Morie Gertz: Good day. And thank you for joining us for this important VJHemOnc presentation on diagnosis and management of amyloidosis. We’re fortunate today to have two experts joining in the VJHemOnc program, professor Ashu Wechalekar of the National Amyloidosis Center of Great Britain, and Daniel Lenihan, fellow American College of Cardiology, Cape Cardiology Group, Cape Girardeau, Missouri. With that, I think we’re going to just dive right into some of the important issues surrounding amyloidosis. And I think the first is a hematology specific question that I’ll direct to Professor Wechalekar. Ashu, amyloid and myeloma are similarly treated, why is it important to distinguish the two and make the diagnosis of amyloidosis? Why is it important to differentiate?

Ashutosh Wechalekar: I think Morie, that’s an important distinction for two reasons. One is, a lot of patients with amyloidosis may not have active myeloma with end-organ damage. So these may be patients just with a monoclonal gammopathy of uncertain significance otherwise with an end-organ damage or a smoldering myeloma. But more importantly, these patients have significant end-organ damage of heart, nerves, kidneys, in a way which is quite different to myeloma. The clone of plasma cells in these patients is not as malignant, so the response to treatment is very different and the long-term outcomes can be very different depending on the depth of response that is achieved. So a myeloma patient may do reasonably well with a partial response, but an amyloid patient will carry on progressing their end-organ damage with a partial response. And then the last aspect, I guess, is the supportive care that these patients need is also significantly different from a myeloma and amyloidosis perspective. Hence the distinction becomes important from a diagnostic and prognostic perspective.

Morie Gertz: Are there certain myeloma agents that we don’t regularly use in patients with light chain amyloidosis?

Ashutosh Wechalekar: Indeed, I mean, the agents which we would not use regularly would be agents where there is significant toxicity to the end-organs. For example, carfilzomib is a drug which is used in myeloma quite a lot, but used in amyloidosis. Quite rarely, immunomodulatory agents like thalidomide and lenalidomide, which form a lot of backbones of myeloma therapy are, again not used in amyloidosis that frequently, because of toxicity and end organ damage. Pomalidomide, which is usually used in relapsed/refractory myeloma, can be used in amyloid, but with a great deal of caution and monitoring. Similarly, selection of patients for a autologous transplant is quite critical in amyloidosis based on end-organ damage. Whilst with myeloma, most younger patients would still have an autologous transplant as a standard of care after completion of the induction treatment in myeloma.

Morie Gertz: Thank you. Dr Lenihan, why is early diagnosis important? What’s the impact in your cardiology practice when a patient has a meaningful delay in arriving at a correct diagnosis?

Daniel Lenihan: This is a super important question, and if there was anything, any message that I would want to convey from this presentation would be, you really need to consider AL amyloidosis as a cardiac emergency. So if you’re suspicious of it, you need to do the evaluation, whatever’s necessary to make the diagnosis definitively and as quickly as possible. And the reason is, is that, and I’m sure you and Ashutosh will talk about these types of details, but depending on the stage of disease where you make the diagnosis of AL amyloidosis, it has a huge impact on overall outcome. So if you wait until it’s very obvious to everybody that AL amyloidosis exists, then at that point your chance of meaningful treatment response is very low. So the cardiac manifestations are so important, and if you can catch it before there are any real cardiac manifestations, then the outcome of your treatment is much better.
Morie Gertz: What do you see as the barriers to a diagnosis of cardiac amyloidosis? What are these patients referred to you with before any correct diagnosis is established?

Daniel Lenihan: Well, it’s tricky. Definitely in the whole amyloidosis space, cardiologists and particularly heart failure specialists talk a lot about ATTR, and in that case you have imaging characteristics that you see on Echo or MRI or even EKG, that can tip you off that amyloidosis may be present. The problem is, is that in ATTR, you don’t have that sense of urgency necessarily. You can kind of take your time to make the diagnosis, but honestly, to get to the diagnosis of ATTR, you have to go through the evaluation of AL first, because all of the basic tests, they’re not as specific. Even Echo or MRI or a amyloidosis scan, those tests are only truly accurate in terms of detecting amyloidosis, they’re not accurate in terms of distinguishing the two. So I think that it’s absolutely important that if you’re suspicious of amyloidosis at any level, that you need to do the appropriate evaluation for AL, really as fast as possible to make the diagnosis or exclude it.

Morie Gertz: How common is it for a patient to be referred to you with hypertrophic cardiomyopathy or hypertensive cardiomyopathy, and that was an incorrect diagnosis and it was infiltrative cardiomyopathy amyloid?

Daniel Lenihan: Yeah, this is a great question and I would say that it’s pretty common. An estimate would be 5 or 10% of people that you’re seeing that have some evidence of heart failure, and maybe they have hypertrophic cardiomyopathy by some test, that in the end, roughly about 10% of those will ultimately end up with a diagnosis of amyloidosis. So if you have a patient that you’re being sent that has hypertrophy on an Echo image or some other image, then you need to make sure that amyloidosis is not present in a fairly expeditious way. So I think you can’t just sit on that one and say, “Oh, I’ll treat whatever existing hypertension may be there or give them a diuretic and follow them up in six months.” That’s not good enough.

Morie Gertz: I’m going to share my screen for a moment, because I’m going to discuss a patient and Professor Wechalekar actually alluded to this a bit earlier. This is a patient of mine who was found to have a monoclonal IgA, KAPPA protein, a small M spike, that’s 13 grams per liter, in US, 1.3 grams per deciliter an IgA of under 2000 milligrams per deciliter. The urine was not measured, because the patient was assumed to have a monoclonal gammopathy of undetermined significance. And let’s just put that onto presentation mode. And she diddled around for a year and the problem here is that the patient did not have evidence of any CRAB criteria, calcium normal, renal function normal, no bone lesions, no anemia. But when she came for a second opinion, her symptoms which were not CRAB, included weight loss of 30% of her body weight, inability to feel her feet, recurrent syncope, diarrhea and systolic hypotension. And this patient who had a positive fat aspirate, a positive bone marrow on the right for Congo red and in the middle, a liquid biopsy, died three months later of her advanced GI and cardiac amyloidosis. And I’ll stop sharing. And Professor Wechalekar, can you just briefly discuss amyloid kind of masquerading as MGUS and smoldering myeloma?

Ashutosh Wechalekar: So if I get a question rightly, this is early suspicion of amyloidosis in a patient with MGUS or smoldering myeloma. So most patients with AL amyloidosis will have a preexisting gammopathy for some time, and we have a chance of detecting these patients developing amyloidosis if we do the right tests. The two or three common organs which are involved in amyloid typically tend to be the heart and the kidneys. And then of course you do have the involvement of the gut and the nerves. So symptoms such as unexplained fatigue, unexplained weight loss, early satiety in an MGUS patient should certainly raise red flags. A simple urine test for albuminuria would also be quite valuable in patients where there are atypical features, particularly lambda light chain MGUS. This patient had started losing weight in the setting of an MGUS, which would automatically trigger a red flag. Well follow up, the challenge is that most MGUS patients will have their bloods tested every six months, every 12 months, every 18 months, and in between it’s forgotten.

The other interesting bit with this patient is what often gets forgotten with MGUS is not to test for the light chain or urine for Bence Jones proteinuria, because again, that would be a suspicion. Patients with light chain MGUS with high light chains, particularly the lambda variant, are more likely to have a risk of developing amyloidosis than those with probably normal serum free light chains.

Morie Gertz: What do you see as the current standard of care for patients in the US and Europe, and what is your goal of therapy?

Ashutosh Wechalekar: So our current standard of care for patients with systemic AL amyloidosis is directed at the underlying plasma cell clone MGUS, smoldering myeloma or myeloma. The daratumumab with cyclophosphamide, bortezomib, and dexamethasone, the Dara-VCD regimen, which was studied in the ANDROMEDA clinical trial, a randomized Phase III trial, randomizing patients to daratumumab-VCD versus VCD. Clearly showed the superiority of Dara-VCD in achieving hematologic responses in these patients, which led to this being licensed as a treatment for newly diagnosed patients with AL amyloidosis. And currently this would be the first line standard of care for majority of the patients with AL amyloidosis. Patients with limited organ involvement would still be potential candidates for an autologous stem cell transplant, but less and less patients are getting an upfront stem cell transplant. And most of the patients will get an induction treatment often with Dara-VCD, and then some patients will proceed to a transplant.

Our goal of therapy is to reduce the clonal light chains to as low a level as possible, ideally achieving a very good partial response, which is the difference between the involved and uninvolved light chains of less than 40 milligrams per liter or a complete response, which means normal light chains and no detectable monoclonal protein in the serum and urine. As we understand amyloidosis better, it is becoming more and more apparent that complete responses, probably our goal of treatment in most cases. We really don’t have agents which help us to remove the amyloid protein deposits. So we are just targeting the precursor and then expecting that the amyloid deposits will spontaneously regress.

Morie Gertz: Dr Lenihan, 70% of AL amyloidosis patients and nearly a hundred percent of ATTR amyloid patients have cardiac involvement. Could you talk to me and our audience about the management of the cardiomyopathy and the associated rhythm disturbances these patients have?

Daniel Lenihan: This is a very challenging scenario because depending on the extent of amyloidosis involvement, these problems become more and more difficult. What commonly happens, or at least certainly in my observation, is when people are diagnosed with AL Amyloidosis, the beginning part of their treatment, you may deal with hypotension on a pretty significant basis. And so what you’re trying to do is support them through that. So commonly we have to use medications like midodrine or even droxidopa to try to manage their hypotension that is partially related to peripheral neuropathy, but also to autonomic dysfunction. So these are sort of counterintuitive, when you have somebody who’s developing heart failure, usually you want to use vasodilators and beta blockers and these types of traditional therapy for usual heart failure. You cannot use those medications in these patients and frequently what you have to do is use a combination of diuretics, but also these other medicines to support their autonomic dysfunction.
Now, as their treatment goes along, especially if they’re responding well to the plasma cell-based treatment, then usually these medications can be gradually weaned off. But those are real challenges trying to manage somebody’s hypotension during a induction type therapy.

In terms of rhythm problems, that is a super difficult and complex, individual based challenge in every patient. AFib is a common problem, there’s a certain rate of ventricular tachycardia and sudden death that may occur. Some people wonder whether that’s primarily just a rhythm disturbance, and other people may argue that the myocardium is not responsive to whatever stimuli you’re giving it. So even if they have a defibrillator in place, they may still die anyway, because of inadequate myocardial capture of the device.
I think that these are very challenging questions, and when you’re talking about how to manage rhythm problems in these patients, you really do have to individualize what exactly their situation is and how aggressive are you going to try to be to correct atrial fibrillation, for example. And then of course, this definitely brings in the whole concept of anticoagulation into the mix. And anticoagulation is a very important concept in these patients, partially because of the disease, but also because of the treatments that they’re getting.

Morie Gertz: You mentioned not using afterload reduction or beta blockers in patients with cardiac amyloid. What happens exactly?

Daniel Lenihan: For the most part, their blood pressure’s already borderline and you give them some sort of vasodilator, or in the case of a beta blocker, you’re reducing their ability of their heart to compensate for a low blood pressure, so you’re reducing the heart rate response. And then like I said, they also have problems with autonomic dysfunction, so you’re really just kind of adding fuel to that fire. For the most part, there may be occasions where you would use a beta blocker in such a patient, but it’s a challenge. And if you do use them, you got to be very careful.

Morie Gertz: Professor Wechalekar, you mentioned specifically on the treatment to stop light chain production. Could you talk about the investigational horizon regarding the use of experimental therapies? I’d like you to touch on, if you would, birtamimab, the Caelum antibody and the Atrialis imaging/therapeutic approach.

Ashutosh Wechalekar: Thank you, Morie. So I think our goal really is to remove the fibrils that are damaging the tissues. It has been very well shown in experimental models that if we use monoclonal antibodies to tag the fibrils, it identifies them to the immune system, that then triggers the macrophages to hopefully clear the fibrils very rapidly in animal models. And we have the three agents that you mentioned. Birtamimab is the one that has most advanced, it’s an anti-fibril antibody, which also binds to the misfolded pre-fibrillar aggregates. And in the post-hoc analysis of the Phase III clinical trial that Morie, you just published, along with all of us in Blood, showed that in patients with advanced stage four cardiac amyloidosis, birtamimab showed a significant survival benefit, which also translated into a significant functional benefit in terms of quality of life in a six minute walk test.
So this antibody is now currently undergoing a further Phase III confirmatory clinical trial with a 2:1 randomization between birtamimab to standard-of-care along with chemotherapy. The Caelum antibodies are also antiviral antibodies, and in early Phase I and Phase II studies, they’ve also shown evidence of cardiac and renal responses in patients with AL amyloidosis. Two large Phase III clinical trials have now completed recruitment. One of the studies looked at patients with very advanced cardiac amyloidosis, the so-called European Mayo stage 3B disease where there’s very poor prognosis. And the second trial looked at patients with stage 3A disease. So these trials have now completed recruitment and we are awaiting the results.

And the last agent that you mentioned, the Atrialis program, is a small peptide, which initially was developed as an imaging agent for amyloidosis. It is an agent which binds to all types of amyloid rather than just AL amyloid fibrils. And at least in the early studies seems to be a very novel agent, which can image amyloid deposits in the heart, liver, spleen, kidneys, and even soft tissue amyloid deposits. This small peptide has then been conjugated to a monoclonal antibody so that the peptide will bind to the fibrils, the antibody will trigger the immune response, and in theory, this could potentially be applicable to all amyloid types. And this is now undergoing Phase I clinical trials, and we look forward to the early results to see where this goes further. So at the moment, we’ve got a number of exciting agents that have either completed or are in Phase I to Phase III clinical trials, which may help us to clear the deposits, so trigger an acceleration of the clearance of the amyloid deposits.

Morie Gertz: Do you have any reflections on the VJHemOnc audience regarding which patients should be given standard-of-care locally and when they should be referred for participation in a clinical trial?
Ashutosh Wechalekar: That is a difficult one to answer because I think my bias is that if there is an available clinical trial with an anti-fibril antibody, we should refer all patients to available clinical trials. The challenge is that this is a rare disease and often the trials are running in large centers which may not be geographically accessible to patients. And sometimes the sickest patients who may benefit the most from clinical trials may not be able to access these clinical trials. But I would certainly urge any of the listeners that if they have any newly diagnosed patients with AL amyloidosis, please think of a local trial center before you start treatment, because a lot of these trials are upfront trials and once they’ve started chemotherapy, you cannot enroll the patients in the clinical trials.

Morie Gertz: Perhaps a phone call to your local amyloidosis center to make the inquiry regarding eligibility before therapy initiates?

Ashutosh Wechalekar: I completely agree.

Morie Gertz: Questions for both of you. I’ll have you answer in turn starting with Dr Lenihan. And what do you see as the role of the cardiologist in treating patients with amyloidosis? Where do you see how you fit in an accurate diagnosis and the initiation of appropriate therapy?

Daniel Lenihan: Yes, I would love to answer to this question in some detail, but before I do, I would just like to echo what was just said about, if you make a diagnosis of AL amyloidosis and you are not in a major center, that you reach out immediately before treatment, because just like Ashutosh said, most of the current studies that, thankfully are enrolled, but when there was a restriction in enrollment once you started chemotherapy, you were not able to enroll those patients. So I think that having a good line of communication with a referral center is absolutely essential. So if you’re in a smaller location and you are astute enough to make an early diagnosis, which is great, then as you said, pick up the phone and contact your local or most local referral center, that’s a critical step.

As far as what we can do to be involved in this is, so the truth is, if you think about it from a patient point of view, a patient may present with profound weight loss like the case that you had, but chances are that the condition has existed for a long time for that to be the manifestation. Now, what usually happens, and I would say more than 50% of the time, is that a patient begins to have fatigue and perhaps edema, these types of non-specific findings, and they may or may not get admitted to a hospital and given diuretics in a diagnosis of heart failure.

So where cardiologists can step in, is in that setting if it’s not easily explained by some other cause, the fatigue and an edema, that you should consider amyloidosis and make the diagnosis as quickly as possible. So where cardiology would really help out in this setting is early diagnosis. And then once you make the diagnosis of AL amyloidosis, you are definitely going to be calling one of you guys and say, “Okay, we need to get going here.” And so where cardiologists really could be the frontline basically. So you’re going to be the provider that on average the patient is encountering first.

Morie Gertz: Professor Wechalekar, really the same question for you, how you see your role as the hematologist in accurate diagnosis and therapy in patients with amyloidosis?

Ashutosh Wechalekar: I think as a hematologist, we see a lot of patients with monoclonal gammopathies and smoldering myeloma who are at risk of developing amyloidosis. So it’s really important that we keep our level of suspicion high in these patients if they develop unusual symptoms like peripheral neuropathy, autonomic neuropathy, unexplained, non-selective proteinuria, albuminuria, or as Dr Lenihan said, heart failure without a good explanation. We need to think about amyloid, we need to refer on to the appropriate specialists, arrange for the imaging or consider biopsies. And then when the patient is diagnosed with amyloidosis, hematologists end up with a central role, because chemotherapy still remains the mainstay of treating these patients. And we have to learn to be hematologists, but we have to work with the support of our cardiology colleagues as a lot of these patients are in heart failure with hypotension, with arrhythmias, and therefore the chemotherapy itself may sound relatively straightforward, but supporting the patients during chemotherapy, managing their blood pressure, managing their fluid overload, managing their hypotension and their cardiac rhythm disturbances often makes a big difference to early survival. And I think a lot of patients will die or have hospital admissions if these things are not managed properly.

Morie Gertz: As we move into just kind of summarizing our thoughts, Professor Wechalekar, if you could just reflect on why a multidisciplinary approach is so important. Your group is really well known for having cardiology integrated into your group. Dr Fontana comes to mind of course, and others. But I’d just like as we finish up, discussion a little bit about your collaboration with cardiology in managing patients.

Ashutosh Wechalekar: We find it invaluable to work as a multidisciplinary team. It not only helps us to diagnose amyloid patients, but it also helps us to monitor these patients very, very closely with a number of different imaging modalities and evaluation methods that the cardiologists use, but also from a renal perspective with our nephrology colleagues and addressing all the complex multi-system problems these patients have. Each one of the specialties brings a slightly different perspective to the patient and therefore, it is really important to have somebody who’s experienced. And as Dr Lenihan said, managing heart failure in an amyloid patient breaks the traditional boundaries of heart failure management. You cannot use the standard drugs, you have to use a different approach, and therefore having cardiologists with an interest or expertise in amyloidosis certainly gives a different angle to how you can diagnose as well as treat these patients in addition to tracking the amyloid protein deposits.

Morie Gertz: Dr Lenihan, you worked in an area in Cape Girardeau where there’s some really quite well-known hematologists: Dr Dickey, Dr Moore. Could you discuss how you collaborate with your hematologist colleagues in order to effectively optimize care for these patients?

Daniel Lenihan: Yeah, so this is one of my favorite topics, of course. With what Ashutosh said, it’s essential that you have a multidisciplinary team. And so if I am talking to my cardiology colleagues and I’m asking them to be aware of this condition and do the initial investigations, whatever they may be. So it’s frequent that, for example, I might order serum free light chains and they’re abnormal and immediately I would ask my hematology colleagues to help, not only interpret those results, but guide us in terms of what’s the next step. So it’s essential and you have to have a close collaboration, whether it’s by some sort of email messaging service or whatever, or text to their cell phone or however you best communicate. But that has to be an immediately available process so that you can really do an expeditious evaluation, but then as you’re undergoing treatment, as Ashutosh also said, managing the rhythm issues and the blood pressure issues and all of that is a daily challenge.

Morie Gertz: Professor Wechalekar alluded to the use of the free light chain assay as being critically important in patients with monoclonal gammopathy of undetermined significance. As a cardiologist, how have you incorporated measurement of the light chain into your practice, into your workflow as patients are referred with cardiomyopathies?

Daniel Lenihan: This is also a great question, but I would say we haven’t talked about cardiac biomarkers as of yet on this call, but cardiac biomarkers are an essential piece in making the diagnosis, but I would also add, obviously that serum free light chains are as well. So whenever I have a patient who has heart failure that doesn’t quite fit the normal explanation of heart failure that we typically see, then I will do cardiac biomarkers and serum free light chains, and then a serum protein immune-electrophoresis, those are standard tests from just a cardiologist perspective. The problem is, is that once those tests come back, not the cardiac biomarkers, but certainly the protein electrophoresis comes back and it has an abnormality, that’s where you really need to have a close collaboration. But certainly measuring cardiac biomarkers is an early step, it is not uncommon that you would hear a story where a patient came in maybe with some degree of heart failure and they measured a troponin, for example, and it was mildly elevated, and they repeated that test and it was still mildly elevated, and then they look down the coronary artery disease pathway and they don’t really find anything revealing. And then they say, “Well, it must be nothing. It must be a false positive.” And yeah, we cannot explain it away that way. I think that something like a mildly elevated troponin could be the sentinel mark of amyloidosis and so you can’t let that one slide.

Morie Gertz: We’re smiling simply because we’ve seen that quite frequently. Just because of our audience being hematologists and oncologists, what are the cardiac biomarkers?

Daniel Lenihan: Well, the two most studied and sort of make up the Mayo classification system are, troponin T and NT-proBNP. The Mayo Clinic originally proposed a staging scale, I think it was in 2012, and then revised it a little bit later. But those are the markers that they use in their basic analysis. BNP, which is a different version of a natriuretic peptide and then troponin I, have been investigated at other institutions and probably also have utility. The challenge is that if we just talk about those two markers, they started out as whatever they were, and then five generations later, we have super ultra-sensitive troponins, et cetera. So you probably don’t want to get into those weeds, but basically troponin and NT-proBNP would be the most important markers that we need to know about.

Morie Gertz: Thank you very much, Dr Lenihan, and I want to thank our viewers and on behalf of VJHemOnc, I’m delighted that you chose to tune in and view this important presentation on the diagnosis and management of amyloidosis. Thank you so much.