 OK, so good morning, everyone. I hope you had the chance to rest last night after the last dinner we had in Brussels and everything. I'm welcoming you. As you know, today, I'm very happy to say that this is the third year that we're going to cover the AL ameliodosis topic here in the Myeloma Patients Europe, AGM. So we have a full morning. First of all, we have a lecture, and it's my pleasure to welcome Professor Natalie Mueleman. She works at the Matrology Department at the Institute Jules Bordet in Brussels here. And she's also the president of the Belgian Society of Matrology. And in these first sessions, she's going to explain to us more about what is AL ameliodosis, how is this diagnosed, how is it treated, which I think is a great challenge to condense all this information. But we're very happy to have you with us. So Professor Mueleman, the floor is yours. Thank you. So first of all, thank you for the kind of invitation and the introduction. So I think that my task today is very complicated, because ameliodosis is not a simple disease to understand. It's not a simple disease to diagnosis and to treat. So I will try to be as clear as much as I can, but don't hesitate to interrupt me if you have any question. First of all, I will try to give definition and to explain what is ameliodosis. I will then try to explain the link with the multiplomyeloma and how to diagnosis and how to treat this disease. Decrease them. Yes. So, hello. Just starting, just give the introduction and nothing else. So if you want to give a definition of ameliodosis, we have to first say that it's not a disease, but it's a group of different diseases. And there is different kind of ameliodosis. I will give a brief explanation on that, but we will focus on AL ameliodosis, the ameliodosis which has a link with multiplomyeloma. So it's a group of disease and it's a rare disease. And probably not so rare that I think that we under diagnose this disease. And the disease is due to the deposition of extracellular ameloid. So what is ameliodo, ameloid? Ameloid, it's insoluble protein. It's a fibril protein that will assemble with special configuration. We call it cross-betasheet conformation. I will give you a picture later. And so you have in the cells the production of small protein. Here you have normal protein and here you have some protein that can give ameloid protein. And so this abnormal protein will have an abnormal configuration and will have a misfolded configuration that will give an high propensity to self-aggregate. And after the misfolded of those small protein, they will aggregate in with other small component in ameloid fibril. And those protein will go in the organ and give the organ dysfunction. And so in those ameloid fibril, you have about 95% of those fibrillar protein but also 5% of other protein. And it's important because new treatment who are coming, we hope they are coming in next year, will also target those glycoprotein. And so the dysfunction of the organ will come from the deposition of this abnormal protein but also of the coming from the direct toxicity of those precursor of this ameloid fibril. And so the small cell can induce the death of the cell by a mechanism that we call apoptosis. So this is another way to explain it. So you have the naive protein, then the misfolded protein that will aggregate in a small component of oligomer and then in proto fibril and then the fibril that will link with other glycoprotein and give this specific configuration of the ameloid fibril that will go in the organ. And so ameloidosis can give a lot of organ dysfunction. The fibril could be deposited on the liver, on the heart, on the spleen, on the liver, on the brain, on the kidney. And we will see that in AL ameloidosis, the two organ that are more frequently attained by this disease are the heart and the kidney. So as I told you, ameloidosis is a group of disease and there is many kinds of ameloidosis. We have identified more than 30 different precursor protein and we can have different subgroups of ameloidosis. So ameloidosis can come from an aging process and so a normal protein that could have an antrassic propensity to have a pathologic confirmation that's the case of the senile systemic ameloidosis. You can also have an abnormal prolonged exposition to normal protein that could also cause this ameloidosis. And it's the case with heart rates, chronic heart rates. We call it ameloidosis, it's patient with chronic inflammation and the protein from the inflammation could also give this fibril of ameloidosis. Patient in dialysis could also have accumulation of beta-2 microglobulin, but it becomes more rare with the new technique of dialysis. You can have also remodeling of normal protein precursor that's the case also of Alzheimer disease. And the last subgroup is the presence of abnormal protein and we know that there is a second most frequent is a mutation in what we call transteritine protein and also in this subgroup we have the immunoglobulin light change called RL ameloidosis. And today we will talk about this RL ameloidosis and I will explain you just after what's the link with the multiplomyeloma. So ameloidosis is a very complex disease with very different process that could give this dose complication with organ dysfunction. And you can see on this slide, it's confirmed that it's a rare disease, it's about nine cases per one million of persons. You can see also that the incidence is stable for the RL ameloidosis. So coming from the monoclonal protein, the incidence of ameloidosis coming from the inflammation is decreasing because we have no more powerful treatment for those kinds of disease, polyarthritis and other one. And the senile ameloidosis and the transteritine ameloidosis, mainly cardiac ameloidosis, the incidence is increasing probably because we have more efficacy tool for the diagnosis. And so you can see that RL ameloidosis, so Lichens ameloidosis is the more frequent ameloidosis, at least in Europe and in other continent also. So what is RL ameloidosis? I think that you all have some kind of link with myeloma, you probably all know that the plasma cell are producing antibody. In those antibody, you have what we called AV chains, such as IgG, IgA, IgD, IgM, but you have also the production of Lichens. That's the Lichens that could be linked to the AV chains or be circulating in the blood. And there is two kinds of Lichens, the Kappa Lichens and the Lambda Lichens. You probably also know that normally we are secreting those plasma cells as secreting a lot of different antibody, what we call polyclonal antibody. And sometimes you can have a mutation that will give monoclonal plasma cells, a clone with all the same plasma cells that will give a monoclonal protein, what we call monoclonal peak on the electrophoresis. And so that's a link between ameloidosis and multiplomyeloma. In fact, multiplomyeloma are coming from the development of those monoclonal plasma cell clone and ameloidosis is coming also for the development of those clone. So ameloidous, the ameloid fibril for the AL ameloidosis is coming from the secretion of abnormal Lichens from those clone of plasma cell. So as for the multiplomyeloma, the median age of diagnosis is between 60 years old and 70 years old. And so the link is the expansion of the monoclonal plasma cells. But we also know that about 10 or 50% of the patient with multiplomyeloma could have at the diagnosis or during the evolution of the disease an AL ameloidosis. So AL ameloidosis is a disease that could come without any multiplomyeloma or other hematological malignancy cells such as wild and shrimp disease. But it's also a disease that could complicate a multiplomyeloma. And sometimes when you are doing the diagnosis of AL ameloidosis, you will also find an associate multiplomyeloma. So there is a close link between the two disease. And so we also know that probably if you are searching AL ameloidosis in all patients with a multiplomyeloma, the incidence will be much higher than those 15%, about 30% and probably that those 30% a lot of patients have no symptoms and it's just a small component of ameloid fibril. But some of those patients could evolve during the disease with a symptomatic AL ameloidosis complicating the multiplomyeloma disease. So for the AL ameloidosis, the process is the same for the fabrication of the ameloid fibril, but it's coming from a plasma cell clone. And so it's very important when you diagnosis, we will see that later, the ameloidosis to be sure that your ameloidosis is an AL ameloidosis linked to this clone because if it's another type of ameloidosis you will not treat the ameloidosis with the same drug that for multiplomyeloma. And so the treatment are very different according to the subtype of ameloidosis. And so the plasma cell clone will produce the antibody and it will be the light change of those antibody, mainly the lambda change that will be this miss fault configuration and then the aggregation of those small protein and give this ameloid fibril. But we really know today that the organ dysfunction, yes it's sure it come from the deposit of this ameloid fibril, but it come also from a direct toxicity of those abnormal light change. And so it's very important in AL ameloidosis to have this in mind because you have to clear the blood if you want to have an improvement of the symptom of the patient. And this direct issue toxicity is mainly affecting the earth, the earth, sorry. And so in AL ameloidosis we will see the incidence but we will have most frequently arts dysfunction. And then the second most frequently organ that will have dysfunction is the kidney but we can have also some bleeding tendency. And this is a picture, classical picture of the patient you see only that if in ameloidosis you have a vertebra or bleeding around the eyes and you have also, you could have also an enlargement of the tongue, some nail dystrophy. So here you can see the incidence of the organ failures or the, it's not always a failure but the deposit of ameloid fibril on the organ and the art is the most frequently more than 70% will have deposit of ameloid fibril in the art. And so it's because the art is one of the most frequently organ that will be damaged. It's a serious disease and it's very important to diagnosis it as early as possible because it can lead to life-threatening organ failure. And so the second organ that will be damaged in this disease is the kidney but you can see that you can also have neuropathy, peripheral neuropathy, such as in the multiple myeloma with the treatment or with the disease you can have all those symptoms and also gastrointestinal system, liver function could also be damaged. And so that's typical picture you can see when you have those kind of picture you are pretty sure that there is an ameloid dose. The problem is that when you have those clinical picture it's probably too late to have good treatment and to have a good prognosis for your patient. So the goal today, it's to improve of course the treatment of your patient but it's to diagnosis it earlier. So here you can see the same purpura around the eye, the enlargement of the tongue but also of the shoulder, the patch shoulder symptoms is here you have an enlargement of the liver, the salivary gland, you can also have pulmonary dysfunction and infiltrate and some in localized ameloidosis, some nodules also. And so what will be the symptoms that the patient will have when there is ameloidosis? The patient could have what we call dyspnea so shortness of the breath but also swelling of the ankles and the legs and it's coming, it could come from both renal or cardiac dysfunction. Also severe fatigue and weakness and it's difficult because it's a very common symptoms especially also in patient, multiple myeloma patients and also the peripheral neuropathy with numbness, prickling, tingling or pain in hands and the feet. Sometimes what we call orthostatic hypotension so it's the lowering of blood pressure when there is suddenly a standing up. There is also some kind, sometime digestive symptoms such as common symptoms also in multiple myeloma patients, chronic nausea, diarrhea, possibly blood diarrhea or constipation. You can also have from this accumulation in the digestive systems some unintentional, significantly weight loss. So we saw the pictures of the enlarged tongue. They could also have some skin chance so there is tendency of easy bruising and also what I saw you purplish patches around the eyes that it's unique to the amyloid doses. Sometimes with their heart involvement irregular heartbeat. Sometimes difficulty to swelling, the shoulder path syndrome and also I show you the picture of the enlargement of salivary gland. So some of those symptoms are common symptoms and could also mimic or the more common condition and it's why it's frequently late diagnosis and you could imagine that if a patient come to his doctor saying, oh, I have some kinds of fatigue, a little bit nausea, some swelling of the ankle. Doctor will not especially think first about the diagnosis of the amyloid doses and there is typical pathway of the patient with regularly seeing seven or eight different doctors before the diagnosis of the amyloid doses and sometimes the patient are seeing three or four different cardiologists before the cardiologists think, oh, this picture could be a typical pictures of amyloid doses and I have to search this disease. So the information is very important to give this point of information to the patient but to the doctor also and you can also imagine that for patients with multiple amyeloma, if you have those kind of symptoms, this peripheral neuropathy could also come from the monoclonal protein with amyloid doses could also come from the treatment, bortezomib, Velke, and so on and the weakness is very frequent, the diarrhea or the constipation depending on the treatment or the disease. If you have a lot of pain killer, you have constipation, if you have linalinomide, you have tendancy to have diarrhea and it's sometimes difficult to do the part to see the symptoms in sling to the multiple amyeloma, to the treatment of the multiple amyeloma or to this complication. And so this is the message which is give to during a lot of hematological symposium, it's that the most important diagnostic step for the amyloid doses, it's to early and correct diagnosis of this disease and also to suspect it earlier that it's not done. And that's a sentence from Merlini and so it always says that early diagnosis of AL is crucial to avoid and organ damage. When the patient has an organ damage it's very difficult to treat the patient and there is a high risk of mortality due to the disease and due to the treatment. And in that regard, Merlini and all the experts today recommend to search even in the patient with monoclonal gamopathy of no significance so not the amyeloma disease but the precursor of the amyeloma disease and we know that a lot of early patients have this abnormal blood protein circulating but today we recommend to check it to see if those patients have no amyloid doses and by measuring some cardiac test, what we call anti-probian P and the cardiac marker and the protein in the urine. If you have in the urine protein and it's mainly the monoclonal protein, it's not an amyloid doses but if it's a mainly albumin, you have to suspect it. And so when you suspect, then you have to diagnosis and for the diagnosis of amyloid doses, you need a tissue biopsy. You have then to investigate the presence of paraproteinemia, sorry, paraproteinemia. If it's not in the case of a multi-plemyeloma of a patient with a multi-plemyeloma, then you have to assess the organ involvement and you have also to exclude that your patient have not a symptomatic multi-plemyeloma. And so one question is which organ you have to biopsy to have the diagnosis. So it's difficult, the gold standard will be to biopsy the involved organ. That's the best way but it's not easy to perform a biopsy of the heart of the kidney. There is a risk of bleeding. We know that AL amyloidosis patients have more frequent bleeding and so there is a risk if you are doing those biopsy. But we know that when you have amyloidosis, AL amyloidosis or other amyloidosis, there is also an accumulation of those fibrils in the fat tissue. And so usually we are performing a fat abdominal biopsy and as we want to exclude also an association with the multi-plemyeloma, we will also search it on the bone marrow biopsy. And so this is the way we perform the fat tissue biopsy. So it's very easy to perform. You don't need, you need only a local anesthesi. And so if you perform the abdomen fat biopsy and the bone marrow biopsy, you will have the diagnosis in about 90% of the patient. If you still have high suspicion of amyloidosis but still not your diagnosis on those biopsy, then we will perform a biopsy of the salivary gland or rectal biopsy and then only a biopsy of the cardiac or kidney according to the organ involvement on the gastrointestinal tube, that's more easy. On the biopsy, we are to say that you have a biopal amyloidosis. We are using the Congo red, it's a specific coloration and when you are making the coloration of the biopsy with the Congo red, you will have these specific pictures. So after the coloration with Congo red, we are looking at those biopsy with a special light, polarized light, and there will be this specific, what we call biorefringence, very Congo red picture for amyloidosis. But then you have positivity of Congo red, you know that you have an amyloidosis but which type of amyloidosis and that it's an important and not easy part of the diagnosis. You have to type in the amyloidosis and so we have some technique, what we called immuno-histochymistry, it's antibody that will recognize the lambda or the kappa, light chain or the AI in the inflammation, but it's not always specific and so you will miss about 30% of the case. Then you have more specific tools such as immuno electron microscopy but it's highly specific but there is really limited availability and the new gold standard for the diagnosis for the typing of the amyloidosis is what we call mass spectrometry of amyloid deposit and we obtain that by laser capture. So first we are doing abdominal fat aspiration or biopsy, then you are doing your red Congo collaboration and then the part who is positive for the red Congo collaboration, you will perform microdissection with a laser and after this microdissection, there will be digestion of those protein by some enzyme and then we will analyze with a specific machine, what we call a spectrometry, mass spectrometry and a computer algorithm, the analysis of the protein and the computer will compare those protein to a reference database and so you have here the Congo red without the polarized light. You can see already some abnormal deposit here so you have the suspicion and then you have the B-reference with the Congo red. You can see that if you use here the antibody against anti-Kappa, there is no significance link to this antibody, no anti-transteritine. There is some competition with the Kappa light chance and then there will be the digestion of those protein and then analyze with the computer and then with this, you are pretty sure that you have the good diagnosis and why is it so important because some people could say, okay, we have the red Congo positivity and we have a monoconal protein in the blood so we are pretty sure we have an AL amyloidosis but no, we are not pretty sure because as I told you before, AL amyloidosis is median age of diagnosis is about 65 years old but it's the same for monoclonal gamopathy so those small monoclonal protein we vote clinical significance and not associate with a multiple myeloma. So you could have a patient with both and there is no link between the amyloidosis and the monoclonal protein and so there is a lot of publication, some publication demonstrating that you could miss diagnosis, hereditary amyloidosis and think that it's AL primary amyloidosis and this study about more than 300 patients analyze the subtype of amyloidosis and all those patients were diagnosed as light-sheen AL amyloidosis and about 10% of the patients it was a misdiagnosis, it was a hereditary or another type of amyloidosis so it's very important this step in the diagnosis and because as I told amgus, so monoclonal protein of no significant is common over 65 years and the senile amyloidosis or the transteritin amyloidosis is leading to some mutation also and there is other publication about the same subject so it's not rare that some hematologists, some doctors or cardiologists could give not the good diagnosis and as I told you, it's very important because if you have a senile or for transteritin amyloidosis there is no need to give treatment for, that will target the monoclonal plasma cells because there is no link between the both and so you will give treatment with potential side effect and with no activity on the amyloidosis is if it's not an AL amyloidosis and so sometimes you do not have easy access to these new gold standards with micro dissection, laser micro dissection and analysis with the spectrum mass and you could also if you, and we did it in some patients if you have an hesitation with AL amyloidosis you are sure because you have your immunostochemy negative for chronic inflammation that it's not that and you are hesitating between transteritin senile amyloidosis or other transteritin amyloidosis and AL amyloidosis but by performing a simple bone scintigraphy so it's first it was not developed for those but more for searching metastasis for post heart cancer or other bone anomaly and incidentally some years ago we discovered that transteritin link this technosium 919 that we use for bone scintigraphy so if you have an hesitation you could perform this exam it's easy to do it and you have an access in every hospital to the exam and if there is AL amyloidosis there will not no captation, art captation of the technosium but if you have transteritin senile amyloidosis you will have a captation and sometimes it's also an easy way to help the physician in the diagnosis so to summarize confirm the presence of amyloidosis for the diagnosis it's a required step you need it with your red Congo you have to confirm the subtypes the subtype of amyloidosis and this requires considerable expertise it's why there is a reference center for the amyloidosis it's complicated to diagnosis to suspect to diagnosis and to give the good diagnosis and then you will also need to exclude and to make all the different exam we are preferring for the multiple amyloidosis to exclude the presence of a multiple amyloidosis and we have also to know that for AL amyloidosis we will have a lot of patients who have no monoclonal circulating protein in the blood so AL amyloidosis a lot of patients will have a small clone of circulating monoclonal protein and it's why we have to search it also in the gamma-pati monoclonal of a determinate significance and so if we have no monoclonal protein circulating protein in the blood it's not possible to say there is no AL amyloidosis you have to first make a more performant exam in the blood such as the dosage of the light change but even the light change could be negative in the blood and you have to perform the analysis on the serum but also on the urine the electrophoresis but also the immunofixation and the dosage of the light change and if you are performing all those exam plus the bone marrow evaluation you will find new monoclonal protein but we do not have to stop the process because there is no circulating monoclonal protein and so for the patient we will have the evaluation of the plasma cell clone so the urine, the serum the light change dosage, the bone marrow evaluation and it's very important as for the multiplomyeloma to perform the cytogenetic evaluation because in those clones we will have some abnormal translocation in the gene and the response to the treatment depend of those cytogenetics such as in the multiplomyeloma so we will perform also bone evaluation to be sure that there is no bone lesion due to the myeloma, such as the anemia and what will be an important step is to search the cardiac involvement and for the cardiac involvement we are doing two biological marker the troponin and the anti-pro-BNP and those marker are very important they are mostly always increase in the diagnosis of AL amyloidosis with heart involvement and we will see it's also a prognosis factor we will of course make a necrography of the heart and an electrocardiogram we will analyze the function of the kidney in the blood and in the urine the liver function, the coagulation test then they see to have some bleeding and due to abnormal coagulation test we will make a clinical assessment searching for peripheral neuropathy and most frequently we are also doing MRI of the heart some ulter so to you are during 24 or we are analyzing the rate of the heart to be sure that there is no abnormal earth beating it's very frequent in this disease sometimes if there is gastrointestinal symptoms but we will perform on the scopy with biopsy and according to the other symptoms respiratory function test scanner of the chest yes, yes, cytogenetics so we will perform on the bone marrow evaluation on the plasma cells we will research some abnormalities in the chromosome of the cells and there is a different way to search those abnormalities and we are using mainly what we called a fish technique so you have some probes that will recognize some abnormality and in multiple myeloma we know that we have deletion, 70p which is giving bad prognosis and translocation for 14 1Q abnormalities and in amyloidosis in those chromosomes we will mainly search the translocation between the chromosome 11 and 14 because we know that those patients are not so well responding to bortezomib velcade and also the 1Q abnormality so you know we have 46 genes on the 1Q we couldn't, so on the chromosome one you can have some mutation on the part what we call Q or P and we will most frequently find some abnormality on the 1Q chromosome in the amyloidosis or those translocation so you have two chromosomes and there will be one small part of one chromosome will go to the other chromosome and some kind of there is translocation of some small part of the two between two chromosomes and that gives us information about the prognosis of the patient but also the way the patient will answer to different treatment and it could help for the treatment of the patient I don't know if it's more clear and so we have also to give a prognosis of the patient and it's really the cardiac involvement that gives the most important information and also those cytogenetic information if we found more than 10% plasma cell in the bone marrow so we have to face a multiple myeloma patient even if there is no, sometimes we have 11% of plasma cells but no bone lesion, no anemia, no anemia, no kidney dysfunction that it's a kind of asymptomatic multiple myeloma with RL amyloidosis and we know that it's better to have less than 10% in the bone marrow for the prognosis and we are also looking the difference between the dosage of the kappa and the light and the lambda chain and if there is a big difference between those dosage its patient is ever less good prognosis. We will also take a look to the number of organ which are involved to the systolic blood pressure if the patient have a low systolic blood pressure it's not a good prognosis because it's reflecting that probably there is an autonomic neuropathy and if the patient is doing complication in fiction complication with an heart involvement also a nervous system involvement there is less answer to the inspection and the patient will have some difficulty to maintain a good systolic pressure and there is a high risk of death due to these dosage complication. Performance status, or healthy is your patient if it's all days in the bed or the patient is still active it's important to know it and it will be also a prognostic factor and the presence of those dysneuropathy. So what you could see here it's what we call the myoclinic stage and the myoclinic stage is based on the dosage of those cardiac markers so the anti-probian piece so we are doing that routinely in blood tests or troponing and if you have some level of according to the level of those two cardiac marker we can say that the patient will have a better or worse survival and a worse prognosis and for the patient with the monoclonal the gamopathy of monoclonal protein gamopathy of no significance or patient with multiple myeloma to detect this complication we can perform this simple test of dosage in the blood anti-promed men P and if it's above these dosage you have to suspect and to ask maybe it could be because you have also an increasing of those dosage with alteration of the kidney function or with the age maybe there is nothing to do with amyloidosis but if it's increased you have to refer your patient to the cardiologist to a cardiologist, an expert cardiologist and ask exclude secondary amyloidosis. And this is a new myoclassification always based on those two cardiac marker but also based on the difference between the two light change, the kappa and the lambda light change and you can see that we can separate the patient with those prognosis with those simple biologic marker we can give the prognosis of the patient and you can see that the patient with advanced disease we are losing rapidly a lot of patients with advanced disease and you can see that if you are diagnosis those patients earlier in the disease the prognosis is really better and that's why we are fighting to have earlier diagnosis for those patients. Here it's very difficult patient if usually this function you are begin treatment there is complication, infection, heart complication and those patients are rapidly dying more than 50% of those patients because of the disease and because of the complication of the disease and sometimes because of the treatment. So the number of organ is also important for the diagnosis and so we will treat the patient according to this risk so we will perform the myoclinic system we will give the stage of the disease and also of course according to the age and the performance status for patient and the aim of the treatment is to obtain a rapid and profound decrease of the light channel level. If you are not cleaning the blood because this light chain is toxic for the heart you will have no organ response and the goal is to have an organ response to amyloid, the cardiac, the kidney function or the liver function and so it's very important to have a rapid response and so also if you want to take out of the amyloid fibril from the organ you need to have at least a complete very good partial response so decrease of 90% of the monoclonal protein but as in the myeloma in the amyloidosis we have some other way to calculate but it's mainly the same. So that's indispensable for organ response and it's what's the most important because the organ involvement is responsible of the death of the patient so we need the very quick answer. We will effectively adapt the treatment to the age of comorbidity, the extent of the organ involvement so we know I don't have the time I saw that I have maybe to be more rapid I don't have the time today to say it but there is some treatment for cardiac treatment for hypertension or other cardiac problem it's not possible to give it, it's toxic to give it to amyloid patient so it's very important to see a specialized cardiologist because you could not give beta-blocan you could not give some other treatment and the suporti cave is very important for those patients also. Just to show that the prognosis of the patient is really linked to the hematological response. The first steps when you have to, you will decide if you will tweet the patient, say is there a place for all patients for a high dose of chemotherapy so high dose of melphalan the same than for multiple myeloma and autologous stem cell transplantation. There is a lot of debate about that and why there is a lot of debate because the first 2D that I've been performed with autologous stem cell transplantation show that there is high TRM so transplant related mortality. So in some study we have lose a lot of patients during the transplant but even during the stem cell collection. So if you want to collect stem cell for transplantation you need to hospitalize your patient for the stem cell collection and to perform to hospitalize but also to have a cardiac monitoring during the stem cell connection and blood pressure monitoring. So it's very, you need a specialized center and so you can see that in the first study there was more than 20% of patients dying during the stem cell collection or in the 100 day after the transplantation. So it's too big to propose it to all patients but you could also see that the median survival there is a wide range in some studies that's only 1.8 years and in other more than eight years. And so we learn to improve the supportive care of those patients to hospitalize the patient for the stem cell collection and so with this all the centers there is a different publication showing that there is an improvement of the result and a decrease of this mortality in the most recent year with more supportive care. And so this is one study showing that there is more than 40% of the patient with long-term survival, more than 10 years. If you are selecting in a good way your patients so younger patients, good performance status not so bad kidney function and also the most important classification for the heart involvement not an important heart disease. And so today we are performing in Belgium, we are taking those guidelines but you can see that the last IMWV Congress, Merlinis, same the same and there is a lot of publication saying the same. So there is only a small proportion of the patient who will be a candidate for the transplantation about 50% of the patient because you need some younger patient we vote high level of cardiac markers, we vote important cardiac dysfunction, we vote important kidney dysfunction with a good performance status and we will perform the autologous stem cell transplantation as in the multiple myeloma with the male phylandi dose. But if what's different from the multiple myeloma is that if you have no more than 10% in the bone marrow, you don't need an induction, you can directly go to the stem cell collection and the stem cell transplantation. But if you have more than 10%, then we will use the same drug than in multiple myeloma, cyclophosphamide, bortezomid dexametazone, two cycles and then perform the autologous stem cell transplantation. And if after the autologous stem cell transplantation the patient is not in complete remission, we will give as in the multiple myeloma consolidation. That's the recommendation of the French society and the French society are not so routinely given even in good performance status patient with no heart involvement, a lot of autologous stem cell transplantation. So those recommendation is to treat your patient according to the myostage. And so if you have a stage one or two, you are giving simply male phylandi dexametazone and if it's more advanced disease, you are giving Velcade, bortezomid with cyclophosphamide and dexametazone. And what it's important in those recommendation is the same with American recommendation or European recommendation. It's that you have to very quickly evaluate the response disease. And if for the stage two or three with cardiac involvement, if after one cycle or six week you have not a decrease of 50% of the monoclonal protein, we will never require this for multiple myeloma, then you have to change your treatment, to add bortezomid or change a treatment if the patient is on bortezomid. And you have to have at three months at least a very good partial response because we are really searching this quick answer to try to have an organ response. And for the low risk stage one, we are less strict and we are requiring at three months the 50% reduction of the difference between the two light chains and at six months a 19% reduction. It's the same in the, that's come from the Mayo Clinic, so the American guidelines, what we know see that if you have a severe, really severe cardiac involvement with this marker at a very high level 90 from BNP more than 8,000, it's very complicated, you don't have the choice, you have to use bortezomid to have a quick answer but you have to do it with cardiac monitoring because the risk of heart toxicity of the treatment and of some sudden death on the treatment. So difficult, difficult to treat the patient with advanced stage. So for the patient who are not candidates for autologous stem cell transplantation, we will use oral melphalon dexamethasone and for the stage two free as the French guidelines and the American guidelines and the European guidelines, Velcade, cyclophosphamide dexamethasone, we will do a risk-adapt bortezomid. So if the patient has some kind of neuropathy, we will give it a weekly or if the patient is older, if it's low blood pressure, we will monitor the patient if there is a severe cardiac dysfunction. And as I told it before with some specific chromosome abnormality, we know that bortezomid has not such a good result. So we will use melphalon dexamethasone or if we want to use bortezomid, you need to use melphalon with bortezomid and not only doing bortezomid with dexamethasone. We know also that sometimes, especially here, it's an example for the kidney function, you perform the transplantation, you have at three months the hematological complete, hematological response and you have to, you will see a slow amelioration of the renal function measuring by the urine protein and the serum albumin and you can see that the complete organ response is for this patient only at three years after the diagnosis. So it will take time to have a good organ response. So just to, sometimes there's nothing to do with the systemic L amelioridosis but you can have some localized amelioridosis. There will be deposits only at the site of light chain production. It's rare and small way than systemic L amelioridosis and usually there is only locale recurrence. So those patients have very good prognosis and you could find it in tracheal, bronchial, or pulmonary gastrointestinal skin but it's different. It's the same way to develop those nodules but it will stay localized and you will need only a resection with laser therapy or sometimes radiotherapy. And so I think that I use all the time a little bit more that I have but oh, we will improve just to say that no we are using chemotherapy or not chemotherapy but new drugs but signaling plasma cell but in the future we will use new treatment which are targeting the fibril component of amelioridosis or the small other component of those fibril deposits, the glycoprotein. We can try to make a destriteration of those ameliorid fibril and so there is interesting data showing that if you are adding doxycycline so it's an old antibiotic to the treatment of your patient it will interfere with ameliorid fibril formation. We have first data from most models but now we have also clinical data and we are using frequently this association. New treatment for multiple myeloma are also arriving such as Daratumumap. Daratumumap are very, very promising results. It's not a toxic treatment and it's very effective also as in the multiple myeloma patient in AL amelioridosis. There is also ongoing data on polyphenol which are in the green tea and there is a preliminary data showing that if you are giving extract of green tea to amelioridosis patient there will be, you could have some cardiac answer and there is control trial ongoing. And there is a lot, I have a basket slide if you want but I think that I have no time. No new antibody targeting the different component of the ameliorid fibril who are very, very promising and we have a lot of hope in those new treatment but it will be only, the phase three will only start or are just starting now and so it's not before some years that we will have an access to those new drug but it's very exciting and very promising. And so of course we think that we are now better for treatment and with the way to administrate the treatment especially for the autologous stem cell transplantation so we can see that there is an improvement of the survival of the patient but you can see that we are always losing during the first month a lot of patient and so this is due because those patients are diagnosed too late and so we are waiting all those new drugs but I think that we have to work on this early diagnosis to improve the prognosis of our patient so I hope that it's a little bit complicated disease a little bit complicated treatment and so on but I hope that it was clear. I think that the first step will to think about amelioridosis and when you have a patient with amgus or with multiple myeloma to ask for the symptoms and even if you have not those symptoms but you have an increase in patient amgus so that's the patient with monoclonal protein without clinical significance if there is an abnormal light chain ratio you have just to perform the anti-probion P dosage and if it's above 300 you have to refer to patient to cardiac assessment to search the albuminary it's an easy way but if you are performing this to all your amgus patient and also to your multiple myeloma patient probably you will have more diagnosis and I think that we have also to give this information to other doctors than a methodological doctor and we have to give this information also to cardiologists but a lot of cardiologists do not know very well these diseases and how to diagnosis that's the first step the first important step is to think about it and when the patient with amgus or is coming before I'm tired, I'm losing little bit weight some chronic nausea, just okay we will search it and try to find it then I think that we do not have the spectrometry mass but we are sending it in France so there is possibility to work with other specialized center because I think that it's not available in all the country and I think also that with the immunochemistry you can always exclude AA with the kappa lambda it's sometimes difficult because there is sometimes we have a capitation for you have positivity for both kappa lambda it's difficult to see it and I think that a good amnesis to be sure that there is no a story in the family there is no a story of cardiac dysfunction and such if there is this story to search mutation and hereditary amyloidosis and then if you are at the end of the day is it eating between AL or senile or transteritine amyloidosis the bone scantigraphy it's a good way to help you but I think that you have to work with to try to involve some cardiologists in your pathway of the disease and to search it with simple biological marker albuminerial and anti-promine P and then two. Oh, thank you. And we also know that for AL amyloidosis the treatment is adapted you talk about risk adapted chemotherapy it's not the same dosage for AL than for myeloma so how do you treat patients who has concomitantly multiple myeloma and AL amyloidosis? We treat, it depends. If we have just 11% of plasma cells and no crop symptom or new myeloma marker for aggressivity, we will treat the patient just as amyloidosis but if we want to perform a transplantation we will make before we'll do before an induction with two cycles or four cycles or a proteasomy per cycle for swami dexamethasone. But it is a multiple myeloma, symptomatic multiple myeloma with AL amyloidosis. We will treat the patient according to the... Sorry, it's the allergy. Yes, but it's time for allergy and so on. Thank you. So we will treat the patient according of or multiple myeloma guidelines but so sometimes we will have access to different drugs and it's better for those patients, especially in the context of the relapse of not or we are not happy with the answer, we will have access to the diarhochimumap. And so that's easier for us to have access to the new drugs. But at the time of diagnosis, so if the patient is a candidate for the transplantation, we will treat the patient as for the multiple myeloma as we are using the same drug, but we will perform more tests, cardiac tests, we will have less patient candidate for the stem cell transplantation. So we will also, we will follow a mix of the myeloma and the amyloidosis guidelines. We will use the drug of the myeloma but we will use the criteria for stem cell transplantation of the amyloidosis. The only thing that could change is the fact that if we have a translocation 11-14, we would like to add a male phalan in the induction treatment because we know that the patient will not have a good answer to the bortisomib. And for the patient with who are not candidate for transplantation, in Belgium we have the gold standard. The first line is MBV, male phalan prednisone, Velcade or the nalidomid dexamethasone and we will prefer male phalan with Velcade. As in first line, we have not a lot of data with the nalidomid and we know that we have a more rapid answer with proteasome inhibitor and so unless the patient have really severe cardiac function, severe neuropathy, we will use the nalidomid. You spoke a little about losing patients even before the stem cell transplant. Yes. And in 100 days after, is it just the heart involvement or what's that data correctly? That's mainly patient with heart involvement. And so the improvement is due to measuring anti-pro BNP? Pro BNP is a marker of the cardiac involvement and so we improve patient with severe cardiac dysfunction during the first months, we have not so impressive improvement of the prognosis of the patient but as I show it, for the patient candidate, for the stem cell transplantation, we are not selecting a patient with severe heart dysfunction and I think that in the first study with stem cell transplantation, we were less strict and so some patients had severe cardiac dysfunction and have an autologous stem cell transplantation and we know that today it's not, it's not, there is no way for those kind of treatment for those patients, it's too, too easy treatment but we also for those patients make the amelioration of the prognosis because of the monitoring of those patients and the collection of those patients and also after the stem cell transplantation, we know those patients have more frequently bleeding and we know that for multiple myeloma patient after the stem cell transplantation during the aplastic phase with the low placate number, we will give transfusion when the patient have less than 10,000 platelets in the blood but for AL amyloidals, we will be more strict, we will search blood in the two NB, the stool and we will also make the transfusion at 20,000 levels and so it's all those kinds of things that improve the pronostic of the stem cell transplantation but also the fact that we are better selecting more patients. To confirm the diagnosis for my suspect of geometry. So we are first performing the immunochemistry, we are doing also sometimes electronic microscopy and then when we have the red congo, we have, if you have the, we are sure, sometimes we are sure of the diagnosis with immunochemistry, you have only positivity for lambda or kappa chain and all this difficulty to see that you could experience and so we are not referring the samples to other center in this case and sometimes it's very difficult, the pathologists could only say okay, it's not an amyloidosis, it's only what I can say and those kinds, sometimes we are performing, we are always performing a bone CT but even if we see that there is a transteritine, sometimes it's difficult to say which one you have to search mutation and then for those case we are sending or samples. I think that we have to, it's a rare disease. At this time in Belgium there is no, this tool to analyze and we have for rare disease, we have to work between experts to be sure of the diagnosis and so we are, even for the multiple myeloma, we are also, not for, we are not sending samples but we are working with the IFM group with the, so it's always important to have collaboration and to work together especially for those rare disease, so we do not hesitate to contact them and to send them the samples and they're always happy with that, so there is no, thank you.