 Good morning. My name is Dr. Monique Minema. I work as a hematologist in the UMSI Utrecht in the Netherlands. And today I will give the presentation about developments in AL amyloidosis, diagnostic centers of expertise, treatment pathway and stages of disease. And I would like to thank the myeloma patients Europe organizations for inviting me to give this lecture. This lecture will be has certain elements if we go to the next slides. I will talk a little bit about some disease specific information on AL amyloidosis about epidemiology, the current standards for diagnosis and which centers have expertise in Europe. I will explain a bit why it is so complex to diagnose and treat this disease. And I will also talk a little bit about treatment goals and treatment pathways. But I know that later on in the Congress you will hear more about it. So I will shorten that section a bit. So first of all the disease specific information on the next slide. Importantly is that AL amyloidosis is one of the plasma cell diseases that we have that we can diagnose. And many patients hear about that they have AL amyloidosis with amicus or with myeloma. But that's not correct. So it's a separate disease, a separate entity. And of course it's a quite rare disease and multiple myeloma is well more known to doctors and to patients. But also amicus monoclonal temopathy of unknown significance is a much more known disease. And I highlighted multiple myeloma and AL amyloidosis because during the presentation I will compare these two a bit so you can more clearly see the differences between those two diseases. And on the next slide you can see the basis of the disease AL amyloidosis. So like all plasma cell diseases it starts in the bone marrow where you have plasma cells that become malignant or pre malignant and we call them clonal. So clonal plasma cells that divide and divide and these plasma cells they maintain their normal function. So the function of a plasma cell is to produce antibodies. And plasma cells that form the disease AL amyloidosis especially form free light chain. So that's a little part of the antibody. And it's depicted as the small little bars that you see. They are in the bloodstream and through the bloodstream they can enter or they pass every organ in your body. And what's so different about the free light chains of plasma cells in patients with AL amyloidosis is that they have a dysfunction in the way they are formed. They are shaped so in that three dimensional structure. And already in the bloodstream they have an intermediate stage. So they become a bit different in their shape. And when they reach the organs they shape differently a little bit more and they form fibrils. It's like deficits that are attached into the cells or next to the cells of several organs like the heart but also the liver and also your bowels can be can have deposit of amyloid fibrils. Also the kidneys is an organ that's much involved and also the neurological system that makes you sense or regulates your body. And if you go to the next slide I would like to stress out that not every systemic amyloidosis is a form of amyloid light chain amyloidosis. We have several precursor proteins in our bloodstream that can form amyloid fibrils and it is of the utmost importance to diagnose the right precursor protein so the right type of amyloidosis. Most amyloidosis are AL so that's the more frequent form but the more but the other amyloidosis are mostly inherited so you get them from your father or mother besides the ATTR wild type so that's also a form of amyloidosis that's more common but that's developing during your lifetime. So AL amyloidosis is something that you acquire during your life and the precursor protein is the amyloid light chain that is produced by your plasma cells and in the green the green bar you can see what happens when a precursor protein in AL it's the light chain dismantles and forms a misfolded protein and then it forms fibrils and those fibrils are the same in every type of amyloidosis and they are deposited in your organs. If you go to the next slides you can see the differences in complaints between multiple myeloma patients so they are in the blue bar on the right and the complaints that AL patients have and they are in the pink bar. So shortness of breath, fatigue, edema, foaming urine but problems swallowing or eating, diarrhea and weight loss, low blood pressure is very common in AL patients, property bleeding of the skin, having a large tongue, difficulty speaking or difficulty swallowing and carpal tunnel syndrome not in one hand but two hands are all typical complaints that you can have with AL amyloidosis. So you can see they are quite different than the complaints you can have with multiple myeloma, hypergalcemia, renal insufficiency, anemia or bone lesions and the problem is that with multiple myeloma you have four separate entities but in AL it's quite different and if we go to the next slide you can see that sometimes I hope that we can find an acronym so we can more easily detect AL amyloidosis because the acronym in multiple myeloma is CREP and that's easy to remember for many physicians if you think about multiple myeloma. In the next slide you can see why what are the problems with AL amyloidosis, it's a very rare disease so not common I think most physicians never heard about it and it's a very complex disease you have those more than 30 different subtypes, the subtyping of the amyloid fibres is important and you have complaints related to heart, kidney, nervous system, soft tissue with bleeding and they present with different combinations and different severity in each patient's individual and the problem with our healthcare system is that we are divided in organ systems you go to the cardiologist when you have problems with your heart and you go to the nephrologist if you have problems with your kidneys so for them it's very difficult to think about a systemic disease that can cause all your complaints of your heart for example and the other problem is that heart problems with AL amyloidosis are not typical in their presentation so your cardiologist normally thinks about other types of heart diseases and not of AL amyloidosis so that's also one of the difficulties in diagnosing this disease and sometimes it's like finding a needle in a haystack it's very difficult for an organ specialist to think about these systemic type of diseases if you go to the next slide I will talk a little bit more about the epidemiology and again you see AL in contrast with multiple myeloma and you can see that the median age but also the division between men and women are quite the same in both diseases but AL is a very rare disease six patients per million persons per year and multiple myeloma 70 patients per million per million persons per year the median time to first from your first consultation to diagnosis is already pretty long in multiple myeloma 163 days but in AL it's median in the Netherlands it's 441 days so that's extremely long before a doctor thinks about this diagnosis so we have to improve on that I think that's one of the most important tasks that we have and the median survival increased a lot in multiple myeloma it's now six to seven years median but in AL amyloidosis it's shorter the median survival is only a little four years after diagnosis so also there much improvement is needed and if you go to the next slide you can see that we do improve on overall survival so this is a study from the national national amyloid center in London and you could see different time periods with different lines so at diagnosis 100% of the patients are alive and on the vertical bar you see the time when they elapsed so you see that patients die during their disease course but you see improvements so the red line is the latest period of 2008 to 2012 and you see the improvement in survival is there but it's still not enough and what's also striking is that we have a curve in a different mode of way tempo that patients are deceased so in the beginning if you go to the next slide we have a very high mortality rate so in the first two years almost 50% of the patients die because of the problems with the heart and with the kidneys for example but if you go later on and if you go to the next slide you can see that in the end the curve is almost vertical again so it seems that if you survive for a very long time let's say after eight years your prognosis is much better because then perhaps some patients are cured from this disease so high amount of problems in the beginning but later on it seems to do a bit better than myeloma and on the next slide you can see how we stage AL patients so we don't stage them like myeloma patients but we stage them from the organ that is most important for their survival and that's the heart and the heart has some enzymes that they release into the blood stream we call them biomarkers and we can measure them when we take a blood sample and the two most important biomarkers are anti-pro-BMP and troponin so they are cardiac enzymes they are released from the heart and the higher they are the worse your heart is so if you have stage one disease both troponins and anti-pro-BMP are low but if they are elevated above 332 and also your troponins are elevated then your median survival is much worse and in this old scheme only four months later on an addition was made by the european amyloid working parties and they defined that patients with an anti-pro-BMP above 8500 picochroms per milliliter did even did even worse so now we have four stages of cardiac we have four cardiac stages and the staging system has to be used for every patient before you start treatment of AL patients because the patients who are the most fragile have the most severe heart disease so the stage 3B patients they cannot tolerate a lot of medication so they have to be treated differently than stage one patients and in the next slide you can see the survival in those in this cardiac staging system so on the left again AL amyloidosis patients and you can see the stage one patients who have little or no cardiac heart involvement do much better than the stage 3B patients in which death after diagnosis is very high in the first year already and you can also see that's very different from the multiple myeloma staging system that we call that the revised ESS and they use different parameters like better to microcobaline that are all parameters from the plasma cell dynamics and they have a different survival which is much better than for AL patients except for AL patients that don't have cardiac involvement and if you go to the next slide you can see in Europe where the centers of expertise are but we do have a problem there so in Europe we have organizations they're called European reference networks so they are the European organizations where expertise centers in every country in Europe can organize themselves together and try to enhance the knowledge and the treatment of patients with very rare diseases but for AL amyloidosis but for all amyloidosis they are divided again against different types of specialists so we have Euro blood net that's the ERN for hematologist but then we also have Rita and that's the ERN for immunologist and rheumatologist and they treat more ALAA amyloidosis so that's with inflammatory diseases we also have card heart they are specialized in heart diseases and euro and MD and they are specialized in neurological and muscle diseases so here you see the same problem as we have in diagnosing this disease is also that the centers of expertise are divided in four different European reference networks but if you look from a different perspective there are in many rest of European countries there are national amyloid centers so in London it's arranged very nicely but also in France Germany Italy Greece and in the Netherlands we have the UMC Groningen which is the national amyloid center but I'm from another hospital I'm from the UMC Utrecht in the Netherlands and we are more specialized in the more common forms of AL amyloid the more common forms of systemic amyloidosis like AL and ATTR amyloid doses so we have two centers in the Netherlands at the moment in the next slides you can see how we diagnose your disease so AL amyloidosis follows the rules of the IMWG diagnostic criteria and they were published in 2014 and all four criteria must be present so you must have organ damage caused by amyloidosis so you have to have heart failure or liver problems or complaints of your nervous system caused by those amyloid fibrils if you have just fibrils but all your organs function normal then you don't have amyloidosis to prove amyloidosis we have to have a biopsy so we have to have a biopsy that is positive for the conco-red staining for example you can do fat or bone marrow biopsy but the conco-red staining has to be positive if it's negative you don't have amyloidosis and after you prove amyloidosis you have to type the amyloidosis so it has to be tied by immuno-histochemistry but that's not very easy to use and most of the time it doesn't work that well but now we also have mass spectrometry also in Europe we have several centers that use mass spectrometry it was developed in the Mayo clinics and for example in Italy and we in Utrecht we have the immunoelectron microscopy so that's also a very nice way to type your amyloid and then when you type you know the precursor protein and then you will know how to treat it and for AL amyloidosis of course you have to have the precursor protein in your blood or your urine so you have to have measurements of your free light chains and you have to have a clonal plasma cells in your bone marrow and if you go to the next slide you can see where you can biopsy to see if you have amyloidosis so if you do a bone marrow puncture we always advise to do the biopsy and not only the aspirin because in the biopsy you can see the you can do the conchorette staining and on the right you see how conchorette looks through a microscope so this is a fat tissue and you can see the red lighting up and that's the conchorette dye that's that is attached to the fibrils and if the pathologist moves the microscope to another light bundle you can see it's lighting up in a green yellowish color that's very typical for amyloid fibrils they are the only ones that do that so we have a very secure instrument to diagnose amyloidosis what we do a lot of times when we see patients in our expertise center is that we ask for old biopsies to be taken because you remember most patients it takes around two years now not two years one and a half years before the diagnosis is made so sometimes they already had biopsies taken but nobody looked for conchorette for the for the amyloid so nobody did the conchorette staining I mean normally see when we ask for those old biopsies to be sent to us that we can't see already the conchorette the amyloid in in the stomach for example so that's a very important that always has to be done when you are seeing patients with AL and also if we if the bone marrow puncture of our old biopsies don't show amyloids we can do an abdominal fat tissue biopsy so it's important that you puncture the fat cells and not the skin so that's more a technical failure but that has a very high sensitivity for diagnosing amyloids in tissue and also salivary salivary glands biopsies also have a very high yield to diagnose amyloids so these are the most preferred organs to biopsy but if it doesn't work if you go to the next slide you can also biopsy the organ that has the problem so if you have a kidney involved with amyloidosis so we have an nephotic syndrome most of the times you can do a kidney biopsy you can do a heart biopsy you can do a liver biopsy but because there are a little bit more bleeding problems with those biopsies we only tend to do those when the other on the left side fail importantly we never biopsy the nervous system because they the biopsies very painful and they give a lot of complaints of pain afterwards so the nervous system biopsies can't be done if you go to the next slide you see some of the frequently observed problems after biopsy is taken and they are related to the underdiagnosis and we as an expertise center we see them a lot and we try to to warn our colleagues about it all the time so if a clinician has a patient with problems for example kidney problems and they do a biopsy but they don't ask for this specific concurrent staining or they don't mention the differential diagnosis amyloidosis in the remark to the pathologist the pathologist won't do this separate staining so therefore amyloid is not seen and it's not reported but it's there another more frequent problem if you type if you go one more next is that the concurrent staining is done but the pathologist think it's negative and that's something sometimes relates to the experience of the pathologist but also to the type of microscope the pathologist is using or sometimes the biopsy is too negative it's it's really not there and then the clinician thinks oh I can reject amyloidosis and no other biopsy is taken but you if you really think that amyloidosis is the problem then you should biopsy another organ for example the target organ or the pathologist should send this biopsy material to an expertise center like ours so the expertise pathologists can do the concurrent staining again and I think in a substantial amount of cases they do see the the amyloid present and another problem if you go to the next is that the concurrent staining is done it's positive but it's not subtyped so for example the fat biopsy is done they see amyloidosis the patient is an older patient also has some plasma cells or a free light chain in the in the in the bloodstream and they immediately think oh this will be AL amyloidosis but this can also be for example ATTR amyloidosis so subtyping is extremely important and this is I think one of the most important problems and this was published already in 2002 by the national amyloid center that in 10 percent of the patients with which they thought other centers thought they had AL really had ATTR amyloidosis so those patients received chemotherapy well they didn't do anything about that their amyloidosis because TTR amyloidosis is not treated with chemotherapy so subtyping is also extremely important if you go to the next slides you can see some my thinking about the problems and diagnosis so one of is one the first problem is that the clinician should think about it and the other problem if we move one more further is that after they think about it they should prove it and both think about it and prove it are very difficult in AL amyloidosis so what can we do about it if you move further on the slide you can see that we think about it by giving education education post-education training and repeat repeat repeat so that's my experience that we have to repeat ourselves every time again so we can reach as many clinicians as we want to as we need to we also have to give this education to several disciplines I can't only teach hematologist about this disease I also have to teach cardiologist neurologist neurologist about this disease because the patient doesn't enter the hematology clinic they enter the cardiac clinic or they enter the nephrology clinic with their problems so several disciplines has to be targeted and when we educate clinicians we talk about red flags so there are some typical things for example with cardiac disease that can help the cardiologists to think about AL amyloidosis we publish guidelines and we make publications and also for the diagnostic part we give education if you move on and the education is especially about the knowledge of the several techniques when to use it and how to subtype but also to offer our help so we have expertise centers in Europe and if you think about amyloidosis but your pathologist can't prove it send the material to us and we will help you with it and of course also national guidelines but also European guidelines are very important in this aspect if you go to the next slide I also think about this so prove it thinking about it again are we missing an acronym and I think perhaps with all the patients together now listening to this talk perhaps you can help us creating an acronym for this disease and I think it will help us a lot to educate our colleagues and our clinicians in diagnosing thinking about this disease and also proving amyloid in our patients next slide please some words about the treatment pathway if you go to the next slide so I talked about the precursor protein that's the the concept that we see and type our amyloidosis patients and in and the general principle is that we have to treat the precursor protein so in al it's done by lowering the free light chains in the blood and we can lower them by treating the plasma cells that are present in the bone marrow and we know how to do that because we have very effective anti plasma cell director therapies so if we treat a the plasma cells we stop the sink form from filling filling filling with amyloids and then the the body itself can try to break down some of the amyloid that's B so the total amyloid load will then lower a bit in the patients but the only thing that we can do as AL specialist is turn the tap closed so stop the amyloid growth stop the free light chains and stop the plasma cells from producing those free light chains so that's the general principle so how are we going to do that in the next slide you can see that there's no established anti amyloid treatment so I think we would prefer to have some type of treatment that we can remove the amyloids that in in the body of the patients like some kind of a dissolving mechanism or some other mechanism that we can stimulate your body to clean up the amyloid itself but we don't have it so that's a big area of research and we almost thought that we had it so this is also two publications from the amyloid center in London and they had developed an antibody that could really clear amyloid from your body and if you type one more if you go to the next slide you can see patients this is a sepscan and a sepscan that's only available in London and in Groningen so in the Netherlands in the complete world so that's a very special scan and that can visualize amyloid in the liver so in on the left side you see a liver full with amyloid and you see a patient in a trial that was given this antibody and they really cleared the amyloid in the liver because you see the intense black coloring diminishing but this drug proved to be also very dangerous to patients so they stopped the development of this drug and at the moment we don't have a clear anti-amyloid treatment besides if we go to the next slide perhaps an antibiotic so in patients with severe heart disease sometimes this antibiotic is given in addition to anti-plasmus cell treatment because there are some reports that it could work for patients but we are waiting the final there's a trial going on at the moment so we are waiting the final results of the trial another general principle is that patients with AL amyloidosis are frail they have problems with organs inside their body and they are much more sensitive to side effects and they can't tolerate treatment as myeloma patients do so my big message to all clinicians who are seeing patients mostly hematologists are don't treat them as if they were myeloma patients and also AL patients need additional care for their problems with their heart kidney and so on so for example in myeloma patients when you have a lot of cancer cells in your bone marrow sometimes the nurse will say to you drink a lot of fluid because when we start treatment all those plasma cells are going to die and you need to drink a lot to help your kidneys clear those plasma cells but in AL patients who have heart disease they can't tolerate a lot of treatment because they will have edema everywhere and they will have problems with the heart so they mostly have a limited fluid intake so the care for the organs is very different in myeloma patients and we really need experts on that field and we really need coordinating nurses or physicians that that can help the patients a way through all those difficult complaints they have when we are also starting chemotherapy anti plasma cell treatment so in the next slide you can see how we are going to do that but first the last general principle is that if we do it very well if we treat the plasma cell clone extremely well and if you go to the next slide you can see how that works so this is again a survival plot and you can see that patients who are reaching a cr that's the blue line so these are patients where the plasma cell clone and the free light chains in the bloodstream are completely gone so there's no plasma cells the free light chains are normal again we call that complete remission and if they are 90 degrees we call that a very good partial remission so feed gpr and if you can reach that with your chemotherapy treatment your outcome is much better than if you don't reach that so you can see the heart is very prognostic in al patients but secondly how we respond to treatment is also extremely prognostic if we can um treat the the plasma cell clone very effectively your prognosis will be much better than if we don't succeed with that so if you go to the next slide you can see why that is because if we stop the the the amyloid forming free light chains and we if we stop that completely then your body will have time to clear up the amyloid itself and there are cells in your body that can do that we call them macrophages so we can see that in patients who are having a cr or a feed gpr with years to follow that organs do improve we see that with the heart we see that also with the kidney and we don't see that as much with the nervous system for example and we also don't see it in all the patients but they can only reach that goal of organ improvement if we first stop the production of new amyloid forming free light chains and on the next slide you can see how we do it so this is a very nice overview that was published by the italians and you can see that we have the cardiac station in place because that will guide us through the treatment choices so low risk patients with some but are non-cardiac disease who are functioning well are aged below 70 their kidneys are still performing well and there are some other important things but mostly the heart they can have the most intensive treatment that we have and that's autologous stem cell transplantation but only 20 of the patients will have this treatment and that's different from myeloma where most of the patients below 70 can have this treatment so low risk patients can have an autologous stem cell transplantation the intermediate patients that's almost 60 of the whole AL group they will have chemotherapy and they will be treated with portesimib, dexamethasone and cyclophosphamide and that's a scheme we call it cyborg D that looks a lot like the scheme that's also used for myeloma patients but it's dosed differently so the doses of cyclophosphamide, portesimib and dexamethasone is much lower than in myeloma patients and also the frequency is lower than in myeloma patients because if you treat them like myeloma patients they won't complete this treatment and the very high risk patients so that's the patient with the cardiac stage 3b so where the heart is very much involved of the disease we are still struggling how to treat them well at the moment we have a european study for those patients with DeraTumorMap that's a monoclonal antibody treatment that you will hear more about later on in this day but we are still searching for that so sometimes we try just one of the cyborg D regimen for example only the portesimib and if it's tolerated we introduce another agent but we have to go very very slowly very well you don't have to go slowly but we have to go very careful with those patients because if you treat them with a harsh regime of chemotherapy patients won't tolerate it and they can die because of this very toxic regimen for them so I think we are moving to my last slide now this is again one of the differences that you can see with AL on the left and multiple myeloma on the right you can see the differences in autologous stem cell transplantation we still believe that it's an effective regimen but only 20 percent of the patients can tolerate it and you can see that the long-term survival is around 30 percent of the patients are still alive 20 years after they received their AL day autologous stem cell transplantation so that's very promising but it's a very selective treatment it's not for everybody and if you look at newly diagnosed multiple myeloma patients almost 80 percent of the patients can receive the autologous stem cell transplantation but their survival at 20 years is a bit lower than in AL patients because there the disease is more aggressive and will relapse more often than it does in AL if we go to the next slide you can see our general conclusions so if we treat AL we can only treat the plasma cells we can't treat the amyloid itself and the drugs used to treat those plasma cells are the same in AL as in multiple myeloma it can be well treated because it's mostly a small clone it's not that aggressive and remissions induced are longer than the myeloma but the dosing and schedules used are different side effects are different and also the co-medication is much different and if you go to the next slide you can see something of the future I think what you really need besides more early diagnosis more awareness of this disease is that we also need more treatments for the plasma cell clone that is less organ toxic and with the monoclonal antibodies like Darotumumap I think we have a very important tool in hands now and I know that later on in the day you will hear more about it from Professor Matteu's presentation but another development is targeted therapies and for example the fenetoclax that's sometimes used in multiple myeloma seems to be very effective in patients who have the 1114 translocation and the 1114 translocation in your plasma cells is the most frequent translocation in AL patients so almost 50 percent of the patients will have this translocation so we think that also fenetoclax can be a treatment option in the near future for our patients and you can see the results of a small trial in which many patients responded very well to fenetoclax treatments with combined with dexamethasone and only one patient in the gray bar did not respond but this patient also did not have this specific translocation so perhaps in the future the analysis of the mutations in the plasma cells can help us guide treatment for our patients and in the next slide I would like to thank you all for listening and I would like to think Mirjam Brink sees her research from the Dutch cancer registry and so she provided me with some data that I presented to you and I would like to thank the team in my hospital the UMC Utrecht and especially Dr. Rooslegheut sees our pathologist and you see her here on the picture with Dr. Laura Verca sees the pathologist from the amyloid center in Pavia Italy and they trained us to do the electro immunohistochemistry for typing the amyloid in biopsy material so we are very grateful to them as well thank you for your attention