 Okay, good morning. Good morning to all our cameras. I'm Ron DeLumi, board member of AMAN Israel. We'll open this morning with a session about updates on current diagnosis and treatment. The session, we are honored by the presence of Dr. Sonia Siegman. Dr. Sonia Siegman is the head of the department of hematology in Amsterdam, VU Medical Center in Amsterdam. Dr. Siegman will guide us through how myeloma and other related diseases such as allameiodosis are currently diagnosed and treated. The session will last until 10 o'clock. We will leave time for questions and answers at the end of the session. Without further notice, please, Dr. Siegman, the floor is yours. Good morning. Well, thank you very much for this kind invitation. I'm from Amsterdam. This is our research building. I'm working in close collaboration with Hank Lokhorst and Niels van der Donk and Ingenayov and they will be happy to be later in future meetings with you here. I want to give a short update on the current diagnosis and the treatment of myeloma. Of course, I will leave amyloid to Professor Malini because he knows much more. I have some false slides as a muse and then Professor Malini will talk on that later. The things I will discuss are we diagnosing multiple myeloma earlier than before and therefore treating also earlier than before. I want to talk about the treatment of the younger patients who are transplant eligible, the treatment of the older patients who are in general not transplant eligible, what to do when the disease relapses and also a short notice on the novel developments but that will also be later in the program. So I will have only a few slides on that and a few slides on amyloidosis. So the diagnosis of multiple myeloma earlier than before. So there are now novel criteria for the diagnosis of multiple myeloma and they appeared in the end of 2014 and that leads to an earlier treatment. So there were patients with asymptomatic multiple myeloma whom we did not treat and now we start treatment earlier already. And that is of course to prevent the symptoms of especially bone disease. Probably you know this picture. It's one of the first patients that has been described in the literature in 1844 and you see here the devastating effects of bone disease and especially you and the doctors want to prevent the development of bone disease and you would like to treat earlier in time. On the other hand, when you do the oath as a doctor, the first thing you promise is to do no harm. So when you start treatment earlier, you all know that you will experience side effects of the treatment. So you should have a benefit from the treatment which is more than the side effects that occurs during the treatment. And what we did in the past, only when there were crab symptoms so when you had a high calcium, renal failure, anemia, bone disease, you started treatment of multiple myeloma. But actually from a Spanish investigator group, so the Petima led by Dr. Marivi Matheus and Dr. Jesusa Miguel, they started to treat patients with small ring myeloma, so patients without any symptoms. And they started to treat those patients with lanalidomide and dexamethasone and the other half of the patients were not treated. And what you can appreciate from these curves is that when you start treatment here, the blue line, you see that the progression of the disease is less than when you give no treatment and you would have expected that because when you start treatment, you will delay the development of the symptoms. So every time a patient develops a symptom, the line goes down and here less patients do develop symptoms than when you give no treatment. But the other even more important observation was that when you started treatment earlier, also more patients did survive. So the overall survival was also better. So you did not only delay the disease symptoms, but patients also survived longer. And that was actually very important because then the benefit-risk ratio is very positive. So then we asked ourselves should we start earlier treatment and in whom we should start because not every patient with small ring multiple myeloma will develop symptoms in short notice. There are also patients with small ring myeloma for years, not developing symptoms and you wouldn't like to treat these patients. So what actually is small ring myeloma? How we diagnose small ring myeloma? So whenever you have more plasma cells than 10% in the bone marrow or end, your end protein level is high and you had no crap, you would say this is small ring myeloma. And 8 to 20% of the patients who have a diagnosis of multiple myeloma have small ring myeloma, so no crap symptoms. So what is the natural cause of the patients? So when you look to these patients with small ring myeloma, how the natural cause is? So here you see the patients with small ring myeloma and the risk of the chance to develop multiple myeloma. And what you can appreciate from this slide that in the first 5 years patients have 10% risk to develop multiple myeloma. But after 5 years the risk is less than it's 3% per year after 5 to 10 years and thereafter only 1% of the patients do develop multiple myeloma. So whenever you don't develop multiple myeloma in the first 5 years there's a, the risk to develop multiple myeloma later on is lower. So who are these patients? As a doctor could you predict which patients will develop multiple myeloma with symptoms short notice, in short time because these patients you would like to treat to prevent the development of symptoms. And actually what we did in the myeloma community we said whenever we are able to predict who will develop multiple myeloma in 2 years with a 70 to 80% risk those patients you would like to treat early. So when in the first 2 years 80, 70 to 80% of the patients would have developed multiple myeloma then we would say these patients you really should treat because the benefit-risk ratio is positive. You will have more benefit than risk. So there's several methods to now predict whom will develop multiple myeloma with a 70, 80% risk in 2 years. One is here you see the normal immunoglobulin. So every normal person has antibodies in his or her body in order to protect against infections. Patients with multiple myeloma you know probably have a monoclonal and protein. So only one type of immunoglobulin and the immunoglobulin consists of 2 heavy chains the orange bars and 2 light chains. So what you can see in patients with multiple myeloma that they have an M protein which is increased which sometimes is the whole M protein so both the heavy change and the light change but some of the patients have an additional production only of the light change and when you look to the light change you could have a look to the free light chain ratio so the kappa and the lapda ratio so because you have 2 types of light chains kappa and lapda and whenever the ratio is abnormal you know that these are monoclonal. Now when the ratio is more than 100 so the malignant chain either kappa or lapda is 100% higher than the normal chain and that occurs in 15% of the patients you have a 72% risk to develop symptoms in 2 years so now we don't only treat patients with crap symptoms but also patients without symptoms but with such a ratio of the kappa and lapda change we now start to treat those patients already before the development of symptoms that's also applicable to the patients when you do a bone marrow and you look how many malignant plasma cells are in the bone marrow the patients who have more than 60% of malignant plasma cells in their bone marrow so depicted here are the malignant plasma cells when they're more than 60% in the bone marrow 95% of the patients will develop symptoms in 2 years so whenever you perform a bone marrow and they're more than 60% of plasma cells and they're no crap symptoms now we start treatment already in those patients because almost all the patients will develop multiple myeloma in 2 years some of the symptoms are really devastating like bone disease or renal failure so we start treatment already well the other thing has to do with a football player we have a very famous football player in the Netherlands which is Johan Cruyff who happily deceased but he had very specific remarks and one of his statements was you only see it when you get it and I would say in multiple myeloma that might be too late and now it comes to the next slide because you probably all know that we have several techniques to investigate bone disease and when you investigate bone disease with a classical x-ray like here this is just a perfectly normal classical x-ray of a patient and as a doctor you would say to the patients you don't have bone disease nothing the matter but when you do an MRI of the same patient you can see here that there's a myeloma lesion so you would have said no bone disease when using classical x-rays but when you do an MRI you would say to the patient you have myeloma bone disease and when you perform either a CT scan which is the only the bony structures without the colors you could already observe here also a lesion which is the same lesion but when you also add a radiolabeled sugar you can even see that the lesion is also active so when you either perform an MRI or a CT scan your sensitivity to detect bone disease is much higher and when you have bone disease you would like to stop that and start treatment so that's the third reason now to already start treatment in patients without crap to the classical definition whenever you have an MRI not with one but with more than one focal lesion 70% of the patients don't have symptoms in two years so also these patients are now being treated and that brings me to the crap criteria so we don't only treat patients now with crap, with the classical symptoms so hypercosemia renal failure anemia, bone disease but we will also treat patients now with plasma cells more than 60% in the bone marrow MRI more than one lesion and an epilepsy ratio which is higher than 100 because these patients will develop symptoms in relatively short time there's one other thing I know that in many countries there's no access to the CT scan but actually we would favor to do CT scans in every patients who comes to the clinic because of the suspicion of multiple myeloma because when you look to the CT scan and you would observe an osteolithic lesion like this which you won't see with a classical x-ray you can already observe from here that it is very important to treat this patient because this is already maybe collapsing in several months and you really would like to prevent that so whenever there's an access to a CT scan we would like to do a CT scan in every patient with the suspicion of the diagnosis of multiple myeloma it doesn't need to be a PET CT scan a PET CT scan costs approximately 1200 euros maybe in some countries the price is less but approximately 1200 euros whereas just a plain CT scan is approximately 200 euros and it's also more convenient to the patients so when you have your classical x-ray some of you will know you'll have to do 12 photos which is rather complicated and a CT scan is being done in 2 minutes and in most countries it's not more expensive than just classical x-rays so we would favor to do a CT scan whenever you see one lesion of more than 5 mm you would start treatment already whenever you know everything I tell and you want to proceed faster please let me know so now we have patients who were diagnosed at small ring myeloma a part of these patients we now start treatment earlier because of the high plasma cell level FLC ratio or MRI so still there are patients with small ring myeloma and should we treat those patients and those patients we don't know yet so I think it's very important to promote young patients who participate in clinical trials and so we will know whether other patients with small ring myeloma with other characteristics than I showed here will also benefit from earlier treatment so and there are several clinical trials now going on in Europe in order to learn more about that so that about the new criteria which are now implemented in the clinical practice so the treatment of younger patients being transplant eligible the current standard of care in many parts of Europe and I know Europe is very diverse but when you would have had access to these drugs you would like to start with Bortezumib, a proteasome inhibitor which I think is necessary in all induction therapy for patients who are younger and transplant eligible plus either thalidomide or cyclophosphamide I think the French have shown that thalidomide is superior so you would like to give thalidomide and the Italian colleagues did a retrospective case analysis also showing that thalidomide is somewhat better than cyclophosphamide and dexamethasone and then you perform a stem cell transplantation but when we have the proteasome inhibitors available the Bortezumib and the imids the thalidomide the results were so good the complete remission rates were so high they were approximately the same with what we used to reach earlier with stem cell transplantation so then there came the question in the multiple myeloma society do we actually still need a etologist stem cell transplantation or could we only treat with the novel drugs well there's several trials I will show a lot of abbreviations I'm sorry for that but there are so many drugs so it's good to have many abbreviations because we have so many drugs available but V is Bortezumib that's because it's Valkate K is Carfilzumib Chiprolis, Ixazumibacy so these are proteasome inhibitors I'll come to that later so V, K, NEI, the antibodies Darvatumumup, Ielotusumup so you will read in many papers Mara Illo the H-deck inhibitors so this is Dutch which is Spanobinostat the immunomodulatory agents the imids which are thalidomide lanalidomide, pomalidomide and we have of course Melphalan which is still being used and very effective cyclophosphamide, prednisone and dexamethasone but I will repeat whenever necessary so is a stem cell transplantation Italian study either an autologist stem cell transplantation or cyclophosphamide lanalidomide dexamethasone all patients receive maintenance treatment and when you now look to the progression free survival so the duration before the diseases relapse that's much longer when you perform a stem cell transplantation 43 months versus 28 months when you don't give a stem cell transplantation so you postpone the relapse very pronouncedly by performing a autologist stem cell transplantation so not only novel agents but novel agents plus a stem cell transplantation and also when you look to overall survival we can't say exactly whether that's better there might be a trend that also the overall survival is better and we will do meta analysis of many trials which have been performed in Europe because such a similar trial has been done in France also a similar design with almost exactly the same progression free survival in the transplant arm and in the non-transplant arm so a stem cell transplantation is of added value we performed a study in the Netherlands showing exactly the same the benefit of a stem cell transplantation and also the English the MRC performed a trial comparing just novel agents with a stem cell transplantation and again a stem cell transplantation was of added value so a stem cell transplantation is required and now we are even asking ourselves maybe even too because we did an Italian a German an Italian Dutch trial which was an EMN trial and Dr. Zonnefeldt at the latest Ash and the ESCO presented the data and when you look now to the patients who got two stem cell transplantations so you got novel agents one stem cell transplantation a second stem cell transplantation and then maintenance therapy you see when you look to the high risk multiple myeloma patients and the high risk multiple myeloma patients are the patients with specific cytogenetic abnormalities in their chromosomes not because it's an inherited disease but during the course of your life you develop abnormalities in your chromosomes and then you develop multiple myeloma and the patients with a abnormality on chromosome 17 so a deletion they lose a part the translocation between chromosome 4 and 14 and the translocation between chromosome 14 and 16 so they stick together these three abnormalities we know is very high risk in multiple myeloma and we know the outcome of those patients is inferior as compared to the rest of the patients now when you look to the high risk patients defined as I just stated you can see that when you perform two stem cell transplantations the delay of the disease of the progression is much longer in the patients you transplant two times here you see the curve for two times so you start with 100% of patients and every time there's progression of the disease the line decreases and when you look to the patients who receive two stem cell transplantations as compared to one stem cell transplantation you see that the progression free survival is here 26 months and here 46 months so a 20 month delay with two stem cell transplantation of the recurrence of your disease that's almost two years so we are now currently writing in the Dutch guidelines that when there's a high risk patient with cytogenetic abnormalities we would perform two transplant this is a very early analysis so there are some doctors saying well we'll have to wait maybe a little bit longer before to decide on that so it's an individual balance and you will discuss with your physician whether it's required or not but in general we are really discussing and thinking of two transplants in high risk patients so what about the maintenance therapy so we were not used to give maintenance therapy after stem cell transplantation but that was actually because we hardly had any medication to give us a maintenance therapy in earlier times and I even wasn't at practice we gave malphalan as a maintenance therapy but it was very toxic and it didn't increase the overall survival and the progression free survival was a little bit superior sometimes but sometimes not but here you see the curse with lanylidomite and a low dose of lanylidomite and in it most of the patients will will be able to continue that for a very long time and they will experience complaints like feeling exhausted diarrhea but diarrhea we have some medication for that and it's specific for lanylidomite I'll come to that later but here you see the maintenance therapy with lanylidomite and again the progression free survival is much longer so half of the patients will experience a relapse after 51 months and you have no lanylidomite treatment half of the patients will have developed a progressive disease already after 28 months so again postponent of the progression of the disease and it's not only the English trial also the Italian trials the French trials the Dutch trials have shown similar data and when you combine all these trials you see that the progression free survival is better but also the overall survival is improved so you will live longer with your disease using maintenance therapy as compared to having no maintenance therapy the only hesitation we still have is in the high risk patients whether the overall survival is better but also in high risk patients you will postpone your relapse so now we know that it's difficult to have these drugs available in every country for maintenance therapy but the EMA the European Registration Authority did state that there's a registration for lanylidomite maintenance therapy so that about the younger patients what about the further developments that is the incorporation of antibodies in the first line of therapy and I will come to that later so then about the newly diagnosed patients with multiple myeloma who are elderly and are not transplant eligible it's difficult to state whether you're transplant eligible or not there's a doctor from the USA which is Bart Barlogy and who states everyone is transplant eligible I'm not convinced about that whenever you're over 75 the toxicity will be much much higher so patients over 75 you would certainly not give an autologous stem cell transplantation but 65 was a very limited limit so now we increase the limit to 70 years of age we look through the we have an eyeball test and we think well this is a patient who can receive a stem cell transplantation but there are patients who are not transplant eligible and there are two standards of care in Europe either Melfland, Prednisone and Bortesimip or Lanylidomite Dexamethazone what about the last regimen should you give it continuously or only 18 cycles I think that's very important in clinical practice for patients should you have your treatment all the time or are you able to have a treatment free interval which might be very important because then you won't experience the side effects of the treatment now when you look to the latest update of the first trial and the first trial investigated Lanylidomite Dexamethazone continuously only 18 cycles versus MPT and what you can appreciate from this slide is that the overall survival is better with Lanylidomite Dexamethazone versus MPT so when you have Landex available you would favor to treat patients with Lanylidomite Dexamethazone but when you look to the overall survival there is actually no difference in continuous therapy or 18 so in general you could say only give 18 cycles then you have a treatment free interval you will have a treatment free a treatment holiday they say sometimes and you will have similar overall survival the only thing I would like to say is that when you have a very good partial remission or a complete response with this regimen then your next treatment will only be in 6 years when you continue Lanylidomite Dexamethazone so in many patients I see who have a very good partial response or a complete remission on Landex I would continue because these patients do very well on the treatment and they will have their next treatment only 6 years later so suppose you have a patient in front of you who is 76 his next treatment will only be when he is 82 and the next treatment will be a free drug regimen with many side effects so I would in general give 18 cycles patients with a very good partial response or complete remission I would continue the therapy is it possible also to give it in the very frail patients because many patients are older than 70 and even 80 when they are diagnosed with multiple myeloma and these patients mostly not included in the clinical trials so we don't know how these patients are experiencing the treatment so first what is frail we know actually frail is not age you have this is a very nice documentary which is the autumn goals and it's about the olympics for very elderly patients and this is in the category over 80 I don't know whether I will do that when I'm over 80 but of course we know we have also the over 80s who are like this and I heard Céry Loulin which is a hematologist from France once say and so this is blackade there are 50 shades of gray so it's difficult to say who is frail and who is not frail so we use now in general practice the frailty index so we look to age because over 80 really negatively impact the outcome we know that we look to the activities or daily living can patients dress themselves, bath themselves we look also to the instrumental activities of daily living which is can they handle their telephone can they do their finances and to the co-mobilities and the group of Antonio Palumbo in Italy has made a frailty index and it's not on this slide but it's very easy to do it online I can provide you the link later on so your physician can just answer all those questions then you get the frailty index and we know that the patients who have a frailty index of 2 or more we really should adapt the treatment and when they have a frailty index when they're unfit having a score of 1 you also should adapt the treatment so it's very easy to use in clinical practice and I'm quite interested in trying to predict frailty even more better so what we are also doing in the Netherlands is that we look to sarcopenia so to the muscle fat ratio because then when you have less muscle you might have more side effects because the pharmacokinetics of the drug is very different and we also look to markers in the skin that reflect biological age so we try to predict frailty more better even than with the frailty index but coming back to the French trial and MPT is it also feasible in the frail well we know that approximately 50% of the patients in the study were frails so quite a lot in this study this is not the best slide but when you look here you see the fit patients here the unfit patients here and the frail patients here you still see that the green line which is RD is in all the patients is better than MPT so whenever you can treat a patient who is frail with RD you would favor to give RD but when you look here to the fit patients the unfit patients the blue line and the white line we still have some steps to make for the frail patients because the outcome for those patients is less you see that their overall survival is less as compared to the fit patients but you can use it Lendex also in the unfit frail patients so yes better than MPT but less effective than in the fit patients so we need to do more we in the Netherlands also look to MPV the other standard of care in the Netherlands Melfel & Prenyzone Botasimip and we only looked in unfit and frail patients so 24% of the patients were unfit 76% of the patients were really frail and what we saw in these patients is that almost half of the frail patients half of these have to discontinue the therapy the first nine cycles so it's very difficult to treat frail patients but when you look to six cycles that was possible to give in 70% of the patients and their overall response rate was similar as compared to nine cycles so what in general will be done I think in clinical practice whenever you have a frail patient or unfit patients give a shorter induction therapy so only six cycles five cycles for all we don't know but give less and then continue with maintenance therapy because then you will have more effect shortly about the diseases relapse in general and that will be discussed in the afternoon please consider a second transplant if the first was very effective because then you have a progression free survival which is of benefit and in general you give lanylidomite when you were treated with lanylidomite switch to botasimip and vice versa there are several novel treatments the novel proteasominibitus this is napels when they didn't collect the rubbish and when you look to the persons who were living in napels at that moment you see that there was a lot of stress at that moment and that's actually the working mechanism of a proteasominibitor because when you look to a proteasominibitor also in the cell there's a rubbish bin and the rubbish bin is the proteasome and when you block the rubbish bin in your cell your cell becomes stressed and then your cell will die and that is what the proteasome inhibitor does actually so botasimip can do that only reversible so when you gave botasimip it will block the proteasome so there's rubbish in the cell the cell becomes stressed and will die but it goes on and off and when you have carfilzomip it will do that continuously carfilzomip which is even a more potent proteasome inhibitor as compared to botasimip we have the monoclonal antibodies and it will be discussed later on in the morning and in the afternoon which are daratumumup and elutuzumup and what you see here with daratumumup you see here the myeloma cell which see the 38 on it and when you give a monoclonal antibody like here is the monoclonal antibody against daratumumup it attracts several effector cells and these are cells that are killing the myeloma cell so the monoclonal antibody does something in itself it can lead to cell death directly but it also gets some friends to help to kill the plasma cell so that's the working mechanism of daratumumup in multiple myeloma and elutuzumup does something different it also directly kills the myeloma cell but it also activates the natural killer cell well natural killer cell it's all in the name the natural killer cell will be activated and also kill the myeloma cell so with daratumumup you have friends helping to kill the myeloma cell and here you have also a friend which is the natural killer cell which is activated by elutuzumup and then the myeloma cell will be killed this is the HDEC inhibitor and I already see that I'm talking too long so this is also kind of a rubbish bin blocker because when you block the rubbish bin which is the proteasome and you also give panobinostat you also block the second rubbish bin which is the agregorosome and when you block them both it will be more helpful so panobinostat is also a drug you can use and I think the landscape totally changes these novel drugs because whenever I stayed when you were treated with lanalidomide you give proteasomib and vice versa now you have novel combinations and you can see that the delay of progression of the disease is much better than only with two drugs so suppose you have been treated with lanalidomide before for a long period of time because of maintenance treatment and you develop a relapse normally proteasomib with a progression free survival of approximately 10 months so after 10 months your disease will reappear when you look now carfilzomib the irreversible rubbish bin blocker you see that the progression free survival is almost doubled so much better and when you combine proteasomib with other drugs like panobinostat telotuzumib the progression free survival was also better in these studies and especially I think the use of daratumib will really change the landscape because the progression free survival has not been reached but here you see a number which is the hazard ratio what means that you delay the progression of the disease with 100 minus 38 percent so with 60 percent 61 percent delay of the disease so these drugs will really change the landscape of the treatment of multiple myeloma there's one issue and I think you will discuss that these drugs are very very expensive and I think we really have to work together to get these drugs accessible in all parts of Europe and not only in the rich countries and even in the richer European countries it is a problem to have these available because it's so expensive but also in countries like the Netherlands daratumimab has been placed in the lock by the minister of health so we don't have it available in combination only in later lines but we really should put an effort together doctors and patients and you in order to get it accessible because this will really change the landscape of patients with multiple myeloma well here you see it for the patients who have been treated with botasomib so botasomib then you have relapse when you only give lenelida my dexamethasone progression free survival of 15 months when you combine it with these drugs it's much better again with daratumamab not even reached and you see that also in the patients with high risk which I commanded on earlier the progression is being improved with the addition of several drugs so also here it is much better than before is there something simple because patients also want to have a pill instead of getting infusions two times a week etc I would like to show the data of something which is which is very easy to give and very very cheap and we developed that actually Ingenayov and Nielsen the Donk in the Netherlands in our institution they observed that patients who were treated with lenelida myte and they were progressing on lenelida myte so they were refractory and when you give only one tablet of cyclophosphamide which is very easy to give once a day hardly any side effects it is very very very cheap when you add it to the lenelida myte and we call it Rep lenelida myte endoxan so cyclophosphamide prednisone that 56% of the patients responded again for more than 12 months and when you compare it to the other regimens I showed which are rather expensive I think this is really a good drug to give in every part of the world and we don't know whether you should combine it with lenelida myte probably it does because these results are much better than giving only cyclophosphamide but I thought it would be nice to show that here actually when you compare this 65% of response 30% of patients who respond this is much better much better not head to head compared so it's not good for me to say that it's head to head compared but when you look at it this is a much more expensive regimen 30% of patients and duration of the response of 8 months and think when you have pay for performance models it is very nice because you only pay for the 30% of patients who have benefit and they will benefit for 8 months so that's very worthwhile so thinking about novel models in order to get it funded this is the last slide and then I think I will leave amyloid just here after to professor Malini because he knows much more and then we have some time for questions what about individualized therapy because now we treat all the patients in the similar way maybe not only for high risk it's a little bit different and like I said there are two transportation but this is something else which we can use and I think what will be increasingly implemented in the clinical practice is the depth of the response and I told you we look to very good partial response and we look to complete a remission we did look at stringent complete remission so we looked at the FLC ratio but still we know when we don't see anything by the eye in the bone marrow or by the free by chain ratio there must be some disease because the disease recurs, relapses so there must be some disease so are there very precise methods to detect the limited disease which is available in the bone marrow and one of the possibilities to do so is to do effects analysis so immune for unotyping of the cells and you can find 1 in 10,000 1 in 100,000 cells with such an analysis what you do actually I showed the cell and I showed the CD38 expression on the cell but there are several markers on a cell which are present on a malignant plasma cell but not on a normal plasma cell so when you look to these characteristics with a immunofinotyping with labeled antibodies you can see 1 in 100,000 cells I forgot to implement a graph of that how it looks but the French study recently looked at patients who were treated with botasmic gland in the mydexamethasone they either got a stem cell transplantation or not and then they received maintenance therapy and they had this very precise method to detect minimal residual disease and when you look to the patients who have no minimal residual disease anymore there is the upper line and you look to the patients without progression you see that here these patients progressed much less as compared to the patients who were still MRD positive so MRD determination is a very prognostic marker what we don't know yet is should you now stop therapy in patients who are MRD negative or continue because they might really do well with the treatment you're given you should continue therapy and you should change the therapy in patients who are MRD positive so the next type of trials which are now being developed and are started in some countries in Europe already is to look at the MRD negativity and positivity and then randomize the MRD negative patients with either stopping or continue therapy and in the MRD positive patients either continue therapy or add something different and then we will know what to do with MRD negative patients and MRD positive patients but it certainly will change the landscape and the trials in the coming years it will have consequences for patients because this can only be done in the bone marrow so patients will have to say that they agree with having additional bone marrow because when you want to do this you should repeat your bone marrow after the treatment after 6 months, after 12 months because that's the only way we can learn so that's the problem I think with these type of trials but we really hope that with this we can individualize the treatment and make the world of multiple myeloma patients better and especially know whether we can have a treatment free interval in the MRD negative patients or not so I think it's really important so I will leave this in the talk hereafter I think that's much better because then we have 15 minutes left for questions you could understand thank you so much thank you I complete whatever Anita said because they extremely comprehensive but I would like to say something else I am grateful for your remarks regarding the cooperation for the reduction of medication because in front of sickness and death we are all equal and the medication should not be addressed only to the millionaires but I also have a question for you madam Doctor please you have mentioned the newly emerged recommendation during EHAR regarding the two stem cell transplantation you have also mentioned that for the young people the recommended period between the two is two three years what about the other people people over 50 between 50 and 65 who are also eligible to take to receive stem cell transplantation what would be the recommended period because this has not I did not hear it maybe and the second one you mentioned the benefits of 46 and 26 46 months after the first one 26 has it been established why a reduction of 20 months already are we talking about an overall benefit of 46 plus 26 all in general thank you very much I will show the slides you are commenting on I think the question you had about the two transplants sorry sorry it's here we started with induction therapy and then you do a randomization between either one or two transplants and the patients who you give only one transplant the disease will be suppressed for 28 26 months in the patients you will do two transplants approximately 3-6 months after the first transplant you do a second transplant the disease will be suppressed for 46 months so the patients who got only one transplant after a median of 28 months they will have a relapse of the disease and they will have another treatment your doctor will start another treatment finally I think what is very important to see whether the overall survival is longer because I don't see a flip over but what you see also with maintenance I think is very important because we had a lot of discussions with my patients because when you suppress the disease for a longer period of time and you live for approximately I say 6 years and you suppress the disease for 4 years and then you have 4 years of additional treatment and when you don't give maintenance and you have a treatment free interval and your diseases relapse after 2 years and you have 4 years of additional treatment but in the end you both live 6 years you would be able to omit maintenance therapy because your overall survival is similar and then you have a treatment free interval so overall survival is very important but for maintenance we show that the overall survival is better it would be better with a flip over what I'm saying now I think but maybe you understand so that's about the 20 months difference this is a very early analysis so I would like to wait the longer follow up of the analysis is this an answer to your question? yes thank you very much for the excellent update you already answered my first question so I have small questions for you when you're talking about transplantations you're always talking about אותологous transplantations right? are there any trials with unrelated transplant settings this is the first question the second is do we expect a sort of cure in the near future without transplantation? and what would be because most of the audience is patient advocates what would be your take home message to these people because there are too many different protocols and diverse landscape etc so what would be the take home message for the advocates thank you your first question about allergenic stem cell transplantations either from a family donor or from a match unrelated donor will be discussed later during the day by my colleague so what has been done with allergenic stem cell transplantation first we didn't have all these drugs available we did an allergenic stem cell transplantation very late in the course of the disease and we really know that that's not the time to do an allergenic transplantation because you only had the side effects and almost no benefit although of course there's several patients in the world who did benefit an allergenic stem cell transplantation at that time but when you take all the patients together in general there's no benefit in later lines of the disease what we did then is that we said okay in later lines of the disease it's not a way to go should we combine it in the young patients with an auto so we do first an autologist stem cell transplantations followed directly by an allergenic stem cell transplantation and there have been several studies performed in Europe especially and when you look to these studies the final answer I think is that it's not of benefit in general because the survival curves are similar so it's not a general approach but sometimes we as doctors when patients are approximately 40 years of age you might think about doing an allergenic stem cell transplantation at the first relapse not in the start so auto although so now we know the first relapse is that a place to go and I have regular discussions with my patients at home because when they are young and they only benefited from the autologist stem cell transplantation with novel agents for approximately 18 months you know that you have many drugs available but when someone is very young certainly his life will be shortened so then you think well should we give an allergenic stem cell transplantation at that time what I don't do is whenever there's the relapse already within 6 months after the autologist stem cell transplantation we looked at the patients we did an allergenic and all the patients sadly died so within 6 months the biology of the disease is so progressive that you won't save those patients with an allergenic between 6 months and 18 months I have very long discussions with my patients and sometimes we do and sometimes we don't and it depends on the age on the life whether they have children whether they have a job which they want to continue, whether they want to have the risk of dying in the first year which might be 10% with an allergenic or they say no no my children are 4 years of age I really want to see them grow older and I know it's limited but I don't want to die in the first year so it's very difficult discussion so I can't give a very clear answer not at late stage not fully at the start at first relapse discuss with your patients what is wise to do so that's about the allergenic the take home message I think yeah it's always difficult to take home messages I dislike a world in which we try to say everything in one or two lines and that's the trend that is increasingly being adapted in life because this is such a difficult subject this is so full of emotion this is very hard to state in a one liner but I really think I grew up in the time when there was only Melfelin actually available and it is completely different at the moment so I think this are much better times for patients with multiple myeloma although you really don't want to have multiple myeloma but whenever you're diagnosed with multiple myeloma these are much better times because you have so many possibilities to treat and therefore extend life hopefully also in a good quality of life I really think that there's an unmet need for the treatment of bone disease because it's really devastating so we should look in depth into bone disease in extra medullary disease which is very difficult but we have better outcomes for patients and I think the take home message then also is and I said it earlier already we would like to have access to all these novel drugs for all patients with multiple myeloma and we'll have to work together also with pharmaceutical industry in order to find models to get these drugs paid but times are much better and we are having much better times also in the outpatient clinic when you're discussing because there's a future for patients so that's I think very important yes I have a question which might be specifically relevant to the new and very expensive drugs how is the dosage decided and what kind of studies independent from the pharmaceutical companies are performed to decide the dosage to use myself as an example I get on a special program data tumor mob but that much lower dosage than recommended by the pharmaceutical company and it works very well so that of course also will bring down cost if you can give it a lower dosage yeah I do agree I think of course there is investigation there are investigations how to dose the drug and really also when these drugs are developed in actually all pharmaceutical industry there is extensive research on the dosing because you want to have the drug available for the patients but also on the market for pharmaceutical industry so whenever the dose is too low it won't be good so there is extensive investigations what I think is difficult with the monoclonal antibodies is that there is a difference between the traditional pharmacokinetics and the long term effect because we did a lot of research on our own laboratory and what you see is that there is not only an anti myeloma effect but it really changes the immune environment in patients because it also affects the T regulatory T cells which are suppressing T cells it activates cells which are able to kill myeloma cells and the long term effects might even be just more immune modulation than direct killing and we don't know what the pharmacokinetics is so in this case you can't blame that we didn't do the research at lower doses because there was an unexpected effect of the drug and I think what we really should look for and I agree with you that knowing this it's very interesting to look can we give it once in four weeks, once in eight weeks once in even less and also what we have available in our university and I think that's also very interesting is the immunopat method so what we can do is that you can label the drug with a radionucleide and then you can see whether the drug is actually going to the tumor because we also know in multiple myeloma that it's a patchy disease so when we measure levels in the blood it might not reflect what is available in the tumor so I think also for immunopat there's a role so there's there's a lot to be done it is a little bit more difficult than only blaming industry but I do agree with you that we should look in depth and also look some of the oral drugs you give a certain amount every day but maybe you can do it once every other day and we know that when you buy by example 25 milligram versus 5 milligram that the 5 milligram is relatively more expensive than the 25 so when you can taper those over several days you will save money so it's interesting it's really interesting and I do agree yeah okay thank you very much because look man and now we will have a 10 minute break if you have question you can approach yeah so you have two types of frailty I think where I was talking about was just frailty in in general so frail persons or unfit persons who are not able to do everything in life because of old age but also because of comorbidities for this type of frailty it is important to see whether there are frail and you can do it very easily with the IMW frailty index and I will provide the link and you should adapt the therapy so lower the therapy give less intense induction therapy and then continue with with maintenance therapy so that's the kind of frailty in which you would adapt the therapy frail bones is also important because bone disease and multiple myeloma can be really devastating and I think what has been shown that whenever you got multiple myeloma you should give something which inhibits the osteoclasts because the osteoclasts are the cells that are eating the bone and when you give drugs that lower the activity of the osteoclast less bone will be eaten you get less osteoporosis and we know you will have less fractures and less bone disease these are the bisphosphonates and the bisphosphonates you should give in multiple myeloma patients for at least two years every month and you can either use intravenously permidronate or zolendronate what to do after two years we actually don't know I think whenever there's still active disease you should continue the therapy and by example every three months so lower the frequency but continue bisphosphonates we're really looking for drugs that are also increasing the osteoblast because your bone is eaten by the osteoclasts but being grown by being produced by the osteoblasts and we know by example that the proteasome inhibitors like Bortesmib are increasing also the activity of the osteoblast so for bone disease we think that Bortesmib is a very good drug but it's not really very well investigated but for bone disease bisphosphonates two years every month is I think required and should be done in patients with multiple myeloma I hope I answered your question are the exercises yeah that's difficult but I think whenever you're able to do exercises you go to a physiotherapist and it's good to do you should of course be careful about the spine because it's just exercises in a controlled way not doing weight lifting etc but in which you keep your muscles in a good condition that's of course good because when your muscles in a good condition it starts it's along the spine and it will be helpful yeah okay thank you very much and before the coffee break we'll have a short brief by Ananda about the logistics