 I have the pleasure of introducing Dr. Jeremy Larson. He has joined City of Hope Phoenix in November 2022, where he serves as the assistant clinical professor in the department of hematology and hematopoietic cell transplantation. He is involved in patient care and clinical research for multiple myeloma, lichen amyloidosis and related disorders, and he has served as a primary investigator for numerous investigational studies for multiple myeloma and AL amyloidosis. He graduated from Creighton University School of Medicine and completed internal medicine residency and hematology oncology fellowship at Mayo Clinic in Rochester, Minnesota. Okay, well thank you very much, and yeah, packed house, I'm delighted to see this, and so I think this is a good sign that we're starting to move the needle in the right direction in terms of awareness and obviously excitement about amyloidosis. So, you know, as a hematologist the disclaimer is when I use the word amyloid I'm likely referring to AL unless I specify otherwise. So, you know, we're going to take you through a few clinical cases today. I will feel, I would say, I feel like amyloidosis is a disease that some of the, you know, the troubleshooting that can happen in these kinds of talks is education. We kind of need to know what tests to do, but I think also as kind of engineering the system, you know, from a nomenclature standpoint of the testing, I'll try to clarify some of this, because I think we all, you know, I need to order an SPEP, I need to order a free light chain, but it turns out there are lab orders for total light chains instead of free light chains, and so there's lots of little little snags that we'll kind of try to highlight as we walk through this, so making sure we're getting the right testing at the right time. So, a few disclosures listed there, so we'll walk you through a common clinical scenario where screening would be indicated, we'll talk a little bit more about the options for testing, and then kind of go through that algorithm when amyloidosis is suspected. So, as many of you are aware, you know, MGUS, or this monoclonal gamopathy of undetermined significance, that mouthful is extremely prevalent. So, depending on the patient population you're screening, older patients, 65 and above, anywhere from 3 to 4%, and if we go into patients of African descent, that may actually be as high as even 6 to 7% incidents. So, extremely, extremely common, and when we talk about the kind of slice of the pie here, you know, it's hard to give you a specific number, but you know, at least probably 3.5 million and above, you know, with MGUS, many of those patients are unaware they have it, whereas we talk about kind of the end organ, you know, complications that develop from a disease like multiple myeloma, that's a tiny slice of the pie. And as hematologists, I think we all have a little bit of, you know, I'd say, I guess, blood on our hands from a perspective of the late recognition of AL, I can't tell you how many times in my not that long of career that, you know, patients are followed for years in a hematology clinic, and they're tuned in for looking for crab symptoms, the hypercalcemia, you know, the anemia, the bone lesions, and all the time this patient has ongoing nephrosis, nephrodic syndrome, and nephropathy, et cetera, and so kind of being tuned into, you know, these other complications from plasma cell disorders. So, not going to obviously belabor, you know, the plasma cell in great, great detail, but I think some knowledge of what we're kind of talking about, you know, can help, you know, really be aware of what the cell we're dealing with is here. So, a plasma cell, as you may recall from early, you know, education is essentially a B cell that's sort of gone to postgraduate school. It's a B cell that's been activated by some form of exposure. It's saw an antigen, a T cell activation. I kind of sometimes joke that sort of, you know, plasma cell development is essentially nature's first two-factor authentication. Essentially, it gets exposed to something, a T cell activates it, and so we're now using that technology, but this is something, you know, our bodies have done for a long time. If you look at the actual, you know, function of a plasma cell, these are protein immunoglobulin synthesis powerhouses, and so that, you know, kind of design, you know, term of, you know, form follows function. The plasma cell is a perfect example of that. So, you may recall this kind of pale area right outside of the nucleus. We call it a half. It's loaded with Golgi apparatus and endoplasmic reticulum. These are pumping out proteins, immunoglobulins, or the other term that you're probably familiar with would be antibodies. So, the structure of an antibody, and I'll get to why we're talking about this in just a second, is this Y-shaped construct. And at the kind of business end, the arms of the Y is the antigen binding site, and that's, you know, really designed to recognize millions of different antigens. So, that's something that's variable, and then that's attached there to the heavy chain construct. And so, at the, you know, the arms, we have the light chain, the antigen binding site, and we have what we call the FC fragment, which ultimately, once an antibody binds to something, activates our, you know, effector cells, things like NK cells, macrophages, et cetera. And so, we have five different types of immunoglobulins. You probably remember this from boards as well. So, the key things we see clinically, as you heard earlier today, IgG, IgA are the most common variants, but we actually do see rarely IgM-related amyloidosis. It has a little bit different phenotype, and I think that's in large part due, when you see this IgM pentamer, it's a gigantic protein construct. And so, we tend to see more incidents of, especially those profound neuropathy complications in our IgM amyloidosis patients. So, many of these patients also have Waldenstrums, for example, a little bit less tendency for cardiac involvement, but definitely more soft tissue, neuropathy, and often times renal involvement. They can be very challenging to treat. So, we'll kind of get into the business here and make it real for you. So, you know, we'll kind of put on our clinician caps here, and so, you know, we're walking into our first patient of the day. So, in this example, gentlemen, very, very, I would say, representative of our patient population. So, you know, near Medicare age, he's got some metabolic syndrome, he's overweight, he works a sedentary desk job, he's diabetic, hyperlipidemia, hypertension, notes, you know, he's not quite doing as well on his diet as he should be, his A1C is suboptimal. When you look at some of the symptoms, he's got mild grade one, distal neuropathy, primarily in the toes, little bit of the balls of the feet, you know, going up a couple of flights of stairs or up a hill, he is short of breath, no chest pain. CBC is unremarkable, he's got maybe mild renal impairment, trace microalbuminuria, TTE is done, grade one, diastolic dysfunction, EF looks normal. So, the question is, is this the patient that we need to go down this diagnostic pathway? And I would argue, obviously from a, you know, utilization standpoint, there's gonna be a lot of MGUS screening for this type of patient if we were doing that. So, you know, as you heard earlier today, you know, some of the patterns that we're gonna talk about, it kind of, you know, depends on the severity, depends on if there are other clinical factors that could easily explain their neuropathy. So, in this gentleman, you know, we have diabetes that can likely explain his trace microalbuminuria and, you know, some of the other changes we're seeing here. So, I would argue that's probably not the patient that needs screened. So, we'll walk to our next door neighbor here, our second patient of the day, we're feeling good after the first one. So, this is now an 81-year-old woman, very, you know, high functional status, but has developed somewhat unexplained edema of the lower extremities and also now is starting to have kind of a weeping ulcer over a right lower leg. She's kind of a second opinion for you. She's already seen a vascular specialist. They've worked her up for PAD. They've looked into possible IVC compression that's negative and so, she at this point is now a year into this. She's gone through wound care, et cetera, et cetera. This keeps happening and she's on diuretics, but the edema is not going away. And so, in this example, you know, we're gonna kind of walk six months forward now. We won't say what was done then, but six months later, there's now a TTE that's updated and she has a new pericardial effusion. So, as you heard earlier today, that should probably be a red flag. She goes through a pericardiosynthesis, cytology is negative for malignancy. So, we're happy about that. The TTE outside report is unrevealing as it's kind of carried forward in the progress notes. Turns out, you know, she had been sort of labeled with half-pef, essentially. And a well-intentioned provider says, I'm gonna screen for amyloid. So, good, they thought about it. They did that first step, bravo. Second step, unfortunately, is where they got tripped up. So, they ordered an S-pep. And as you heard nicely earlier today, that's not enough. But unfortunately, they anchored to this. They said this isn't amyloid, her S-pep is negative. So, six months pass by, symptoms continue to get worse. This is actually where I met the patient two years into her journey. At this point, she has profound peristegias of the feet, painful neuropathy, autonomic dysfunction gets dizzy and falls when she stands. She was previously independent, she was a widow and she is now in a care facility because she's unable to care for herself. And with even walking to the bathroom, she's short of breath. And so, I actually met this patient in the hospital because she had new oxygen requirements. Those were what her legs looked like. So, not good. And so, the diagnostic testing that then is carried forward, this is kind of textbook AL. And unfortunately, this patient is way too far downstream where 24 months before, we probably could have done a lot to help this woman. She has all the classic manifestations, low voltage, QRS. Her TTE at moderate to severe, concentric increased LV wall thickness. She still has the pericardial effusion. She's anemic, she has renal impairment. Her albumin is low and she has predicted about four grams a day of albuminuria. The SPEP, still negative. And actually, in this case, the serum immunifixation was also negative. Sometimes that will pick up kind of dimerized light chains. So, it's not uncommon to see a monoclonal Kappa or a monoclonal Lambda on immunifixation. We'll talk a little bit more about what this test is. But in her case, it was the free light chains that really were kind of what gave us the diagnosis. So, her Lambda free light chains were quite elevated. And not all patients will have light chains to this degree. So, in this case, 32.4 milligram per deciliter. So, that's about 15-fold higher than normal. Her ratio is suppressed. If you want to flip that, as a hematologist, we often times think about what we call the DFLC, the difference between the involved light chain, which in her case would be Lambda minus uninvolved. So, if you subtract those two, 30.7. That's very high. Her bone marrow biopsy is done. She has a plasma cell dyscrasia, 9%, Lambda restricted. Her fish is positive for one of the most common cytogenetic abnormalities we see in amyloid patients, which is a rearrangement of the 11th and 14th chromosome. And this also highlights what we heard earlier as well, that the bone marrow biopsy is not the end-all be-all for screening for amyloidosis. So, her report was read as equivocal. But it highlights, and I think you're gonna hear more about this in the next talk as well. But from some of our internal data, we would suggest that roughly about 50% of patients with AL amyloidosis may have a positive bone marrow. But on the other hand, that's gonna tell you're gonna miss 50% of the patients, if that's what you're anchoring your diagnosis on. So, in her case, we also did an abdominal fat aspirate, and that was positive for what should be Congo red stain, and mass spec confirmed an amyloid subtype of Lambda type amyloidosis. So, we have a diagnosis. So, in this case, the patient was profoundly symptomatic, and actually after long goals of care conversation, she decided to go to hospice and passed away about six or seven weeks later. So, this is an egregious example. Obviously, way too long went on without people kind of looking into the diagnosis in the first place, and then obviously, submit opportunities with the testing. But this really just kind of goes to highlight all of us, I think, our job is to really recognize these patients, ideally, far more upstream. And cardiologists in the room, you guys are huge gatekeepers for this, but our GI docs, as you've kind of heard a moment ago, with patients get EGDs, colonoscopies, for diarrhea and malabsorption, and still see all the time that Congo red stains aren't done. Have seen a couple of examples now of someone who presents their ENT doc with macroglossia. They get a tongue biopsy, and we're applauding because no carcinoma, but they didn't do Congo red staining. And so, you know, I think there's lots and lots of examples of these kind of things, but I'd say if there's one thing we can really do better as a medical community, would be early diagnosis, because therapy really can change these patients' lives. But as you're kind of heard, once the kind of cat is sort of out of the barn, that's not their expression at all. But, well, I'm gonna coin a new one here. We're gonna go with that. So, you know, obviously there's sometimes limited therapy of what we could do. So these are just some of the patterns. We're gonna talk a little bit about this. I highlighted this slide specifically because of that lower panel. I don't know how well that shows up, but the soft tissue involvement, so those ulcerations, those non-healing ulcers of lower extremities, likely we're in part due to the edema, but also, you know, we also will see soft tissue kind of plaques and ulcerations sometimes form. You know, from a GI tract perspective, there's the autonomic standpoint, the dysmotility, et cetera, but also many of these patients have friability, and so we'll see kind of that, you know, the coagulation deficits also can manifest with the easy bruising. You know, in high alkyphos, hepatomegaly, Dr. Rosenthal and I just kind of share a patient who is a gentleman who was having very refractory ascites getting tapped repeatedly, had a hepatomegaly, what looked like severe cirrhosis, and, you know, his liver was chock full of amyloid, and now several years later, that patient's living a fairly normal life, and so therapy can also be extremely helpful for these patients when we recognize the diagnosis in a timely fashion. So, you know, this is just a highlight, you know, there is a disconnect between hematologic response in terms of watching those light chains go down and the time to organ response, and so, you know, Dr. Lerne, who's an nephrologist in Rochester who has really pioneered and has kind of been, I think, a very big advocate for this term, what we'll call kind of delayed renal response, but this is a specific case where a patient who went through an autologous stem cell transplant, that's kind of the time zero on the bar. So, in this schematic, what you're seeing, the dotted, you know, line there is their protein area, so they started roughly around 13,000 milligrams per day, and their serum albumin is a solid line there, so what you can kind of see, obviously as the urine protein levels dropped, the serum albumin rises, but really from a complete organ response standpoint, all the way out to three years before this patient technically, you know, had normalized their protein area, and oftentimes, you know, the NT-ProBnP and the troponin follows a somewhat similar pattern, and it's very common in those first few months of therapy to see cardiac biomarkers actually rise significantly because of, you know, the added stress of the chemotherapy. So, ideally, recognizing those patients earlier on in their journey, that therapy is gonna go a lot more smoothly. So, when to consider, you've heard a lot of this already, I'll harp on just a kind of a couple of things here. So, you know, when to consider screening protein area, obviously, you know, if there's no other explanation, the renal insufficiency comes late, so if you're just waiting for their creatinine to rise, you probably already missed the boat, the amyloid perpura, so kind of termed raccoon eyes, you know, as one of those very pathodynamic things, we don't see it very often, but if you do, you know, obviously, some alarms should be going off. The neuropathy that you heard nicely from Dr. Goodman just a moment ago, the restrictive cardiomyopathy, so this half-path-like syndrome, and I think, you know, with advances in imaging, we're, you know, hopefully labeling fewer and fewer patients with athlete's heart and these types of things, but I would say, as a hematologist, one of the things that, you know, many of us don't do would be, you know, screening cardiac biomarkers, so as part of the routine follow-up for MGUS, you know, we're doing CBCs and metabolic profiles, but, you know, lots of patients who have shortness of breath necessarily aren't getting appropriate testing, so I would oftentimes advocate, you know, to my colleagues, that that is something that could be, you know, especially for those patients who have some of those types of symptoms, and NT-propion P could be extremely helpful, you know, the macroglossia, obviously, and then that hepatomagliate, you know, an elevated alkyphos in isolation without, you know, the other LFTs is also a big tip-off for these patients, so, you know, this is more for, you know, from my standpoint, when we have a monoclonal gamopathy, what are the big things that we're thinking about? As hematologists, we're all tuned in, you know, we're looking for myeloma, but, you know, the periprotein-related syndromes are what I would say we still kind of fall short on, and so, you know, these are kind of the, you know, the big things that as we start this testing cascade we're thinking about, so it's probably once or twice a year that I meet a patient that referred for a stem cell transplant, and I started looking through their records, and it's myeloma, it's myeloma, it's myeloma, and it's because, let's say, they were anemic, they had a bone marrow biopsy, 10% or more plasma cells are found, you have myeloma, we're starting therapy because, you know, you're anemic. No one really thinks about, yeah, I guess I did have some neuropathy, you know, I am short of breath, more than usual, et cetera, so it's very, very common that I meet patients who actually have bonafide amyloidosis, they don't have, they have more than 10% plasma cells, but they have no bone lesions, they don't have the classic renal impairment, and so I put the, you know, the periorbital perpary here as this is a couple of years ago, in my time at Mayo that I met, a woman walked in to the clinic and this is maybe not quite this severe, but profound periorbital perpary had been on treatment that was not going well for the prior three months outside and had never heard the words amyloidosis, she had terrible neuropathy, she had terrible autonomic dysfunction, she had periorbital perpary, but they were anchoring on the fact that she had more than 10% bone marrow plasma cells, so the diagnosis of myeloma versus amyloid really comes down to the clinical phenotype, we know that patients with amyloid with more than 10% bone marrow plasma cells, the prognosis is inferior to those with lower clonal burden, so this is probably, you know, for more directed towards my hematology colleagues, but just kind of food for thought. So you've heard a lot about, you know, the diagnosis, so really this is kind of four essential pieces, so we need a syndrome that we've kind of talked a lot about, we need tissue conformation, and ideally we'd start with some form of staining looking for the amyloid, most commonly congo red, some facilities still do electron microscopy, and then once we find amyloid, the next key step that I would still say the adoption of is not where it needs to be, would be actually doing amyloid subtyping and that mass spec or amyloid protein identification would be the key thing, and then lastly we need some evidence of the monoclonal plasma cell disorder, and so that's usually kind of towards the top in terms of the cascade of this, but as we'll kind of talk about the laboratory evaluation, this is kind of gonna be the first step. So the S-PEP, as we call it, the serum protein electrophoresis is an old test, this is not new, this is a gel agarose based, essentially a kind of a Western blot style test, and so antibodies or immunoglobulins tend to drift into that far right portion of the graph, the gamma globulin range, and so this is a pretty normal example, but when we have a very large monoclonal protein, we tend to see almost a tower or a spike-like presentation, but the hard part with many amyloid patients, they may have a 0.1, a 0.2 monoclonal protein, and it doesn't stand out much on that gamma globulin peak, and so that's where the sensitivity of the S-PEP, it's still a helpful tool in my mind, we do advocate to perform it, because it helps give you quantified information, it says how big is that monoclonal protein, but in many amyloid patients it's small. So a common question is what is an immunofixation? Well, ultimately what it is is it's an immune precipitation, so this is a more of a yes-no test, it's not gonna give you a number, but what it's gonna tell you is what type of monoclonal protein is there, and it's the most sensitive screen we have in the blood, specifically looking for something like a heavy chain plus a light chain, so the IgG lambda, for example. And so what you're seeing in this schematic here, so in the G heavy chain and then the L light chain band, essentially we've precipitated out a monoclonal protein, so we know this patient has an IgG lambdas, you'll see the report come back, I identify in this. So up to the kind of upper right quadrant here is specifically referring to the immunoglobulin free light chain assay, and so there's a number of different proprietary assays out there, the first one on the scene is called the free light assay by a company called the Binding Sight, and ultimately what they're taking advantage of is the fact that I pointed out in these earlier constructs, we have a light chain bound to a heavy chain, and that's where most of our light chains circulate, but we also have soluble free light chains, so as it goes to tell you, there's no heavy chain bound to it, and historically, before about the early 2010s, around that time is really when these assays became readily clinically available, but before that, the way that you needed to find free light chains was, as this term we're probably all familiar with, is Bench-Jones proteins, which these are light chains in the urine, and so the 24 hour urine protein electrophoresis plus the immunification was the way we found free light chains, so now we're privileged that we can actually have a readily available tool from the blood work to identify this, but I would say the downside or some of the hazards of relying only on the free light chain assay is that there are many false positives, so as you heard a moment ago, physiologic increase in Kappa light chains especially is common with renal impairment. The other thing increasingly I'm seeing is I think with the rise of the obesity epidemic, many patients with non-alcoholic fatty liver disease ultimately have what we term polyclonal hypergamoglobulinemia because of kind of the hepatic inflammation, and so we also see abnormal light chain ratios commonly in that population, so it's a very sensitive tool, but it's less specific, and so that's where ultimately the urine immunification is still really, really helpful because what you can sometimes see is a mildly abnormal free light chain ratio, but their urine immunification comes back negative, and that's oftentimes reassuring, and so this is just a schematic that I think kind of tries to illustrate where these ratios are coming from. We all make Kappa and Lambda light chains, they're part of our normal immune system. Normally we have this tight band, and depending on the center that you're at, they'll publish their reference range, but around one and a half is sort of the upper limit of normal down to all the way to 0.5. That renal reference range that we call it can go all the way up to about three to 3.1 for someone who has renal impairment, but if we're overproducing Kappas, we're overproducing Lambdas, that's where kind of that teeter totter starts to shift, and you'll see marked elevation of either your Kappas or suppression with your Lambdas, and I kind of point out, once we have a patient who has known monoclonal gamopathy, knowing what their involved light chain is actually really helpful for monitoring, so especially for our amyloid patients who've gone through therapy, seen some patients just recently, for example, their Lambda was their involved protein. They're on surveillance, they're in remission, they get a vaccine, they get COVID, they are dehydrated when they do their labs, and their labs come back and they have a mildly elevated Kappa Lambda free light chain ratio, and they see that number in the portal, and they're panicked, because they're like, I'm out of remission, but knowing that patient had Lambda free light chains, I don't worry if their Kappa Lambda ratio is a little high, because they're Kappas that are up, because I know it's not from their amyloid, it's a physiologic factor, so these are just some of the nuances, it's a test that requires some interpretation, and so that's really where, pairing with a hematologist you trust that it can help kind of decipher some of this. So with the bone marrow aspirate biopsy, I've kind of quoted a roughly 90% sensitivity that might overshoot it a little bit when we combine a fat aspirate plus a bone marrow biopsy. A lot of this comes from older Mayo data that was looking at in-house, the as we so quote unquote called the Mayo clinic experience. I think one thing that is a little bit to me, put sort of an asterisk on this, because these are very experienced pathologists who are sort of, they're all tuned in to amyloidosis, the providers who were doing the fat aspirates are tuned into knowing how to properly get the tissue that's needed. So in less experienced hands, we know that these things, even if the right tests are done, can be missed. And again, I kind of highlighted earlier with the greater than 10% plasma cells is a higher risk factor. We'll do fish testing, and as a hematologist treating these patients in that population that have the translocation identified here, it's a helpful tool that actually predicts therapeutic response to one of the oral therapies that can be used subsequently. Oops, wrong button, sorry. So this is, I guess my plug to sort of know your reference lab. So know what system you're working in as you heard earlier, kind of set up your order set. I think that's a perfect, perfect advice because even in town, I'm just representing two major labs. So in house at Mayo, there is a whole panel, we call it the monoclonal gamopathy diagnostic serum. And what it is, it's an SPEP, it's an immunification, which we've now shifted to a newer form of that. It's also mass spec based, we call it Malditoff, but a little bit more sensitive. But essentially it's an SPEP plus a serum immunification plus a free light chain. So one test, one order I should say, and you get all three of those. And then we also do advocate for doing your own immunification. I'm a realist, and so I know that it's a big ask for my cardiology providers. If you're seeing a patient that's got a mildly abnormal echo, you're concerned about amyloid, but you're not quite sure. It's a big ask for, to tell you to collect a random 24 hour, urine and immunification. So I'm a realist, so even spot protein with a urine immunification, I think that's a good start. You're gonna miss very few patients. If you've done those top three blood tests, very few patients are gonna be missed with just a random urine immunification on top. So that would be a common test panel to order, whereas with SinuraQuest, their nomenclature is a little bit bizarre. So monoclonal gamopathy DX PNL. So I guess diagnostic panel comma AL amy is the test ID. And so with that, you actually get all four. So serum, those three key tests that we talked about, plus urine protein electrophoresis immunification. But it depends on where you're at. We call these same tests different things in different sites. So kind of knowing what your in-house tests are called and then save that to save yourself some pain. So this is a kind of a flow that comes actually off of the Mayo Clinic labs. I like this schematic. And this is something that's online available. And you can actually click into it and it will tell you more about each of these tests. So that's out there for everyone's reference. But in that scenario, you have a clinical pattern that you're concerned. You're gonna initiate monoclonal protein testing. And one of those tests come back with an abnormality. So it's an immunification that's positive. It's an abnormal free light chain. The next step obviously would be to involve a hematologist and in our practice, traditionally we do those two tests listed here. So the bone marrow aspirate and a fat pad biopsy or a fat aspirate, both of those with Congo red staining, looking for this, knowing that that's not the end all be all. So in those patients, you have a high suspicion for amyloid. You know, if those tests are positive, perfect. We have a diagnosis, but if those tests come back inconclusive or negative, you know, you see the plasma cells but you don't see the amyloid, that's where as you're highlighting here, our next step would be an affected organ biopsy. And it really kind of depends on how these patients flow into a hematology clinic. There are patients who come to me as MGUS and they're undifferentiated. And that's where I'm the one kind of directing some of this, but I also meet, you know, many patients who've also, you know, they've already gone through this whole pathway or cardiologist, colleagues have handed this over on a silver platter and you guys have already done the work. So it kind of just depends on where this patient enters in. You've heard about this nicely today. I kind of highlight, this is a throwback. So Dr. Gertz and Dr. Kyle, who I kind of think are sort of the mayo goats of amyloid here, you know, at 1987 we're publishing screening PYP scans for cardiac amyloid. You know, the conclusion on this is interesting because ultimately they were saying, they were trying to say, is this a sensitive tool to pick up cardiac amyloid? And their takeaway was no, it's not a sensitive tool, but they were looking primarily at AL patients. But what they could see is that a number of patients with AL will turn positive. So more for historical interest, but as you heard from Dr. Rosenthal earlier, probably close to a quarter or maybe 20% of patients with TTR amyloid may have an immunoglobulin abnormality. So, you know, again, this is one of these big clinical pearls we've harped on so far today is that just because there's MGUS, that does not equate to AL amyloidosis. You need to take that next step and do the amyloid subtyping. And, you know, if any of you have attended, you know, amyloid support group meetings here locally, you know, there are some patients who routinely come there, you know, were treated for six months with cyborg E and they had MGUS and they had TTR amyloid. And so that's a story that I think is unfortunately probably very common around the country that we obviously don't want to repeat. So we have the tools to be able to decipher these. And so again, this is the staging. This is getting a little old. But I know there are some efforts underway to likely refine this schema. And I think these overall survival numbers are also very outdated given the fact that ultimately our tools have improved quite a lot over the last decade. But this goes to highlight the more cardiac involvement, the worse the prognosis historically is, and we're still lacking, especially in those stage four patients. So with those two readily available cardiac biomarkers, the NTPRO BNP, the high sensitivity troponin, and then we also factor in their light chain burden. So that DFLC that I referred to earlier. So with those three things, you can stratify this into a four stage group. So we are absolutely, you know, I think improving outcomes a big picture. So, you know, this would say a patient with stage one amyloid, for example, they have one risk factor in this data, you know, it was saying about three and a half years. I think we're doing a lot, lot better there, but ultimately the takeaway is that the more advanced cardiac involvement, the worse the prognosis is, so early diagnosis again. So my talk today, you know, out of scope to really get into the nitty gritty of detail, you know, a lot of these medicines are borrowed from multiple myeloma, but the big thing that I would point out, especially that red column, the IMIDS, which, you know, two of the medicines you're likely very familiar with. So thalidomide just from obviously, it's notoriety, and then with lenalidomide, which is more commonly used today in the United States, and then a subsequent version of pomalidomide. There are workhorse and multiple myeloma, but in amyloidosis, there are often times not well tolerated, and actually some of the early trials that, you know, in myeloma, lenalidomide dexamethasone was a blockbuster combination that improved outcomes a lot, when they said, okay, how does this work in AL amyloid? The trials were actually shut down early because of excess death on the intervention arm with Len Dex, and it turns out, patients with AL amyloid, especially with cardiac involvement, do not tolerate full dose, lenalidomide and full dose dexamethasone. So, you know, the reason I put this slide in is that there are nuances here, so the hazard of labeling a patient with multiple myeloma and going down that pathway of Revlimid-Velcade dexamethasone, and they're getting blasted with corticosteroids, the wheels fall off pretty fast in those patients. If, you know, as a hematologist, no one really thinks about, you know, the amyloid, you know, underlying diagnosis here. Dr. Rosenthal, again, kind of hinted at this with the Andromeda study. The reason I kind of highlight this is that hematologic response, essentially everyone has benefit, so, and these are very deep responses. You heard more than half of patients actually get to the point where their monoclonal protein is entirely undetectable, so we call that a hematologic complete response. But the other thing that's really, really impressive is when we actually translate that to organ response, which is ultimately what we really care about. You can see four out of five patients have significant renal recovery, and when we look at the cardiac population, more than half of patients saw cardiac response, and that's more than two-fold higher than what we saw with cyborg D. So just with the addition of a monoclonal antibody that really honestly adds very few side effects, couldn't really move the needle for patients. But again, it's those patients who were detected early on who really maximally benefit. So, you know, with conclusions here, we've kind of harped on this again. The early diagnosis is key, and so hopefully as a medical community we'll continue to improve there. I sometimes think amyloid is the perfect syndrome that AI ultimately will likely help us. I just heard a recent story of a mother. On chat, GPT entering her daughter's symptoms, she had a rare neurologic degenerative disorder and she'd seen countless neurologist neurosurgeons, and ultimately chat GPT suggested the diagnosis after her mother entered this slew of signs and symptoms from her medical report. So I think amyloid in some respects could be similar because it's all these various different clues and sort of seeing the forest in the trees. Screening algorithm we talked about, so the ASPEP, you need an immunofixation of the serum, you need an immunofixation of the urine, and the serum-free light chain, and so if you can do those key tests, that's gonna be huge for detecting these patients earlier on. And then ultimately, you're gonna hear more about the tissue biopsy in a moment, but our pathway is to suggest doing a bone marrow biopsy plus an abdominal fat-pat aspirate. Knowing that a bone marrow with conger red staining is not enough, the fat aspirate will pick up additional patients, but probably close to one-fifth, maybe even one-fourth patients, you'll still need to go on and do targeted end-organ biopsy. So the key thing from a provider standpoint is knowing that if that bone marrow, if that fat-pat comes back negative, to not stop there in those patients with high suspicion. So with that, I will close. Thank you so much.