 Welcome, welcome to this webinar on EHA 2023, Miloma and Aylem Miloides highlights organized by Miloma Patients Europe. I'm Solene Cladroel and I will be the moderator of this webinar. I will first briefly introduce MPE and our speaker before giving him the floor. And I will go over some few housekeeping rules. So Miloma Patients Europe or MPE is an umbrella organization of Miloma and Aylem Miloides patient groups across Europe. We have currently 49 members based in 31 countries. And our mission is to provide education information and support to our member groups and to advocates at European national and local levels for the best possible research and equal access to treatment and care. So today we're going to talk about EHA 2023. So EHA is a non-governmental and non-for-profit membership organization that is guided by the mission to promote excellence in patient care research and education in hematology. It stands for European Hematology Association and it connects hematology's worldwide. It's the largest Europe based organization that brings together medical professionals, researchers and scientists with an active interest in hematology. And it holds an annual congress to facilitate that mission and that's what we will talk about today. So this year's annual congress was held at the beginning of June in Frankfurt, Germany with more than 10,000 people attending. And we have organized this webinar to share with you the highlights of the conference so you can ask questions related to the latest results in the Miloma and Aylem Miloides field. So I'm very, very pleased to welcome our speaker of the day, Professor Mohammed Moti. He's the professor and head of the Hematology and Cellular Therapy Department, Saint-Antoine Hospital and Sorbonne University in Paris in France. And his department is one of the largest hematology department in France and Europe. He has a strong expertise in clinical research and deep knowledge in the field of stem cell transplantation, therapy of leukemia and multiple Miloma and many others that are on site. And over the last decade, he has played a key role in the approval of different hematology drugs. So thank you so much, Professor Moti, for being there today and for dedicating some of your precious time to Miloma patients Europe. So before we start, I would like to give a short reminder on how to use the Zoom webinar app to our audience. So first one is that as attendees, you will not be able to see or hear the other attendees in the webinar. You should be able to see and hear the presenters but not other attendees. And if you can't hear the presenter, make sure that your speakers are not muted and that the volume is set high. You can watch the webinar in gallery view to enable you to see all of the presenters in a tight format on your screen. 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Thank you so much for being here again and the floor is yours. Thank you very much, Soland, for the kind introduction but also the invitation that I really appreciate. And I'd like also to emphasize and thank you and say how grateful we as healthcare professionals to what Maloma patient Europe, you as a team are doing for the benefit of the patient and their families. This is a horrible disease a chronic disease and the support of advocacy group like MP is really crucial. But of course, I can't start this webinar without saying how humbled and grateful I am to the patient who really trust us and actually they put their life in their lives in our hands as physicians and healthcare professionals. And I'm always very moved by the trust and you are the driving force you as patient behind all what we do and what we would like to achieve. So I've been asked by the team to give you a summary about what happened at EHA 2023. Obviously, we can spend a full one, two, three days to give the total summary. So I have to select, and on any selection there is a bias, because what I selected is what I personally view as the most attractive but also the studies and drugs that are already I would say available, or will be available soon because I thought it would be less interesting to speak about study that will come to us in four or five years will have ample time to discuss. But of course I'm more than happy to take the questions. If you have any specific question about future studies. Just for the sake of introduction and to give historical overview about the treatments of multiple Maloma. I don't know of course the history of each individual attendee, but until the mid 90s for multiple Maloma, we were almost exclusively using conventional chemotherapy. And that started in the early 60s late 50s. And for 35 years there were no single there was no single drug approved. We had to wait until the late 2000, early 2000 late 90s here, where the little mind was introduced so they image family. And then we had very quickly in a little mind, but it took almost 10 years to get Puma little mind. So you can see the advances started like 3035 years, then 1015 years and there is now an acceleration. We had also the first in class Protestant inhibitor porctezumid. And then we had to wait for another 10 years before having second generation Protestant inhibitors like exazumid or carfizumid. Then we had the first monoclonal antibody by the mid 2015 14. Especially there are tumor map and more recently is the tuxima elitism abyss has been around for some time, although it's not very widely used although it's very safe drive, but the efficacy is a little bit moderate. But then, by the early 2020s, we had the full advent of immune therapy. And here you can see that the acceleration, it's about like two or three years for the advent of a new agent. So huge acceleration. And this is providing a lot of hope. And you will see that the keyword from the Congress. And I heard there's a debate that we may call it EHA personally call it EHA it's easier for me. But also before EHA we had the ASCO Congress and we had the Komi Congress, and actually I can assure you the focus is about immune therapy and how to manipulate the patient immune system so it's like a dream where we always say, oh, how can I use my body to fight my cancer. Well, immune therapy is typically this story. And why do we need immune therapy, especially in the most advanced patient but in the future, we will see it being used earlier, because if the patient have received already linalidumide, pulmalidumide, bortezumib, carfizumib, there are tumor map, isotuximib, you know, they become what we call pentarefractory. This is like you have received five drugs and the disease has become resistant. And here the outcome is quite dismal. So you need the new options. And this is exactly the role of immune therapy, where you have two ways of manipulating the immune system of the patient. And when I say manipulating, it's in a positive manner to educate this immune system to fight the malomas. So either you can do it, let's call it in vitro, so you take the T cells of the patient, these are your own body T cells, they are taken by atheresis. They are manipulated engineered in the lab. There is a manufacturing time of, let's say three, four, five weeks, six weeks. And this is about the car T cells, the chimeric anterior receptor T cells. And once they are manufactured, engineered in vitro, they are reinfused in the body. And they are educated to go to find the plasma, the malignant plasma cell, the maloma cell, and kill it. So we have another immunotherapy technology. And this is about actually what I would call manipulating the immune system in vivo. So you don't take the cells out. We would send an antibody, we call it a bispecific antibody, that on one hand will go and capture the T cell through a marker called CD3. And on the other hand, it can also link to the tumor antigen on the malignant plasma cell, for instance BCMA, which is the most popular one. And by catching the T cell through the CD3, it can bring it by hand, you know, to the maloma cell. And then you have the killing cascade. And at EHA, at 2023, we heard a lot about these bispecific antibodies, which are really quite amazing in terms of efficacy. We had the long-term follow-up of Ticlistamap, which is already approved and available in many European countries, either commercially or on a compassionate axis. And I will not go through all the details, but this is a relatively large number of patients, 165. You can see the characteristic of the patient. You can even give it to elderly patient, to patient from all ethnicities, patient with extramedatory disease, patient with lots of risk factors, but also as you can see, patient who received a median of five lines of therapy. Remember, I told you, pentarefractory. So when you have received all kinds of drugs and become refractory, actually, there is a confirmation here with a long-term follow-up that more than 60% of the patient will respond. 45% will be in complete remission, which is quite incredible, I would say, for such a heavily advanced population. So let's talk to the overall outcome of the patient, whether the whole group or the patient who are in CR. Actually, we're talking about more than two years of median progression-free survival. So really, if you take everybody, then we're talking about roughly a little bit less than a year, 11.3 months. See, it's really quite amazing to achieve in patient where they are supposed to have four, five, six months maximum. You're going up to 12 months, and if they got their chief CR, it's more than two years. And if you look to the overall survival, it's even better, of course. And this is quite amazing. What about the side effects? Well, we need to be aware, and this is important for the patient to know that it is about the infectious complications. And because when these antibodies mobilize and stimulate the T cells of the body, all these T cells are going to fight the cancer cells. So remember, these same T cells have a role on infections, infectious complications. They are our soldiers that protect us. So obviously, they will become exhausted. And this is why you see a higher incidence of infections. The message for the patient is more about to really being very strict on prophylaxis and prevention measures, because there are some very important prophylactic drug that would allow to avoid these severe infections. And we have another very exciting agent, another by specific antibody called a ranatoma, which is actually very similar to teclistamide, and both of them are really being developed very quickly. And I had the opportunity to update the results of this Manitism III trial. You can see here the schema of how it works. It has like two bindings. On one hand, it captures the T cell, and it brings it to the tumor cell, and then you have the killing cascade. And here we had the update of one cohort from the study. 123 patients. Again, we can give it to the elderly patient. The oldest one was 89 years old. So very important. And what you can see here is also that these are heavily pre-treated patients, five lines of prior therapy. These are the initial results. And when we look to the updated results, we confirm that the updated results were captured in a blinded fashion, which is a very powerful tool to assess objectively the responses. So you can see that, again, similar to teclistamide, you have the same range of response, but also you have 35% more than complete remission. So if we look to the duration of responses, well, these are really very, very elegant responses. I don't think I need to spend a lot of time to highlight how these curves are very beautiful being in a plateau. It's quite amazing, for instance, to have a PFS progression-free survival at 15 months, almost 90% in those patients who achieve complete remission, 51% in the overall population. So you can see teclistamide and renatamide are already available, at least on a compassionate early access programs. And they are easily, I would say, can be administered in almost all hospitals. And my best guess, they will become more and more popular. And given these results, as you may guess, the idea is to combine them with other effective drugs, because here we're talking about single agent. To use them in earlier lines, yes, if it works very well in highly advanced patient, well, it should work perfectly in earlier stages of the disease. But also, if we can target using the bispecific technology, one tumor antigen like BCMA, maybe we can target other antigens, and then it gives more, I would say, options to kill the tumor cells. And this is exactly, for instance, about talcatamide. So talcatamide is another bispecific antibody. It's not yet approved or commercially available, but we have it in clinical trials. And I think it will become rapidly available. That is my hope. And it targets a different antigen called GPRC5D. So it's different from BCMA. So very excellent opportunity. And we have the update at IHA of this so-called monumental one trial. I will not go through the details of the trial, but you can see that these are high number of patients, median age 67 up to 84 or even 86. Same story. These are patients who received the different available drugs. They have received actually a median of five or six lines of therapy. But also, they have received even some of the modern agent like Valentimab and they have received the usual suspect. If you look to the response rate, well, again, we are talking about response rate more than 70%. So see, with these bispecific, the responses are between 60 to 70%, which is very unusual. Usually, in a refractory multiple maloma patient, you would expect like 30% of responses historically. So we're doing at least double 60%. And the follow up of these studies is already quite decent for such a heavily pretreated population. And if you look to the duration of responses and outcomes, again, these results are quite, I would say, amazing in such heavily pretreated population. But that was the beautiful part of the story. As usual, unfortunately, we have to be careful about the side effects. So we have the infections I mentioned with the other by specific but they are less frequent, probably because the target is different, GPRC5D. GPRC5D is less involved in the immune system compared to BCMA. But here, there is a sort of an off target side effect, which is some skin toxicity, but also what we call dysgosia, when the patient, you know, for instance, you don't feel the taste of what you eat, which is, I must confess, quite annoying. Usually, it doesn't stay forever, so things will improve, but you need to be aware of it because otherwise, it can be a surprise that you don't feel anymore the taste of salt or sugar or whatever. So it needs to be known. And as I said, as I mentioned, the infection, the incidence of infection is lower, but they do exist in my message here again, please follow the instructions of your doctor in terms of prophylaxis, in terms of taking your prophylaxis medication. And then of course, as I said, if every by specific antibody alone works very well, why don't we put them together, and then it will be even better. Exactly. What has been done in this so called redirect TT one study, where actually they combine to click them up, the one I presented first, and they'll get them up. This is the one I have just presented. I mean, I don't think we need to go into the details of the design of the study, but it is very exciting, because in this study, they have really included some difficult and hard to treat patient, especially the patient with extra medullary disease because you know very well that multiple maloma is a disease of the bone marrow. But sometimes, especially an advanced patient. The disease will go out, and you have what we call extra medullary localization in different organs. And when the disease is out of the bone marrow. That means it has become very aggressive. And they are, these patients are more difficult to treat. And this is why one third of them were included in this trial. And actually, you will see the results were very attractive. Well, first question is, is it safe to combine to buy specific. The answer is yes. Of course, we always see the usual side effects when it comes to the low blood counts, some anemia, some low platelets. We of course see the side effects of every by specific. You can see the dysgosia I mentioned, you can see the kintoxicity the nail disorders but also the infections. But on the other hand, so yes, on the other hand, you have a really incredible almost, you know, 100% response rate 96.3%. Combining the forces of two highly effective agents. Actually, it can lead to very, very potent responses. And although the follow up is still relatively short. Actually, the median PFS is already around 21 months. Actually, given that one third of the population was very hard to treat. And the median time to achieve the first trespasses rather quick in less than two months. We'll respond. And if we put a focus actually on the patient with extra medullary disease. And here it is really a very strong signal to say maybe these very difficult patient may benefit from this combination you can see they are responding extremely well. During the presentation, the authors showed this example. I don't need, I don't think I need to spend a lot of time you can just observe the skeleton, all the black spots are about the Maloma localization. And you can see here on the right hand side, how things were really clean and disappeared. So this is really quite promising. And of course, hopefully at some point we will be able to use these combinations. What was, I would say what I consider as a summary of the most attractive and hottest agent when it comes to by specific antibodies so these are the immune therapy in vivo directly in the blood you don't need to take anything out. But if you want to engineer the T cells and get the CAR T cells. Well, we have heard during EHA in the plenary session. A very important study, the results of a very, very important study called Cartitude for. And this study is actually as a study which randomized. A CAR T cell construct called SILTA cell to a non cellular therapy treatment standard of care, namely pomalidomide bortezumid dexamethasone PVD, or deratoma pomalidomide dexamethasone. These are very common regimens, because you may remember that CAR T cells today, they are exclusively used in those patients who are very, very advanced. Here's the idea is to give CAR T cells for early relapse, for instance, between the first and third relapse. If CAR T cells work very well in very advanced patient, do they work also? Can they work better than what we give with the usual drugs? So you have patient to receive standard of care, so no CAR T cells, and then patient to receive CAR T cells. So, obviously when we say randomized, then half of the patient go in one group, half of the patient go in another group, but the two groups are very balanced, because obviously if you want to compare in a, I would say, compare manner, because this is the idea in clinical research where you have to compare, and a fair way to find out whether treatment XYZ is better than another treatment. They need to be balanced, and obviously here they are very balanced, and I would like to draw your attention that in contrast to auto transplant, for instance, CAR T cells can be given easily. Well, easily, at least routinely up to age 80 and beyond. So CAR T cell eligibility is different from auto transplant eligibility, but this is the most, I would say, beautiful result of the Congress and of the article of the study of the paper, where you can see that actually the CAR T cells, the SILTA cell is doing really much, much better than our conventional drugs, even if they have included the ratumoma. And the hazard ratio is 0.26. What does mean hazard ratio of 0.26? It's very simple. It means that you have 1 minus 26, this is 100 minus 26, this is 74. It means you have 74% improvement with the CAR T cell, the blue curve, compared to the green curve. So the conclusion or the corollary of this is that probably at some point, hopefully we will get the approval of CAR T cells to be even used in earlier lines of therapies. And why is it important? Because, obviously, CAR T cells are a single shot treatment. You give them and the patient is treatment-free. So you can enjoy some treatment-free interval. Of course, we need to be honest about it. The patient will continue to relapse because otherwise there is cure, but still the results are really very impressive. And why the survival results are impressive? Well, because the response rates, because really the SILTA cell, CAR T cell is able to destroy the maloma cells, and you can see almost 85% of response. And these are really deep responses. Because if you look to MRD, and I'm sure many of you heard about MRD, so MRD is the technology by which we look really to the lowest amount of disease remaining in the body of the patient. And actually, the CAR T cell are able to achieve, to lead to really very deep MRD negative. And the safety is very good. Safety is very good because although this is cellular therapy, but usually the toxicities we see with CAR T cells when we treat lymphoma or leukemia, acute leukemia, are less frequent and less severe in multiple maloma. Of course, it requires hospitalization, so I'm not saying it's going to be a holiday or a vacation to get CAR T cells. You still need probably three to four weeks of hospitalization. You usually use some form of chemotherapy before, because you prepare the ground before infusing the CAR T cell, then you have you infuse the CAR T cells, your CAR T cells start proliferating. You know, it's like, you know, you're trying to grow a grass or whatever. And then it takes some time, but then the responses are very quick. There is maybe a signal that we need to be aware of and the patient need to be aware of that some patient may develop some unusual neurological toxicities. And they are usually what we call maybe Parkinson-like symptoms. They are reversible, so they disappear, but they can be quite worrying, I would say, and very unusual, because if you are a young patient and suddenly you start having like Parkinson-like symptoms, that can be very impressive to the patient and to the family. So you need to be aware of this, but definitely the results of this CAR T for trial are a milestone for, I think, the approval of CAR T cells earlier in the line of the Maloma disease. And they are actually similar to another trial that was published four or five months ago called Karma III trial, which has used a different CAR T cell product. And it has led to similar results showing that the CAR T cell is able to do better than the standard of care. So in summary, I would like to leave you with this slide, which in my opinion, summarized really the huge advances. You can see these beautiful curves going up when it comes to survival. And I believe that today in 2023 and in the next few years, with the use of bispecific, but also CAR T cells. Of course, I deliberately focused on this, but there are other advances and we may discuss them if you wish, about small agents called cell modes. There are some other form of immune therapies. There's the antibody drug conjugate. There are small molecules like malphlufen, like selenexor available. So if you put all this together, the future, in my opinion, looks brilliant. And today, again, I keep on repeating this to my patient. The best ally for a patient is time. So you have to gain time. And if you, what the American colleagues say, if you buy time, then you can be ready for another line of treatment. But you can see, even the most advanced patient, we are able to achieve some relatively long remissions. So with this, I'd like to thank you all for your attention. And of course, I'll be more than happy to take questions that I can see there are already plenty of questions. Thank you very much. Thank you very much, Professor Morty, for this very comprehensive presentation and of the most relevant results presented that he had this year. Yeah, let's move to the question and answer session. Maybe I'll start with one question regarding alamyloidosis because we, we also have alamyloidosis patients in our community. And I would like to know if there is anything to share about new or improved alamyloidosis treatment that you might have heard of at EHA this year. Yeah, so I didn't mention amyloidosis, but definitely amyloidosis has been, I would say, dramatically in a positive way. Alamyloidosis has been dramatically improving. And we know that the backbone for the treatment of amyloidosis is actually based on anti-CD38 monoclonal antibody, namely direct tumor map, plus combinations like VCD, which is the direct tumor map cycle for swine dexamethasone. But the novelty is that with the near future, we will also see other antibodies, other more targeted specific agent that are capable of stopping and controlling the amyloidosis secretion. A general message for the patient who are struggling with amyloidosis, it's relatively straightforward and easy to understand all the drugs that work in myeloma actually work very well in amyloidosis. Of course, amyloidosis is an orphan disease, so you would rarely see specific trials for amyloidosis and for many years we've been using the drugs in amyloidosis off-label, because they didn't get a label specific, but also now that our tumor map is approved. But definitely, all the advances we see in myeloma are relevant actually to amyloidosis. Okay, thank you. Now I will move to the audience questions. We have questions around bispecifix, around CAR-T, questions that apply to both, so I will try to sort them out. Maybe one question regarding the expression of CD3, and you know, maybe we can make this question a bit broader, speaking about receptor expressions in general. So the question was, do all myeloma patients have CD3 on their cells, and maybe we can expand that to BCMA or even GPDRC5D and other receptors, and how this can impact treatment efficiency. Yeah, no, very good questions. So just to clarify, on the tumor cell, on the plasma cell, you have antigens, and for instance the most popular antigen is BCMA. The CD3 is an antigen and a marker of T cells, so it has nothing to do with the myeloma cell. And when you give a bispecific antibody, it has like two legs. On one hand it goes and captures a T cell, and on the other hand it goes to the BCMA, and by capturing both of them, actually they bring them together. And when they get in contact, this is where you have a killing cascade, and your myeloma cell will start being killed. The important question is that if you want your bispecific antibodies to work very well, obviously you need to have enough T cells, and a good immune system, because they are the soldiers that are going to do the job. And this is why I mentioned in my talk, the issue that at some point we see some what we call T cell exhaustion. That it's like, you know, in any fight, in any battle, if you have an army and soldiers, I mean if they keep on fighting day and night, without any rest, well they would be exhausted, you're soldiers. This is why now there are studies, but also approaches trying to say, okay, can we stop the treatment of bispec, with bispecific antibodies after a certain duration of time. The protocol is not yet, but I think this is the way to go. But also, it's easier for the patient, and actually we see less infections, because obviously, you are hammering less the immune system. So clearly, on one hand, you would target and capture the tumor cell, and on the other hand you capture the T cell, and you put them together. And when they get in contact. So the tumor is supposed to start to disappear. Thank you, Professor Marty. I hope these answers. Well, the question that was asked on the on the chat. And now I have two questions that are related to each other one about how to decide between the therapy and by specific treatment, and the other one around sequencing, but maybe we can ask you your personal experience of how you go for one versus another with with your own patients and what what is first advice to relax with factory myeloma patients. How to decide, it's not easy. Well, first of all, if you want to decide it means you have access to both, which is not always the case, because CAR T cells are still difficult to find I would say they are concentrated in a few centers, and there are very few slots, but I agree, assuming both of them are available. The issue is that for the CAR T cells. It takes several weeks before getting them ready. So you cannot I cannot see a patient today and say okay I'll do CAR T cells tomorrow morning. I can see a patient today now tonight and say okay we'll start the by specific tomorrow morning. So availability and feasibility and how easy is a crucial issue. And remember, in some relapse patient the disease extremely aggressive. So you cannot wait for five, six or seven weeks to get the CAR T cells. So, it is a balance about availability about the kinetics of the disease. But of course, CAR T cells patient likes them because it's a single shot treatment by specific you need to come every week or every other week. So it's a continuous treatment. But on the other hand, they are easily available, and even in smaller hospitals so you don't need to travel to the big academic university hospital, etc. For me, we should not oppose them. These are options that are available and whatever is available, I would say, let's take it. Because at the end, if you look to the results, they are quite decent for both. Yes, I think we have several questions that are indeed related to access. People in the Q&A are asking if you know how much those treatment costs and what's the outlook for access to this therapy in Europe today. Well, I don't know the exact cost, but I would say a lot. They are very expensive, but they are bringing value, they're improving the survival and the outcome of these patients. And of course, as a physician, my role is to advocate for availability, accessibility and affordability for all patients, but I must confess I'm not the guy who decide on the price. I've never been asked my opinion about, you know, which price or whatever, but definitely our hope and our work is to push, to lobby, to make these agents even if they are supposed to be expensive, to make them available to the majority of patients everywhere because all patients, wherever they are, they deserve to receive the best and most innovative treatments as soon as possible. And whenever needed, of course. I see. And do you see CAR-T therapies and by specific therapies coming to earlier lines of therapies? Absolutely, absolutely. And this is, for instance, what I have shown you with the CAR-T for trial, but there are already trials trying even frontline testing CAR-T cells frontline. And by specific are being tested even frontline and in earlier lines of therapy. I think by for the next 10 years, we will see a significant, a huge change in the treatment algorithm. And I believe the by specific and CAR-T cells will be incorporated in the new algorithm of treatments early in the disease. Because as I said, if you have something that works so well in advanced patient, actually you have to take advantage of it in early patients, in early diseases. So you anticipate longer overall response rates and duration of response when therapy is given at early stages or even first line of therapy? Well, at least I hope it will be the case. But as you always know that if we're doing the trials, it means we don't know the answer because if we knew the answer, we won't do the trials. We have a speculation that that will be the case. But sometimes we've got it wrong. But here, I'm quite optimistic and you can see the CAR-T for trial clearly could show that by using CAR-T cells early, you can do better than your usual standard of care. Also the standard of care, please don't misunderstand me, is already excellent, but you can be better than excellent. You can be like excellent plus. Do you think CAR-T will replace or even go up front, step-step transplant? Yes, if the trials that are ongoing currently prove to be positive, but probably it will take us another five years before we get these answers. And now if I go on the other side of the treatment journey, what if patients have exhausted all options? They've already tried one CAR-T cell therapy, one by specific, and then they progress again. What treatment options would be available to them? Are there by specifics with different targets? Are there CAR-Ts with different targets? What are your thoughts regarding refractory patients? Well, I mean, there is no single answer to this. Again, as I mentioned, the goal is to buy time. If we are able to gain time, there are always new things. Every two, three months, I can see new things. There are plenty of trials. For instance, I described to you the by-specific antibodies, but we're already doing trials with tri-specific, with several. I mentioned to you two antigens, BCMA and GPRC5D, but there are other antigens like FCRH5. So for me, is that we have a lot of tools. Of course, maybe, I mean, some patients will not live long enough to take advantage of all of them. But we work very hard, and we all are optimistic that with time, more and more options will be available. So just about buying and being resilient until the next line of treatment. Yes, thanks. But all of this comes with some, of course, we need to acknowledge this because I always like to be balanced and honest with the patient and families that these advances, they have a cost for the patient, not in terms of money, but they have a cost in terms of side effects. And this is why we need to learn how to manage the side effects to alert and create awareness about these side effects for the patient. Because the more we know the side effects, the profile of the safety, the better we can handle them. And because I saw some comments from the audience that they have experienced similar side effects to what we described in the trials, which is true. But then, you know, it's always the balance between the efficacy of the treatment and the side effects. And if your efficacy is higher than your side effects, then we consider it as a treatment that is worse. Speaking about side effects, do you have any sense of what, what the added toxicity, toxicities are over time, one treatment after another, the long term toxicities that add up with time. This is a very important question. And this is what I alluded to when I said it has a price. All of these progresses and advances and modern treatment, they come with a new safety profile. So, for instance, yes, there is some additive immunosuppression and the risk of infections can be aggravated over time because the patient are more and more immunosuppressed. When it comes to the additive risk, we take the basic example, the historical example of peripheral neuropathy related to Bortesimib or even Thalidomide, some of the very old patients have received these in the early 2000s. And we know that some patients will keep these side effects for many, many years. And this can be annoying for the quality of life. When it comes to the additive side effect, for instance, most of these treatments are hitting on the bone marrow because this is where you have the malignant plasma cell. So your bone marrow, especially if the patient got a prior transplant, is becoming a sort of weaker, your bone marrow reserve, because you have like a reserve of bone marrow. And if you keep on hammering it, then you are using your reserve. So yes, they accumulate over time. But again, this is why it is important that we do these trials in a very strict, very stringent manner to really capture all of these side effects. I think one of the big hope is that at least with CAR-T, there's the whole treatment-free period of time that is associated with good quality of life. But now we are hearing about adding maintenance therapies to it and so on. So how do you see that setting in the future? Are we, is it going to be the standard? How often people will have to come to the hospital anyway for any kind of supportive care and maintenance treatment following CAR-T, or even by specifics? Because now they're also talking about fixed duration of by specifics. Yes, I think this is a very important question. Today, as I mentioned, the beauty of CAR-T cells is that it's a single shot treatment and the patient will enjoy some good time, I would say, especially if they respond it. But I agree with you, some of the next trials are testing the use of some maintenance therapy after CAR-T cells. So whether we like it or not, actually the reason rational behind this, because obviously if the effect of your CAR-T cell was like 100% response and everybody is cured, it's okay. But in order to amplify or to improve the efficacy of your CAR-T cells but also maybe eradicate the residual tumor cells, we may need maybe one, two or three years of maintenance. For instance, some of the ongoing trials are going up to three years of maintenance, but I agree with you. It would be a bit disappointing because the idea of the CAR-T cell is about a single shot. But you need to find, again, an equilibrium between single shot but also trying to get rid of the disease because at the end of the day, if you are able to get definitely rid of the disease while the patient is going to be happy. Thank you. I think that was really helpful. I learned a lot and maybe I will ask one last questions before leaving you with the last words of the session. I have one question regarding COVID. How COVID is impacting treatment choice or, you know, the hospital setting associated with the different treatments and what are the current recommendations for the patients? Yeah, so, well, obviously the COVID situation can be different from one place to another, even within the same country. So I can't speak on behalf of every place, every center. All I can say is, for instance, for us here in France, COVID is not really a matter of concern and it doesn't interfere with the choice of the treatment or with the way we manage our patients. Obviously, my Loma patient paid a very high price for COVID because they are very vulnerable to the viral coronavirus infection and we learned more and more how to handle this. But at this stage, I touch wood, you know, I believe things are under control and I encourage the vaccination if it is still available or whatever. But for the time being, I would say the case is under control. Okay, thank you. Well, that's good news. Well, this is the end of our webinar. Thank you so much everyone for attending and so much here on behalf of MP and everyone attending the webinar. Thank you so much for being there with us today and for sharing these highlights from Hiha and for answering all those questions. So maybe you want to share with us one last word before we close the webinar. Well, first of all, thank you for inviting me. I always enjoy debating and discussing with the patient. I always believe they are really the heart of everything we do and they give us a motivation and a passion to fight. One keyword for the patient and for the families is that we need to be optimistic. Yeah, you would hear everywhere that Maloma is an uncurable disease, but actually doesn't matter. You shouldn't care about this idea of being curable of uncurable. It's about living long and dwell. And this is a goal that we can achieve these days. And that is the most important. Thank you so much. Thanks for the hope message. And I wish everyone a very nice evening. Yeah, bye.