 Good afternoon everyone and welcome to the first webinar of the educational program planned to replace the MPEAGM annual general meeting which as you know was cancelled due to the outbreak of the coronavirus infection. This is the reason why MP is organizing a webinar series to cover all topics included in the agenda. Today's webinar on myeloma and ielamiridosis treatment updates will be given by Dr. Inger Nyhoff, Department of hematology university medical center in Amsterdam the Netherlands. For your information this webinar will be fully recorded and will be uploaded to the myeloma patient Europe website which is www.npu.org. It will be also available in the MP YouTube channel so in case that you would like to share the webinar or watch it again you can do it in our YouTube channel or in our website. Before we start I would like to make a small summary of the webinar agenda. As you know the webinar is scheduled from 6 to 7 so the presentation will last around 40 45 minutes and then I will open the session for questions. There are basically two ways in which you can ask questions to the doctor. The first one is using your microphone in your computer as I'm doing right now just press the right hand button and that you will see in your screen I will unmute you and you can ask the question directly to the doctor and the other possibility is to that in writing say but using the question and answer window that you will see also in your screen I will receive those questions and I will bring them so the doctor can answer them. So Dr. Nyhoff on behalf of myeloma patient Europe I would like to thank you for your collaboration for your time to prepare and to give this webinar today. Thank you for your kind introduction it's really a pity that we can't see each other but of course this is an alternative and I'm glad to be of help in this way. We're going to talk about multiple myeloma and AL amyloidosis and I'm from the Netherlands I'm a hematologist with a focus on multiple myeloma also in research but also in the treatment of course. I cannot move my slides now. Okay so we're going to discuss the diagnosis of multiple myeloma and also of course of amyloidosis then the current treatment a little bit about the newly diagnosed transplant eligible patients but also about the transplant ineligible patients. We're going to tap on relapsed patients of course I'm also going to say something about the treatment of AL amyloidosis and then we're going to tap shortly on the new treatment developments the near future. Well multiple myeloma we call it an orphan disease it's a rare disease of course that's not the case for doctors as us working in Santa seeing a lot of patients with multiple myeloma but it is a rare disease. It is an uncontrolled growth of monoclonal plasma cells in the bone marrow. All of us have plasma cells in the bone marrow but normally there are different kinds of different families but in the case of multiple myeloma these are monoclonal that means they're all of the same family and they're causing problems especially and organ damage like hypercalcemia a high level of calcium is that renal impermanence anemia and lytic bone and lytic bone lesions. Well I said it was an orphan disease but it accounts for approximately one percent of all malignancies and it's the second most frequent hematologic malignancies so there are a lot of patients especially in the specialized centers. The median age of diagnosis is 69 70 years old but there are a lot of patients younger and also older and though it's rarely curable Fortunately multiple myeloma is a highly manageable disease nowadays because of its rapid medical attachments over the past decades. Here you can see a picture of the IMWG and it states again the myeloma is the second most common blood cancer. We do a lot of research trying to optimize therapy. A lot of people living with it worldwide 230,000 it was a picture of 2016 70% of patients experience pain which is most often the symptom of which research has been done and the diagnosis has been going into the light and as I said the five year overall survival rates have increased fortunately due to all the new treatment options we do have now. Who's at risk? Well men are a little bit more likely than women one half more and the most frequently diagnosed in the 65s until 74 but what I said also younger patients and all the patients we do have of course but it's the peak and twice as common in people of African descent. This is Sarah Newbury on the picture sees the first described multiple myeloma patients in 1844 so that's the first patient we recognize and then we didn't know what to do that's why he was so happily damaged by the disease. Of course that's not the case nowadays fortunately. Like I said multiple myeloma are malignant plasma cells in the bone marrow. Normally like you can see in the picture we all make normal plasma cells in the bone marrow and these normal plasma cells make antibodies they have a function in the immune system but when the patient has multiple myeloma then they're all from the same family these plasma cells they're abnormal they're monoclonal so from the same family and they all made the same antibody which we call an amprotein. It can be a whole immunoglobulin it can also be only the light change I will show you on the next slide and as I said the main criteria the symptoms are hypercarcinia, renal insufficiency, anemia and bone lesions, osteolytic. Osteolytic means I will show you a slide further, two slides further. This is the amprotein and aminoglobulin which is a happy chain in blue but also has light chains in red. 20% of patients just to have the light change then they don't have the blue ones in it but most patients 8% of them have a whole immunoglobulin. Like I said normal plasma cells are from different families and they make different antibodies so we have a repertoire which has a function in the immune system but multiple myeloma patients just have one immunoglobulin it's a monoclonal one and you can measure that in the blood you can measure it for diagnosis but you can also use it during treatment. If it lowers during treatment it's like a tumor marker then it's a sign that the treatment is working and then you don't have to go into the bone marrow every time to check if the treatment has effect and this is what I said patients can have a whole immunoglobulin or they can just have the free light chains. What's the frequency of symptoms? Do all patients have the same symptoms? No that's not the case. When the diagnosis is made then 13% of the patients have a high level of calcemia, hypercalcemia that's due to the fact that there is an increase of osteoplastic bone resorption so the calcium is going out of the bones. 20% of patients do have renal failure that's because of the amprotein or the free light chains who are gathering in the kidneys and making damage or because of the hypercalcemia or because of the multiple myeloma cells as their cells or because of amyloidosis which can be also there in patients with multiple myeloma or can be there just as another disease. But I will focus on the amyloidosis part a little bit later on. Anemia is present in 35% of the patients and diagnosis that's caused by the bone marrow infiltration of the plasma cells because the percentage of plasma cells is growing there's less space left for the normal cells and of course anemia and like I said a lot of patients have bone pain at a diagnosis well different research said different marks of course but between 60-70% of the patients do have bone pain because of the lytic bone lesions and pathologic fractures as a consequence can be there and here you can see it this is a patient here you can see the spine and in dark you can see with the marks here you can see a dark spot a dark spot these are lytic lesions so these are actually little holes in the spine in the bone. So what will we do when we think of multiple myeloma then we check the blood for an amprotein of course for anemia but also for the other healthy blood cells for the kidney function like we talked about then we check the urine because there can be a lot of protein loss in the urine we also do a bone marrow sample because there is where the six cells are where the monoclonal plasma cells are and we would like to see them and color them and see them with a microscope and we also other research with the bone marrow prognostic fat will have prognostic value like cytogenetics that the cytogenetic information within tumor cells so it's not an heritare disease that's important to realize but in tumor cells the heritare information cytogenetics are changed and we can look at these cytogenetics and they these have prognostic value that's what you can see here so the genetic effluation then we look at the bones most likely nowadays by a CT scan but also confidential x-ray is used in Europe and newer research is MRI or PADCT to look at the bones and at the PADCT you can also look at plasmacytoma so at a lot of plasma cells together which can be there in the body not with all patients but some patients do have that also a diagnosis and you can see it at a PADCT you can't see it that good at x-ray for example these are the six cells the myeloma cells in the bone marrow so when we take out of the bone marrow we do a bone marrow biopsy like you as patients have experienced most of you unfortunately then we take a little bit of your bone marrow out of it and we look under the microscope and these blue cells are the malignant plasma cells some they look like each other sometimes are a little bit different but these healthy blue color of these held blue color is the color of the multiple myeloma cells when do we start treatment of course when we have made the diagnosis but can we do it also before the diagnosis of multiple myeloma while the art precursor states we call it angus or asymptomatic multiple myeloma schmoldering multiple myeloma is not a name so the art patients will we know have an amperage in level or we know have monogonal plasma cells in the bone marrow but they don't have symptoms yet how do we know these patients of course we don't know all of them but we know some of them because when a patient has osteoporosis for example then a lot of doctors check for amprotein level and then we check are there any symptoms of multiple myeloma but when you're not there then you can call it a precursor state of multiple myeloma and depending on the level of amprotein below or over 30 grams per liter or depending on the percentage of sick plasma cells in your bone marrow under over 10% we call it angus or asymptomatic multiple myeloma when a patient has symptoms then it becomes multiple myeloma every patient with multiple myeloma have a precursor state only we don't know it always because when the patient has back pain and we're going to evaluate then we don't know that in this case how long it was there but we do know from sampling in countries just screening for all multiple myeloma patients had a precursor state angus or multiple myeloma asymptomatic so if we know that that we know from a patient that he has an amprotein level or monogonal plasma cells are we going to treat them or not they are not symptomatic yet why do we ask because we do have novel diagnostic guidelines based on your insight with more sensitive techniques and we're trying to predict which of these patients with precursor states are going to develop multiple myeloma is everyone that are just a part of the patients and in what time because we want to prevent symptoms of course but every treatment has side effects and we don't want to harm a patient if you won't get sick or or it takes years to get sick so when will we treat when there is benefit this is a graph with only y-axis the probability of progression when a patient has an angus or a small ring multiple myeloma the higher the line the higher the chance of developing multiple myeloma in time this is years five years ten years 15 years and as you can see for an angus patient there's approximately one percent of the patients a year who develop multiple myeloma so when you look at that one percent a year then you can say the majority never does develop multiple myeloma so we should not treat angus because then you give them the side effects of the treatment and most of the patients won't develop multiple myeloma do not harm only when the amprotein itself but these are exceptions is causing problems but what about the small ring multiple myeloma because you already saw the other line and this is steeper so after 20 years here you can see that after 20 or 80 percent of these patients have developed multiple myeloma so here it's not a story but can we know which of these patients will develop multiple myeloma in a short time and does it have any benefit yes it has because these are high-risk small ring myeloma patients in reds the patients who are treated in blue the patient who did not have any treatment like we do it normally and then you can see how long they have progression for your survival but also the overall survival how long will these patients live and when you treat them the high-risk small ring myeloma patients then their progression for your survival is better but also the overall survival so the time they respond they don't have any complaints is better but also they live longer so it's really important in this group to know which patients we have to treat after five years after a patient has small ring myeloma he has 10 percent chance a year thereafter after he is known with small ring myeloma for more than five years then the curve is less steep so then the chance of developing multiple myeloma is is less big so we should define these patients to treat them sooner than waiting for the criteria because we would like them to protect from renal failure or bone disease now do we protect how do we predict it well I already told you this is an amprotein disease the free life change 20 percent of 30 percent of the patients only have free life chains and a lot of patients do have an amprotein and free life chains we measure them a diagnosis so we measure the amprotein level but also the free life chains and then the free life chains are really high higher than hundreds then you can see this is the chance of developing multiple myeloma for the patients which small ring myeloma will have a free life chain ratio higher than hundreds it's significantly higher to develop multiple myeloma then when it's low so you have a big risk of 72 percent in two years that these patients have multiple myeloma that's such a big risk that we're going to treat these patients nowadays already the same whole rule when we do a bone marrow sample and we see a lot of safe plasma cells in in the bone marrow more than 60 percent then there's not anemia or something yet but we know that the chance that the patients develop problems is even 95 percent in two years so we're going to treat these patients that's the that's already what we do now in europe and america all over in our guidelines and the last new thing is the MRI so if we know a patient has small ring multiple myeloma and he has no osteolytic lesions on CT we make an MRI and when we look at the MRI and we see more than one full collision on the MRI and other way of looking at the bones then also there's 70 percent chance that each patient will develop multiple myeloma in two years and that chance is so high that we say nowadays it's not only with crap criteria that we're going to start treatments so not only with hypercosmia, renal insufficiency, anemia or bone lesion but also these other criteria are important so the bone marrow the plasma cell percentage over 60 percent high levels of pre-light chains of more than hundreds and more than one focal lesion on MRI so we look at this a diagnosis and even if there are no crap criteria but one of these symptoms are there we're going to start treatments so the definition of small ring myeloma is a little bit changed now because more than 60 percent already treatments already multiple myeloma and of course you don't have a small ring myeloma if you have also amyloidosis because that's also a reason for treatments. What is amyloidosis? Actually you have a lot of forms of amyloidosis but we're going to talk about AL amyloidosis for the patients who are listening with AL amyloidosis we're going to start on that topic now there are patients with multiple myeloma we also have amyloidosis but there are also a lot of patients who only have amyloidosis it's a protein misfolding disease so the proteins the sick monoclonal plasma cells are making because it's also a disease of sick monoclonal plasma cells but in this case they're making proteins who are misfolding and making fibrils long fibrils and these fibrils are going to organs and and cause problems in the organs when we when we go to the AL amyloidosis then the the protein which is causing the problem is the free light chain the free light chain is there but it is making these sick amyloid fibrils and these fibrils are going these are dangerous they are going to the organs and they are causing organ dysfunction and because organs are not functioning normal animal animal the patients get sick 76 percent of the patients with AL amyloidosis have heart involvement and of course we do need our heart very much and 68 percent of the patients with AL amyloidosis have kidney involvement also liver can be involved the gastrointestinal tract soft tissues like the skin and also the nerves so peripheral nerves or the autonomic nerves but most patients do have heart and kidney can we detect them in time with a heart there is a failure a measurement anti-pruobaline p-colds and that's a sensitive marker of myocardial dysfunction in AL amyloidosis here you can see a graph with a level of anti-pruobaline p on the left patients with AL amyloidosis with cardiac involvement on the right the normal failures and a significantly higher in these patients even before symptoms that's really important so there are patients who are not symptomatic yet they have an amgus so if we know patients have an amgus then we should check for the anti-pruobaline p because it's important to detect AL amyloidosis in time before there are any symptoms of the heart and the other thing an other early red flag you can call them next to the heart is the kidney so when the kidney is damaged then it loses proteins also albumin so when you lose a lot of albumin proteins in urine and we can measure that then it's a sign that then you have a suspicion that there might be amyloidosis so that's why patient doctors especially Dr. Malini and Paladini who are walking in Italy the whole life already with patients with AL amyloidosis stayed very much to other doctors and patients please patients with an amgus and an abnormal pre-life chain ratio should have also tested on the biomarkers for the cardio function and the renal function with anti-pruobaline p and albuminuria because of this research we do that and we can detect amyloidosis patients earlier and that's really important so when should inhomatologist think about amyloidosis well of course with the amgus and the anti-pruobaline p and albumin in the urine of course but what are the symptoms we should think of AL amyloidosis well for example when a patient has a fair fatigue and unexplained weight loss these can go together with a gastrointestinal tract for example lack swelling due to the proteinuria also carpal tunnel syndrome especially when it's on both sides so then patients have complaints in the fingers they're not feeling or have thinsals in it also patients with peripheral neuropathy so when they have a sensory loss in their foot or in their hands not because of treatment or because of diabetes but unexplained autonomic neuropathy so that means at hypertension when you're standing or a rectil or bladder or bowel dysfunction and also with hepatomagallate so when your liver is really big and we don't have an explanation for it then we should think about amyloidosis and test for it what is the test well first you have to think of it of course then you can do the biomarkers like the freelike chains and the anti-proven pee and the albumin in urine but then you can search for the amyloid fibrils a place where we'll have a lot of amyloid fibrils is the abdominal fat so we can take some of the abdominal fat and we can color for the fibrils if there is some amyloid in it and we can also color the bone marrow sample if there is amyloid in it and together it has a sensitivity of 90 so if you think of it then you should test it in the abdominal fat and in the bone marrow and of course you can check the organ which is involved like the kidney or the heart or the nerve or the liver you can take a biopsy about it in that organ and color it for amyloidosis so that was about the diagnosis let's go back to multiple myeloma treatment for multiple myeloma and amyloidosis uses the same medication not in the same exactly the same way but the medications are more or less the same because you're treating the sick plasma cells the sick plasma cells is the cause of the problem in multiple myeloma and also in amyloidosis only in amyloidosis the freelike chains are making the fibrils and there's also a problem with the gathering of these fibrils in the organs when you get rid of the sick multiple myeloma cells then you're treating both diseases to multiple myeloma any amyloidosis fortunately the improved the survival multiple myeloma patients have improved very much and here you can see a survival curve a graph with on the y-axis the survival on the x-axis the time in months and then you can see here that for years there was not that much improvement but when we look in the 90s to the 2000 years then there was a big improvement in survival the this red one and it was because of the the development of high-dose malvalent and then we needed the otology stem cell transplantation because when you give high-dose chemotherapy to a patient then not only the plasma cells are bothered but also the the normal cells are bothered so to to have the healthy cells back we give the otologies stem cells to the patient after the high-dose chemotherapy the high-dose malvalent and then the healthy cells recover but the multiple myeloma cells suffer and you can see the second big shift in the overall survival line is after 2000 approximately and this is mainly because of all the novel Asians for multiple myeloma and here you can see 1814 like we started the first documented case with multiple myeloma we didn't know what to do we gave the patient rabab and orange peel steel quinine it didn't work and it stays for years that we tried a lot as doctors but there was not really helping for the disease it took until 1950 then there was malvalent a classical chemotherapy it was low dose at that moment it worked but when they discovered in the 80s 90s that you can give it also as a high dose and then with an otology stem cell transplantation there was a real shift in overall survival as you could see in the prior slides and the development of the novel agents like teledomide, potassium, lanolinamide these are not chemotherapy but these are medications who are walking directly or more directly on the multiple myeloma cells and also working on the immune system of the patients a little bit shaping the immune system which is actually not favorable for multiple myeloma cells and that's working very good especially when you combine them and after these novel agents there are even newer novel agents second generation for the third generation and there are already we're newer medication I will a little bit tell you about that in the sake of time I can just tell I can't tell everything unfortunately but but I will of course tell you something about it and what's really important that with the development of the new medication when you look at survival it was a little bit increasing with the chemo therapeutics with supportive care but with the new medication there's really a good advance in overall survival so how do we use them how do we use all of these medication now well these are the as well guidelines for patients who can have a transplant so the high-dose mouth blend and the otology stem cell transplantation these are all European doctors and multiple myeloma doctors writing these guidelines together also in our center we're working with these guidelines and writing with these guidelines and the frontline treatment for transplant candidates or patients who can tolerate high dose chemo therapeutics and otology stem cell transplantation so the younger patients are first treated with these newer agents with botasomib, teledemide, lanalidomide combined with botasomib, dex medicine, these induction regimens so a few cycles and we combine different combinations of these newer agents and after four to six of these cycles the multiple myeloma is responding and then we go to the consolidation phase so to the high-dose mouth blend and the otology stem cell transplantation to treat it even better so when the multiple myeloma is very low then we go to the high-dose mouth blend and the stem cell transplantation to keep it away as long as possible thereafter after that otology stem cell transplantation nowadays since a few years we offer the patients lanalidomide maintenance so when you offer the patients a maintenance treatment it adds to the progression pre-survival so when it adds to the time that the disease is responding before it's coming back but it also adds to overall survival how long the patients is living so this is more or less the standards in whole europe we give induction cycles to lower the burden of disease thereafter we do consolidation therapy with high-dose mouth blend and stem cell transplantation thereafter lanalidomide maintenance this is for the patients who can tolerate high-dose mouth blend and otology stem cell transplantation of course we always have questions because we always want to improve so are we now with an optimal induction regimen or can we further improve do we still need the high-dose mouth blend and otology stem cell transplantation because there are newer medication newer novel agents if we combine them do we still need the high-dose mouth blend and stem cell transplantation right away a diagnosis or later on at relapse once or even twice some countries are doing that also in the Netherlands for high risk before but for example do we need consolidation therapy so like there are there are countries working with induction regimens induction cycles and after the stem cell transplantation they repeat two or four of these cycles if we call it consolidation is it really necessary or not can we improve it if we use it and is the maintenance optimal now is it only lanalidomide is it for every patients how long will we give it can we adapt it when the patient have a real deep response while these questions are all questions who are in research like all the lessons we have learned in the past we did with research and we're continuously performing research to further optimize the treatment and to further improve prognosis of our patients and fortunately there are newer kits on the block like newer generations of the lanalidomide telidomide like pomalidomide newer generations of botasmic like carfil's mib or excessive mib but also antibodies and these are really new what's an antibody well in FOMA for example we already had them for other solid tumors we had them for years but we didn't have them for multiple myeloma so there was a search for it what are antibodies they're like a flag you give it intravenously or subcutaneously to the patient and they're like a flag to who is marking the tumor shell and when it's on the tumor shell then your own immune system recognizes the tumor shell and can kill it you need something to bind on the the flag has to stand on something on the multiple myeloma cells there are some of these markers but we had no monoclonal antibody for multiple myeloma for years but recently since a few years we do have and especially monoclonal antibodies against CD38 on the multiple myeloma cell and against CS1 on the multiple myeloma cell are record carry used now for frontline treatment even but especially nowadays in the relaxed setting it's moving to the upfront setting and the most well known and most used one is there a tumor map which binds to the CD38 on the multiple myeloma cell the flag on the CD38 on the multiple myeloma cell here you can see it multiple myeloma cell here's the flag and because of this flag the normal complement which is in the body the normal macrophages which are cells of your immune system the normal NK cells can do their job and kill the tumor shell they are there but they need the flag to do their job also direct to them up can kill multiple myeloma the cells so there are more working mechanisms than just one and they can modulate the immune system the T cells of the of the patients so T cells are normally working the two viruses malignant cells but in multiple myeloma they're not working that well but when you improve them then they can function better and they can kill the multiple myeloma cell so it has multiple working mechanisms and we're very glad that we have monoclonal antibody therapy now also for multiple myeloma what you can see here is that even as a monotherapy so only the the direct tumor map is giving response to one approximately one third of the patients normally you don't give an antibody and you can give it as a monotherapy but normally you would like combine antibody therapy with other agents and that's also what we do a lot for multiple myeloma and then you can further improve then it works together and then it works synergistically together and that means that one and one is not two but even three so the monoclonal antibody can work synergistic with other medications given for multiple myeloma and then it works even better and this is the example of a combination of deratumumab with lenalidomide these are the response rates on the left for the patients treated with lenalidomide and the deratumumab 94 percent of the patients are responding versus patients treated with lenalidomide 77 percent of the patients are responding so you can further improve response rates but also the duration of response how long the patients are responding that is what you can see here in this graph the time the patients are responding and alive notice sorry the percentage of patients who are responding and alive and here's the time on the x-axis and the higher the line the longer the patients are responding and alive and for the combination of deratumab and lenalidomide this line is much higher than the line for only lenalidomide so the combination really improved and really benefits the patients there are also so these slides just to tell you there are also other monoclonal antibodies and also these antibodies are working together with our therapies and are also options to treat our patients with like allotuzumab which is binding to CS1 on the multiple myeloma cell it has no single agent activity this one so you have to combine it you have to combine it with other agents deratumab you can give it on its own so what for our patients who can't be treated with a transplant because they are not that fit and they can't have they can't tolerate high-dose gamma therapy well the doctor who started with transplant said well everyone is transplant eligible but that's not completely true it's not at least it's not that black and white and it's also not the case that 65 years of age is the limit per se also all the patients can be very fit and can be and can have benefit of a stem cell transplantation although you have to select these patients because then the less fit patients will have more problems will more have side effects and we can also lose these patients because of the high-dose malcaline and stem cell transplantation sometimes they don't survive the treatment so we have when a patient is older they can benefit a stem cell transplantation but we have to select these patients very well and that's what we do nowadays but are there also other options for these patients yes there are for years in Europe we used potassium and malvaline pregnancy so a tree drug or linolyte linolytomydexamethasin and that worked very well but of course also here we want to improve and how do you well you can combine it with daratumumab for example the monoclonal antibody and that's what we do with the VMP combination and the RD combination which we used for years one of these two both of them in trials are where combined with daratumumab and they proved better the combination so daratumab is already approved by AMA and reimbursed and it will be a matter of time and that will also be the case for daratumab linolytomydexamethasin you can also combine the botasmic with the linolytomyde and you can also make even a quadruplet so that you even add the daratumab to botasmic and linolytomyde these are still studies so this is not current treatment we have to await for these results but here you can see the results of the patient's freedom with daratumab linolytomyde versus linolytomyde and there you can see the same curves so in the higher the line the longer the patient's response and the longer they live and for the combination with daratumab linolytomyde the line is far above the yellow line so it adds for the patients also for the elderly patients to treat them with the combination this is upfront treatment so newly diagnosed elderly patients treated with the combination of daratumab linolytomydexamethasin versus linolytomydexamethasin and the counterpart the other the FEMP combined or not combined with daratumab is giving the same scheme so the FEMP like we did in the past or combined with daratumab and then you can see the same picture in purple the patient's FEMP combined with daratumab in orange the patient just with FEMP and also here the line is much higher so the patients are benefiting the combination with daratumab they are living longer and they are longer progression free so what if they relapse then we should look what was their prior treatment what were side effects what's the age what's the general health are the comorbidities of course but then we can get another combination than that the patient had before with botasamid we can combine daratumab for example but also other medications and lutetiumab was the other monoclonal antibody for example and combinations always do better than just one medication when they cooperate together that's what the same old truth patients who were treated with botasamid first and are treated with linolytomydexamethasin that relapsed when you combine the linolytomyde with daratumab we have already seen that's better but the same holds true if you combine it with the proteasome inhibitor the next generation botasamid carfilismid for example or exasamid the oral variant then it's better than just the linolytomyde itself and also the linolytomyde is combined with lutetiumab the other monoclonal antibody so normally we switch class was patient treated with linolytomyde before then we go to the proteasome inhibitor and we make combinations as long as that's possible because combinations do better and normally especially with daratumab when you add it to the regimens then there are not that much more side effects because it's also very important that the quality of life is very good and side effects are more or less the same when you add daratumab to linolytomydexamethasin as the side effects are with linolytomydexamethasin so that's also very important point going back to the AL amyloidosin looking at the time i think we should go a little bit faster because for the amyloidosis we use the same medication melphilandexamethasin was of course the first at the low dose and we also tried etiology stem cell transplantation it works for amyloidosin but for the patient with severe cardiac or renal failure it's dangerous so we should select the patients very good also here the new medications like botasamid combined with cyclophosphamide an alternative for melphiland and dexamethasin improved versus melphiland dexamethasin so also here there are newer regimens, newer combinations will improve response rate and progression pre-survival and more tolerated very well and when you look at the advices also from Malini from Italy then you can see for the patient who are transplant eligible which is a smaller part in amyloidosis because of the cardiac and renal function only 20% of patients can have a transplant but when they have then we give them cyborgy, the botasamid cyclophosphamidexamethasin or botasamid dexamethasin if necessary especially when the plasma cells percentage is high then the etiology stem cell transplantation and we just give them consolidation or maintenance if the response is not that good however when patients do have cardiac especially severe but also moderate cardiac dysfunction and renal dysfunction then we treat them with cyborgy longer but no transplants but also other all the regimens are regimens we still use and as more advanced the patient is the less optimistic it is for the survival so we would really treat these patients in time also for the amyloidosis all of the newer agents are in clinical trials also for amyloidosis and also benefit these patients and especially here in red the diratumab the monoclonal antibody doesn't have that much side effects but has tremendous response rates there's also here the monoclonal antibodies especially the diratumab is moving into the amyloidosis which is really beneficial for our patients and one remark I would like to make is that also doxycycline for the al amyloidosis patients is added especially for the cardiac involvement it's an antibiotics actually but the patient who are treated with it do it better in survival and that's because in all the treatments for amyloidosis the the the the clonal plasma cells are treated but we don't treat the amyloidosis which is in the organs the body itself has to clean it doxycycline seems to work seems to help cleaning the amyloidosis in the organs the fibrils still studies are ongoing but certainly for our cardiac patients with amyloidosis we give them doxycycline because of these curves so what are the newest developments the newest developments are T cells I already told you there are different parts of the immune system and T cells normally do have a function for viruses like coronavirus for bacteria but also for tumor cells however in multiple myeloma, multiple myeloma paediatric actually in every malignant disease they feel they should do their job but they don't clean it because this disease is there the cancer actually escapes to the T cells by different ways because normally when a T cell is binding to a tumor cell it's making granules and then the tumor cell is going to die and this we can make T cells of patients theirself we can take them out of the body change them a little bit and gave it back for patients with ALL and for certain forms of lymphoma and it works not for every patient unfortunately but for a lot of patients with ALL it works we can even cure them within relapse disease so of course we're really thrilled that we can do these things also for our multiple myeloma patients now it's just in research but we're making progress and that's really important we make it getting the T cells out of the patients we're giving them some extra tools in the laboratory so they can recognize the multiple myeloma cells better and kill the multiple myeloma cells better and then we have given them these armitarium then we're giving their own T cells of the patients with this extra back to the patients and then it's going to do their job that's the ID and in clinical studies only but in clinical studies we're treating patients with CAR T and a lot of what you can see here in this table you don't have to go into detail but what you can see is there are not that much patients treated yet of course this patient number is growing because of the clinical trials we're running worldwide and also in Europe but we can see tremendous responses in patients who have been heavily treated so that's great unfortunately in almost all of these patients there are relapses but the time of response is really tremendous for patients who are happily treated so there is really hope also for this new treatment and what's also a message is that there's not only CAR T for this T cell or immune treatment there are also by specific antibodies so there are also other treatments who are who have the same goal to improve the own T cell function of the patients against the multiple myeloma cell so for the future immune therapy will be important in the course of the disease it will also move forward if it works in the in the relapse setting then it will go to the upfront setting and of course these are CAR T's but these are all so by specific so antibodies who are binding as well as the multiple myeloma cell as well as to T cells bringing them together and also other forms of immune therapy and then I would like to end with an optimistic view we hope that this trend of improving survival for our patients will further develop with our new treatment options and will it maybe let's say will further improve the the the the survival rates will be really great and especially when it when it comes when it comes with a good quality of life of course that's our goal and this is the point when there are any questions left maybe thank you Dr. and I have this wonderful presentation and now I will going to open the floor for questions just quickly remind you that there are two ways to ask questions one of them is using the microphone as I'm doing right now and as they play to the doctor to do that just click the right hand button so you have any question you just going to start in clicking and the other way is to send their question in the in the chat window so I can receive them and and read them to the doctor one of the questions that we already received is you mentioned there are myeloma treatments in clinical trials for ielomaidosis when can we expect any of them to be approved and well it's going faster and faster I would say and that's because of the cooperation between countries and and also between continents so the CAR-T studies for example are running in Europe and also in the United States and it I told you it's a rare disease not that rare for myeloma doctor for a patient of course but it is a rare disease but when you cooperate then you can treat in a short time a lot of patients with these new promising treatments and then you have sooner the answers are they working like you hope so like you hope to and are they having also really the benefits so also the side effects of course are really important the how they walk but also the side effects and when you know that when when the treatment is really better benefiting the patients then you can offer it to to the authorities and then they then they will approve it and thereafter there is reimbursement so the insurances of course have to have to have the arrangements how to implement it but these tracks are faster and faster as we are working more and more together thank you doctor we have a couple of hands in the panel so first of all of them Ilydeo Arisi you can ask your question now Ilydeo not sure if you are can you hear us well it seems he's not hearing us so with the second question Hans please Hello this is Hans Schurro from the Netherlands I have one question according to the induction stage the treatment of myeloma at the moment in most cases VCD or VTD is given as a pre-chemio for before auto stem cell transportation but I was wondering will VRD so with a reflimid replace this and is there a role for daratumum up in the in the induction stage yes really good questions and I just was brought on this one with a slide that we are going we're trying to improve this well VRD has never been randomized against VTD and VCD and that's the problem for the authorities because they actually need randomized trials to say if it's really better or not when we compare the studies then we see that maybe the response rate is a little bit better or at least comparable however the tolerability for linolytomite is better that's why we would like to use VRD now instead of VTD but it's not approved so we cannot do that at least not in Europe it is approved in in America so there is there is possible but because of it's more or less the same in the response rate it's not approved yet however studies are running because we would like to approve we would like to offer the data to the authorities to get this approved and also studies are running for the combination with daratumum up as well as with VTD as well as with VRD and these studies are not that far that it is approved yet but it will just be a matter of time thank you very much very much doctor I can see you did your hands again rising so I let's try again well it seems there are some technical questions so I just suggest you just send me your question by by writing and then I will ask the doctor another question that we have here is it is expected that treatments that we have now in relapse setting are used in their in earlier phases of the disease could that mean more efficacy exactly exactly when when you treat the patients when they have newly diagnosed disease then they are then they have the best chance of responding deeply and longer so when you give the best shot at the beginning then the patients have the best benefit of that regimen but of course when there is a new medication you should first know for sure because you start in the laboratory you start with multiple myeloma cells in laboratory you start with mice research and then it's going to translate into studies when you have really good good treatment because the treatments are already very good when you compare it to 20 years ago for example but when you have new treatments you should first prove that they are really working there are and that they are safe so that they are not having that much side effects indeed and then thereafter you have to prove that they are better so it takes time but like I said it's going faster and faster because we're doing a lot of studies always with the intention to improve the treatment and we're working together thank you very much next question the combination of therapy is mostly lenalidomide when lenalidomide is not possible anymore because of side effects are there alternatives for lenalidomides or should you continue with monotherapy no well sometimes when you that's not tolerate a certain regimen then you can not give it to the patient because of course the quality of life is also is maybe even the most important and so you'll have to anticipate on that there are newer generations in it so pomalidomide for example which is given less polyneuropathy it can also give other combinations with possibly less polyneuropathy so then that that was the slide where I tried to say when you have relapsed disease for example you'll have to take into account how has the patient treated before but also these side effects is he are there any comorbidities and then you adapt the treatment and that's fortunately possible because we have options thank you very much next question what could you say there are the main challenges in myelo mind the upcoming years well there are a lot of challenges as long as the disease is not curable we would certainly search for that and for now on for now still up till now I mean high-dose mouth lenanthology stem cell transportation is a standard care treatment but it's also a happy part of the treatment we would like the treatments so good that we don't need it maybe anymore or or spare it for the future but also there are very how do you say well we have it's not only having new treatments it's also showing to the authorities that they should approve it and also to the insurance the reimbursement and of course with all these new treatments patients living longer with myeloma but also living longer in general so needing more treatments and all these treatment options are also very expensive there are also some problems maybe in that and we should take care of that with each other also thank you doctor next question cortisol therapy is one of the most promising treatments in myeloma but clinical trials are done in a small number of patients when can we expect to have them close to the clinical practice or in the clinical practice yeah because of time I couldn't go into depth into the CAR T for ALL so the acute lymphatic leukemia and lymphoma we are further with it but it's working a little bit better there so there are a big part of patients who are cured when we give that treatment when we give to multiple myeloma patients that's the same for our other treatments up till now we can give them time and we can really give them deep responses but we can't cure them yet and so there is improvement necessarily also for CAR T but there are a lot of clinical studies now also randomized phase trials because you start with phase one trials a low dose then you start with phase two trials then you give it to more patients in the in a beneficial dose so you know what was working but also what's safe and they're after the phase three trials and then you're randomizing against another treatment and you need that because you have to prove that it's better and that it's safe and that you can only prove if you compare it to the good regimens there are so that's the these studies we need and these studies are running thank you very much next question how long can a patient remain on maintain maintenance therapy linoleumite in this case till progression or should the maintenance be stopped at some point yeah that's also a research question actually and we give it up until progression in our guidelines because that these this was done in most of the studies and this was where the beneficial where the most proof is that it's beneficial but that's because of the design of the studies and now we're going now there are other studies looking at when we look at really deep responses can we maybe stop stop it maybe give it back if the responses less deep for example these are questions because when you take medications for years for example then sometimes there are more side effects and is it necessary to treat all patients the same or other specific sipsets who benefit from continuing and other specific sipsets who can stop and we don't know this yet these are also research questions thanks doctor we are running out of time but we have time for the last question could CAR T therapy work also in the L amyloidosis that's a good question and it's not right in amyloidosis as far as I'm aware of that's also because I didn't go into the side effects now but but also CAR T has side effects especially when you gave it to the patient the first few weeks we see side effects and especially a cardiac amyloidosis patients may not tolerate these side effects but we don't know yet but when you look at the deratum map and all the other medications for example they benefited the multiple myeloma patients they benefited the amyloidosis patients this one you look at that way I guess also the CAR T will benefit but it has to be safe too so also there we need trials thank you very much doctor thank you very much for this interesting webinar and just remind you all that this webinar has been recorded and will be available in the mp website which is www.mpurot.org and will be available also in our youtube channel thanks again doctor for for your help and your collaboration with this webinar and have you all a nice evening thank you nice evening too for you too