New Insights for Amyloidosis in Myeloma | Suzanne Lentzsch, MD | #ASH24

Hello, my name is Suzanne Lench. I'm a professor of medicine at Columbia University in New York, and I'm here at the sunny San Diego. And I would like to share some insights on a satellite symposium, which I gave together this Dr. Morrie Gertz and Dr. Santra Valla. We know that around 30% of the multiple myeloma patients can develop amyloidosis. And that switched a little bit our treatment approach. In drugs we cannot give in patients with amyloidosis and multiple myeloma, for instance, the immunomodulatory drugs. And we have to focus on a very deep remission because that is very important to induce organ response. So, let me share a little bit of what I discussed on Friday. So, first we discussed how important it is to diagnose amyloidosis in patients with M-Gas and with multiple myeloma. We gave certain criteria what should doctors make aware or consider amyloidosis. And this is, for instance, a heart failure with preserved ejection fraction. Patients have a left ventricular hypertrophy but have a low blood pressure. When a patient with an M-Gas or multiple myeloma suddenly reports, you know, doctor, I have a very low blood pressure when I get up or I need to reduce my blood pressure medications, that can be a sign of amyloidosis. Other signs include proteinuria but also neuropathy. So, that can overlap with multiple myeloma. So, early recognizing or early recognition of amyloidosis is critical because what we know is that the outcome of patients with amyloidosis depends on the stage. So, the median overall survival of patients in stage one is 96 months. And that's from 2012. So, today it would be much better. But patients who have stage four have an overall survival of only six months, median overall survival of only six months, which is very dismal. So, that means early diagnosis when patients are in stage one is really critical. We further discussed how to make the diagnosis of amyloidosis. Once you have a suspicion, you need an organ biopsy. Usually we recommend to start with a FATPAT biopsy. That's an easy biopsy, can be done in the clinic. If the FATPAT biopsy is negative, the sensitivity is around 60 to 70 percent, then we recommend an organ biopsy, heart or kidney biopsy. What is also critical is that you type the correct amyloid type. Why is this important? We know that around 30 different proteins, among them light chains, can cause amyloidosis. And we know this in aging patient population that many patients develop TTR amyloidosis. And they also can have an M-GAS. So you should not conclude from, for instance, a positive FATPAT biopsy, Congo Red, that the patient might have AL amyloidosis if he has the same time or she has also light chain M-GAS. So, it's important that you do mass spectrometry of the tissue of the FATPAT biopsy or the organ biopsy. So, once you have a diagnosis of AL amyloidosis, it's important that you give the right treatment. We have one approved treatment based on the Andromeda trial, which is Darra-Cyboridine. I mentioned already we should not give imides such as pomalidomide or Revlimid to patients with AL amyloidosis. That is important because they do not tolerate those drugs very well and can cause heart failure. So, we have the Darra-Cyboridine based on Andromeda. But what do we do with patients who fail this clinical trial or relapse? So, we discussed here that in patients with translocation 1114, we should consider venetoclax. Patients who do not carry the translocation 1114 benefit from Toclistamab. So, we took the BCMA bispecifics from the multiple myeloma patient population to our amyloid patient population and have very good results. Almost all patients have a deep response with an overall response rate 100% and a CR rate of 80 to 90%. So, excellent data with the bispecifics in AL amyloidosis. We also discussed transplant. Transplant plays a role in amyloidosis, but only 20% of the patients are transplant eligible. But we recommend in patients who have a good performance data that they should undergo transplant. Last, but not least, Marie Goertz talked about the use of antifibral therapies. That means monoclonal antibodies that target directly the amyloidosis. We have two monoclonal antibodies in the clinical development, Anzalamimab and Botamimab. Again, the clinical trials are ongoing. Phase II clinical trials and ad hoc analysis of former phase III clinical trials are promising. But again, we have to wait for the data and hope they are positive and will get FDA approval. The summary and the conclusion of our discussions was that the outcome of amyloidosis had improved significantly over the last years and that we have an early detection and very potent drugs such as CD38 monoclonal antibodies, daratumumab and BCMA bispecifics such as teclistamab. The overall prognosis has improved dramatically. I think it's of utmost importance for us as hematologists to be aware that in principle each patient with smoldering multiple myeloma, MGUS or overt multiple myeloma or even low grade lymphoma, all patients who produce an excess of monoclonal light chains can develop amyloidosis. So when we talk about MGUS and smoldering multiple myeloma and progression to overt active multiple myeloma, we discuss and we focus a lot on bone lesions, anemia, hypercalcemia, renal failure. We forget a little bit that those patients can also develop light chain amyloidosis. And each hematologist should watch out for patients with an MGUS, especially with lambda light chain MGUS because 80% of the AL amyloidosis patients have lambda light chain amyloidosis. The lambda light chains are more prone to form amyloid. So if you have patients with lambda light chain production, smoldering multiple myeloma or MGUS, please watch out for symptoms. We call that red flags and one of the red flags is the ejection fraction that is preserved, but at the same time the patient has heart failure, shortness of breath for instance. Those patients that's a typical symptom for AL amyloidosis, also low voltage in the EKG. We recommend that you do an NT-ProBNP, that's a marker, and also troponin to rule out early onset of cardiac amyloidosis. Other symptoms include proteinuria. Patients can have nephrotic syndrome, large amounts of proteins over one gram in the urine associated also with peripheral edema. Also static hypotension, low blood pressure. Patients come and say, doctor, I could reduce my blood pressure medication. If this is, you know, somebody telling you that should raise a red flag, you know, and think about that, listen, what is behind that? Why do you reduce your blood pressure medication? It can be a sign of autonomic dysfunction. That means the amyloid is around the autonomic nerve system and impacts the regulation of blood pressure. Also, dysmotility, for instance, that patients have really problems to digest food. They have no appetite, diarrhea. Those are symptoms of amyloidosis. So just think about amyloidosis when patients present the source symptoms.