Sascha Tuchman, MD
University of North Carolina at Chapel Hill
Interview Date: May 14, 2021
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Light chain Amyloidosis (also called AL Amyloidosis) is a condition that can occur in addition to multiple myeloma. Learn more in this informative show from Dr. Sascha Tuchman of the University of North Carolina about the signs and symptoms, how amyloidosis is diagnosed, how it should be treated and the clinical trials that are running for amyloidosis patients. All AL amyloidosis physicians are myeloma experts, but not all myeloma experts are amyloidosis physicians. Just one more reason to have a qualified expert on your care team!
Jenny: Welcome to today's episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. We'd like to thank our episode sponsor, Takeda Oncology, for their support of the Myeloma Crowd Radio program. Now before we get started with today's show, I like to mention just an upcoming event we have later today. We'll be hosting a webinar about using BLENREP in the clinic. It will be an hour-long discussion with Dr. Joshua Richter from Mount Sinai at 4:00 p.m. Eastern Time. You can find that on myelomacrowd.org/events.
Also a reminder, we are running a genetic study inside of HealthTree to learn which treatments are showing the best results for different segments of genetics in patients in the real world. To join that study, you can go to healthtree.org and request that we help complete your profile for you. We have over 500 patients participating so far in that study and breaking patients down into subgroups requires a significant number of patients to be really meaningful. There's sufficient data for each subtype like 4;14 patients or deletion 17 patients or 11;14 patients or the like you can find that on healthtree.org
Now on to today's show.
AL amyloidosis is a condition that can occur in conjunction with multiple myeloma. It's typically harder to diagnose, and patients with amyloidosis need careful care. With us today is myeloma and amyloidosis expert, Dr. Sasha Tuchman. I've had the pleasure to meet Dr. Tuchman last week in person as we performed HealthTree University video interviews. He explained amyloidosis beautifully. I invited him to participate on the show. Dr. Tuchman, welcome to the show. We're so pleased to have you with us.
Dr. Tuchman: Good morning. Thanks for having me.
Jenny: Now, before we get started, let me just do a short introduction for you. Dr. Tuchman is Clinical Associate Professor and Director of the Multiple Myeloma and Amyloidosis Program. He's also Associate Chief for outpatient clinics and outreach in the Division of Hematology at the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill in the Raleigh area. He's a regular speaker for continuing education on myeloma and amyloidosis topics and has received significant funding for his academic myeloma and amyloidosis translational research.
He has been an author for books and chapters on both topics. He has received many awards, including the Duke University Eugene Stead Teaching Attending Physician Award, the Burroughs Wellcome Foundation Travel Award, the ASH Travel Award, and ASCO Merit Award. I was so impressed by the number of scholarships that you got at Georgetown and your summa cum laude honors - over nine scholarships. I thought that was very amazing. I know you've done a lot and also geriatric work in multiple myeloma. We're just excited to talk to you about multiple topics today.
Dr. Tuchman: Thanks for the extremely kind introduction.
Jenny: Well, Dr. Tuchman, let's get started with just some basics. What is AL amyloidosis? And then how does that differ from other types of amyloidosis?
Dr. Tuchman: So AL amyloidosis is a protein problem. We all, of course, have proteins in our body. They are natural part of skin, muscles, many other parts of the body. Amyloidosis of any form is a problem involving different types of proteins. There's multiple different types of amyloidosis that comes from or really stems from what type of protein the amyloidosis was made from, but basically an amyloidosis, in general, what happens is that you have an abnormal protein that deposits in different tissues. That can be the heart, can be the kidneys, can be nerves, can be many different parts of the body. As that abnormal protein deposits from the different tissues, then they have trouble functioning. So that protein interferes with normal organ function. So that sense, when we do a specific test on biopsies, you can see that protein under the microscope, and we refer to that as amyloid protein or the condition of amyloidosis.
So again, amyloidosis or that protein can come from different places. That's really one of the very interesting parts of this condition, and the one that's most relevant for multiple myeloma. How I got into this is this form of amyloidosis called AL or light chain amyloidosis. All the different types of amyloid have different subtypes, and they all start with this abbreviation system that starts with a letter A, and then there are some letters after them.
So AL stands for amyloid light chain. So in light chain amyloidosis or AL amyloidosis, what happens is that you have abnormal cells in the bone marrow, which come from the immune system called plasma cells. Those are incidentally the same cells that are sick in the multiple myeloma condition. But when people have amyloidosis, then the sick plasma cells in the bone marrow make abnormal protein which circulates in the blood, which is most often this protein called light chain, which again the familiar term for anyone who has multiple myeloma. And then again when people have this amyloidosis condition, then that light chain protein sticks in the different organs and forms that amyloid which again sort of gunks up the machinery of the different organs. So it most commonly involves the heart and the kidneys, but also commonly involves the GI tract, nerves, can involve the lungs, can involve skin, many different organs. So again, that's light chain amyloidosis, where the problem starts in the bone marrow with the plasma cells, light chain proteins circulating in the blood, and then that light chain protein deposits in the different organs and causes them not to work quite right.
So in terms of how that's different from other types of amyloidosis, that's again one of the very interesting parts of this condition, and that there are other forms of amyloid which come from completely different processes that have nothing to do with plasma cells, nothing to do with light chain, nothing to do with the bone marrow. But what happens in those other types of amyloidosis is that that abnormal protein comes from somewhere else, some other disease process in the body. That different protein deposits in some of those same tissues, and then still forms that amyloid proteins.
The most common form, for example, in the United States is called TTR or transthyretin amyloidosis. The abbreviation for that one is ATTR amyloidosis, unlike AL, which we talked about a couple minutes ago. That's when TTR amyloidosis, that's actually a protein that comes from the liver. Liver synthesizes this protein called TTR. Sometimes it makes normal TTR. Sometimes it makes a slightly abnormal form of TTR protein, and that protein deposits primarily in the heart or the nerves and causes those organs not to work right. When we do the testing for the biopsies and the staining, we still see that amyloid protein. But as you can discern, it's coming from a completely different place from what we see in light chain amyloidosis. It's really important to sort that out because it, of course, heavily influences how we manage and treat the condition.
Jenny: Right, what's the root cause of the amyloidosis, so you can attack it properly? How many people are diagnosed with AL amyloidosis every year? And then can you just describe the relevance or the association it has with myeloma? Like what percentage of myeloma patients might have this? Do you find it in some of the earlier precursor conditions?
Dr. Tuchman: Sure, great question. In terms of how many patients are diagnosed with light chain amyloidosis every year, it's probably about 3,000 patients are diagnosed with amyloidosis every year. When I think about this in clinic, I think about it in terms of being about 1/10 as common as multiple myeloma.
Multiple myeloma is diagnosed in about 30,000 people per year in the United States, a little bit more than that, and then light chain amyloidosis closer to 3,000.
These conditions are we often talk about them in conjunction with one another because these conditions are related. I think of them as sort of cousins in the same family. They're different, but they're related. The reason for that is that in both light chain amyloidosis and multiple myeloma, the problem boils down to those plasma cells in the bone marrow, again sick plasma cells in the bone marrow that are growing there and sometimes causing trouble.
Those sick plasma cells make those abnormal proteins that float around in the blood. Sometimes it's M spikes, sometimes it's light chain, but the the behavior of the cells and/or the protein in the body can be quite different. In some people, the problem is multiple myeloma where the damage that the cells and protein cause in the body fit the specific patterns that we see in multiple myeloma like bone spots and anemia and high blood calcium levels in contrast to amyloidosis wherein those people that abnormal protein in the blood sticks in the different organs and forms amyloid which can be quite different, congestive heart failure, chronic diarrhea and nerve trouble, which again is very different from multiple myeloma.
So these two things really exist on a spectrum in the sense that they're both plasma cell disorders. They both stem from those abnormal plasma cells in the bone marrow. But again, how they affect different people can be quite different. In terms of how many patients with multiple myeloma develop amyloidosis, that number hasn't exactly been mapped out as the question is specifically phrased, but what we do know is that about 10% to 15%, maybe 20% of patients with multiple myeloma have amyloidosis with it. People can have multiple myeloma by itself which is most common. People can have amyloidosis by itself which is less common but still certainly we see it. Then some patients have sort of an overlap, meaning that they have a plasma cell disorder with some features of multiple myeloma plus some features of amyloidosis. But in general, if you look at the textbook, it's about 10% to 15% or 20% of patients with multiple myeloma that have amyloidosis also.
Jenny: That was going to be my question. I knew you could have myeloma without having amyloidosis, but I didn’t know you could have just amyloidosis without having any myeloma involvement. That's interesting.
Dr. Tuchman: That's one of the really fascinating aspects of these conditions in the sense that it really again all boils down to sick plasma cells in the bone marrow and abnormal proteins in the blood. But how these two sort of parts of the same condition affect an individual patient is completely different, and a lot of that derives from how those plasma cells are behaving in the bone marrow and then probably also the structure of that abnormal protein that's in the blood.
In terms of behavior, so we know that there are many patients that have some of those abnormal plasma cells in the bone marrow, and they may be in the bone marrow and growing abnormally but not causing trouble, like the things that we see in multiple myeloma. The blood calcium level is normal. They're not anemic. They don't have kidney failure, other things along those lines. That's really driven by again the behavior of those cells. In some patients, they cause those problems. In some patients, they don't.
Similarly for that protein, some patients have an abnormal protein that's in the blood that comes from those plasma cells, and it's perfectly structured so that that protein can stick in the different organs and form that amyloid. That's a certain number of people. But then there are other people whose plasma cells make an abnormal protein that really can't form that protein no matter how much of it is in the blood.
So we see this clinically in the sense that sometimes we have patients with multiple myeloma who have extremely high levels of these abnormal proteins in the blood, be that M spike or be that light chains, and they don't form amyloid protein. Then other times, and this is pretty common in amyloidosis actually, that we can have patients who very clearly have clinical manifestations of light chain amyloidosis. They have severe heart failure, they have severe kidney injury, and yet the levels of those proteins in the blood are quite low. That just tells you that it's really driven by the structure. Depending on the structure, it either can or cannot form amyloid.
So again, back to your question, that's really one of the fascinating aspects of these conditions in the sense that it's all about plasma cells. It's all about those abnormal proteins in the blood. So when you do the blood tests, you do the bone marrow biopsies, it looks quite the same. But then when you walk into a room and see someone in clinic, what a patient looks like and what problems they can have related to this can be completely different.
Jenny: That's so fascinating. When someone is diagnosed, when you have that 10% to 15% of myeloma patients that have amyloidosis, does it show up like as they're presenting with myeloma? Does it show up later? If you're a myeloma patient, do you have to kind of watch for it for something that could occur later that didn't occur at your initial diagnosis?
Dr. Tuchman: It can. Most often when we diagnose the people who have multiple myeloma with concurrent amyloidosis or basically they have sort of the overlap of both conditions, most often we pick that up at diagnosis, meaning someone comes in with myeloma and we figure out that they have amyloidosis also or vice versa. They have amyloidosis and then we figure out that they have multiple myeloma too. That's most common.
But sometimes patients do develop something else along that spectrum later on in the disease, meaning someone has multiple myeloma. In the beginning, it was pure multiple myeloma. No amyloidosis. They've had it for a few years. That's come back a couple times. Then later on in the disorder, they develop amyloidosis. Conversely, someone can have amyloidosis, and then later on the disorder developed multiple myeloma. That probably has to do with the evolution of those cells over time, of the protein over time, and things along those lines. Yes, it can evolve from one and to the other over time.
Jenny: Can smoldering myeloma patients have amyloidosis?
Dr. Tuchman: They can and that's a little bit controversial. From a fundamental perspective, yes, they can in the sense that any plasma cell disorder in which there are plasma cells in the marrow and then the abnormal proteins in the blood can form amyloidosis.
But what to call smoldering myeloma when somebody has amyloidosis is a little bit tricky, and this is more semantics. But what I mean by that is that by definition, smoldering myeloma is asymptomatic, meaning a patient can't not only not feel it, but they also can't have the other manifestations of, let's say, multiple myeloma like high blood calcium or kidney problems, anemia, bone lesions, the classic CRAB criteria that we refer to in the medical textbook. But similarly, they also really shouldn't have amyloidosis. They shouldn't have other manifestations of the disease that demonstrate that the cells and/or protein are causing injury. It's sort of a terminology issue for what it's worth.
When I have patients, if they have light chain amyloidosis, I don't refer to smoldering myeloma, but some myeloma and amyloid experts do and more just as a statement of basically how many of those abnormal plasma cells were in the bone marrow. In the sense of classic amyloidosis often has a relatively low number of plasma cells in the bone marrow, but sometimes patients have more. That's sometimes referred to as light chain amyloidosis with smoldering myeloma. More of a terminology issue but from a fundamental sort of basic perspective, yes, that can happen for sure.
Jenny: There are some of the myeloma experts want to sort of get rid of that whole smoldering myeloma designation anyway, like you either have MGUS, or you have active myeloma. But maybe there's not something in between. I don't know. That's sort of controversial right now, I know.
Dr. Tuchman: I's hard. I mean, there really is a spectrum to a lot of this. When I have trainees in clinic, I often tell them that this is quite different from something like lung cancer, for example, where if the patient has a lung nodule and you do surgery and you take it out, it's either cancer or it's not. There's no gray zone really. But in these plasma cell disorders, be that MGUS, smoldering myeloma, light chain amyloidosis, multiple myeloma, there really is a spectrum to this. So I think a lot of the benefits that patients have from seeing experts is that we do this a lot. We fully understand the spectrum as opposed to sometimes people who don't see a lot of these disorders, and they don't fully understand the spectrum and how these things are sometimes nuanced, and it's not always completely clean.
Jenny: Well, that leads us to signs, symptoms, and diagnoses. On the myeloma side, we are always advocates for getting a myeloma specialist on your team just because myeloma care is so nuanced. From what I've heard about amyloidosis, it's even more so. Like the symptoms might be a little harder to pick up, or the diagnosis might be a little harder to make if you don't know what you're looking for or whatnot. Do you want to just describe how it's properly diagnosed? Is it hard to diagnose?
Dr. Tuchman: Sure. Yes, it can be hard to diagnose. Amyloidosis, you're exactly right, can be tricky in the sense that it's sneaky. It's sometimes tough to pick up. One thing is that it really can affect different organ systems, and so it's hard to give a specific checklist of watch out for these three things and as long as you don't have these, we're good. A lot of that has to do with the fact that amyloidosis really can affect almost any organ in the body. It most commonly involves the heart and the kidneys, but it also can involve the GI tract. It can affect the nerves. The ones that go to the hands and feet that give sensation, and so the thing called peripheral neuropathies that damage the nerves. It can affect the lungs. It can affect the skin. It can involve lymph nodes. It can go to multiple different places.
So again, giving a checklist of specific things to watch out for is somewhat challenging. But I would say that there are certain things that more for the clinicians as opposed to the patients that clinicians should watch out for. Of course, good always for patients to be vigilant, but a lot of this is just the clinicians need to have need to recognize red flags with someone who "just has multiple myeloma" to recognize that they may also have the amyloidosis condition. So some of those things that we think about again fit with the origins of this that amyloidosis most typically involves, and that's the heart. So somebody with new onset congestive heart failure, especially what we refer to as heart failure with preserved ejection fraction, which is a specific type of heart failure, that can be a red flag for amyloidosis. Someone with bad peripheral neuropathy, so again numbness and tingling in the hands and feet.
Another one is somebody with new onset significant GI symptoms. It can be nausea, diarrhea, constipation, just changes in sort of normal bowel function. Low blood pressure, so that's another common one that happens in amyloidosis. Amyloid loves messing with the nerves in the body that regulate blood pressure. Somebody, for example, previously had high blood pressure, and all of a sudden they've been able to come off their blood pressure medications. In fact, their blood pressure is kind of low despite the fact that they're no longer taking blood pressure medication, that's another red flag for amyloidosis.
Then there are two things that I'll mention which are really classic symptoms that occur in a minority of patients, but they're really classic symptoms that really should tip off the clinicians to the fact that we need to think about amyloidosis, and one is called macroglossia. That just refers to the enlargement of the tongue. What happens with that is that that same amyloid protein that can deposit in other organs of the body deposits in the tongue. It can make the tongue thick. It can interfere with speech. Speech can become somewhat slurred and even can interfere with swallowing in people who have it to a severe enough extent. That's one and then the other is basically bruising around the eyes. Sometimes when amyloidosis gets into the skin and makes the skin thinner and more delicate and fragile. So the skin around the eyes is, of course, fairly thin and fragile already. So when you add some of that amyloid, sometimes people have very easy bruising. It's just that there's this phenomenon called raccoon eyes, if you look in the medical textbook, which is basically bruising around the eye that looks almost kind of racoonish. That's another red flag for amyloidosis.
So the big things and when we do education with, for example, neurologists and cardiologists and nephrologist, we really go through these sorts of symptoms and say that if you have patients with unexplained, let's say, heart failure or unexplained kidney problems with amyloidosis, things like that, then we say we really just need to think about the amyloidosis condition and do the testing to look for it. Then similarly, especially for the hematologist, oncologist who may be listening in, when we see patients with a new diagnosis of multiple myeloma but they have some of these other symptoms, which really do not typically come with multiple myeloma but that are classic amyloidosis, then we have to think about amyloidosis also and do the appropriate workup to figure out whether or not a patient has that.
Jenny: Some of these things, I mean, having a bigger tongue or bruising around your eyes, that's probably pretty obvious to a patient if that's happening. Patients should probably speak up and say something too.
Dr. Tuchman: Exactly.
Jenny: Then the neuropathy can be confusing, right? Because myeloma itself can create neuropathy.
Dr. Tuchman: It sure can. This is sometimes very tricky. This is more often neuropathy from time of diagnosis, meaning that somebody who has not been on myeloma therapy before, new diagnosis of multiple myeloma, they don't have diabetes or other things that commonly cause peripheral neuropathy, that people like that come in with really numb feet, numb fingers, and then especially some of the blood pressure issues that I mentioned, that's another red flag for the amyloidosis condition. Again, something to think about.
Jenny: Okay. Well, definitely things for patients to watch out for as well. How do you treat AL amyloidosis either by itself or -- I mean, you mentioned earlier that there are like 3,000 patients diagnosed with AL amyloidosis per year. Then that seems to be, you know, there's like 10% to 15% of myeloma patients who have that. So maybe the bulk of that is patients that also have myeloma. But how do you treat if they have myeloma, and then how does that differ from if they don't have myeloma?
Dr. Tuchman: Treating amyloidosis or just to be clear, light chain amyloidosis, not the other types, but treating the light chain amyloidosis is very similar but different to treating multiple myeloma. This kind of makes sense. It's similar because again it all boils down to those sick plasma cells. When we think about the drugs that we have available for treating multiple myeloma and amyloidosis in general these days, these drugs are almost entirely focused on killing plasma cells. Lots and lots of different drug classes as I know you've discussed with your audience on other shows, but all these different drugs, they're all just different ways of attacking those bad plasma cells in the bone marrow.
So in multiple myeloma, you kill off those cells. The cells cause less trouble. The protein levels come down, and the trouble in the body that the multiple myeloma was causing clears up and hopefully goes away. In amyloidosis, it is a similar concept but a little bit different in the sense that in pure amyloidosis in the absence of multiple myeloma, the cells in the bone marrow usually are not doing much in the sense that they're usually not causing much trouble. There may be a few cells there. They're growing in a way that they're really not supposed to, but they're not causing a lot of the trouble that we see in multiple myeloma such as the high blood calcium levels that occur when those myeloma cells are chewing on the bone. They're not causing severe low blood counts because the myeloma cells are taking over the bone marrow.
In amyloidosis, those cells are often fairly benign. But as we know, what happens is that those fairly benign cells secrete that abnormal light chain protein which deposits into different tissues and forms the amyloidosis. That's really where the problem comes in. It's when those organs aren't working, right that that's what patients feel and what can even become life-threatening in amyloidosis.
So again, back to your question of how we treat these, it's the same principle in amyloidosis in the sense that we often use and, in fact, borrow a whole lot of drugs that we use to treat multiple myeloma, and we use these in amyloidosis in the same way and that we use these different medications to kill off as many of those bad plasma cells as possible. Hopefully, those plasma cells, just because there are fewer of them around, they then secrete less of that abnormal light chain protein that's in the blood. As that protein comes down, there's then less of it around to attack the different organs like the heart, like the kidneys, like the nerves, like all the different organs that amyloid likes to mess with. As we sort of shut down that attack by those abnormal proteins, then those different organs, the function hopefully stabilizes. Or in many cases, the function can actually get better. The kidneys can heal. The heart can heal. The nerves can get better. The different organs can heal up. Again, it's because those organs are no longer under attack by those bad proteins.
So again, treating amyloidosis is very similar to treating multiple myeloma and a lot of the same medications. But one critical thing to realize, and this is both for patients and for clinicians, is that it's similar but it's not the same as treating multiple myeloma in the sense that it's easy to look at multiple myeloma treatment regimens and just say, okay, we'll give this in amyloidosis. But the key is that lots of regimens that are often very tolerable and effective in multiple myeloma are not necessarily tolerable in amyloidosis because of the different ways in which amyloidosis affects the body.
So one common thing, if we think about, for example, first line treatment of multiple myeloma these days for a lot of patients is a so-called RVd regimen. So R, of course, is Revlimid, that's lenalidomide. V is Velcade, bortezomib. And then d is, of course, the dexamethasone. When we think about that regimen, it is generally highly effective and also very tolerable for many patients with multiple myeloma. Not everyone, but that's the standard regimen because it works and it's tolerable and it's a good one. But when we try that regimen, as is published in patients with amyloidosis, it often is not tolerable. So as examples, when we think about the dexamethasone that we give with the RVd myeloma regimen, it's typically if you give it according to the way it's initially published, then 20 milligrams four times a week, so 20 milligrams on day 1, 2, 4, 5, so pretty good dose of dexamethasone. When patients with amyloidosis already have heart failure and what's called nephrotic syndrome, which is a kidney problem that leads to a lot of swelling, those patients already have a lot of trouble with fluid retention that we don't see much in multiple myeloma can happen, but it's usually not a major problem. When you give somebody with amyloidosis that essentially 80 milligrams a week of dexamethasone with all the combined doses, then it can lead to severe problems with fluid retention and even congestive heart failure up to the point that it can lead to hospitalizations. So dexamethasone specifically is a drug that's problematic in multiple myeloma too, but when used at myeloma doses in amyloidosis, we can really hurt people.
Then similarly, if we look at Velcade or bortezomib, again a very common drug that we use in multiple myeloma, we know very well for multiple myeloma that bortezomib or Velcade does cause peripheral neuropathies, the numbness and tingling in the fingers and toes, and can cause low blood pressure, but generally not a major problem as long as it's watched closely and doses are adjusted if those problems start to come up. But you can imagine that for a patient with amyloidosis, you may already have significant peripheral neuropathy coming in, meaning they can feel their hands and feet. On top of that, if they come in, their blood pressure is already very low to begin with because that amyloidosis has messed with the nerves that regulate blood pressure. Then you give them some bortezomib or Velcade on top of that, and they have much less threshold to tolerate or much less reserve to tolerate the low blood pressures that that drug can cause. Again, when given a standard multiple myeloma doses, the Velcade bortezomib drug can also be problematic in amyloidosis.
So this just brings me back to your initial question of they're similar in the sense that we use a lot of the same drugs to treat multiple myeloma and amyloidosis, but it's not as simple as just saying, okay, whatever works in myeloma works in amyloid. Just do the same thing. It really helps. That's why it's important to see people who do amyloidosis because we can make those adjustments and do the translations, so to speak, appropriately so that we can get the benefit of those drugs from multiple myeloma but not hurt people in unexpected ways by just again doing the same thing that we always do in multiple myeloma. There's a little bit of finesse and art to it, I think.
Jenny: I was going to ask you too about like even the Revlimid or replacing the Velcade with Kyprolis because the Revlimid, you might have kidney issues, right, on Revlimid? Do you see that or no? And then Kyprolis, if you're swapping out Kyprolis for Velcade because the neuropathy, are you impacting the heart in any way?
Dr. Tuchman: Yes, so Revlimid or lenalidomide, that drug is, of course, affected by kidney function in the sense that it is cleared by the body through the kidneys. So in any condition, multiple myeloma, amyloidosis, any other condition in which we're using that drug, if kidney function is impaired, then we have to reduce the dose. But even beyond that, in amyloidosis, lenalidomide or Revlimid is tougher to tolerate for reasons that aren't totally clear and that don't totally stem from kidney function. This has been shown in studies done by Boston University, which is one of the big amyloidosis centers, where they did studies even 15 years ago initially looking at lenalidomide or Revlimid in amyloidosis, and pretty quickly found that the standard 25-milligram dose that we use in multiple myeloma is generally not tolerable in amyloidosis. If I remember correctly, when they did the study, the first eight patients on this study got 25 milligrams of lenalidomide or Revlimid, and all of them needed a dose reduction pretty quickly, which is very unusual for multiple myeloma. We just don't see that, but that just goes to show you that patients with amyloidosis really had trouble tolerating that "normal myeloma dose."
Then even you mentioned Kyprolis or carfilzomib, a great drug in general for treating multiple myeloma and can be helpful in amyloidosis, especially for patients that do have significant peripheral neuropathy or low blood pressure to begin with. But again, so one thing that we see in amyloidosis pretty commonly can be significant heart failure and, of course, Kyprolis or carfilzomib is associated with heart failure in multiple myeloma. So that's again one that can be helpful in amyloidosis but can be tricky in a patient who already has heart trouble. Because of that, carfilzomib or Kyprolis has had somewhat limited success in amyloidosis so far, but it does have a role for certain patients for sure.
Jenny: So like this is very nuanced, in my opinion, and even for myeloma experts, do all myeloma experts treat amyloidosis or -- because I know there are a few of you throughout the country that do specialize in amyloidosis as well. Do you suggest that amyloidosis patients kind of go to those specific centers where there is expertise, or if you're with a myeloma specialist, do you consider them knowledgeable enough to do the care?
Dr. Tuchman: So what I'd say is that anyone who does light chain amyloidosis, I'd say anyone who specializes in light chain amyloidosis almost always does multiple myeloma also. It's very difficult to be just an amyloidosis physician largely because there's so much overlap and because multiple myeloma is much more common But the converse is not necessarily true, meaning that among multiple myeloma physicians, some do amyloidosis also and find it interesting, enjoy it and have clinical expertise in it, but there's a decent number of multiple myeloma experts who do not do amyloidosis. So it is important for somebody with multiple myeloma who also has amyloidosis as a significant part of their problem to ask their myeloma expert if they regularly do amyloidosis also. Seeing a myeloma physician does not necessarily mean that you're seeing an amyloidosis expert.
Jenny: That's good to know. We will include that in our directory as well. We have that in some of the descriptions so patients can -- well, I'll do a better job of noting that on the directory because that's important for people to be able to find a specialist. You talked about -- I mean, when you're talking about RVd or KRd or something like that as a standard induction therapy and you kind of went through reasons why some of the -- like all of them might be a problem, then what do you do? Do amyloidosis patients do transplant, or do you use monoclonal antibodies up front then instead, or what what's the standard of care right now for AL amyloidosis patients?
Dr. Tuchman: So happy to report that it's finally evolving, and that's for decades now. Everything in amyloidosis has basically been borrowed from multiple myeloma. The drugs, of course, get approved in multiple myeloma and then smaller studies are done in amyloidosis, but the larger studies have never been big enough in amyloidosis to actually result in approval which meant that we're always borrowing drugs again from multiple myeloma. But that finally changed this year and I should say last year, and then approval came this year based on this study called the ANDROMEDA, like the Andromeda galaxy, where this was a study looking at patients with newly diagnosed light chain amyloidosis, not myeloma, just light chain amyloidosis. It was a study in which patients got a standard regimen called CyborD, which I'm sure your audience is familiar with, that that's cyclophosphamide-bortezomib, which is Velcade and dexamethasone, and then all patients on the study got that regimen and then patients were also randomized to also have the drug daratumumab or Darzalex added to the regimen. So half of patients got the daratumumab. Half of patients did not. The daratumumab improved outcomes in patients who have got it, and so that combination has been approved by the FDA and the European Medical Association for treatment of the light chain amyloidosis here in the United States and in Europe.
So that arguably is the standard of care for newly diagnosed light chain amyloidosis these days. Again, there's always a little bit of nuance to it, but that's arguably the standard of care currently with close attention paid to things like bortezomib or Velcade dosing, dexamethasone dosing. Using the same doses that we use in multiple myeloma is not always the way to go. That's probably the regimen. We just have to be careful with it.
Jenny: So you can take it. It's just that your doctor has to watch it closely, and you might be done suggesting, like you're saying.
Dr. Tuchman: That's right.
Jenny: Yeah. Okay, so when we talk about myeloma, I know there are different kinds genetically of multiple myeloma. Do you see the same thing in amyloidosis? How does that work? Or do you just go with potentially genetic features? Like if a patient has 11;14 or something like that, would you use it in their myeloma and then they have amyloidosis too, would you use the venetoclax or something like that for them?
Dr. Tuchman: We can see a lot of the same genetic abnormalities in amyloidosis that we see in multiple myeloma. The prognostic and therapeutic significance of those abnormalities has not been nearly as well mapped out in amyloidosis as it is in multiple myeloma, although I'd say that even in multiple myeloma, we have a ways to go to figure out what to do with those different genetic abnormalities. But the one that's been clearly reported with the greatest significance in amyloidosis is the one that you mentioned that the t(11;14), so that phenomenon in which all the chromosomes, of course, have numbers, 1 through 23, and then 11;14 that we refer to just means that a piece of chromosome 11 and piece of chromosome 14 got switched. So when patients have that, we refer to it as t(11;14) and that's a relatively common finding in multiple myeloma, and we see it even more in amyloidosis.
As you mentioned, that's a drug that often predicts response to the drug venetoclax which does things in the cell that's particularly effective in patients who have that t(11;14) abnormality. There's a lot of interest in using that drug in amyloidosis currently. Studies are ongoing. We do use it in some patients. It's hard to say that it's the standard of care just because there's not a whole lot of data for it yet, but we certainly do think about it for patients with that t(11;14) translocation in amyloidosis typically after they've been through other therapies. We wouldn't use that frontline but often later on.
Jenny: It hasn't been FDA approved yet in myeloma yet, but I know they're working on that.
Dr. Tuchman: It is not. That's right.
Jenny: But I do know some patients who have been able to get kind of get early use of it when other things are not working.
Dr. Tuchman: We can generally get it. Amyloidosis is sometimes a little bit trickier just because there's not as much literature to support it. But as you know, in multiple myeloma, not FDA approved. It's compendium listed, meaning that some authorities say that we should be using it. In general, it's a matter of insurance approval, but we usually can get it in appropriate patients with multiple myeloma.
Jenny: Is stem cell transplant used in amyloidosis AL or light chain amyloidosis patients?
Dr. Tuchman: It is. The stem cell transplant is used in light chain amyloidosis. Again, much like what I said about other things as it relates to multiple myeloma. It's used, but it's a little bit more nuanced, and a lot of that has to do with the fact that transplant is inherently somewhat riskier in amyloidosis than it is in multiple myeloma. A lot of that has to do with the heart issues that we commonly see in amyloidosis that we don't in multiple myeloma.
So we saw this 15, 20 years ago when the first larger studies were coming out in amyloidosis in the sense that -- so when these studies were done, they saw a much higher death rate with stem cell transplants in patients with amyloidosis compared to you what we would typically see for multiple myeloma, for example. So what I mean by that is that in multiple myeloma, in most centers, when we talk about anticipated mortality rates or rate at which people die during the transplant, it's typically one, two, maybe 3%. It's a real number, but it's a relatively small number. But early amyloidosis studies looking at stem cell transplant mortality rate was up to 25% or 30%, one of the three patients, which is just way too high, especially for a therapeutic modality that's not curative. It's not like that it was worth the risk because it cured a lot of people.
Then what we figured out is that was largely driven by heart trouble. So amyloidosis commonly causes heart trouble. When patients had significant cardiac or heart involvement by amyloidosis, then when we tried to do stem cell transplant, there was a much higher risk of low blood pressures, other complications, arrhythmias or abnormal heart rhythms, kind of short circuits of the heart, and many people didn't survive. So what's happened since then is that we figured out how to appropriately risk stratify patients with amyloidosis for stem cell transplant, basically how to pick the candidates that are likely to do well with it. So we do it, but again it's a little bit more nuanced than it is in multiple myeloma.
Jenny: Oh, that's fascinating. I did not know that. Okay, that's so interesting. Then let's talk about new approaches because, as you're very aware because you're involved in all the research, immunotherapies like the bispecific antibodies and antibody drug conjugates and CAR T therapy are being tested. Are there studies that are using these therapies? And then what are you seeing if so?
Dr. Tuchman: I have not seen any studies involving that yet. So given the fact that amyloidosis is often tricky to treat due to the heart trouble and some of the other trouble that those patients experience and the fact that it's a rare disorder, there's often a lot of hesitancy to use the new therapies in amyloidosis. So what often happens is that things as we've seen historically, even until now, drugs get developed in multiple myeloma. We get comfortable with using them and then trials startup in amyloidosis also. So this is where I'd say a lot of the current immunotherapies are in amyloidosis. Some of the early trials are starting now. But there's not a whole lot of data yet to say how useful those therapies are in patients with amyloidosis.
So things like CAR T, it makes a lot of sense that if CAR T works in multiple myeloma, it should work in amyloidosis also. But amyloidosis patients again probably have a higher risk of some of the cardiac and other complications that we can see from CAR T. So understandably, with a relatively new technique, there's a lot of hesitancy to do that. Those things are coming, but really not a whole lot of data to speak of yet.
Jenny: If a patient has multiple myeloma and they also have AL amyloidosis, can they join clinical trials, or is that an exclusion criteria for many of the trials?
Dr. Tuchman: So this is a really unfortunate gap in clinical research because the long story short is that generally, no, they can't get on clinical studies unless we really prove that the amyloidosis clinically insignificant, and the way that that happens is that sometimes patients have a bone marrow biopsy. The pathologist stains it for amyloidosis using this test called congo red. They see the amyloid there, but the patient him or herself clearly has no heart trouble, kidney trouble anything else to suggest that this is real amyloidosis. It's almost an incidental finding.
But other than that, typically patients with kind of "real multiple myeloma" can't go on trial for amyloidosis. And conversely, patients with real amyloidosis can go on trials for multiple myeloma. That's just the way the trial eligibility criteria are typically written in the sense that multiple myeloma trials typically say patients with amyloidosis are excluded and then amyloidosis studies typically say that patients with multiple myeloma are excluded. A lot of that just has to do with the fact that even though they all boil down to abnormal plasma cells and abnormal proteins in the blood, clinically these patient populations can be quite different than. So you can imagine that when we do these clinical studies, if we have a really heterogeneous or variable group of patients going on to really make the trials tricky.
As I mentioned before, drug dosing is often different in amyloidosis as opposed to what we use in multiple myeloma, which in clinical studies dosing is typically standardized. So you can imagine that picking a dose that would be appropriate for somebody with amyloidosis may not be the same as picking that dose for somebody with multiple myeloma. It's an unfortunate situation, but often patients who have both conditions would be excluded from clinical studies.
Jenny: Yes, that's tricky. Very hard. With the way the studies are designed probably. Well, do you want to share open amyloidosis clinical trials? I know you do a lot of academic research on the myeloma side I'm sure.
Dr. Tuchman: Sure. Two things that I'd mentioned, which I think are extremely exciting in amyloidosis. One of them is that basically new drugs that are coming, which will hopefully help to break down amyloidosis and tissues already, and this is completely separate from multiple myeloma. It's nice because amyloidosis kind of finally has its own thing. It's not just borrowing everything from multiple myeloma. What I mean by that is that again when people have light chain amyloidosis, we said cells in the bone marrow, light chain protein in the blood, light chain protein deposits into different tissues.
When we think about all the medications that are currently FDA approved for treating light chain amyloidosis, they're all geared at killing off those bad plasma cells, which we said earlier reduces the level of that abnormal light chain in the blood, and then that results in less of that light chain protein being available to beat up on the different organs in the body. Then we basically keep our fingers crossed and hope that those organs can then heal up.
What has not existed, we've really needed is some drug or some other way of breaking down the amyloid protein that's in those organs already because, unfortunately, that's really what what people feel and that's what's life-threatening in this disorder, meaning that the cells are in the bone marrow, proteins are in the blood, amyloid protein is in the organs. When we do successful chemotherapy, stem cell transplant, whatever we're doing, we may kill off 99.999% of those bad plasma cells. The light chain protein drops down to normal levels. So for all intensive purposes, we hematologists, oncologists are patting ourselves on the back because chemotherapy has worked beautifully. But the patient still feels awful and can still even pass away from the disorder because the organs are still beating up. That's because those drugs that we use to kill plasma cells do nothing to clear out that amyloid protein that's already stuck in the heart, that's stuck in the kidneys, that's stuck in the nerves, stuck in the different organs.
So what happens currently is that we suppress those bad proteins as best we can in the blood. Those organs can then start to heal up. But we know that that process can take many months, if not years. So often when I see patients in clinic, I tell them that I hope that they'll start to feel better. But in reality, we typically don't see or a meaningful organ improvement in amyloidosis for at least six months after starting therapy. That's very different from multiple myeloma where if somebody comes in with, let's say, high blood calcium levels, you can fix that in 24 hours. In amyloidosis, that protein is stuck in the organs and basically just takes the body a long time to break down that abnormal protein that's already stuck there. So that brings me to the really exciting new developments, which are unique to amyloidosis, which is new drugs that are directed at basically sticking to that amyloid protein that's stuck in the different organs already and helping to break it down. So basically helping the organs to recover more quickly.
So there was one drug that we had a couple of years ago called NEOD-001 and that was a drug that was in a couple of clinical studies a few years ago. The studies, unfortunately, didn't pan out in the sense of this drug was not shown to be effective. But the long story short is that there's another trial which is opening soon looking at NEOD-001 in patients with severe cardiac or heart amyloidosis. That one will hopefully show that the drug has a benefit for healing up amyloidosis in the heart for those patients.
Then the other study, which is ongoing now, looks at this drug called CAEL-101. That's a drug that is being looked at in randomized clinical trials for patients with newly diagnosed amyloidosis of the heart. All those patients get standard chemotherapy and then a certain percentage of patients are also randomized to receive the CAEL-101 drug basically to ask the question, okay, for patients getting standard chemotherapy, so medicines that kill off those bad plasma cells, will this CAEL medication also help them break down some of the amyloid that's in the heart and help the heart to heal up faster than it would otherwise?
So super exciting in the sense that we've never had drugs that really help to break down that amyloid in the organs that are already. That's really what we need, because that's what gets people with this condition. So hopefully, these trials will show that there's a benefit to using that medication. That's really one way. That's one thing that I'm excited about.
Jenny: Oh, it is. Interesting. What target does that go after?
Dr. Tuchman: It goes after amyloid protein. It is basically that when the amyloid protein is formed in different organs that has a specific protein sequence and that's targeted by the antibodies designed to basically stick to amyloid. Think of this like a laser-guided smart bomb in the sense that the drug goes in. It sticks to amyloidosis that's in the heart, and basically immune cells are able to look for that target and basically chew up the amyloidosis, we think, cells called macrophages. It's really cool technology. I say that as somebody who had no -- we had the trials open, but I had nothing to do with the drug development. That's really neat stuff.
Jenny: Wow, wonderful.
Dr. Tuchman: I was going to mention one other study, which is also really exciting, and this is one called the SAVE study. That stands for Screening to Improve Survival in AL Amyloidosis. This is one that we're participating in who's led by my good friend and colleague, Dr. Ray Comenzo up at Tufts Medical Center in Boston. The idea behind this is that, back to your question about smoldering myeloma earlier, one of the keys to fixing amyloidosis basically is diagnosing it early. You can imagine that and when that light chain protein is in the blood, it deposits in different organs over time, and it may only show up in patients when they become very symptomatic. That's usually when the organs are heavily involved already. We can get at this at an earlier phase before those organs are so significantly involved. That would be even better is to get it early.
So this is a study done led by Dr. Comenzo in which we're looking at patients who have lambda light chain MGUS, so monoclonal gammopathy of uncertain significance, or smoldering myeloma, so these are patients that have that protein that's in the blood, but they have no evidence of damage to any organs from that protein or the cells. It's basically looking at the sequence of that protein to determine if we can predict who's more likely to develop amyloidosis with the idea that we can do closer surveillance or even interventions early. This is just based on what I said earlier about how protein sequences likely play a critical role in this condition in the sense that again some patients can have really high levels of that lambda light chain protein and never develop amyloidosis, and then there are others who have really low levels of that lambda light chain protein, but it's perfectly structured to form that amyloid protein in the different organs. Therefore, it goes ahead and does that. This study is really looking to basically sort that out at a scientific level that we can then use in patients to say, okay, does Mr. Thompson have smoldering myeloma with a lambda light chain sequence that's likely to form amyloidosis? In which case, we need to watch closely or even think about intervening sooner. Or does Mr. Thompson have a light chain sequence that's not likely to form amyloidosis? So we still need to be vigilant, but at least we don't have to worry about that condition. So really exciting stuff. Basically, looking at early diagnosis with an eye toward interventions and doing things about it before it becomes such a severe problem. So very exciting.
Jenny: That is very exciting. Is lambda type of disease just more likely to develop into light chain amyloidosis than the kappa?
Dr. Tuchman: It is. So it's both kappa and lambda can form amyloidosis, but it's about two to one, meaning lambda is about twice as more commonly causes amyloidosis as opposed to kappa. A lot of that again just has to do with the structure of that lambda light chain protein versus the structure of the kappa light chain protein. Lambda light chain is just more likely to have the structure so that it can form amyloidosis in tissues, but really either can do it.
Jenny: I did not know that. I'm learning all sorts of new things in this show. I think we will share that as a clinical trial because that is really important for patients to participate in. That's really important. Super important for amyloidosis patients to learn from those types of studies.
This is something that I think all patients should know what type of myeloma they have. I mean, at the very basic, you have kappa or lambda light chains typically. Then you can have heavy chains, which are like IgG, IgA, IgM, and things like that too. If you don't know what kind of myeloma you have or the kind of disease that you have, ask your doctor or your nurse and just so you know that. That's something that we gather in HealthTree because it is important to see these connections between kappa versus lambda. What you're trying to do is treat patients as individuals and not just generically anymore.
Dr. Tuchman: That's right. I couldn't agree more.
Jenny: Are there any other studies that are open for amyloidosis patients or light chain amyloidosis patients?
Dr. Tuchman: Well, those are the key ones at this point.
Jenny: Yeah. Okay. Great. Well, I want to leave some time for caller questions. So if you have a question for Dr. Tuchman, you can call 347-637-2631 and press 1 on your keypad. We will go ahead with our caller question. Go ahead with your question.
Caller: Hi, I've really enjoyed the show so far. I did have a question. You mentioned earlier that some of the side effects like kidney damage and heart problems can be reversed. Can patients actually gain back full organ function if we catch it early?
Dr. Tuchman: Yes, for sure.
Caller: But about if it's caught late?
Dr. Tuchman: Well, I mean, it really depends on the type of injury and most organs, if there's very significant involvement, then most often the organs won't completely recover to normal, but they can and even beyond that, even if the organ doesn't completely recover to normal, meaning we do our testing and we still see evidence of problems related to amyloidosis. Nonetheless, a patient can still feel extremely well in the sense that the body learns to work its way around problems. Symptoms can entirely resolve even if the organ remains a little bit impaired. But in general, if it's early involvement, meaning low rate organ involvement, that a lot of times that can resolve entirely, whereas once the organs are more severely impaired, then complete resolution of that is a little bit less likely. But still a lot of patients feel better, which is a great reason to still be hopeful.
Jenny: Okay, great. Great. Thank you for your question, and thank you for your answer. I guess I will ask you just a final question in terms of just finishing up. If a patient is listening and is diagnosed with AL amyloidosis, what do you suggest as the steps that they should take to get properly cared for? And then how do they work like if they're in a remote facility, like how do they work with an expert in conjunction with maybe a local doctor?
Dr. Tuchman: So a lot of times, that can sometimes be tricky. I mean, especially in the age of virtual medicine, which COVID has pushed us into, it's made things a little bit easier. So at least within individual states, we have increased capacity to do virtual visits, meaning video visits. It's always better for us to see a patient in person, but doing things from via video for patients who are truly too far away to make it our center, that's an option. Then one big thing that I'd say, it is just encouraging your local physician to reach out for help, recognizing that most of the systems are a smart people, and they may be very good at what they do. But amyloidosis is extremely rare, and even multiple myeloma is to some degree, but amyloidosis even more so. So I think it's completely fair for amyloidosis patients to ask your physician, how much of this have you seen? How comfortable do you feel with managing my condition? And do you think that we need to get help? And if so, what's the best way to do that? It really depends on where they are in the country, what the closest centers are, that sort of thing. But I think the first step is really getting a feeling for how comfortable your physician is with managing the condition.
Jenny: So it's time to ask your doctor lots of questions, I think.
Dr. Tuchman: That's right.
Jenny: And then find a specialist who can -- like, you know, when you work with myeloma specialists, we always encourage patients to especially meet with a myeloma specialist to consult with decision making, essentially, when newly diagnosed and then at each relapse. Is there a greater frequency that you suggest patients talk to in amyloidosis expert, or is it kind of similar that -- and does amyloidosis -- well, if you have it, you just continually have it? It's not like myeloma where it relapses, or is it like that?
Dr. Tuchman: It's very similar. It's a little bit different. It's similar from the perspective of the plasma cells. So much like in multiple myeloma, we kill off a whole lot of cells. They stay down for a while, but they like to come back at some point later. Amyloidosis is the same, so same issue with the cells growing, rising light chain or M spike protein in the blood, that sort of thing. But the thing that's a little bit different than amyloidosis is that the organ damage can remain. Even I had some patients that we treated 10 years ago for amyloidosis, and their amyloidosis is in remission, meaning that the light chains in the blood are totally normal. The bone marrow biopsy is totally normal. I don't see any evidence of those abnormal cells, but they still have the organ impairment from the condition. So sometimes that's more long lasting than the actual extent of the light chain protein in the blood.
But in terms of how to monitor it, it's a lot of the same strategy that we use for patients with multiple myeloma, meaning that when things are busier, if the condition is coming back, if we're having trouble with increasing clinical symptoms, toxicity, that sort of thing, then patients may have more contact with us as amyloidosis experts, whereas if they're in remission and doing great, then we can probably spread that out. So much like everything else in multiple myeloma, it's really sort of a waxing and waning, or sometimes more intensive, sometimes less so.
Jenny: Okay. Well, this has been so valuable today. It's really incredible to talk to experts in the disease because it's so nuanced. It's just incredible. Dr. Tuchman, thank you so much.
Dr. Tuchman: It is. It's difficult.
Jenny: Yes, I know, right? So you need to have the best people possible on your team. If you have AL amyloidosis, which we suggest going to a specialist every time. It's so important for your care. Dr. Tuchman, thank you so much for joining us today.
Dr. Tuchman: Thanks for having me. This is good.
Jenny: Thanks for sharing your experience. I was talking to another doctor who works on AL amyloidosis a little bit, and she was just saying, I feel like it's kind of like the, you know, sometimes neglected family member that we need to make sure we take special care for these patients. She has a special place in her heart for them. I can tell you do too.
Dr. Tuchman: I do, for sure.
Jenny: Yeah, thank you so much. We wish you all the best with your continued work. We will share your studies that are open, so patients are aware of what's available to them. You can find out a lot more especially with that precursor condition study. So just thank you so much.
Dr. Tuchman: Sounds great. Thanks so much for having me.
Jenny: Yes. To our listeners, thank you so much for listening to Myeloma Crowd Radio. We invite you to join us next time to learn more about what's happening in myeloma research and what it means for you.
about the author
Myeloma survivor, patient advocate, wife, mom of 6. Believer that patients can help accelerate a cure by weighing in and participating in clinical research. Founder of Myeloma Crowd by HealthTree and the HealthTree Foundation.