(Guest Lecture): Amyloidosis | Experts Discuss Relapsed/Refractory Myeloma, Amyloidosis

[Music] so um dr zonder is here to join us and start with a discussion of amyloidosis and this doesn't really get covered enough in my opinion so doctors we're so happy that you have joined us for this thank you i'm really happy that you asked me to talk about this particular topic um i agree with you we don't talk about it enough i'm going to try and share my screen here and i guarantee nobody will forget the start of this lecture once i get the slide view up can we see me you see the slides yes and yikes no one's going to forget this right and i'll explain what this picture is showing later in the lecture but we're going to be talking about a specific type of amyloidosis called al amyloidosis and let's see it is not advancing maybe it okay now we are there we go so uh today we're going to talk about basics of ale amyloidosis we're going to talk about how it's related to multiple myeloma we're going to talk about the role of light chains in the disease process and also typical symptoms of amyloidosis and then we're going to focus in on treatment and we're going to talk first about how we assess response what standard therapies and the standard therapeutic approaches and also a new uh some new emerging therapies that are sort of possibly changing the paradigm of treatment a little bit in the future these are my relevant disclosures some of these companies are specifically doing research in amyloidosis and you'll see that over the course of my slides so as we heard about earlier from dr calendar um antibody the plasma cells their their main job is to to make antibodies and antibodies uh plasma cells and antibodies are part of our normal immune system and antibodies have a general structure that looks like this there's there's two heavy chains and there's two light chains and boy um if you uh think about the structure as resembling a barbecue fork we definitely know which end of the barbecue fork is the business end and it's the same for an antibody this is the end that binds to something but it fits that something more like a key than like a point and so the the um the antibodies are in in the normal healthy immune system are generated to attack something specific that they bind to in myeloma that's actually not the case there they are antibody proteins um but they are not antibody uh proteins that are directed at anything specific or useful they're just there as a marker of disease and the same is true in amyloidosis although uh in most cases of amyloidosis uh what the the patient's plasma cells make are free light chains now um in in any antibody the light chains are both either kappa light chains or lambda light chains but it's not a mix of both and also in a normal polyclonal plasma cell situation each plasma cell's antibodies are all either capalite chain containing or lambda light chain containing and so in the picture on the left here i'm showing you a polyclonal or normal situation where you have a mixture of different unrelated subsets of plasma cells in roughly equal numbers and there's no excess of one or the other but in the second picture on the right there's a monoclonal outgrowth where one of the lambda light chain producing plasma cells give rise to a bunch of additional um clonal cells and so that skews the ratio of cells that are making one type of light chain versus another and so predictably when you measure the light chains in somebody with a monoclonal plasma cell disease with this kind of expansion you would see an excess of lambda light chains in their blood relative to capillate chains in in multiple myeloma we get this overgrowth of cells and sometimes it's quite an excessive overgrowth of cells and that leads to symptoms that we heard about this morning the crab criteria which is elevation of calcium renal or kidney injury anemia or bone lesions in amyloidosis although there's also an overgrowth of these clonal plasma cells it's often less pronounced sometimes you only have three or five percent plasma cells rather than 10 or 20 or 50 plasma cells like you do in myeloma and these plasma cells make clonal light chains which misfold and when they start misfolding they form toxic soluble clumps and then eventually these clumps coalesce into strands which we call fibrils which deposit in organs in throughout the body now we have a light chain test which allows us to measure the uh the serum free light chain assay allows us to measure misfolded light chains we can't measure the downstream species but we we infer the burden of these toxic forms of light chains by measuring the the misfolded light chains that we that we can measure upstream um amyloidosis is often missed and this is a key point it's often unrecognized for years and surveys of patients have shown that many amyloidosis patients see three to five doctors over a period of two to three years before they end up having a diagnosis successfully made sometimes amyloidosis is a presenting symptom of multiple myeloma but that's not usually the case most of the time when we find amyloidosis it's by itself um and doesn't present simultaneously with myeloma there are certainly all of us in our clinics have cases where that is where they do present together more commonly though over the long course of somebody's myeloma amyloid-related symptoms may develop because the the light chains that their myeloma clone is making form amyloid deposits gradually over time and that may affect as many as 10 or 15 percent of cases and the exact number probably depends on how hard we really look for it and another important thing as far as other plasma cell dyscrasias and dr calendar sort of alluded to this this morning is that a lot of amyloidosis patients are misdiagnosed as having mgus monoclonal gammopathy of uncertain significance and um the main reas you know some myeloma clinics don't like to see mgus patients because they don't have a treatment requiring cancer i have to say i i like to see mgus patients for a variety of reasons but one of them is to make sure that we don't miss amyloidosis or other less common plasma cell disorders and mislabel these patients amgas by definition has no symptoms and so when a patient who comes to clinic with this diagnosis has unexplained neuropathy unexplained edema or congestive heart failure or excessive amounts of protein in the urine those should be red flags that lead to at least further work up to look for the possibility of al amyloidosis um symptoms depend on what organs are involved and so any any organ really can be involved um the top picture is a picture of somebody's tongue usually it doesn't have that nodular appearance but it's not that uncommon to see a slightly enlarged tongue um probably 10 percent of amyloidosis patients can have it in large tongue more common involvement is the heart or kidney the second picture is a picture of somebody's kidney and when the kidney becomes injured the the uh it starts leaking albumin or protein um in the urine and that can lead to problems um and the bottom picture is somebody's heart and so i drew this cartoon just to orient you in terms of what we are seeing here in this picture if you open up the heart and you're staring down into the bottom chambers of the heart that's what you're looking down on and what you can see here is that the walls of the heart are very thick and on an echocardiogram or an mri you can actually measure how thick this this wall between the bottom chambers are that's the intraventricular septal diameter and um you can see here that it's it's markedly thickened um in terms of staging amyloidosis is different than other other plasma cell diseases or cancer for that matter what what staging is across all these different diseases is really just a method of assessing prognosis at the time of diagnosis now in solid tumor that has to do with anatomy and it's kind of logical right i mean the the likelihood of a good outcome with lung cancer as the example i'm going to use here has to do with how likely is it that you can resect it surgically uh to cure it right and so stage one cancer is a localized tumor that's that has the best prognosis once it spreads to regional lymph nodes it gets it's a little bit less likely that you can cure it surgically if it spreads to more original lymph nodes less likely but then once it's in bones or other distant sites you can't treat that surgically anymore or at least cure it surgically and so the prognosis for stage four lung cancer is different it's worse now myeloma is a systemic disease from the outset and so we already heard a little bit about myeloma staging but we basically do staging according to labs abnormalities and labs like beta2 microglobulin and in the most recent iteration of staging we incorporate cytogenetics and fish testing to add to our prognostic scoring now in amyloidosis the staging the key to staging is heart involvement so the degree to which the heart is involved and uh to which heart function is impaired at the time of diagnosis determines the stage of the patient and we base this really on just a couple of um labs troponin and you can use troponin i or troponin t and then another test called nt probe bnp and basically if one both or neither of these is uh elevated um across a certain threshold that's how we determine if somebody is stage one two or three there's also a staging system from boston university that uses a different test called bnp rather than nt probinp but the idea is the same and it still relies on an assessment of heart injury at diagnosis the way we think about treating al type amyloidosis is sort of shown in this algorithm that i'm going to go through right now the first question we ask is this al type amyloidosis i'm going to explain a little bit more about this question but it's it's kind of the key first question if this is not the kind of amyloidosis where light chains are the issue where plasma cells are the issue you can't consider chemotherapy as the treatment and importantly for some types of amyloidosis like transtheratin amyloidosis there actually are fda approved therapies for that and so if you um fail to recognize a different type of amyloidosis for which there's therapy you're not doing that patient any favors also you might be exposing them to chemotherapy that they don't need but assuming that you nail this down as plasma cell driven amyloidosis the next question is is this patient a candidate for stem cell transplant and it's the same kind of high dose melphalan with autologous stem cell transplant that we see in that we use in multiple myeloma sometimes we need to use reduced doses of the melflin because of the way the organs are involved in the fragility of these patients but um either way whether you you are taking a patient to transplant or whether you're using standard non-transplant therapy uh the goal of therapy is to lower the light chains if you get the light chains adequately lowered we generally stop therapy maintenance is not really a standard part of therapy the way it is in multiple myeloma and if you fail to get a good light chain response then you consider additional therapy right at that time but again that's not maintenance that's additional therapy for active disease now i mentioned let's let's go back to that first question again because i'm gonna you're gonna see me repeatedly use the abbreviation al amyloidosis there are about there are over 30 different types of amyloid and the the nomenclature is shown here it's it always starts as a for amyloid and then some other letters or numbers or a combination of both to reflect the kind of protein that is turning into the protein deposits uh in the in the body tissues and so a l amyloidosis is amyloid made out of light chains there's another kind called ah amyloidosis which is amyloid made out of heavy chains that's also a plasma cell driven disease but most other types of amyloidosis are not the result of light chain or antibody type proteins and so if if it's not um a disease of clonal plasma cells in the bone marrow you would not use chemo um how do you distinguish between these you know we we do biopsies of an organ or we or the bone marrow or something called a fat pad aspirate where we suck out a little bit of fatty tissue from under the skin in the abdomen and we do a special stain called congo red staining congo red staining when you look at it under polarized light looks fluorescent green or apple green and that that tells you that the patient has amyloidosis but it doesn't tell you the type so you have to do another step of testing and a commonly used one is called mass spectrometry and what this basically does is it's it's um sort of molecularly characterizing the uh the uh congo red deposits on the biopsy and it allows us to distinguish between the different types of amyloidosis so key important first step is making sure when somebody is diagnosed with amyloidosis that it's really al type i i can't emphasize that enough um particularly important point is that um both mgus and myeloma but also one type of non-al amyloidosis called transtheratin or attr amyloidosis those are all more common in african-american people particularly older african-american people and so it's a common mistake to assume that an african-american patient diagnosed with a monoclonal protein and amyloidosis has al amyloidosis but in fact they may have mgus and attr amyloidosis if if what i'm saying right now is confusing and you can't hear me over the lawn mower in my backyard right now we can address it further in in the question session uh at the end let's focus in on al amyloidosis patients um that all amyloidosis treatment once you've secured that diagnosis this is a table of agents we use and if you look at the general categories across the top you'll see that these are agents that we use to treat multiple myeloma and a lot of these these are the and we borrow therapy from other plasma cell dysplasias other uh treating plasma cell cancer to treat this plasma cell disorder amyloidosis and so for instance a common regimen cyborg d that we use in myeloma but that we also use an amyloidosis is really just pulling agents from different columns and combining them into a regimen um that is useful in targeting the plasma cells that make the abnormal light chains our goals of therapy are a rapid deep sustained suppression of the amyloid-forming light chains and we do that by attacking the cells that make those light chains so our our first goal is to get those light chains down so you stop making amyloid but the other important thing to remember is because the diagnosis is typically made after there's been organ damage that you're going to need to recruit the help of experts in different fields of medicine to help manage um the the equation that i'm showing here it's a picture of the heart which um because uh because the heart function can be impaired and the kidneys because you can leak protein and have fluid redistribution in your body and then nerve involvement because it can not only can you get the sensory neuropathy that we're used to seeing uh in in myeloma patients who've had certain therapies but you also get autonomic neuropathy which affects the your body's control of blood pressure all of these things together can add up to really severe and difficult to manage problems with blood pressure and so it's it's it's essential really to um to have the expertise of people in each of these areas of medicine so how do we measure response uh in um in amyloidosis it's it's a little bit different than in multiple myeloma we have the same response categories but we use different criteria to put those patients put patients into those categories so the first important concept to understand is a measurement of something called the difference in the free light chains and that's abbreviated dflc here so remember i told you you have two different kinds of light chains one is the involved light chain the light chain that's turning into amyloid in that cartoon i showed you before it was a population of lambda producing cells so the lambda light chain was the involved free light chain and the kappa free light chain was the other normal free light chain and so you can measure the levels of each in the blood and the difference between them is the difference between the free light chains dflc with treatment if you knock that down by 50 percent the difference between the bad light chain and the good light chain we call that a partial response if you knock it down even further and the difference between the bad light chains and the good light chains is four milligrams per deciliter or less we call that a very good partial response now in myeloma remember that's a 90 reduction in your m protein so it's a slightly you're measuring something slightly different now if you manage to normalize the freely chains and completely suppress the presence of clonal plasma cells in the bone marrow we call that a complete response and generally speaking in amyloidosis we're happy if we get to a very good partial response or better because by that point you've sort of shut down light chain production to the point that um you're you're forming less amyloid deposits at that point now in addition to measuring blood response or hemologic response we also measure organ response and that lags behind blood response often by months or even sometimes a year or more we measure that nt probienp blood test and we also assess the echocardiogram for changes when we're assessing how the hearts responded with the liver we can use ultrasound but more importantly we use alkaline phosphatase measurements and for the kidneys we're measuring the amount of protein in the urine and sometimes just the filtration function of the kidney these are sometimes not as easy to apply as you'd think because the results of certain tests like the anti-probian p or the amount of protein in the urine can fluctuate a lot over time for various reasons and so you really have to ultimately rely on general trends rather than any one specific time point measurement now let's uh let's talk about uh therapy let's give a few examples of specific therapy um uh before we um move on to sort of newer agents so um cyborg is a regimen that i mentioned before i gave you the example of what what constituted cyborg d and this regimen actually has mostly been studied in amyloidosis as case series it started being used heavily after a very small series from mayo clinic just 17 patients showed very high response rates but a subsequent larger series from the european union involving about 200 patients showed that roughly two-thirds of patients responded meaning had at least a 50 percent reduction in the in the difference between the three light chains but only about 40 percent of the patients 43 achieved that deeper response that we were happy with um that's actually very similar to what we saw in in one of the few randomized studies that's been done comparing a similar regimen melphalan velcade and dexamethasone melphilan's another drug in the same column as cytoxan and what we see here again about three quarters of patients responded to this three drug combo and about half of the patients had that deeper response so like in myeloma three drugs does seem to be better than two drugs especially when you add an active drug like bortezemib but one has to be careful because unlike myeloma there's a much higher percentage of patients that will have a difficult time tolerating a triplet in al amyloidosis than in straight myeloma one disappointing thing about this trial though is if you look at this survival curve even though there was a slight improvement in survival favoring the triplet it wasn't statistically significant and importantly the survival over the course of that first year is really superimposable and that's where the majority of the mortality happens remember i told you that the degree of heart involvement at outset is what determines prognosis and so patients during that first year particularly may be prone to fatal cardiac complications of their amyloidosis while we're trying to get the disease under control so current standard non-transplant induction therapy induces that vgpr type of response or better in only about half of patients so what can we do to improve on that the first thing is we could try adding newer agents we will hear we have heard and will hear that in myeloma adding antibodies to standard regimens can make them much more effective we're very excited to see the readout of a study comparing cyborgi with or without daratumumab and in this particular study it was subcutaneous daratumumab we don't have the readout of it yet but we did have a safety run-in phase where 25 patients got this experimental regimen and the results looked pretty interesting there were very few infusion reactions to the daratumumab most of the common side effects that we saw were actually the ones that the patients were already experiencing related to their amyloidosis although it's very hard to rule out how chemotherapy added to you know it certainly could have contributed to diarrhea or nausea or anemia but the hemologic response rate was very high over 90 percent and um over three quarters of patients had that deeper response so this is encouraging and hopefully the randomized study will hold up and look more like this and if it does it probably will move the field forward by making the addition of antibodies to standard chemotherapy the usual course of treatment now in relapsed amyloidosis we still continue to use myeloma type drugs uh imids are more commonly used in relapse setting than than up front cardiac tolerance can sometimes be a challenge and with lennolitamide in particular you need to use lower doses than you do in multiple myeloma ninlero or exacemib was recently studied against standard of care and the trial disappointingly was read as negative but it has to do with the fact that not all of the prospectively identified endpoints were positive but some of them were so for instance the duration of response was more than twice as long with exacerbate compared to other agents and organ response was much more common in patients treated with exac than in the standard agents studied there as well and so the takeaway from this is whether or not this will ever be an approved treatment in relapsed amyloidosis it certainly shows that this can be an effective therapy and has the advantage of being an oral agent daratumumab by itself has been studied there have been several case series in relapse amyloidosis we were co-authors on one with cleveland clinic which showed very high single agent response rates higher than myeloma again relapsed myeloma patients treated with dara have about a 30 35 response rate um and the response rates are routinely 65 or higher um our response rate of 86 was actually one of the higher ones but they're all all the series have shown response rates in this range um there's one prospective ongoing study dr sanchowalla and colleagues at boston university studying patients with advanced cardiac disease most of whom had already had transplants using the standard iv administration show that the majority of patients within the first cycle have a very good partial response or higher so this is an extremely not just it's not frequent responses but deep responses and fast responses so this is a an important drug in al amyloidosis in addition to the trial that i just showed you with cyborg d randomization isotoxumab which is also called sarklesa has been studied in a phase two study through the southwest oncology group and those results will be reported and then we're doing a study uh using a different myeloma regimen lenolidomide dexamethasone and elotuzumab which is a two-part study with a planned safety and efficacy analysis after the first 10 patients and you can see one of the problems in amyloid research in general is that a lot of the regimens that we have studied in hundreds of patients in myeloma are often studied in just a few dozen patients in amyloidosis but we're happy that this study is going on to look at the utility of elo in these patients now for the last couple of minutes i'm going to just talk about a new general strategy for treatment all of the things i've told you about so far are focusing on killing the plasma cells and by doing that shutting down the factory and reducing production of light chains what about a strategy of ignoring the plasma cells and just focusing on the toxic products that's actually there's been some work in that there have been a couple of antibody studies or antibody programs that have failed to reach desired endpoints but there's one antibody cal 101 which is still in under study for this cal 101 is an anti-fibril antibody that binds to antibiotic misfolded antibody deposits in the tissues and this has been studied in two phase one studies one study had was a single dose study with escalating doses and another one was a four dose study with escalating doses and a total of 27 patients between the two studies were treated um about half those patients were treated at the maximal doses um again these because these this antibody isn't targeting the the the plasma cells it's not expected to lower the light chain levels that we measure in the blood it's expected to help your body clear light chain deposits that are already in the tissues we didn't see any dose limiting toxicity or therapy related deaths and as far as evidence of efficacy uh we saw one patient that had a rash that on biopsy turned out to be antsy body bound to amyloid under the skin that we didn't we didn't actually know was there previously and then there were cardiac and renal responses cardiac responses again are measured by nt probianp reductions and as i said those are tricky to interpret and i'm always a little bit skeptical of small numbers you know small studies with small numbers of patients and i don't want to make too much or too little of this but i do want to highlight that there's been a little bit of additional cardiac work done with this antibody that i think is kind of tantalizing and i like showing this data because a it's interesting in b because one of our former fellows who's now in new york presented this data and it makes me makes me happy to see this this work out there going back to the picture of the heart um again remember i showed you the picture of us looking straight down on the bottom chambers those are called the ventricles now picture if you superimposed a graph on the left ventricle this is the main pump of the heart and then look upward at that from where the arrow is in this drawing if you were looking at this picture from that view this is what you would see from that chamber so the red part in the middle is the bottom it's the tip of the heart and then the base of the heart is out at the edges of this circle and what you can see here um is a different colors and different numbers uh in each of the regions what what the what what this is called is called strain mapping and what it's really measuring is the way each segment of the heart is deforming and moving and twisting and and shortening as the heart beats and you can quantify all those different kinds of motion and the more negative the number the more normal it is and so what you see here is that in the middle by the tip of the heart you have relatively normal numbers that red area but out by the edges those numbers get a lot less negative and the color gets a lot less light and this is a typical pattern where this basilar part of the heart is is impacted more heavily by amyloidosis and some people refer to this this pattern as a cherry on top like you're looking at an ice cream sundae from the top down so you have preserved function at the tip of the heart but you have impaired function lower in the heart and the group that was studying cal 101 actually looked at this strain pattern this functional pattern over time after treatment with this antibody and so what they saw here is amongst the patients who got treated with this antibody who had baseline heart involvement you had a a measurement of the global strain at the start of therapy and three months later and what you can see here is every line here except for one tends to go downward tends to become more negative which means there seems to be some improvement in strain in almost all patients okay and um what i'm not showing you is is a similar graph of the patients on the study who didn't have heart involvement at diagnosis and their strain patterns are flat rather than sloping downward so you have this differential effect on strain where you get improvements in the patients that have heart involvement at the outset and so to me this suggests that this antibody is in fact doing something that results in heart function becoming slightly more normal over the course of therapy we'll we'll find out more about this as it goes on but i think you know this we're really excited about this idea of treating the toxic proteins cleaning those up and um either in combination with therapy that targets the plasma cells or in some cases maybe instead of so to conclude amyloidosis al amyloidosis is a clonal plasma cell disease the symptoms that we see are due to toxic light chains in which organs become involved current standard therapy targets the amyloid-forming plasma cells transplants an option in only a minority of patients but other standard myeloma therapies including antibody therapies are important options and now we're working on therapies that are actually targeting the toxic proteins rather than just the plasma cells this is my email address if anybody has any questions i'll also be available for the questions thanks very much [Music] you