 Good afternoon everyone and welcome to this webinar on NASS 2020 myeloma and ielamilidosis highlights. My name is Ana Vallejo, I'm the communications manager of myeloma patient Europe and I will moderate this webinar today. First of all I would like to thank you all for attending this webinar. As you know our main goal with this webinar is to review the most important updates on myeloma and ielamilidosis treatments presented at us at the American Society of Fematology annual meeting that was held virtually last week. For your information this webinar will be fully recorded and will be uploaded to myeloma patient Europe website which is www.mpurot.org and will be available in the mp youtube channel as well. And before we start I just would like to make a small summary of the webinar agenda. As you know this webinar is scheduled for five to six so the presentation will last about 40-45 minutes and then I will open the session for questions so you have two ways to ask questions to the doctors. One of them is using the microphone in your computer you just have to press the right hand bottom and I will unmute you so you can ask directly to your question to the doctors and the other way if you don't want to use your microphone you can send your question in writing in the question and answer window. I will receive those questions and I will ask them to the doctors so they can answer them. As you know this talk will be given by Dr. Cas Jun and Claudia Steghe. I hope I pronounced the heck or read your name and the BU University Medical Center in Amsterdam the Netherlands and on behalf of myeloma patient Europe doctors I would like to thank you both for your collaboration for your time to prepare and to give this webinar and for the effort to summarize all the updates presented at us around myeloma and the amyelidosis so thank you very much and the floor is yours. Thank you, thank you for the introduction. Good afternoon everybody, my name is Cas Jun and I'm an internal medicine hematologist here in the Amsterdam UMC. And I'm Claudia Steghe you pronounced as well Anna and I am a hematologist in training but I'm doing my PhD in multiple myeloma. In the upcoming 40 minutes we'll try to guide you through all the highlights of the ash 2020 about multiple myeloma and al.emeloidosis. What we're going to tell you today first I want to give you an introduction about how studies work and medicine are developed. Then the first studies we'll talk you through is the newly diagnosed multiple myeloma and the role of stem cell transplant. The next thing is when the disease relapses and the early relapse how can we treat it and the next phase will be when it relapses after more the more relapses so the later relapse and then we're going to talk about exciting new therapies like biospecific and CAR T cells and how they work and we want to end this presentation with a little bit about al.emeloidosis and some take-home messages and after that there will be more room for questions. So let's start with the beginning. It's good to realize that most treatments for multiple myeloma are combinations of different types of medicine so mostly accommodate an imid and immunomodulatory drug like thalidomide or lanylidomide with a proteasome inhibitor like proteasomid or carvilsomid. Recently fairly new is the NTCDA38 antibody daratumumab. It's been on the market for a few years and more and more combinations with an imid or proteasome inhibitor are tested and given. New in the field of treatment is the biospecific antibodies and the CAR T cell therapy we will tell you later more about. When the drug is started for the first time it's studied in a phase one study. It means that they start at the low dose and when the drug is safely administered the doses are increased until they found the recommended phase two dose. Then at that dosage a drug can enter phase two study and in this study they'll further assess the safety and also will look at the effectiveness of a drug. When you find a drug which is safe and effective it can be entered into a phase three study and that means that this drug is given and compared to a current treatment and to see if it's even better than the drugs we have today. If a drug is approved and went through a phase three study and is safe and effective based on this evidence the EMA which is the European Medicine Agency can approve the drug. The next step that has to be taken per country is that the drug is also allowed to be given in your country and reimbursed so that means that actually it's paid for. It's good to remind that we present also phase one and phase two studies and this means that those new drugs are not directly available in your country for treatment and it takes a while before the drugs is actually allowed to give outside of a study. In studies a lot of numbers are mentioned so it can be dazzling a little bit. The most important thing to remember is the ORR which is called the overall response rate. Here you see an example with an ORR of 29 percent meaning that 29 percent of the patients are reacting to the treatment and with a reduction in the M protein. When it's a partial response there's a reduction of 50 to 90 percent. If there is a more reduction higher than 90 percent we call it a very good partial response and if there is a 100 percent reduction in the M protein we call it a complete response. This is to show in studies how good the response is. Relatively new is the MRD which stands for minimal residual disease. This is a more sensitive way of detecting plasma cells, multiple myeloma cells in the bone marrow and see if one in 10,000 or 100,000 cells are still from the disease. Other numbers which are mentioned in studies are PFS which stands for progression free survival. The first thing to know is that when this line is higher it's better. When we talk about a median PFS that means that when 50 percent of all patients at a certain time point are still alive without progression of the disease. So for the treatment with the blue arm the median PFS is 42 months while with the other treatment it's 57 months which is longer therefore better. Sometimes studies talk about a 12 month PFS or 24 month PFS. 12 month PFS means that at 12 months you can see how many people are still alive or without progression of the disease and the higher the better. Just remember the higher the better. Also important in studies are side effects and to be able to research them we classify them in grades. Being grade one and two relatively mild grade three or four is more severe. So you don't want that and grade five actually means that patients can die from this side effect. So today we are going to give you the highlights of the ash and first it's good to know that a lot of presentations investigated therapies for patients treated with newly diagnosed multimyeloma but many more presentations were about therapies for relapsed and refractory myeloma and even actually more studies were investigated therapies preclinically that means in mice or other animals or even cell lines in a laboratory. But I think for you it's most importantly relevant to only talk about the human studies. So let us start by presenting the main results for the newly diagnosed multimyeloma patients and like Kass already told you we can divide those patients between patients who are eligible for a stem cell transplantation an autologous stem cell transplantation and those patients are usually young and fit and we can divide them by the non-transplantal patients so patients usually above 70 years of age are not fit. And when we talk about therapies in newly diagnosed multimyeloma patients the word is daratumumab and Kass already mentioned it very briefly maybe you have heard about it already then it's okay. Daratumumab is an antibody and you see it here and daratumumab can bind to a specific receptor a protein on the myeloma plasma cell so the myeloma tumor cell and this receptor on the myeloma cell is called CD38. So daratumumab is able to bind to CD38 on the myeloma cell and when it binds it can attack and kill the myeloma cell in very in five different ways you don't need to remember but it's very effective and like many other drugs daratumab was first investigated in the first phase one phase and then in phase two phase and it has been evaluated in a relapse setting a couple of years ago and it's already approved in that setting and now it moved to the first line. So daratumumab is in studies added to the standard regimens for both transplant eligible patients as non-transplant eligible patients and first I want to tell you about the study in transplant eligible patients so the younger fit patients and the study that was presented at ASH is the Griffin study and all those studies have names and it's it's because it's easy to remember for the doctor but it's not easy for you to remember so I will just talk you through. In the Griffin study patients were treated with either a standard of care RVD that means lanolinamide bortezomab dexamethasone or they have 50% chance to have the addition of daratumumab to that standard treatment so half of the patients got the daratreatment and the other half received the standard of care. Patients were treated for four cycles followed by an otolica stem cell transplantation and followed by two additional cycles and then two years of maintenance therapy. The standard arm received only lanolinamide which is standard of care nowadays but the DARA arm receives additional daratumab maintenance. What you can see here is the response at different time points here the end of induction so before transplant here after transplantation here after the two additional extra cycles and here after 12 months of maintenance therapy for DARA RVD versus RVD and what you can see only yellow are the people that don't respond actually every patient responds in both arms and what you can also see is that responses especially purple and orange are the best responses so the complete remission disappearance of M protein you see that responses increased over time in both the treatment arms but what you can also see is that more patients in the DARA RVD arm received a better response so responses were better with DARA RVD what you can also see after at least two years of follow-up almost all patients were still allied with progression of the disease and those are really striking findings and that means that both treatments are really good and we need to wait much longer to see whether the addition of daratumab to RVD becomes better than it is now but now both treatment treatments are really good. The next question we ask is there still a role for autologous stem cell transplant for patients treated for multiple myeloma there are actually three studies I'm going to talk you through and then conclude if there is still a role the first study is the fourth trial almost 500 patients were included and they were divided in three groups the first group got KCD which is carfilsamin a proteasome inhibitor the cyclophosphamide and dexamethasone for four cycles then got the stem cell transplant and four more cycles another third of patients got carfilsamib with lanolinamide and dexamethasone with the stem cell transplant and then again four times KRD and then one third of the patients didn't receive a stem cell transplant but 12 times KRD here on the left you see the response rates and in the middle it's the highest almost 90% had a VGPR so a very good partial response or better and that arm was the one with a stem cell transplant with KRD so carfilsamib lanolinamide and dexamethasone if you look at the PFS so the progression free survival remember the higher the better you see the highest line is the blue line and the blue line was the people treated with a carfilsamib lanolinamide dexamethasone with a stem cell transplant so you see that after 36 months which is three years the highest patient the percentage of patients 78 were alive without progression of the disease so yes from this study they're still benefit of stem cell transplant the second study is the EMN2 or Hoval 95 study in this study patients were treated with VCD and then they were randomized between receiving VMP which is portisans mid-malphalon pregnancy or a stem cell transplant almost 1200 patients were included and further previously they were showing that there was a better progression free survival for patients who were treated with the stem cell transplant the red line is higher than the blue line there wasn't a difference in overall survival when they were followed up for almost 70 months but now we have a longer follow-up and this was the previous follow-up and now it's almost 84 months and you see that the lines start to diverge with the blue line being the higher line the patients who received the stem cell transplant so again it seems there is still a benefit of a stem cell transplant in the first line treatment the third study is the IFM 2009 study patients were treated with RVD lanolinamide vortizimib and veximethasone without a stem cell transplant or with a stem cell transplant what you see here is the progression free survival the red line being the patients with a stem cell transplant which is higher than the blue line so there's a benefit for those patients and if you look at the survival it didn't change but then people were treated with the next regimen so to summarize is there still a rule for autologous stem cell transplant based on these three studies I would say yes yes yes it's good to remember that daratumumab wasn't added in those studies because it's fairly new so what the effect will be on daratumumab if there's still a benefit of stem cell transplant is hard to tell because they were not included in these studies as you all might know is that in previous decades we treated newly diagnosed myeloma patients for a limited period for example for nine months and then stopped treating the patient until the disease relapsed but now a lot of studies show that intensifying treatment or giving continuous treatment with maintenance it induces better deeper and longer responses and one of the things you can do to intensify treatment it is to give consolidation treatment cycles and that means you give extra cycles of treatment after stem cell transplantation and Cas already mentioned this trial the EMN 02 HoVon 95 study in which those patients were first treated the same and then were randomized between VMP versus stem cell transplantation but another important thing that they investigated in the trial was whether giving two additional cycles of RVD rotation with the right dexamethasone was better and was beneficial as compared when you don't give extra cycles so what I am going to tell you about is whether extra two cycles is beneficial the red line this is again the progression free survival and what you can see is patients who received those two extra cycles after the VMP or stem cell transplantation had a longer progression free survival as compared to patients who did not get the consolidation cycles and what you can also appreciate is that the patients who received the two additional cycles more often had a complete response so disappearance of M protein so that means that intensifying treatment with two cycles more leads to a better survival and response now let's move to the non-transplantalizable patients so the elderly and again it's all about dyratumumab like I told you the most important studies that were presented at ASH were longer follow-up results of the two largest phase three trials in non-transplants patients the addition of dyratumumab to lanolinomide dexamethasone this was investigated in the Maya trial again a name or the addition of dyratumab to VMP protezumab melphalan prednisone the elcian trial and what you can see is the is when dyratumab is added to either RD lendex in purple or added to VMP the red line the higher like I said the higher the line the better so the progression free survival is better when dyratumab is added to the standard of care and in the Netherlands Dara VMP is already approved and we already can give it to the patients Dara already not yet but it will be approved maybe in the near future and but it depends on in which country and how are the reimbursement reimbursement is this is also very interesting because dyratumumab is beneficial we already talked about it a lot but there's one big a couple of disadvantages of dyratumumab and that is that that you need to administer intravenously so into the vein and that that means that a patient has to be admitted in the hospital for hours and it can also induce reactions after infusion so what they did is they the pharmaceutical industry made dyratumab subcutaneously so you can give it under the skin and that it reduces the administration time and it gives also a little less infusion related reactions but then you also need to know is it as effective as the dyratumab intravenously so what this study did the pliata study was they compared the response of patients treated with dyratumab subcutaneously versus dyratumab intravenously and in different patients groups and with different regimens and what you can appreciate here is that the response rates dyratumab subcutaneously versus dyratumab intravenously is comparable again comparable so dyratumab subcutaneously is not only faster and less infusion reaction but it's also as effective as the intravenous formulation so it has an advantage and I hope it will be approved very shortly. All right for the early relapse I want to talk you through three studies we're based on an immunomodulatory agent, a proteasodium hindater with anti-CD38. The studies are Apollo, CMR-GO4 and Ikema. There's already a question but is that a do we need to do it already or maybe oh maybe at Etienne. We'll continue with the presentation and we will have the question later. I have enough time so the first study is the Apollo study. In the Apollo study, pomalidomide with dexamethasone was combined with or without dyratumab subcutaneously for patients with the relapse of the myeloma who were treated with one or more previous lines. This already has been investigated in a phase one and phase two study and they found it was safe and effective so now this combination entered the phase three study to compare it between each other. Over 300 patients entered the study and what did they see the purple line is the patients who were treated with dyratumab pomalidomide and dexamethasone and this line is higher than the yellow line so the patients who were treated without the dyratumab so it's more effective and on the right you see that the overall response rate is 69% meaning that 69% of all the patients who treated with the combination therapy responded with a degrees of the M protein compared with 46% in the other arm. So the conclusion here is that dyratumab with pomalidomide and dexamethasone is more effective than without a dyratumab. The second study is the CMRG04 study different combination of names but in this study people were treated with dyratumab dexamethasone encyclophosphamide with or without pomalidomide also for patients with a relapse of the disease with one or more previous lines who never had dyratumab or pomalidomide before. 120 patients were included and what did you see the blue arm is the people who were treated with the four drugs and the red arm with only three and the progression free survival is much higher for the blue arm so that means that more people are alive without progression of the disease. What they did next was people who were treated in RMB so without the pomalidomide could still get the pomalidomide and the progression free survival improved in 50% of the patient so you could still get it later so that's good to know. Also good to remember is the side effects and mostly neutropenia which is a low form of white blood cells with a chance of infection so it's always good to keep in mind that more effective but with more drugs also can keep more side effects. The last study for relapse refractory myeloma for early relapse is the Ikema study. In this study patients were treated with carfilzomib and dexamethasone with or without isotuximab which looks like dyratumab. It's an impressive graph here I will talk you through it. The two highest lines blue and red are dotted and it means that the patients who were MRD negative that means that the minimal residual disease the sort of very very sensitive way of measuring disease was negative they didn't find in a bone marrow the myeloma cells or the plasma cells. They of course had the highest progression free survival because it was more clean compared to people who were still where you still found the disease. In those two lines the blue line is the people who were treated with isotuximab carfilzomib and dexamethasone was higher than the for the patients who were treated without isotuximab. On the right you see some columns with the blue column being the people who were treated with all three drugs where the response rate was higher and more deep responses and on the bottom you see that more people reached the MRD negative state meaning that is also in the deep there was no plasma cells or myeloma cells found. So to conclude this regimen isotuximab carfilzomib and dexamethasone gave a longer and a deeper response. These are the combinations with drugs we know but more exciting news is coming from the ash with fairly new treatments like bispecifics. How do they work? You have to look at it as a as a protein with two arms one arm it's called CD3 which is on your own T cells and the other arm binds a protein on the myeloma cell the plasma cell. So what the protein does is bring them together so it brings your defense cells your white blood cells to the six cells and then combine them and makes the T cell kill the plasma cell and this pharmaceutical company produced a bispecific which is binding to this protein GPRC5D on the plasma cell but there are many more proteins one is them is BCMA and the other one is FCRH5. You don't have to remember that but the good thing to know is that bispecifics bind two things the T cell and the plasma cell and brings them together to kill them. So this might be an interesting and impressive table but there were six studies with different targets and they were all phase one which means that they're very early in the development and the patients who entered this study had a median prior lines of five or six so they had quite a lot of therapies already and they they had but there was still a chance of 50 up till 80% they were responded so it's a high percentage chance that the patients responded to this new therapy. One of the side effects we call cytokine release syndrome and the cytokines can be released when this is given and that can give high fever low blood pressure and people can get really sick and even can be admitted to the intensive care unit so there was a special attention in these studies if this was safe and luckily only a few a low percentage of patients developed a cytokine release of grade three or higher so it's fairly safe but remember this is all phase one short term follow-up and before this can be a standard care of treatment we need much more phase two studies where they look at the safety and effectiveness and more phase three studies when the bi specifics are compared to other studies so this will be for the upcoming years on the ash probably one of the topics. Then I have the pleasure to tell you all about cartesial therapy and it's just like the bi specifics it's an enormous advantage and it's really breaking news also this ash and first I want to tell you something about how cartesials work. For cartesials we this is a very impressive slide but I talk you through with cartesials we use the patients or so your own immune system to recognize the myeloma and kill it myeloma is a really smart disease and it becomes invisible for your own immune system he has a lot of features to do that and what we are going to do by cartesials is we change your own immune system so it can recognize the tumor again so in this case the myeloma cells what we do we collect the T cells from the body of the patient just like a stem cell collection for autologous stem cell transplantation and then the T cells are going to the laboratory and they get more information about how the tumor looks like and then the cartesial make new receptors on his service in order to recognize the myeloma cell and when the T cell has this receptor on his service it's called a CAR T cell so CAR T cell is actually your own T cell but with extra information about the recognition of the myeloma cell then the CAR T cells are redirected in the body and in the body they meet the myeloma cells and now they recognize them and they're going to kill it and so what we what all the studies do is they collect the stem cells it's called aphoresis but the manufacturing process here that takes a couple of weeks so sometimes the patients need a little bit of therapy in between after two to four weeks the patient is admitted in the hospital get a little bit of chemotherapy and then infuse the CAR T cells into the body and then what we need to do is wait and look whether the patient responds and also look for adverse events because just like Casette said you can imagine you redirect the T cells in the body the T cells recognize the tumor and you get an enormous T cell you can get an enormous immune response and it can look like you have an infection with the fever and the chills and low blood pressure so it can be dangerous so you must look really good after the patients very impressive slides but what I want to mention is there were 11 ash presentations and so it was really hard and investigating nine different CAR T cell products so there are a lot and it means that we are looking really looking forward to get this in practice all have the same targets on the myeloma tumor cell it's all BCMA and again just like the bispecifics it's all early phase one trials so trials that to find the recommended CAR T cell dose also in those studies all patients were treated were heavily pre-treated with four, five, six million prior lines and luckily we only saw very few cytokine release syndromes of high grades so that was good and again really encouraging over response rates of up to 100% so really really good responses in patients but again we must warn you it's really a short follow-up it is possible that the patient responds really short and then relapse again so we really need to follow up those patients longer and try to get those CAR T cells to phase two and three trials to investigate whether this effect holds but it's still very very encouraging and then lastly about the myeloma another new treatment approach that's the antibody drug conjugate or ADC and ADC's work like this you have an antibody just like the aratumumab that combines to a receptor on the myeloma cell but the difference between aratumumab and an antibody drug conjugate is that the antibody has a package of chemotherapy and when the antibody binds to the myeloma cell it can release its package of chemotherapy very locally so it's really targeted therapy and there are more ADC's investigated in trials but I want to point out one because it's really it's it's it's already added to another regimen pomalidomide dexamethasone and that antibody drug conjugate is called balentamepmephototin it's really hard I call it belamov and the phase one Elgonine study investigated 37 patients and they were not so heavily pre-treated as with the biospecifics or CAR T cells they had three prior median lines and of the 34 evaluable patients almost 90 percent responded to this regimen and importantly also the patients who did not respond anymore to immunomodulatory agencies and linoleumites, Bortezomep and aratumumab all had a response on this regimen so very promising in patients who were pre-treated but on the contrary though they found something disadvantages and that was keratopathy it's really hard for me sorry over 50 percent of patients had that eye toxicity and you can it's like a corneal ulceration with at least a risk of vision loss so it's really important toxicity in over half of patients and that lead it to a dose reduction of this belamov and now lower doses will be investigated in in this trial so this is a really good example how important it is to find the recommended dose because you don't of course you want good response rates but you don't want a very severe eye toxicity or auto toxicity now let's move on AL amylodosis for the for the last couple of slides and I think the most important presentations were about the endromeda trial that is a trial of phase three trial a newly diagnosed AL amylodosis patients and those patients were treated either with vcd bortezomib cyclophosphamide dexamethasone and that's a star a standard of care at least in the Netherlands or again dire tumor map was added to this regimen so it was 50 50 chance to get one of those patients who were treated with dire tumor map and vcd received also two years of maintenance with their tumor map but the vcd arm did not get this maintenance on the left hand side you see the best response in the dire vcd versus the standard without dire tumor and you see a big difference in response and if you look at the right hand side you see the progression free survival between the both arms and you see that the dire tumor vcd arm is higher than the vcd arm so the progression free survival is better with dire tumor map and it's really interesting they did not look only to the patients who were still alive without progression of the disease but they also looked that no organ function worsened and so this is a good regimen also to prevent organs to dysfunction and lastly we want to tell you about a presentation about a collaboration that was started between at least 13 european hospitals to assess real world data about al-aminodosis and as you might know al-aminodosis is a really rare disease so per country it's yeah you don't have a lot of patients and to increase all the knowledge and how to treat patients collaborations are really warranted and for al-aminodosis it has been moving on really quickly and currently there are almost 3000 patients already involved and it will only get more so that's really promising and nice. So to conclude this session what would you what we'd like you to take home is that the treatment in myeloma is evolving rapidly with a lot of new combinations of existing therapy and new therapy coming up and that dire tumor map which is now given in a relapse remitting disease maybe can come to the first line treatment in the future and that there's still a role for autologous stem cell and transplant nowadays and that are new combinations of the medicine we know and most exciting that there's a lot of new promising agents coming up like the CAR T cells the train T cells to buy specific the protein who binds and many more I hope this was clear for everybody if not we are happy to take any questions. Thank you thank you doctors for this wonderful presentation we know it's very difficult to summarize all the things presented at us a lot of information a lot of updates so thank you very much for summarizing that's for for the patient community and also for make it understandable for all of us just quickly remind the people we have in the webinar that there are two ways to ask questions so you can use the microphone if you use the right hand bottom I will unmute you so you can ask the question and the other way is to send the question in writing I know some of you already already did that so we are going to start with the question one of them is in my experience um there are two map uh is this a weekly infusion is superintendent there to move off a still weekly or is it more frequent? That's a really good question and actually there are two map um it depends if you get there are two maps up front so you start with their two map it's the same schedule as you would give uh you you get it IV so first you start with every week and after two cycles you go bi-weekly and after six cycles you go um you get their two map every four weeks and it doesn't matter if you get it subcutaneously or intravenously but um some some patients move from an intravenous formula to subcutaneous formula and then you just go on in your own schedule so you don't need to intensify the frequency. Thank you very much doctor the next question uh what do you think about uh re-treatment with the same or another anti-cd-38? That's a good question as well this is also really depending if uh previously patients were refractory or not so it means if you were treated with their two map and the disease progressed uh then it's not really logic to give it again because you already proved that the myeloma is stronger than the daratumum up but if you had it somewhere in the past and it reacted and it stopped for what reason uh then it's all yeah it's possible to try but it's so it's for every patient it's different and it depends on what has been given in the past and if it reacted or not. And maybe I can um uh say a little bit more about that we know that if a patient gets daratumum up uh then the malignant plasma cells so the myeloma tumor cells will lose their CD38 so the the binding site of daratumum up to the myeloma cell and so eventually the patient becomes refractive to daratumum up but there are now some really new data that sometimes when you wait long uh eventually CD38 will come up on the surface of the myeloma cells again so you can hypothesize that daratumum up will work again or maybe it doesn't work but maybe if you give is esotuxim up the brother or the sister of daratum up then it might might work also and there are some uh there was one presentation at ash uh in which patients got esotuxim up while they were already treated before with daratumum up and there were still some responses I don't know the exact percentage but thank you very much for for that answer uh the next question what is the difference between CAR-T therapies and bytes uh by specific antibodies in terms of efficacy side effects or weight of administration um good question I think to start with like the the mechanism of action is different so the by specific is a protein uh it's uh it's available and you can give it in the subcutaneously or intravenously depends on the study um the CAR-T cell of course the most different is that it's a different manufacturing time so you first need to take the T cells train them and then give them back so it takes a little bit longer which is challenging sometimes but in the end they have the same effect that the T cell trained or guided by the by specific kills the myeloma cells and when when T cells when the immune system is active they can produce all kind of cytokines which give the cytokine release syndrome so um a part of the side effects are the same with the cytokine release which is uh can be really heavily um luckily in these phase one studies and you cannot really compare them the percentage of a grade three or higher cytokine release syndrome was 10 percent or around it or below um and you can also not really good to compare the efficacy it's all phase one so I'm really looking forward to the future where maybe by specifics and CAR-T cells can be compared in studies as well so it's too early to to actually say which one is better maybe uh I don't want to but um I think for by specifics it's also that you give it once in three weeks and then continuous until the patient progress relapsed and CAR-T cell therapy you give it once and then you hope the T cells will persist in the body for a long time and all those CAR-T cell studies also mention how long the T cells are available in the body and there are a lot of studies going on also preclinical so in mice or to increase the persistence in the body of the CAR-T cells so you don't yeah so they work long yeah in fact there is a question around the things that you just said comparing CAR-T giving just one and bytes even until progression so one of the problems of CAR-T is that they are very expensive and in this case which one will be more expensive I know it's a difficult question well first of course it needs to be approved and then the negotiations will start with the pharmaceutical company to lower the price but the manufacturing of CAR-T is really expensive but yeah you only need it once if it works for a long time um so I think by specifics they're readily available uh might be cheaper I don't know but if you need it for a long time and you give it first you give it weekly and then go to every two weeks and every month if you have it for a very long time of course becomes more expensive so it's it's it's too early to say because we still need it to be approved but I think both will be expensive yeah well there's a lot of questions around CAR-T one of them is you said that CAR-T is promising how many more years can we call it promising when in real life all patients relapse within a year of the event treatment do you think it will ever be curative treatment uh what would you suggest if a patient had two choices left Bellama from CAR-T oh that's really really hard we hope it's curative but of course yeah we would solve so early to say um mostly it takes more than a few years to be from from the first investigations to readily available for everybody also thinking about the logistics and and the time to to get the T cells and produce them so it it won't be available for everybody in the near future so mostly in trials and then when it's accepted in a phase three trial then then it will be available yeah but I think it what is really promising is that uh some CAR-T cells are already moved to phase two so they are combined with um other drugs such as diuretumumab or um this in CAR-T I think it's CAR-T with carfil from it so they're already moved a little bit uh towards the first line um and and but um it's the time is always your enemy because um uh those those treatments they move to earlier lines but you need time to look whether this the treatment is effective and the the more effective uh the longer you must wait uh do you understand and um so I think if it's possible try to see whether there are studies around your home uh to to to look whether there's a CAR-T cell study available um but we need time to look uh to the long-term results and I think Balantumab Mavratin is will be more early available than than CAR-T cell because it's already further in all those phases yeah thank you very much uh the next question you said there is still a role for transplant in the future uh with the development of CAR-T and bytes uh with high efficacy rates do you ever think uh there might be a shift uh to the use of immunotherapy and alternative to transplant good question uh the the the studies we we showed on the the benefit of stem cell transplant was with uh induction treatment even without our Tumab so we don't know what that adding might change for the role of the stem cell transplant let alone the role of the CAR-T and bi-specific um if they are approved for the relapse refractory and they're very effective then I think in the future it will be uh uh put in trial for first line maybe and then we'll see uh I hope I hope that in the future uh only immune therapy is needed and no chemotherapy um but yeah it's it's it's still early I can understand why we have these questions but it's still too early to say yeah well thank you very much uh next question is there an alternative treatment under development as maintenance instead of linolydomide? um yes although the the most um studies report linolydomide as maintenance because that improved the progression free survival and overall survival in patients but there are possibilities to give something else as maintenance and the most commonly used is Bortesomib but as you might know Bortesomib if you give it for a longer time it you have more chance for neuropathy and as we showed in this presentation there are a lot of studies going on when darotumumib is added to linolydomide linolydomide um as maintenance therapy and we will know I think in a couple of years whether the addition of darotumib to linolydomide maintenance will be more effective as well and if that is the case then you might get not only linolydomide but also darotumumib um keeping in mind that linolydomide is just a pill and darotumib is a subcutaneous injection and not now even intravenously so you have to come to the hospital but yeah if it's more effective that's a that that's you have to wait those two yeah well thank you very much uh next question how do you utilize MRD in real clinical trials I mean in practical in clinical practice not yet no we know the deeper the response the longer the progression free survival is uh so if if you have a really good response a very good partial response or complete response that's good and if you have a MRD negative response so in the deep we don't see any plasma cells multiple myeloma cells we think it's better and a longer pfs but it's not put in practice yet but a lot of studies of course look at at it because they want to show if it's predictive as well um it's not put in practice but what which what is really uh impressive is I showed you the griffin trial when uh darotumumib was added to RVD linolydomide potassium and dexamethasone and uh we don't only have the griffin trial we also have the parasite trial which actually does exactly the same adding darotumumib to the standard of care RVD but when what they do is they give maintenance until the patient has uh been MRD negative so you don't see myeloma at all anymore in the most specific sensitive way and then they stop treatment and then they look what happens so uh those are the first studies that uh using uh MRD uh in changing treatments stopping or starting treatments and also we will learn from those trials what to do with MRD thank you very much it's really interesting and next question uh was there any presentation at us about COVID-19 in in myeloma patients is COVID more severe in myeloma patient and how is myeloma treatment handling around the COVID pandemic we didn't see any presentation on myeloma and COVID on the ash but it's of course a really relevant question those days what to do with with the treatment and I would say it's really patient specific what to do so you can imagine if you have myeloma new myeloma with a lot of problems or kidney problems or bone problems you need to be treated to prevent new problems and to get it better and then of course the it's it's more important to start treatment than delaying it on the other hand if you had a stem cell transplant two years ago and are on maintenance therapy then there's less urgency to continue and there might be a little bit more benefit of stopping treatments for a little bit but it's so patient specific on what were the symptoms of the disease how far in the treatment how well is the response that is this would be a discussion with your own doctor in the in the room to see do I still benefit of the maintenance or can I maybe stop it to be more safe so we have to discuss it I guess with our doctor because it's really a current question. Well thank you very much the next question if you have low number of T cell from premium chemotherapy how come they are going to cut T cell from the CAR T therapy I am doing right now Dara, the chlorophosphamide and dexamethasone what will be the next in a new relapse. So what's the question how do we get the T cells if they're low? Yeah and and after that also he's asking that he's we start to move out right now chlorophosphamide and dexamethasone what would be the next therapy for if relapse again. Okay so first of all when you want to be started with atheresis to collect the T cells there has to be a certain level of T cells so most of the treatments lower the T cells so then you have to stop for a little bit to measure the T cells in the blood and if they go up and they're above the certain level then you can try to collect them so that this also they in practice it's tricky but yeah that's the way to do it and the second question is now on Dara to cyclophosphamide dexamethasone it depends always for every patient it depends what were the previous treatments what was effective and what was not. So if you have progression under Dara to MAP you would not continue that and to look back if you had a very good response previously on an imit you would choose an imit the immune monolaterally drug if there was a very good response on valgate you can try that again with a combination or the newer generation car fields in MAP if there's if it's safe so for every patient look back what what worked which on under which therapy I was progressive and which combinations are available now to give like current therapy or always look if there's study in the neighborhood in my hospital which I can be included to maybe get by specific therapy car T cell therapy or other new therapy the next question regarding CAR T as well when you combine CAR T and other myeloma drugs in trials how do you know if it's CAR T or the other drugs that are efficient do patients respond to drugs again after CAR T if they have begun refractory to them before CAR T um I think that most of the CAR T studies don't combine yet but if you if if you want to know if if the adding of a medicine works then you divide all the patients into groups let's say in the phase three style trial that you do arm a you say CAR T plus medicine x y z and r and b it's only CAR T and then of course when there are enough patients in it you can see on the average if adding something has a positive or maybe negative result if there's more side effects regarding also regarding CAR T in this case they are asking CAR T can be used for AL amyloidosis patients is there any clinical trial on AL amyloidosis not that we are aware of not but I can I can imagine because AL amyloidosis is is the the problem is in the same cell the white blood cell namely the plasma cell so usually it is when something is beneficial in myeloma patients get treatment for AL amyloidosis get the same treatment eventually as myeloma so I think there are no studies yet but I think when CAR T cell is beneficial has proven to be beneficial it will come for AL amyloidosis as well maybe but it's too early let's see what happened then so the next question how do you choose DLD DMPB or BRD for non-transplant eligible induction again sorry a lot of acronyms how do you choose DLD DMPB or BRD for non-transplant eligible induction yeah it's it's it's an important question and the the yeah the short answer is it depends on the what is reimbursed and approved in your country because here in the Netherlands we always give VMP so rotation with malphaline predisone now added with daratumumab and we don't give linoleum adexumid mesosone that often only in certain cases so it really depends on your country and sometimes you you you give the patient something because the patient wants oral drugs because he lives far from the hospital cannot come for all the potassium injections all the time sometimes because of kidney dysfunction you give that kind of treatment etc so it's patient dependent and country dependent and to add side effect dependence well some people have neuropathy already because of the myeloma and you don't want to worsen that with the felcate the protezumid so then it's easier to choose for an immunomodulatory drug well thank you very much for for answering all those questions i mean that was the the last question and thank you very much for explaining everything and and all the summarizing everything that presented at us regarding myeloma and myelomilidosis just remind and remind all people here that the webinar has been recorded and will be available in the mp website and in the mp youtube channel and also they can access this through our social media channels so thank you very much and have a nice evening