 multiple myeloma. I worked in the research lab of Ken Anderson and really focused on multiple myeloma also in Pittsburgh and coming to Columbia with a very strong background in cardiology, nephrology, pathology. I have to say they have a very strong pathology. I saw more and more amyloid patients and I have a huge amyloid population right now and I think that's the reason why David invited me to talk about amyloid. We also have a very interesting approach how to treat amyloid. We have a monoclonal antibody and I will spend half of my talk to give you a little bit of insight on the newest developments of that monoclonal antibody present some data we have in a clinical research trial. Okay, so to kind of you know talk about amyloid dose I think how do we make the diagnosis? How do we select the right therapy? That's important amyloid doses. We use usually steal all the drugs from multiple myeloma but there are some I would say special things in amyloid doses we have to take into account and we cannot just kind of you know use our approach from myeloma and amyloid doses one to one. I think what is really interesting is the development of the monoclonal antibodies as in amyloid doses to help the body to break down the amyloid. So amyloid doses is a protein misfolding disease and what you can see here nicely you can have over 28 different proteins that are able to form amyloid so that reaches from abnormal enzymes like lysosomes or proteins apolipoprotein transiratine that's especially in older patients the TTR amyloid doses transiratine amyloid doses but we usually deal with the light chain amyloid doses where free light chains form an abnormal protein and typical for amyloid is the congorate staining in another microscope and in polarized light microscopy you've seen the typical apple green staining for amyloid. So what types of amyloid we can have in the beginning as I started to work with amyloid dose I was always confused but all the terms are ALATTR so very simple when you see patients with amyloid doses and they come to your clinic and you see there's a capital letter A that stands for amyloid doses and then second you see this is light chain TTR mutational that's hereditary amyloid doses white type amyloid doses that's H related so the transiratine just becomes clumpy or sticky with H so that's why patients especially older men develop very often TTR amyloid doses other types of amyloid doses fibrino gene apple lipo protein I mentioned that already there are certain organs that are predominantly involved in amyloid doses and patients for instance with AL amyloid doses almost all organs can be involved this is a nerve system soft tissue whereas the white type TTR amyloid doses mainly affects the hearts or kind of you know sometimes the GI tract so based when patients come how they present sometimes we already have a little bit of idea in which direction it goes so this is a nice work from the Mayo Clinic the Mayo clinic has probably the largest population for amyloid doses so they evaluated over 5000 patients which they treat between 1960 and 2009 for the percentage of certain types of amyloid dose and you can see most of the patients have primary light chain amyloid doses followed by localized amyloid dose and then central our TTR amyloid doses and only a fraction or kind of in a very small number of patients have other types of amyloid doses so how does amyloid develop usually monoclonal plasma cells secret free light chains they found the amyloid and indirectly we can only measure the tissue damage there's currently no and that makes it a little bit hard there's currently no test that really tells us this organ is affected or how many organs are affected or what the extent everything is basically an indirect measurement so that results also in the clinical manifestation almost all organs can be affected nephrotic syndrome with real this or without real insufficiency so if you have a patient for instance with an amyloid and an nephrotic range protein urea think about amyloid doses that means if the patient loses four gram of protein in the 24 hour urine that's kind of you know raises a high suspicion for amyloid doses peripheral peripheral neuropathy carpal tunnel syndrome very often we see that very often and when i ask my patients you know have you ever had a carpal tunnel surgery and they said yeah doctor you know i had that couple years ago very often they don't bring it in connection with their amyloid doses hipadomegaly for because of amyloid involvement macroglossia and purpura the typical racoon eyes that can occur spontaneously or after minor trauma or pressure they're very typical but not seen very often so you should also think about amyloid doses when you see your patients suddenly unexplained dyspnea and especially diastolic dysfunction so when you read for instance when i read the echo of an amyloid patients i don't care about the e f the ejection fraction is usually preserved because the ejection fraction is a volume of what you pump out from the volume you have in and it's a hypertrophy and you have a small volume the the left chamber is still able to pump an amount a potentially good amount of volume out of the heart but you have to look really for the diastolic dysfunction that is really important so left ventricle hypertrophy and a systolic blood pressure below kind of 100 110 i asked my patients where you before on blood pressure medication when they come the first time and we kind of you know try to find out do they have amyloid doses what's going on i asked my patients where you're on blood pressure medication and very often they say yeah i was but my doctor stopped it because my blood pressure is low right now so that should always raises you know the suspicion to look a little bit what is the reason for this i mentioned already protea urea epatomegaly for amyloid involvement but also for volume overload very often we see in our patients an increased ALP that is due to the right heart failure autonomic nerve dysfunction low blood pressure that's the main issue we have to deal with i have patients who have such a low blood pressure that they're not even able to leave the bed you know that really brings us it's a huge medical challenge to deal with those patients amgas smoldering myeloma milder than myeloma wall storms just think about amyloid doses when those patients come to you and they suddenly have a low blood pressure or heart failure or more shortness of breath i would think about that almost all of your patients have an echo and if you look for diastolic dysfunction it might give you a good hint so how do we make the diagnosis first the patient presents with some the symptoms with the syndrome then we have to prove um kind that the patient has amyloid doses usually by a biopsy of an organ and then we have to make sure that we type the right amyloid i mentioned already that we have several types of amyloid doses so it's really important that we do the typing either by immunohistochemistry it depends on pathology how familiar pathology is with the typing of amyloid at columbia they have a pretty good method to digest the amyloid open up the binding sites for the antibody that's usually the issue the amyloid does not bind the antibody so when their pathology is not able to do this or they have not convincing results or doesn't fit they some suddenly say okay that's an kappa light chain amyloid doses but you have lamna light chains in the serum then you have to discuss with pathology that this cannot be the right typing then usually mespectometry is the right way to do and mespectometry um we don't do that at columbia i'm sure you know that yeah we send that usually to meo clinic meo clinic is excellent they have an enormous kind of an amount of samples and experience so what we do we send the samples the biopsy samples to the meo clinic and they um do a micro dissection of the amyloid this is a congruent staining so they cut out the amyloid tissue and then they do mespectometry so the sequence and according to the sequence they can say okay this is probably i g g lamna light chain multiple myeloma very elegant method and that really confirms you know i would say 99 or 100 percent you know that you have amyloid doses what about prognosis what determines the prognosis and amyloid doses it's um and it's the heart it's the heart and then hematologic response so we're a little bit lost you know so in multiple myeloma we can achieve responses and we can say you are doing well and amyloid dose unfortunately it really depends on the heart and then we come in with our treatment and then next it depends on the organ response and at last the numbers which are involved kind of how high the free light chains are and in contrast to multiple myeloma cytogenetic doesn't really play a big role in amyloid doses so we know that a lot of patients have translocation 1114 that open up new treatment opportunities we need to collect for instance a bcl2 inhibitor so interesting new drug also maybe for amyloid doses but you can see it differs from multiple myeloma um how did we came up with a response criteria which also differ from amyloid doses so shashi cumo did a very nice job and evaluated a couple hundred of patients for their risk factors and he found out that one of the risk factor is really the difference in the involved and uninvolved light chains so if the difference between kappa and glumna light chain is more than 18 you have a higher risk factor for my amyloid doses and a pro prognosis also and you see that goes back to the heart if the nt pro bnt that's a marker for the stress of the heart is over 1800 1800 or your troponin t is over 0.03 you have additional bed prognostic markers that give you a worse prognosis so based on this he established a prognostic scoring system you can see the difference in the free light chains more than 18 gives you one point troponin t more than 0.025 another point nt pro bmp more than 1800 another point you can get three points three points bring you in stage four and stage four has really a grim prognosis you know this is our kind of you know patient population this is stage four there's a median oval survival of 5.8 months that really beats multiple myeloma so if the patients come late stage horrible prognosis and that slide tells you the responsibility you as a physician or vs physicians really have you know it's really important especially when you see patients with amgas think about amyloidosis because when you have a patient and you diagnose a patient earlier you can see stage one the median oval survival 94.1 months there they're sometimes cured if they come right away they have a low amp spike sorry a low difference in the free light chains they have limited organ involvement we give an autologous stem cell transplant they don't even see a lot of chemotherapy they go in complete remission and they are cured i have patients who are cured that's what i think but 10 years in a complete remission without any amyloid symptoms that's really i would say kind of you know a huge progress we have criteria for the response assessment in light chain amyloidosis which differ a little bit from multiple myeloma you can see complete remission is always easy negative serum and urinary immunofixation with a normal free light chain ratio a vgpr in contrast to multiple myeloma is when the difference between involved and uninvolved light chains is less than four or 40 milligram per liter so that's i would say is a main difference otherwise in amyloidosis we also measure when i say amyloidosis sorry i talk about al amyloidosis just to make sure so in al amyloidosis we also measure the organ response and i think what is most important is to measure the cardiac response and progression usually we use the anti-pro BNP and the troponyl tea here's some kind of you know decreased by 30 33 percent a kind of you know determines organ response yes there's a disconnect between the immunological response and in the organ response and improvement so what is not just advanced stage i mean what do we think of this disconnect yeah there can be a total disconnect because you have to um what i want to emphasize is the hematologic response we can achieve pretty fast many patients go into complete response after transplant but the organ response needs more time the body needs to be able or the body has to break down the amyloid and that takes up to one or two years and usually it's a race when we start the amyloid treatment we want to bring down the light chain as soon as possible but patients can in the meantime undergo organ failure so there's a point of no return for your heart or for your kidneys usually for the heart so we have patients who die from amyloidosis in complete remission yeah so this is more the amount of damage that is already there that is difficult to return that yeah see when you when the structure of the heart is so damaged you know if between the myocytes are so much amyloid you know you cannot reverse this so and that's a big problem and the other problem is the longer you wait and the more organ damage you have the kind of you know the less treatment options you have you cannot do a stem cell transplant you cannot really be aggressive with your steroids 40 milligrams of dex is almost impossible in patients with advanced heart failure so that's why I think early treatment is really key I had an argument with a young kind of you know amyloid patient she was 74 she had her stem cells harvested she was after cyborgy in a complete remission and what should we do should we give her a stem cell or not so we called everybody you know we called the Mayo Clinic Comenzo everybody said give her a transplant she is in good shape give her a transplant that's the best option make sure that you eradicate the disease if the disease comes back I mean she was very sick you know before couldn't tolerate the transplant got chemotherapy got better what do we do you really want to eradicate the disease in order to avoid that the disease is coming back and I would say amyloid is an ugly M-gas and in contrast to multiple myeloma we treat in kind of you know the M-gas because we know if we wait it can really result in a very devastating disease damaging the organ damage maybe we use our kind of you know this from myeloma later and say you know you have to treat the disease early yeah if you go kind of you know really to the kind of you know genetics you will see that the certain certain genetic markers or certain kind of you know variants and the light chains kind of you know have a predisposition to to the organs but that's not ready for prime time it's not that we say okay you have this light chain abnormality you will have you know heart amyloid doses you know that's there some some work how much time do I have but but the tragedy that happens and is that you know somebody gets identified as having a myeloma whether it's molding myeloma or an amyloid or whatever and that the decision is made I'm going to watch this there's no clinical justification so it's that patient who who is is most important to to evaluate for evidence I mean we get those patients all the time they've been watched for 10 years and now they're finally getting symptomatic from from their amyloid and and if we had looked five years earlier or 10 years earlier we could have saved their lives I have patients who had only protein urea, kidney biopsy, amyloid doses so we we we check the free light the free light chains were normal so we did the bone marrow the bone marrow had 3% monoclonal plasma cells we gave the patient a transplant the patient is kind of you know you can see after two years that protein urea goes down and the patients are doing but I mean it's very nice to treat those patients you know when they recover as an organ function they're cured yeah but that brings me kind of you know when do we start treatment thank you for the nice kind of you know transition to my next topic so usually patients present when they have symptoms you know that's that's the problem of amyloid doses what we have doesn't matter which organ is involved if you have a patient and you do a fat pet biopsy and you determine amyloid doses you know usually then we start treatment and we don't wait before they have really organ failure you also treat localized forms of amyloid doses if they kind of you know really have only we'd only treat them and they really have symptoms like I had a patient who couldn't sit anymore because he had big bugs of amyloid and was not able to sit in those cases we treat localized amyloid doses otherwise if it is in the tracheobronchial tract or cutaneous lesions we just wait and watch so we do nothing with this clinical trials I think that's important try to put the patients on clinical trials and we discussed goals of therapy again deep hematologic response and durable hematologic response rates that can result in organ response keep in mind the all the reverse or the breakdown of the amyloid takes one to two years so even if you're in a complete hematologic response it takes one to two years before you have organ response and you only get organ response when you stop the further build up of the amyloid that means no light chains no abnormal light chains that's a challenge for all doctors who treat amyloid doses you need to kind of induce a complete remission but you are very limited by the physical ability of the patients to tolerate transplant treatment options good old melphalan is still an option for amyloid doses believe it or not patients who are really not in good shape very often tolerate melphalan very well I don't use it very often but officially it's a treatment option cyber D usually we start most of our patients on cyber D otologous stem cell transplant if you have any doubt that transplant is not really kind of you know the key player and multiple myeloma I think an amyloid dose is a key player so what we do is very often if patients do not have a lot of or not a high amount of tumor burden only few free light chains we take them to transplant right away I don't know how you do this we don't give any induction we say right now you are able to tolerate the transplant I don't mess around with any cyber D maybe you have side effects maybe you're not able to tolerate the transplant in four months I don't know what will happen with your heart we start the transplant right away heart transplant we do heart transplants not at columbia we send them to mgh usually but in selected cases patients who are younger first the heart transplant and then the otologous stem cell transplant monoclonal antibodies I will talk about that here's some data from proteasone inhibitors you can see cyber D it was a very small trial but I think it's pretty well tolerated it has a nice response rate in amyloid doses so in patients who cannot undergo transplant right away I usually start with cyber D transplantation that's a nice work from mori girls who evaluated 400 patients for the outcome in this cardiac amyloid doses and you can see patients with a limited cardiac stage have an excellent outcome he estimated the transplant related mortality was around 10 percent I think that's a little bit high we don't see 10 percent but maybe we are more selective it really depends on the center when you actually ask him that he says that the that 10 percent transplant related mortality is the same whether they transplant them or not so it's just that the mortality rate is higher but I think 10 percent is high oh what do you think transplant related mortality studies are like in the five percent range but we're more risk-adapted decision making so they're culling out the bad hearts based on what you're showing exactly that's that's really key you know that you but that's the point that I want to make is that they're they're saying we don't want to do transplants on those higher risk patients because the transplant related mortality is so high but it is it is no higher than if you choose not to do the transplant you exactly you can argue you know the patient kind of disease either way right right right that's true so but based on his work he came up on the evaluation of those 400 patients he came up with some criteria that he would not recommend transplantation with an nt probian p above 5000 troponin t if it is above 0.06 also there are certain age limitations I don't agree with a serum creatinine you know I would kind of you know also transplant patients with a higher serum creatinine be careful if more than three organs are involved I think that's important then patients are very often very disappointed when you tell them you know transplant eligible that I tell the patients you know only the minority of amyloid patients are really transplant eligible but but but again the you know you have to understand where he's doing his work and why is it so they're at the male clinic none of their patients are their patients they're coming in from outside and so when they transplant them and they they have mortality you know it's it's a better reputation if you yeah you said the patient at the patient coming back here the reality of it is is that the transplant itself probably isn't contributing as significantly to the mortality rate as you might think it was where you're where you're doing all the care so that for six months of care is all in your hands whereas in the male clinic it's it's either transplant over a home so they don't see the mortality rate so I think that a lot of that kind of data I think I think what we have to keep in mind when he shows the data this is for all hematologist oncologist for all transplant centers and it makes a huge difference whether you transplant one amyloid patient a year or whether you transplant 20 so I think you know centers like kind of you know your center our center are much more generous and really kind accepting patients but when you give a recommendation who to transplant to somebody who doesn't see a lot of amyloid patients I think you have to be a little bit more careful and that's why he kind of you know gives those data so that gives us a little bit newly diagnosed amyloid doses like multiple myeloma we decide first transplant eligible or transplant ineligible if the patient is transplant eligible very often goes right away to transplant if there is the goal is you know at least to achieve a vgpr then we go on observation if there is no hematologic vgpr then the patient needs more chemotherapy in order to bring him to a better remission yeah that's so officially under the amyloid experts there is no role for maintenance in amyloid doses I have patients I put on maintenance I shouldn't say that officially but I have patients who had really kind of you know advanced cardiac amyloid doses were able to I brought them kind of you know through transplant and they still have an M spike should I give them a second transplant should I kind of you know I give induct I give a consolidation with two cycles still there is some disease left I give them maintenance I have to say you know I don't do that on all patients I know you don't believe in maintenance there's again I do that in order to kind of in a void further progression and more organ damage but officially there's no role for maintenance in myeloma I know but it would make sense given the mechanisms are warm the deeper the response from the clinical response but if you a lot of these patients go into a complete hemorrhagic response yeah they probably don't need yes because they don't make their their tumor burden is not high it's because of tissue deposition so they don't need a lot more therapy besides the mouth line because we've eradicated the clone which is small and they probably can get by you know she may have some patients that if they still have something left you could argue for potentially doing consolidation but the majority of these patients did very good hemorrhagic responses yeah we all know that any disease in a completely medical response has a lot of a gynecology right and it's hard to measure the MRD but but it would free free like genes are relatively sensitive okay and so we do pick these up yeah yeah yeah all righty so but there's we talked a lot about chemotherapy but we still have the urgent need to improve organ response and that brings me to my next topic you can see we are able and we discussed it to eradicate the plasma cell clone but we still have the tissue damage you know and that is the question what we discussed you know what can we do to really improve the organ damage or head to break down the amyloid and the idea occurred I would say already 30 years ago as Alan Solomon University of Tennessee in Knoxville had the idea to really create monoclonal antibodies that target not free light chains which are circulating and you produce all the time but only to target light chains that are misfolded and kind of you know to target the amyloid directly so and what he developed he developed a monoclonal antibody 11-1-4 based on a urine of a patient he collected the urine for three days was able to extract the protein out of the urine it was a bench light chain amyloidosis and immunized mice and was able to develop that antibody and the specificity of that antibody is when you have light chains you know this is a native confirmation and when they undergo fibrologenesis they form a new epitope as you can see here in B you know this is not a kind of you know present in the native state but when they form fibroids you see the new epitope and the antibody binds to that new epitope shown here in B so it's very specific for amyloidosis so what he did is he implanted amyloid pieces subcutaneously into mice labeled the antibody with iodine and did a mouse pet CT and I think that's very elegant as you can see here the 11-1-4 antibody binds to the amyloid pieces and glids up in the pet CT he also showed in mice that he was able to shrink with the antibody the amyloid pieces so very he was very excited about that and said okay that's the first time that the antibody might bind to the amyloid directly and helps to break it down he wanted to do a clinical trial at this time point I mean I'm talking about drug development that's probably 20 years ago but at that time point the FDA came and said now you're not allowed to use your antibody in human you first have to show that it's binding to amyloid you have to do a clinical trial and show that 11-1-4 really goes to the organ of the patients so again he labeled the antibody similar to the mice studies with iodine injected the patients with that antibody and did a pet CT and the result you can see here very nicely he could show that the amyloid antibody the 11-1-4 binds to organ which have amyloid deposition here a patient with alumna amyloid doses you know it goes to the liver but also to the bone marrow he also did a biopsy of the liver to make sure that the antibody is really present in the tissue and this is you have to believe me the yellow dots are congo red positive and the 11-1-4 was found in the liver so that was approved that the antibody is really binding to the amyloid infiltrated organs that's another patient you can see here this is the congo red staining of the biopsy out of the liver this is the pet CT so that was very exciting and he was also able to use his antibody not only as a diagnostic tool but also as a marker for response so he did for instance 11-1-4 imaging of a patient with amyloid doses you see here the liver 2009 three years later there was a substantially decrease of the amount of the intensity of the uptake so based on that he wanted to start a clinical trial to use it antibody for the treatment of amyloid doses to break down the amyloid in the organs the FDA gave him finally the okay but at that time he was 80 years old and said you know i'm too old to do this i give it to susanne and to columbia so we started the clinical trial with support from the FDA and nci nci produced the antibody i mean it's a huge huge ordeal to do such a trial you need the drug under gmp conditions produced you need quality assessment stable stability assessments so it's a lot of work sometimes i spend kind of you know 80 percent of my time to do this study objective first was just to do kind of you know to establish a maximum tolerated dosage but also we wanted to see whether there's any organ or any evidence of organ response key eligibility criteria we were pretty generous with our criteria good performance status but you can see patients should have you know a decent ejection fraction and creatinine clearance this was our study treatment plan for the phase one we only gave the drug one time it was a first in human study so we were very careful we started with an extremely low dosage 0.5 milligram per meter square we went up to 500 that's in the rituximab kind of range um but again due to the fact that was first in human study we really wanted to know you know what's what's the side effects of the study so the safety summary it was very very tolerated i have to say we we barely saw side effects um the biggest concern we had was if you have heart amyloid doses and you give the antibody and the antibody breaks down the amyloid will you completely destroy the structure of the heart and will you undergo heart failure um we didn't see this so that was i would say kind of in a big relief for us but nevertheless that was the biggest concern i want to mention one patient really had a grade three for a rash um and i will show you later that patient um but in general we saw patients responding very nicely uh there's a dramatic response especially this patient you know there's an anti pro bnp um this patient um was a patient who had the rash this is his anti pro bnp he started around 9 000 um and was doing excellent this was the response after the phase one treatment only one treatment you also put him on the phase two part of the treatment and yet another response so he developed unfortunately around i would say a week after we gave him the medication a full body rash and we didn't know what what what is that rash we were not aware that the patient had skin amyloid dose and what happened in this patient is that the antibody infiltrated the skin bind bound to the amyloid as you can see here that's kind of you know uh apple green positivity and we were also able to see um the special staining's the antibody around the amyloid so that was really a good example that the antibody binds to the amyloid and induced um a local inflammation a rash that took a couple of weeks before the rash subsided probably the antibody also takes a couple of weeks before you really excrete the antibody but the patient had a dramatic response i have to say uh his anti pro bnp went down from around 10 000 to 3000 uh he was almost bed ridden with anasaka but had another adverse event playing lacrosse versus grand daughter after he finished the trial so that was a very nice adverse event i never kind of you know was happy about you know a fracture of the pelvis um organ response uh around 60 of that phase one trial had an organ response and we are almost close to finish the phase two the phase one b trial um which is listed here the phase one b trial kind of you know includes treatment four times weekly uh we will present the data at ash this year and we have even higher response rates in the phase one b was around 80 percent so in conclusion anybody is well tolerated we were able to establish the maximum tolerated doses without dlt we saw organ response and kappa and plumber patients in both types of amyloidosis again phase b is ongoing um i hope you know i really hope that we can use that antibody not only as a treatment tool but also as a diagnostic tool that would be really great to just label it and do a pet ct and see which organs are involved uh we are missing funding from industry from from the fta but hopefully kind of if we have that soon uh we are planning a phase two trial a smoke phase two trial visit antibody but we are not alone other researchers had the same idea i want to mention the new d zero zero one it's the same principle the antibody binds conformational change in the structure of the amyloid they also presented their data they have a nice response around 60 of the patients have organ improvement under this trial they're planning or the ongoing is a phase three vital trial for newly diagnosed amyloid patients and we are very excited about this um and that brings me to my last slide already i think i'm over the time um when you treat amyloidosis or you think about amyloidosis i think we should try to treat all the patients in clinical trials it's a rare disease and i think it's important to collect the data be certain of the diagnosis um going back in columbia i have a couple of patients before my time who were transplanted with ttr amyloidosis with a senile amyloidosis that's nonsense nothing to do with plasma cell dyscrasia so i think that's really important uh make the diagnosis as soon as possible because it has important implications uh i mentioned the response criteria many good therapeutic options but again clinical trials are the best uh future outlook i think in the future we will use monoclonal antibodies in parallel monoclonal antibodies against the amyloid in parallel there's a treatment probably like right like we use right toxin for lymphoma i'm pretty sure that this will come there is some fine tuning um i want to acknowledge nci you know for their funding especially solomon who is the father of everything and i kind of you know have this from angela dispensary i think that reflects all what we have in amyloidosis