(Guest Lecture): June 2022 - Connecting, Educating, and Empowering an Amyloidosis Community

and empowering an amyloidosis community. And in reality, I just wanted to let you know that we wanted to launch this community because we know that having amyloidosis can be isolating. We hear about multiple myeloma, and while multiple myeloma is a rare disease, there are even more rare forms of multiple myeloma or related diseases to multiple myeloma within that big umbrella. And it can be really isolating to be in one of these rare diagnoses and not really know what is the best treatment for me, what is my future like, what is going to be most successful, and how can I maintain a high quality of life, how can I connect with other people like me. And so for that purpose, we have created this community, and I'm excited to watch it grow and to be able to work with you to further research in this field, and also just be able to learn together at the hands of experts. Speaking of experts, I would like to introduce Dr. Jeffrey Zander to you. He's a professor at the Department of Oncology at the Caramnus Cancer Institute and Wayne State University School of Medicine. He has authored and co-authored numerous original research papers, review articles, book chapters, and research abstracts on both myeloma and amyloidosis. So with that being said, I'm going to stop sharing my screen, and then I'll turn the time over to Dr. Zander for today's presentation. Hi everybody. I'm going to share my screen now. And can everyone see my slides here? Mm-hmm. All right. Yeah, that was great. So I really, tremendously appreciative of the invitation to speak with you all today, especially the inaugural meeting of this community. So fantastic, and I'm really happy that we're doing this. Obviously, I don't know the vast majority of people on this call, and it's really difficult to do, even live, difficult to do a talk that will, like a pre-planned talk that will actually meet everybody's needs. And so my goal really was to do like, you know, 15 minutes, 20 minutes real quick, just to, you know, sort of nuts and bolts, what's amyloidosis, and then, you know, I guess throw out a couple of concepts that maybe people have been wondering about, try and get everybody on a semblance of the same page, but really then turn it over to you to tell me what you need to talk about to make this meeting helpful. If you guys can unmute and start yelling at me if a half hour from now I'm still talking, that is not the goal of this. The goal is to let you ask questions and for this to be interactive. Hoping, these are my disclosures. You can see that I have done some consulting work and had some research support from some of the sponsors of this session, and I will try to be as unbiased as possible. And I just want you to know that there's really actually only one approved therapy for AL amyloidosis. So everything I'm going to be talking about pretty much is off-label usage of medications and I'll try and explain how we use them. I'm going to talk, I'm going to define amyloidosis, put it in the context of multiple myeloma, explain how we make the diagnosis, review standard therapies, principles of therapy, and then that one approved therapy for newly diagnosed patients with multiple or amyloidosis. Talk a bit about how we know whether therapy is working or not, which is different than in myeloma. And then I'm going to describe some emerging therapy strategies to kind of close it out. Sounds like a lot, but I'm going to just sort of blow through it. So amyloidosis is really a group of different diseases and what they all have in common is that there are misfolded proteins being formed somewhere in the body. We classify the type of amyloid according to what that misfolded protein is. And the symptoms that a person with amyloidosis experiences has to do with where these misfolded clumps of protein deposit in your body, because that's the damage mechanism. These proteins form strands, then clumps, they deposit in organs, they affect organ function, and then you have symptoms. And unfortunately, a lot of times, the symptoms are vague initially. And it always looks obvious in hindsight what the diagnosis was, but it rarely looks, it's rarely obvious going forward. And there have been online patient surveys which have demonstrated that the average amyloidosis patient may see four or five physicians over a period of a few years before a diagnosis is made. And by the time a diagnosis is made, a patient can be very, very symptomatic based on the organ involvement. Any organ can be involved. There are some that are sort of classic but not that common, like a big swollen tongue. And the picture at the top here is actually a tongue that's full of amyloid deposits to the point where it's actually hard to, it's sticking out of the person's mouth. It affects the dentition, it affects swallowing, it can affect breathing. And when you see that, there's a very, very short list of things that can cause that. But that only actually happens in a minority of patients. The most common organs are heart and kidney. That's what the two pictures below that are. The middle picture is a microscope picture of a kidney. And the bottom picture is a cross section of somebody's heart. This is actually sort of where we're looking. We're looking down at the chambers of the heart. And I think, can you see my cursor? Okay. So you can see that this chamber, the left ventricle, is really, really thick and the wall here is really, really thick. And when we stage amyloidosis, we're staging it actually on how involved the heart is because it's so fundamental to sort of defining the expected survival and the risks of early complications in patients with amyloidosis. The diagnosis though is actually often not made by biopsying a specific organ. I would say that in my practice, the organ-directed biopsy that most commonly leads to a diagnosis of amyloidosis is a kidney biopsy coming from a nephrologist's office. But the type that's most relevant to myeloma or a myeloma community is AL amyloidosis. And this is, what I put here are three of the more common types of amyloid. And I explained sort of how we name it. There's an abbreviation for each kind of amyloid. And the first letter is always A for amyloid. And then some other letter or numbers, something that's an abbreviation for what the type of misfolded protein is. And so AL amyloidosis is amyloid made out of immunoglobulin light chains. So it's like the light chain fragments that we sometimes measure in myeloma patients. In this case, that's the abnormal protein that is actually turning into amyloid. And the way you tell these apart isn't as simple as looking at a microscope slide. You can do a test called Congo red staining. It's very specific for amyloid. And what happens is when you look at it under polarized light, the amyloid deposits have this bright fluorescent apple green appearance, which we call birefringence. But the problem is any of these types and or the other 20 or 30 something types of amyloidosis that occur in people, all of them will look like this under a microscope when you do Congo red staining. So you have to do additional testing. And I think a pretty accepted standard is something called mass spec, where we dissect the amyloid deposit off the slide and then run it through a machine to sort of analyze the sequence of the protein and help us figure out what that what those amyloid deposits are made of. And AL amyloidosis is probably the second most common type overall that we see. It in multiple myeloma, you have an overgrowth of plasma cells. And those plasma cells have this like aggressive growth pattern. And it causes specific problems like bone lesions, low blood counts, high calcium levels, kidney injury. In amyloidosis, there are there is an overgrowth of plasma cells in the bone marrow. But it's it's often a lot less, it's often less than the 10% you need to make a diagnosis of myeloma. And the problem really isn't like the explosive excessive growth of these cells. It's the misfolded light chains that they make. And what I'm trying to show you here in this picture is this process where you can see the amyloid deposit is a what I'm trying to show you here in this picture is this process where individual light chains are made by the overgrowth of abnormal cells, and then they start forming these toxic clumps that are still floating around in your blood and injuring organs. And then finally, they drop out of the blood and get deposited in the organs in these big long strands called fibrils. And so the the historical approach for AL amyloidosis is to treat it like myeloma, because myeloma therapies shut down the factory. Okay, they they by by killing the plasma cells, you reduce the light chains. The just to talk a little bit more about the light chains. So you can see here from this picture, I labeled the light chains and I also labeled the plasma cells, you can see that every plasma cell is either labeled with a Greek letter lambda, or Greek letter kappa. And basically, those are the two types of light chains. And every myeloma cell, every plasma cell, whether it's normal or abnormal, the antibodies that they make, and that's their job, their professional antibody producers, their antibodies contain light chains that are either kappa or lambda, but not a mix of both. And so when you have an overgrowing clone of plasma cells that are all derived from one bad original actor, whether it's myeloma or amyloid, AL amyloidosis, all of those clonal cells will make the same kind of M protein or light chain. And so in AL amyloidosis, typically, one of the types of light chains is very elevated, because there's an overgrowth of that type of plasma cell. And the other one is normally not elevated. So we call the bad light chain the involved free light chain, and we call the normal light chain the uninvolved free light chain. And you'll get on a report, a free light chain assay, which is a blood test, you'll get a measurement of the kappa, you'll get a measurement of the lambda, and then they'll give you a ratio. The ratio is sometimes helpful, but mostly what we look at is the difference. How much extra involved light chain is there relative to uninvolved light chain? And the goal is to get that excess out. And that's actually how we know whether therapy is working. We don't have to do bone marrow biopsies to count plasma cells. We measure the light chains and see if the excess of bad light chain that forms amyloid is decreasing over time. So the goal of therapy is to get a, like this is as clear as it can possibly be said, rapid, deep, and sustained or lasting suppression of the amyloid forming light chains. And while you're doing that, supportive management to address the symptoms related to the organs that are involved, like the heart, the kidneys, or the nerves. The analogy my patients and appointments will often hear me use is a house fire. Think about a house fire and your expectations in the wake of a house fire. So what happens when the house is burning? The fire department comes in and very quickly puts out the fire. That's chemo. That's antibodies against plasma cells. What you're doing is you're shutting down the source of damage as quickly as you possibly can. And you want it out. That's what I mean by sustained response. But in a house fire, once the fire's out, that doesn't mean you can move right back in. And in fact, even though it took six hours to put out the fire, it might take six months to repair the smoke damage and replace everything in your house that needs to be addressed and make your house actually habitable again. And that is actually what lands you in a rental place or a hotel right after a house fire. It's that smoke damage that prevents you from moving back in. And that's actually kind of the situation in amyloidosis. We can get the light chains down in a month or two. The organ responses take a lot longer. And I'll show you how we measure both. But it's important to understand that there's a difference in expectation in terms of how fast one thing happens and how fast the other thing happens. So I mentioned we want to get the light chains down. So this is sort of like our starting point. Okay. Like there's the uninvolved free light chain in pink or the involved free light chain, the bad free light chain in pink, the uninvolved in green. And the difference between those is our starting point. And there's no, each person's number is different. One person's difference might be 50 milligrams per deciliter and another person's might be five milligrams per deciliter, but you could still have symptoms. Okay. It depends on your light chain amyloidosis' tendency to form deposits. So if we can knock this this difference down by 50%, we call that a partial response. That's kind of, it's similar in a way to myeloma where we say if we knock the M protein down by 50%, we call that a partial response. But again, we're not just measuring the absolute value of the involved free light chain. We're measuring the difference between the good guys and the bad guys here. If we can knock that difference down to at least, by at least 50% and the difference is four milligrams per deciliter or less, we call that a very good partial response. And if we can normalize, well, we used to say if you could normalize the difference or eliminate the difference, that's the definition of a complete response. Sometimes the therapy works so well that you actually suppress the levels below normal. So the difference may not be normal. It may even be negative. You may push the bad guys even lower than the good guys. And that's accepted as a complete light chain response. Also, if a patient has an M protein, which occurs in some subset of patients, we want to see that M protein disappear too, to call it a complete response. But pretty much, because again, the light chains are more important than an M protein, we like to see at least a very good partial response. And we know that survival is improved the deeper the response gets. And we also know that the likelihood of an organ response is higher the deeper the light chain response gets. We assess organ response by different means. So like in the heart, we measure certain blood tests like the NT-proBNP or troponin. You can also see improvements in the echocardiogram, which is an ultrasound of your heart. In the liver, we use a test called alkaline phosphatase as a standard test on a chemistry panel, or an ultrasound to measure the size of the liver. And for the kidneys, we either measure creatinine, or more importantly, the amount of protein leakage that we're seeing in the urine. And we can measure that best on a 24-hour sample. And again, as I mentioned before, the organ response can sometimes lag behind the hematologic response by more than a year. And so that team management approach is super important. So having a good cardiologist, having a good nephrologist, gastroenterologist, you know, super important part of the team management here. The therapy list that I'm showing you here, you know, I could actually change the heading of this almost to therapies for multiple myeloma. It's the same classes of drugs, like for instance, in the green column, immunomodulatory drugs, we see Revlimid, we see Pomelist. In the antibody column at the top, we see three antibodies that are approved for therapy in multiple myeloma, daratumumab, isotuximab, and elotuzumab. And we see older therapies like melphalan in the purple column, right? Even newer therapies like phonetoclax on the far side, we are used in multiple myeloma, some approved, some not approved. In amyloidosis, none of these are approved except for daratumumab, and that's approved in combination with the regimen Cybor-D. And this is Cybor-D is an abbreviation for three drugs pulled from three different columns, and that is the one approved therapy. In the bottom left orange column here, you'll see a second category of antibodies. The top ones are antibodies directed against the plasma cells. On the bottom, you see antibodies that are directed against the protein or the light chains. I'm going to talk about that at the very, very end. The combination of Cybor-D plus daratumumab was approved on the basis of a trial called the Andromeda study, which was published in the New England Journal of Medicine relatively recently, and even the last year or so. And first, we did a safety run-in with 28 patients just to make sure that you could safely give this combination to patients with amyloidosis. We know from myeloma that you can add dara to almost any chemotherapy regimen, and but that wasn't as clear in amyloidosis because amyloid patients tend to be more fragile because of their organ injury. So the strategy that this study ultimately was examining was this combination followed by just daratumumab on a maintenance schedule for out to two years. We saw that 96% of patients had a light chain response with this regimen, and about half of them had a complete light chain response, which was very promising compared to Cybor-D alone, for instance, or to other frontline regimens. And what we saw was that during the maintenance with daratumumab, there was no late unexpected toxicity that we didn't already know about from its extensive use in multiple myeloma. So once we had this run-in and we knew we could do it, we launched a randomized study with almost 400 patients where patients were either randomized to the standard induction therapy, which was six cycles of Cybor-D, or the same thing with dara followed by dara maintenance. So this is not just a study comparing the addition of an antibody to no antibody as induction therapy. It's also looking at the benefit of extending that therapy with a relatively non-toxic therapy over a long period of time. And the key endpoints, again, the overall hematologic response rate, I mean, rather the complete hematologic response rate in each arm. And then there was a secondary endpoint called major organ deterioration progression-free survival, which is what we call a composite endpoint. And it basically said this, if a patient died, if their light chains got worse, or they had deterioration of their heart or kidney function such that they needed the interventions that I listed here, an organ transplant, a ventricular assist device, initiation of dialysis, any of these things happening listed here, all added together. If any of them happened, that was considered to have met the endpoint of MOD-PFS. And we wanted to compare that as well. And the thinking being, if we saw a much higher complete response rate with the light chains, we would also see a much lower rate of these other issues, including progressive organ deterioration. And in fact, the complete response rate in the experimental arm on this study was actually almost exactly the same as the complete response rate in that run-in safety group, a little over 50%. And that was more than two times higher than what we saw with Cyborg-D alone. And importantly, roughly half the patients hit one of these organ-related endpoints criteria if they got daratumumab compared to the patients who didn't. And it was actually on the basis of both of these, since both endpoints were met, primary and key secondary endpoints, this is actually what led to the approval of daratumumab. So this is the first approved drug in AL amyloidosis. What I can tell you is, many of us are hopeful that this will eventually lead to a long-term survival benefit. A few things aren't quite solved by this study. First, in the short term, during the induction, the survival actually wasn't different at all. And what that has to do with is the amount of damage that was sort of already in play and in motion when the patient got onto the trial. And so there were some kinds of heart damage that still ended up being life-threatening to patients, even as they were starting therapy. So there wasn't an immediate obvious difference in survival. The other thing this doesn't answer, because there was only the one initial randomization, it doesn't really tell us if the daratumumab maintenance is key to reaching the secondary endpoint, or not. It's possible that you would have had similar outcomes if you had just done six cycles of combined therapy versus six cycles of Cyborgi without their maintenance. We don't know that yet. And that question about sort of optimal use of daratumumab maintenance, that's being looked at in the future in amyloidosis, and it's also being looked at pretty carefully in multiple myeloma. So this is kind of our general treatment algorithm. I'm actually kind of getting towards the wrap-up here. The first question is, you've made a diagnosis of amyloid, you've done that mass spec typing to prove that it's AL-type amyloidosis, because that's the one where the culprit is plasma cells, and the protein is light chains, and it's the one that you would treat with myeloma-like therapies. All the other types of amyloidosis, for instance, the two that I showed you at the very beginning, ATTR, which is transthioretin, or AA amyloidosis, which is a secondary systemic amyloidosis that you get in inflammatory diseases. There is different therapy for those. What you would never give those patients is chemo, because you don't have a clone of abnormal plasma cells in the bone marrow making the amyloid. In the case of ATTR or transthioretin, the source of the abnormal protein is your liver. Giving Cybor-D and Dera doesn't affect how your liver makes transthioretin, it just affects your bone marrow function. You'd have all the side effects of chemo with no potential for benefit. Right out of the gate, a key fork in the road is making sure you're in the right lane and that you are actually dealing with a plasma cell disorder. The Dera-Cybor-D combo that I just mentioned, because it is the only approved therapy, I think could be considered standard therapy for initially diagnosed patients. I mention here, I say Cal101 and BERT, which stands for Bertamamab. I'm going to explain what those are in a few minutes. I'm going to come back to those. I briefly showed you something about those before, but I'll elaborate. Then what you do is you, you know, whatever you start with, whether it's Dera-Cybor-D as standard therapy, whether it's a clinical trial that uses other agents, at the end of the day, you assess whether or not the light chains went down deeply. If they did, probably you would use maintenance Dera-Tumumab as was used in the Andromeda study. If you didn't get a deep hematologic response, then you need to resort to second-line therapy. Just like in myeloma, if medications from one or two or three columns didn't work, then go for medications that are in other columns. IMIDs, like Revlimid and Pomelist, are generally not front-line therapy in AL amyloidosis, but they are often used in second or third-line therapy. Venetoclax is something of a lot of interest right now in AL amyloidosis. We know in multiple myeloma, the 15% of patients or so who have a specific chromosome abnormality called a translocation between chromosomes 11 and 14, we know those patients, those myeloma patients, are the ones who are most likely to respond to venetoclax. It turns out, well, 15% of myeloma patients have that abnormality, 30% to 50% of AL amyloidosis patients do. There's a much larger subset of AL patients who may respond to that treatment than myeloma patients. There are several trials ongoing to focus on that. Stem cell transplant is a therapy that has historically been used often as part of front-line therapy, but I have to tell you, it's really a pretty small subset of patients who are good candidates. Even looking at sort of older historical data before DERA-CYBOR-D was approved, less than 20% of amyloidosis patients actually got transplanted. Now that number is actually going down significantly because with 90-something percent hematologic response rates, you can usually get to the endpoint that you want without having to go through high-dose therapy. We definitely still use it. It's definitely something that should be considered for fit patients, but on the ground, the numbers have decreased at all centers, at Mayo, at Boston University, at Carmanos, at University of Michigan, and really at many centers we're seeing less transplant being done early on in AL amyloidosis. Now I'm going to just finish up right now five world-directed therapies. That's what Cal101 and Bertamomab are. Those are the antibodies at the bottom of that orange column that I showed you earlier. These are antibodies. Instead of going after the plasma cells to put out the fire and then shut down light chain production and then wait to see how your body cleans it up, it's actually antibodies directed against those fibrils to sort of let your immune system assist in the clearance of those tissue deposits more rapidly because normally your immune system is not great at finding these deposits. We've proved that you can give these by themselves. There's animal data showing that treating animals with antibodies like this accelerates the clearance of amyloid deposits. We've also shown in studies that you can safely combine these antibodies with standard regimens like Cybordie or Cybordie plus dara. Right now there are two Cal101 studies and one Bertamomab study where patients with advanced heart involvement are given Cybordie plus dara with or without one of these antibodies to see if simultaneously addressing the fire and addressing the smoke, hitting the plasma cells and hitting the deposits leads to better outcomes and more rapid organ function improvement than just the plasma cell direct therapy alone. For anybody who's not a rookie in amyloidosis, I'm sure this may not have been a fully satisfying summary of the field in amyloidosis, but the fact is not everybody on here has the same degree of experience. I wanted to stop and let you ask questions. I was full screen so I didn't see the time and seven minutes ago somebody should have unmuted and yelled at me. I said it was really good though. I thought about it, but it was really good information. Just polite, but I could have used, I needed to stop watch. I'm going to shut up and let you guys ask questions. Well, thank you I think the audience would agree with me. That was an excellent summary. That was exactly what I was looking for when I asked you to speak today. Thank you so much for your preparation for this and just being willing to speak in this inauguration of our community. I have a couple questions that I'm going to get started with, but before I start with those I want to talk to my audience to let them know how they can ask their questions. You're welcome to enter your question into the chat and I can moderate those to doctors under myself or you have the opportunity to ask doctors under your question directly. You can do that by if you're on a desktop or laptop computer, you can click the reactions button. If you hover over our faces there's a reactions button. It's a little smiley face with a plus at the top. If you click that and then raise hand, I will be able to keep track of who's raised their hand and call on you to be able to unmute yourself. Dr. Zander raised his hand. Great. Unfortunately, if you physically raise your hand, I won't be able to see you, so make sure that you virtually raise your hand if you want to ask your question in that way. If you're on a mobile phone or a tablet, make sure to click that three horizontal dots that say more and then raise hand in order to do that same thing just in a different way. As we're waiting for those questions and those hands to be raised, Dr. Zander, a couple of questions I wanted to ask you. One of the first ones is we talked about experiences in delayed diagnosis. Often it's several months later that patients are now in dire straits and are finally being diagnosed. What do you suggest that we can do in order to change that? What kind of awareness campaigns need to be run? What can we do in order to help future amyloidosis patients avoid that? There's a few things. First, there is a concerted effort by many amyloidosis support and education communities, the Amyloidosis Foundation and others, to provide educational sessions through things like Grand Rounds and other continuing medical education, not just to hematologists, not to myeloma specialists, but to the people more on the front line who might actually see the patient first, primary care physicians, see the patient first, primary care physicians, cardiologists, dentists, kidney doctors, specialists who frankly are often seen more often than hematologists are. Because most amyloidosis patients don't have a super elevated protein level like a myeloma patient, it may not be obvious what's going on. There's almost always a more likely explanation for congestive heart failure or protein leakage in your urine or neuropathy affecting your fingers or toes. Things like hypertension, coronary artery disease, diabetes, those are super common medical problems and statistically all more likely to be the cause of somebody's symptoms than amyloidosis. That's why like I say in hindsight, it's always like, well, of course, one plus one plus one plus one plus one equaled amyloidosis. I can't believe they missed it except when it was really just one plus one. When it was really just, my fingers are a little bit tingly, I have carpal tunnel syndrome and some swelling in my legs. I don't know which one of my friends doesn't have some of those symptoms. By the end of the day, every single one of us has sock marks on our legs. It really is hard. We spend a lot of time talking with different medical subspecialists about red flag symptoms. The other thing, that's what we do. The other thing is when patients are ultimately diagnosed, I always tell my patients, you should circle back and just inform the docs in as non-threatening a way as you possibly can. I mean, not issued as a letter from your lawyer, but issued as a letter from your being sent with good intention. Let them know what your diagnosis actually was. The next time they see a patient, they think of it because otherwise they're just going to think of you as a patient they never figured out who moved on to other doctors. That's not helpful for the amyloidosis community and it's not helpful for the doc who didn't think of amyloidosis. That's the key is thinking of it in the first place. Yeah, excellent answers. Thank you. One more question and then we'll move on to audience questions. We talked about that this was the Dara-Cyborg-D is pretty much the only approved treatment regimen, but that several others are used. Do you suggest to your amyloidosis patients, do you say here's a clinical trial that you should go in or do you say, you know, let me prescribe this to you and we can work with insurance even though they aren't approved or is it a mix of both? Well, it's easy for me to say let's try a clinical trial because we always have clinical trials for newly diagnosed, relapsed, and we have these trials. So for me, that's easy. Sometimes if a patient's bone marrow did actually happen to have 10% plasma cells in it, you can make the case to an insurance company that this is somebody who also meets the criteria for multiple myeloma and that they're symptomatic because of these plasma cells and you can often get myeloma therapies approved in that situation. The problem is when you have 5% plasma cells or 8%, we sometimes get pushback. It's a very difficult thing, you know, sometimes. Usually with peer-to-peer sort of like contact and working with insurance companies, we can help reviewers understand that the therapy for AL amyloidosis is multiple myeloma therapy. So most of the time we're able to succeed. Sometimes it's a little bumpy to begin with. Wonderful. Thank you. Wendy, I see you have your hand up if you want to unmute and ask doctors under your question. Thanks for being here today. Yes, I have a question about the mass spectrometry test. Is that a blood test or a bone marrow test? All I know is I don't think I ever had one. All I know is they couldn't do a FISH test because I had under 5% plasma cells. I guess I'm just old. I don't know. But how do they do that mass spectrometry? All I can say is I had a complete response, so that's the good news. But I need to know more about how they do that mass spectrometry. From what source do they get the material to do it? So like FISH testing, which you mentioned, that's actually like cytogenetic chromosomal testing that's done on the plasma cells. So that's the type of testing you would do in an ALM allidosis patient or a multiple myeloma patient. Mass spec is done on a biopsy of any tissue where you can see Congo red positive deposits, those apple green birefringence Congo red positive deposits when you stain the sample. And so you can run it on a bone marrow specimen, on a kidney biopsy, a heart biopsy, a lymph node. But the key is you have to be able to, like under the microscope, you have to be able to actually see the deposits so that you can do a laser microdissection, peel it off the slide, and then send it through the machine for analysis. If you need more sensitive testing like electron microscopy or something like that, you can't do the mass spec on that. Okay. So I think I just obviously had it because it showed up in my kidneys, the little Congo red was there and they diagnosed it, that's the only place they ever found it. So the kidney is one exception maybe. So you can do, so on heart tissue and bone marrows, the stains that we use to analyze those tissues aren't very good at staining the deposits. It's not reliable to use like a capestain or a lambastain. In a kidney, you can do testing called immunofluorescence testing where you actually can use fluorescently labeled antibodies to bind to the deposits. And for a kidney biopsy, you actually can make the diagnosis with that initial staining and maybe not need mass spec. Sometimes you do, but a lot of times you do not need that. So I should have been, you caught me because that's right actually. And a kidney biopsy sometimes don't need mass spec. So you probably didn't have it actually. Yeah. Well, that's very helpful because I thought, oh my heavens, but I mean, almost a year out and I had a total hemological response in the very first treatment, but they never found it any other place when they went biopsying, it turned up later. So that's very helpful. Thank you so much. Your talk was wonderful. It was so clear. Thank you. I agree. Thank you, Wendy, for an excellent question. Let's talk a little bit more about the FISH test that she mentioned because that was another one of my questions. I have several questions as I learn about this. So you mentioned that the FISH test is a cytogenetics test that is usually done in multiple myeloma and it seems like it's done in amyloidosis as well. Do they have similar genetic characteristics as myeloma and are the risk factors the same? They do. First of all, there is true overlap between these diseases. Most patients diagnosed with multiple myeloma do not have amyloidosis as a complication of it right out of the gate. Most patients with amyloidosis don't have classic myeloma symptoms, but over time, if you look hard enough, 10% to 15% of myeloma patients probably do develop complications of amyloid at some point over the course of their illness. It does happen. We used to say it didn't go in the other direction, that amyloidosis patients generally didn't develop myeloma-like symptoms, but now that amyloid patients are starting to live longer, most of us have seen patients who have done that, you know, a patient who is amyloid, amyloid, amyloid, amyloid, and then eight years into it suddenly had a bone lesion like a myeloma patient, which is not a typical finding in amyloidosis. But yeah, we see very similar chromosome abnormalities. The frequencies of them aren't the same. So, you know, 50% of myeloma patients have deletion of chromosome 13, and only 15% or 15 to 20% have that translocation between chromosomes 11 and 14, which means chromosomes 11 and 14 swapped pieces. So a piece of 14 ended up on 11 and a piece of 11 ended up on 14. But as I said, like the AL amyloidosis patients are really enriched for that second abnormality. It's two to three times more frequent in AL and definitely has significance with regards to the likelihood of responding to specific therapies, not just venetoclax, but also other therapies like cortisomal containing therapies or transplant. Okay, awesome. Another question here is, should family members be tested for amyloidosis? Well, AL amyloidosis, like myeloma, is generally not thought of as an inherited disease. There's no myeloma gene or AL amyloidosis gene but we do know that people who have myeloma or lymphoma or amyloidosis are more likely statistically to have relatives that do. It's not 50% of your offspring, like if you had sickle cell anemia or Tay-Sachs disease or something like that, but there is a slight difference in the frequency. There are no guidelines recommending screening of family members for AL amyloidosis, but there's interest in this. Just like there's a huge ongoing project looking at familial risk in patients with MGUS, I see a question from Suzanne. We'll one sec. Amyloidosis patients could be theoretically screened in the same type of protocols. I will say that the other types of amyloid that I mentioned sometimes actually are inherited. ATTR amyloidosis, there are over a hundred different mutations in the transthioretin protein that have been identified and it's a dominant mutation. If you have one copy of a mutated form of transthioretin, you're at significantly higher risk for developing ATTR amyloidosis. Patients with other types of amyloid, depending on the type, absolutely you might recommend genetic counseling and screening. I'm going to pipe down and let Suzanne talk. That's fine. Go ahead. I want to apologize. I'm outside. That's why you can see that. That's why I had my video off because I don't know. I'm just not in an office environment. I'm trying to be very concise. It was first of all a phenomenal talk for me. It kind of really twisted my brain around because to make a long story very short, it took seven years to diagnose me. I was diagnosed originally with muscular dystrophy. It was a misdiagnosis. They knew I had a muscle problem. That's how it presented with me. The neurologists, they had no answers for me. Then finally, I was diagnosed with multiple myeloma through the bone marrow biopsy. I'm just wondering if I was one of those patients who may have had amyloidosis first because of the long, long time it took. The fact that my father had exactly the same symptoms as me. He was diagnosed with multiple sclerosis, which also at the end the doctor said, I don't think you've ever had that. It's a complicated issue. What happened is in 2017, I started the cyber D treatment with the autogallus stem cell at the end. I was in remission for three years, came out of remission last September, and started immunotherapy with the DERA and the DEX and the Revlimit. My last blood test, okay, it's been going. I feel good. I still have muscle weakness. There was suspected amyloidosis because they never did the red Congo stain. It was ordered. When my oncologist looked into it, what happened? They had lost the sample. I never had the Congo stain. There's nothing genetic on me, nothing. In order to do that, I would have to have a heart biopsy because it's the left ventricle that's enlarged. Having said that, I was a super active athlete. It's all of this information piling on top of each other. To come to what's happened is that on this treatment now, I've been on it since September, and all of a sudden, just before my last treatment, actually, everything looks good except the kappa went up. My white blood cells went down. There's still no M-spike. There is a very slight M-spike detected. It's not measurable. It's been like that all the way through. That's basically now the picture I was looking at. The kappa is up. I'm free-light trained kappa. That's my issue. The white blood cells are way down. I guess what's happening now is because I'm not officially only suspected amyloidosis. If that's the truth, then I don't even know what kind, but they say suspected AL amyloidosis. I'm just wondering what your take would be on something like that and what you suggest I should do next. I will preface everything I'm saying by I'm not giving anybody formal advice, but I will tell you that the problems you're describing are not unsolvable. The fact is that if your muscles were being affected by amyloid at the outset, if your heart thickness is due to amyloid, there is an extremely high chance that you can diagnose that not by biopsying your heart, but simply by doing the test, that Congo red stain on your bone marrow biopsy. You don't need to do a new bone marrow biopsy to do it. You can have the pathologist cut the slide from your old bone marrow biopsy and do the Congo red stain. But that's the one they don't have. They lost it, right? They lost the whole biopsy? Okay. That's not great. If there's no existing bone marrow biopsy slides to do it on, then you could theoretically do it on the next time you have a bone marrow biopsy. There is also a test called a fat pad aspirate, which is like a little mini liposuction. Basically what you're doing is you're numbing up like a baseball card size diamond on your abdomen with lidocaine, like what you'd use before bone marrow biopsy. Then once you numb up that field with a needle, you can just put the needle in and suck some fat out from under the skin and when I say mini liposuction, you're looking for a wad of fat about the size of a chickpea. Okay. By biopsy standards, that's a pretty big biopsy actually. You can do Congo red staining on that. If you have a sample that's that large, there's about a 70% sensitivity. Seven out of 10 patients who actually have amyloidosis, you'll prove it with that biopsy. If you did it on another, like on the bone marrow as well, that's also about 70% sensitive. Between those nine out of 10 patients, you can make the diagnosis without having to do a heart biopsy or a muscle biopsy. Right. That makes sense. Do I have time for one last question? Yeah. Can I ask you one more too though before you ask? When you were being worked up by neurologists, they concluded you likely had muscular dystrophy. Did someone do a muscle biopsy at some point? Yes. They simply are not getting back to us. This was in Saskatoon. I lived in the center of Canada and they are just not accepting our inquiry. It's really quite, it's the situation. It's quite crazy, but that's just the way it is. If that biopsy is still sitting in a pathology department somewhere, you can do the conga red standing on that biopsy. Okay. I'm going to have to become more aggressive trying to find out what happened to those samples. I'm at Princess Margaret in Toronto now, which is the- Which is a great myeloma and amyloidosis center in Canada. Exactly. It's the best one. Exactly. It's a great center. It was having light chain multiple myeloma. I don't know why I'm thinking that, but it's somebody- and it was listening to one of the videos in Health Tree. I was under the impression that with light chain multiple myeloma, the deposition disease is more likely than amyloidosis. The light chain deposition disease would be more likely than amyloidosis. I understand the difference is that the light chain deposition disease is reversible. That the deposits can disappear again. Do you have any additional thoughts on that? The deposits can disappear in both. Actually, the most common kind of kidney injury in myeloma is casnopropathy, which is clumps of light chains that combine with other proteins and they clog up the pipes downstream in your kidneys. Your kidneys are basically a big bag of filters and then pipes after the filters. Then those pipes all converge into one big pipe and that's the ureter that goes to your bladder. That's how your kidney makes urine. It's like a parallel circuit with lots and lots of different filters in it. In myeloma, it's those pipes that get clogged up with casts. Dehydration, high calcium, and those kinds of things can sometimes precipitate the casts in your right. You can reverse those like IV fluids. It can absolutely reverse casnopropathy. Light chain deposition disease is deposits of light chains upstream in the filter section instead of the pipes. That's also what amyloidosis is as well. Amyloidosis and light chain deposition disease are functionally very similar. They both lead to very similar symptoms. The difference is that in terms of diagnosis, the amyloid deposits have that Congo red, apple green birefringence, and the light chain deposition disease, you can still see the deposits, but they don't have the apple green birefringence. Okay. Thank you so very much. This was really quite an important presentation for me personally. Thank you. Thank you very much for being here, Suzanne. Thank you to all of you for your participation today so that we're able to launch this amyloidosis community. It's really exciting to be together. Thank you, Dr. Zander, again for your preparation and presentation. It truly was excellent and we appreciate you. I'm just going to close with a couple of outro announcements and then we can finish for today. So our next meeting is planned for September. I have planned on meeting once a quarter. That being said, I'm open to your feedback. So if you would like to meet more frequently, I'll make sure that we send out a survey in these resource emails that we send out with the recording and the slides and things so that you can look back on this meeting and take notes and things like that. In those resource emails, we always include a survey because I want to know how am I doing? How did you like Dr. Zander's presentation? What are topics you want to cover in the future? And I'll make sure to include a question that says, how frequently do you want to be meeting? I have some groups that meet monthly, some groups that meet every other month, some groups that meet quarterly. And originally I was planning on meeting quarterly, but I'd like to build the needs of the patients, even if it's just some support group meetings where we connect with each other and hear each other's stories. So stay tuned and let me know in that survey if you would like to be meeting more frequently, but if not, our next meeting will be in September and we'll be talking about different clinical trials that are available and open for this community. You may be interested in other myeloma crowd community events that we have upcoming. On Thursday we have two events. At 2 p.m. Eastern is our African American Myeloma Community Chapter. We're going to be doing a fitness routine with Vanya, who's a fitness instructor. And then at 7 p.m. is our immunotherapy treatment chapter. We're going to be talking about bispecific antibodies, which are an emerging immunotherapy that really could change the future of myeloma and maybe even amyloidosis. And that's going to be with Dr. Cesar Rodriguez. And then on June 28th, which is a great day because it's my birthday, at 6.30 p.m. Eastern is our Florida Myeloma Community Chapter. I do have regional groups that meet across the nation and I'm always looking to create those in different areas if someone is interested in creating a geographic region with me in their area. They're virtual and they meet online for the most part. We're going to be talking about the mental journey of myeloma with Peter Rivkees. He is a myeloma coach and a licensed counselor and he's going to be talking about as a patient how he's carried the burden and what advice he has for other people sharing that mental journey of myeloma. And even if you don't live in Florida, you're welcome to join us. The link to sign up for those events that I mentioned and even more events that I have not mentioned is found at the bottom of the slide, myelomacrowd.org slash events and will be included in that follow-up email that I was mentioning earlier. Another thank you to our sponsors, Bristol Myers Squibb, GSK, and then TechJanssen Oncology and AbbVie. And a big thank you to each of you for helping us build this amyloidosis community. Again, it's just so exciting to be together and I really appreciate you taking the time to be with me today. So have a great evening everyone and take care. Thank you. Thanks again everybody. Thank you. Bye-bye.