product, not a good idea.

(00:53:01) [Susan Stewart]          All right. Next question is, is it possible to do CAR T-cell therapy after allogeneic transplant? That's a transplant using donor cells.

(00:53:13) [Dr. David Vesole]      There's no exclusion for doing that. We're actually doing our first one next week.

(00:53:19) [Susan Stewart]          Okay. Next question regarding Blenrep. Have you heard of patients using bandage contact lens to correct vision problems created by the therapy?

(00:53:30) [Dr. David Vesole]      You're not supposed to wear any contact lenses if you're on Blenrep, and they have you take eye drops at least four times a day. There's no good treatment once you have this keratopathy. Steroid drops really didn't work. The best thing is to keep the eyes moist, which they give you this... I'm spacing out on the name of it. It's a little bit expensive. You can buy it at Costco. Sustene.

(00:54:02) You take frequent eye drops. That's the best thing you can do for it. There's no other therapy that really works, it just resolves on its own over time.

(00:54:10) [Susan Stewart]          All right. This person wants to know, when you make the cells angry and they kill cells, do they only kill myeloma cells, or do they kill other cells?

(00:54:21): [Dr. David Vesole]    Essentially, because the target is... they're only against the red chimney... that red chimney is on, I won't say none, but it's almost on no other cells, so there's very, very little off-target side effects from the drugs. We don't know why people get the neurotoxicity that we talked about. I do not know why. I don't think anyone knows specifically how that occurs. The cytokine release is because of the expansion of the cells. We're not sure why people get the neurotoxicity, but the BCMAs express very few other cells. It's not really an issue.

(00:54:58) [Susan Stewart]          All right. The next person wants to know if cilta-cel gets FDA approval but only for triple or penta- relapsed refractory, and a patient is in their first remission, will centers likely be willing to do this therapy off-label? And if so, will insurance likely approve it?

(00:55:16) [Dr. David Vesole]      No, and no. It's not going to be paid for. Good thought. There's trials being done with that endpoint, but right now it's not going to get covered. Zero.

(00:55:31) [Susan Stewart]          Okay. All right, next question. How close do patients have to stay to their treatment center after CAR T-cell therapy, and for how long?

(00:55:41) [Dr. David Vesole]      We ask them to stay within an hour for two weeks. And it's probably overkill, because again, except for what now appears to be remedied, the late neurotoxicity they saw with the cilta-cel, which now I told you the next 100 patients they didn't see any late toxicities. But right now, we're being very conservative as to therapy. We're asking people to stay within the area for the two weeks, and they may not have to be in the hospital for two weeks. That was the way all the trials were done. But if you're day 10 and you're past that window of getting CRS and neurotoxicity, we can let you out of the hospital earlier. But because some of these patients have low blood counts and stuff, we still ask them to stay within an hour for a total of four weeks, including the hospital stay.

(00:56:29) [Susan Stewart]          Okay. A couple of these, so let me ask. In terms of the prior therapies before CAR T-cell therapy, does the stem cell transplant have to be one of those prior therapies?

(00:56:41) [Dr. David Vesole]      It does not. It has to be an IMiD. Again, I don't want to go back over the definition of immunomodulatory drug. It has to be a Proteasome inhibitor, and it has to be a monoclonal antibody, and you have to have at least four different lines of some combination of those drugs, but you do not have to have a transplant to be eligible for a CAR T-cell.

(00:57:08) [Susan Stewart]          All right. The next question is an interesting one. He wants to know, when you're getting stem cells harvested for a stem cell transplant, should you harvest and save cells in case you need them later on for a T-cell therapy?

(00:57:25) [Dr. David Vesole]      The program for the machine is completely different for stem cells and for lymphocytes, the cells that we juice up, so I don't know. I'd have to ask the people who specialize in apheresis if that could be done and you could do them sequentially. I don't think so. I think you could probably collect the cells before you got your growth factors, and then do your lymphocyte collection, and then do your mobilization with your growth factors of chemotherapy, but it still would be separate. You can't do it one time and send some of the cells one way and some of the cells the other way. I don't think there's a technological way to do that right now. That being said, with fairly rare exception, almost everyone can generate enough of these cells that they manufacture, even if it's after six, seven, eight liens of therapy. We've had failures, but they're really uncommon.

(00:58:27) [Susan Stewart]          All right. This person wants to know what the difference is between the Yescarta, Tecartus, and Abecma therapy.

(00:58:35) [Dr. David Vesole]      Yescarta's, again, CD19. It's against a completely different...it's against chartreuse chimney, which is on lymphoma cells. It's really not much on myeloma cells, so it's a completely different CAR T-cell manufacturing against a different target that they use for lymphoma, and they use it for certain forms of acute leukemia.

(00:59:03) [Susan Stewart]          Okay. This person wants to I think know more about the bridging chemotherapy. You indicated that there's chemotherapy that's part of the process. What drugs do they use? What side effects do they create, and how long do you get it?

(00:59:20) [Dr. David Vesole]      You can't get chemotherapy, according to the guidelines, within two weeks of getting your CAR T-cells. So you get your cells collected, and then they may opt to give chemotherapy. In the initial study I showed you, 88% had chemotherapy, but the response rate was only 10%. And you go, "Wow. Why would I bother?" The trial only allowed you to give chemotherapy drugs that you're already refractory to, and you could take a couple drugs that you didn't respond to and see if you could squeeze them again for a little juice, but it didn't work. So the chemotherapy's not mandated. That's really up to your doctor, if they think that's necessary.

(01:00:00) And now, because it's commercial, we can give drugs that maybe you haven't had and use that for bridging. But that wasn't allowed on the clinical trials, so it was not very effective because you could only give drugs that you already failed. Well now, just for example, we could give you two weeks of Selinexor or some other drug in the interim, and may get a response to reduce the tumor disease during that time period. But that's really individual to individual basis. It's not mandated in the FDA approved one about giving the bridging therapy, nor what drugs you can or cannot have.

(01:00:43) [Susan Stewart]          All right. I think you answered the next question, but I'll state it again because we've got a couple different people asking it. If a patient relapses after one type of CAR T-cell therapy, can they get the other type of CAR T-cell therapy afterwards?

(01:00:58) [Dr. David Vesole]      Right now, there's no other CAR T-cell therapy. If you thought about could you get ide-Cels and cilta-Cels, no data whatsoever on that, and I don't know there will be. Can you get the same one again? It doesn't work. Could you get that one and then another CAR T-cell against a different target? The answer is yes, but the other one that's out there, the one that's furthest along, is probably three or four years at least away from being approved. At least three to four years, if not longer. So essentially, the answer technically is no.

(01:01:35) [Susan Stewart]          Okay. This woman wants to know whether having a tandem stem cell transplant counts as two lines of therapy or one.

(01:01:44) [Dr. David Vesole]      So, that all depends on if it was planned or unplanned. If your planned treatment was initial therapy, transplant one, transplant two, maintenance therapy, that's only counted as one line of therapy. If you've got induction therapy, you had a transplant, you were on maintenance and three years later you had a second transplant, that's a different line of therapy. If it was a planned tandem transplant, that only counts as one.

(01:02:12) [Susan Stewart]          Okay. And even though it's not required, do you recommend having a transplant before trying CAR T-cell therapy?

(01:02:23) [Dr. David Vesole]      I don't think transplants are going to go away, because the duration of remissions right now with transplants are better than they are with CAR T-cells. But take that with a grain of salt because all the CAR T-cells, the ones I showed you, were people that had six or more lines of therapy. So maybe if you give the CAR T-cell earlier in a disease course, it'll last longer. We don't know that that's true or not true. So right now, still the standard of care is going to be induction therapy and transplant. Down the road, maybe you'll get a transplant followed by CAR T-cells for high-risk patients, maybe you'll just go from induction therapy to a CAR T-cell and save a transplant for later. We do not know. Right now, standard is induction, transplant, maintenance, CAR T-cell's not until later on in the disease course.

(01:03:18) [Susan Stewart]          Next question is regarding commercial CAR T-cell therapy. Is it available, and how do you qualify?

(01:03:28) [Dr. David Vesole]      We kind of covered that. It's available to those individuals who had four or more lines of therapy, but you have to go to a transplant center because all the transplant centers are the only ones that do administering CAR T-cells. Even if it's being done as an outpatient, I don't see private practitioners in a group practice with six oncologists giving CAR T-cells in their office. I don't see them dealing with the CRS and the rare neurotoxicity. Essentially, you have to go to a transplant center because they're the ones that are certified by FACT to give cellular therapy.

(01:04:03) [Susan Stewart]          All right. This person has a question perhaps you can or cannot answer. Why is it that chemotherapy alone really can't affect the myeloma disease?

(01:04:21) [Dr. David Vesole]      In general, because the myeloma outsmarts it, so it mutates. It keeps changing. It's sort of like a chameleon. You go from a desert environment to a forest, to a lake, and the chameleon changes colors. Well, myeloma changes colors every time you expose it to a different environment, and that's really the answer. Your first environment may be Velcade, Revlimid, Dex, and then that stops working and you switch from the desert to the forest. You give them Darzalex, Kyprolis, dexamethasone, and that works for a while and then damn that chameleon, but it goes through the lake and says, "I'm going for a swim," and you give it Selinexor, and it keeps changing over time and we can never keep up with it because it swims faster or runs faster than we can manage. So we don't cure it because it changes over time, and because it's resistant to the drug regimens we provide to it.

(01:05:19) [Susan Stewart]          Okay. The last question I think we can take given the time limit, and I believe you've answered it, but again, it's being asked so I'm going to ask it again. Is there an upper age limit to get CAR T-cell therapy?

(01:05:43) [Dr. David Vesole]      There is no upper age limit to get CAR T-cell therapy. There's no upper age limit to have a transplant. It's usually limited by physiologic organ function and performance status.

(01:05:55) [Susan Stewart]          Closing.  All right. So, with that, I want to thank everybody who has participated in the webinar tonight, and I want to than Dr. Vesole for an excellent presentation and excellent answers to the excellent questions that people have posed. Want to thank the audience for participating and raising issues, and participating in the discussion, and I want to let you know that this presentation has been recorded. We will put the recording, along with a transcript, up on our website, bmtinfonet.org, next week sometimes. Everyone who registered for this webinar will get notice when that is up, in case you want to look at it again or share it with other people.

Susan Stewart (01:06:37):

If you have any question or any other way that BMT InfoNet can help you, please don't hesitate to contact us at help@bmtinfonet.org, or by phoning us at 888-597-7674 or 847-433-3313. Thank you, everyone. Have a wonderful evening, and this will end the conference.