 We'd like to bring up our next speaker, Dr. Mohamed Hussein from the University of Arizona, Tucson. We'll be talking about the work of monoclonal gamopathy. Thank you for the introduction, and happy to be here. So my name is Mohamed, I'm an assistant professor at the University of Arizona, Tucson, and I'm a hematologist, talking to a lot of cardiologists here today. And my discussion is work of monoclonal gamopathy. So these are my disclosures. So objective for today's talk is I will be talking how we need to work up a monoclonal gamopathy and then work up a light-chain amyloidosis and staging and prognosis of light-chain amyloidosis. So we'll start with the clinical case. This is the case that I saw a couple of months ago, an 80-year-old man with history of hypertension was diagnosed with heart failure with preserved infection, EF is 55% to 60%. Patient had three admissions for heart failure exacerbation, and ACO showed left ventricular hypertrophy. Then hematology, and that was effort to me actually from a community oncologist. They had already started the work of, they had done the SBAP, IFE, and Free Kappa Lambda issues. So SBAP showed M spike of 0.7g per deciliter. Immunofixation serum was positive for IgM lambda monoclonal gamopathy. Free Kappa light-chain was 20mg per liter, and Free Lambda light-chain was 51.4g, and Kappa Lambda issue was 0.4g for this patient. So we started further work up. 24-hour urine protein electrophysis was done. We showed 78mg per day total protein, and 24-hour urine immunofixation did not show any monoclonal protein. Cardiac MRI was done, which showed that it was consistent with the cardiac amyloidosis. So we performed a bone marrow biopsy on this patient with short 5% CD138 plasma cells, and congoxate strain was positive for amyloid deposition. So we sent this specimen for mass spectrometry to Mayo Clinic, and this confirmed this to be a light-chain lambda amyloidosis. And patient was started on treatment with Darryl Cybodi-based chemotherapy. He has been on treatment for the last couple of months, tolerating treatment well, and the light-chains are improving, and heart failure is kind of stable for him for now. So this has been already discussed, but the AL amyloidosis is on 50% of all the amyloid types. This was a study done by Mayo Clinic, and then the rest are all the different amyloidosis, including the TTI amyloidosis and wild type and hereditary, and also there could be localized amyloid deposition as well. But main focus is light-chain amyloidosis and systemic amyloidosis for today's discussion. This is not working. So light-chain amyloidosis is a rare disease. There are around 2,000 cases per year diagnosed in US. So 6 to 10 cases per million diagnosed per year. And the median age of diagnosis is 64. And 10% of these patients could have Crab criteria and have Concurrent multiple myeloma as well. So pathophysiology of light-chain amyloidosis is mainly a bone marrow disorder, plasma cell disorder, plasma cells, which usually make the normal light chains stimulated by different antigens. But in this case, they start making the monoclonal light chains, and those monoclonal light chains, and can form the amyloid fibres. And those amyloid fibres can then have the systemic deposition in different organs in the body, heart being the most common organ, then kidneys and liver on the second and third. And there could be GI involvement and nervous tissue involvement as well. So we only need a small number of plasma cells for this to cause the light-chain amyloidosis. So only 5% to 10% of the plasma cells are usually enough to cause light-chain amyloidosis. And initially, patients can have monoclonal gemopathy of undetermined significance. And then this can progress to amyloid deposition in these patients. And amyloid, as we said, can cause endocrine damage. And then these patients could be diagnosed with amyloid. So I want to spend a minute on differentiating between multiple myeloma and light-chain amyloidosis. So patients could have enol involvement from the amyloidosis. And they could have predominant proteinuria. But in patients who have multiple myeloma, the enol damage is different than what we see in patients with light-chain amyloidosis. So in patients who have multiple myeloma, usually what we see is the casc nephropathy or what we call myeloma kidney. While in light-chain amyloidosis, most of these patients, if they have the enol involvement, the predominant proteinuria is albuminuria and not the light-chain. So that is one of the differentiating features that we can see. And then those patients, they might not have the myeloma kidney, but they could have the light-chain amyloidosis. So it's important to get that differentiation done. And that can help you differentiate whether it's amyloid or myeloma there. So clinical presentation for most of these patients, cardiac involvement is most common. So patients can present with heart failure, enol involvement, so they can present in the fatigue and proteinuria, which is most commonly is albuminuria in those patients. There could be nervous system involvement and can cause periphaloenopathy, autonomic dysfunction. Could also be seen, patients could be having hypertension, disease spells, syncope. They could have peri-orbital purple skin changes. And then unexplained edema, unexplained soft tissue involvement, elevated liver enzymes, elevated alkylphos and enlarged liver. And in the GI, they could have diarrhea and GI bleeding as well. So diagnosis requires pattern recognition. So most of these patients, if they have on the echocardiography, they have hypertrophy, left ventricular septal hypertrophy. And then some of those patients who were on anti-hepitensive and now they're becoming intolerant to their anti-hepitensive medications and becoming more hypertensive. And then low blood pressures, history of carpal tunnel syndrome. And for the light chain, most of these patients would have heart failure plus, minus, nephrotocaine proteinuria if they have anal involvement as well. And they could have macroglossia and peri-orbital purple. I think macroglossia is more specific with the light chain amyloidosis. I haven't seen many patients having macroglossia with TTI amyloidosis as well. And orthostatic hypertension, pifal neuropathy, and they would have the monoclonal chemotherapy present as well. So heart is the most common organ involved in the light chain amyloidosis. 57% of the patients have cardiac involvement. 44% have renal involvement. And then 22% of the patients have nervous involvement. Liver involvement is around 17%. GI is around 16%. And then other soft tissue involvement could be seen in 5% of the patients. So this is the IMWG diagnostic criteria for systemic light chain amyloidosis. So patients have to have an amyloid-related systemic syndrome. They should have either renal, liver, heart, GI tract involvement, or peripheral nervous system involvement, positive amyloid straining by a congoate in any tissue, fat, aspirin, bone marrow, organ biopsy. And evidence that amyloid is light chain related established by direct examination of the amyloid using mass spectrometry based proteomic analysis, or immunoelectron microscopy, is one of the requirements by international myeloma working group for us to diagnose these patients with light chain amyloidosis. And they have to have an evidence of monoclonal plasma cell proliferative disorder. In the CMEU and monoclonal protein abdominal free light chain ratio, our clonal plasma cells in the bone marrow must be present. So whenever we are suspecting patients to have amyloidosis, we need to order these comprehensive hematological workup, which involves doing a CME protein electrophysicist, CME immunofixation, free light chain assay, 24-hour UN protein electrophysicist, and 24-hour UN immunofixation. I think it's important to do all of these testing because most of the time patients could have just the free light chain disease. Sometime the S-PAP might be negative, but we might be able to pick the disease on the free light chain assay. And sometime patients could have just the kidney involvement, and they could have free light chains in the UN. So it's important to do a 24-hour UN electrophysicist on these patients to determine whether these patients have nephotic and protein or not. So a slide on the interpretation of S-PAP. This is the S-PAP interpretation, mainly patients who have monoclonal gemopathy. They would have a nephic and point there. So patients would have an M-spike, which is presented like this, while the other graphs, they can have more of a monoclonal spike or a polyclonal spike there. So S-PAP usually tells us whether there is a monoclonal gemopathy present or not, and then we do the immunofixation to tell us what type of monoclonal gemopathy is present. And then we use the anti-SEA to determine whether it's IgG, IgA, IgM, or Kappa lambda type. So like in this patient, this patient has an IgG band here and then a Kappa band here. So this is an IgG Kappa monoclonal gemopathy present on this same immunofixation. And then these are the CM-free light-chain ratios. So the normal ratio in a patient with a normal kidney function is usually from 0.64 to 1.92. And then if the renal function goes down, the ratio can go up a little bit up to 2.17. So in patients with IgF are less than 30, the free light-chain ratio can be as high from 0.67 to 2.17. So these are the normal values. If the free light-chain ratio is either more than 2.1 or less than 0.6 in a patient with low GFR, then that is considered abnormal. And those patients need to have further workup for the light-chain amyloidosis. So confirmation of light-chain amyloidosis always involves getting a bone marrow biopsy with congruent strain, getting an abdominal fat pad biopsy, or aspirate, and biopsy of the involved organ if we are not finding the congruent positivity on bone marrow biopsy or biopsy of the abdominal fat pad, and then mass spectrometry to confirm the type of that amyloid fibers. So this is just one diagram showing the amyloid deposition in the arterial regions here, pericapillary, and then positive for congruent strain. And these are the amyloid fibers that can be seen here. So this is one of the diagnostic algorithms which is proposed in Jack for cardiac amyloidosis. So if a patient, there is a clinical suspicion with typical echo and cardiac findings, so the next step that we should be doing in these patients is getting a serum and urine protein electrophysicist and serum free light-chain acid done in these patients. And if that confirms that their patient has a monoclonal protein present, then we will go down this path of involving your friendly hematologist in that case and getting the fat pad aspirate and a bone marrow biopsy done. If the fat pad aspirate and bone marrow biopsy show the amyloid deposition, then we should get a mass spectrometry to confirm what type of amyloid is this. And then if that is confirmed, then we can treat it accordingly, whether it's a TTR or light-chain amyloidosis. If the fat pad and bone marrow are negative in a patient's with monoclonal gemopathy, then if the patient still, we have a high suspicion for amyloidosis, then those patients, we can go to mass spectrometry in those patients. And we can also get the cardiac biopsy if there's a cardiac involvement to confirm what type of amyloid is this. If the amyloid protein is negative, then we can go down this path where we can get the PYP scan in these patients. And if PYP has grade two to three uptake on the PYP scan that confirms the TTR amyloidosis, and we can get the TTR sequencing done. If it is negative the PYP scan, then I think if we still have the high suspicion, then we should get the cardiac biopsy in these patients and the myocardial biopsy to confirm the diagnosis of cardiac amyloid deposition. A slide on the staging for light-chain amyloidosis, it is mainly depending on the cardiac involvement. So patients who have cardiac involvement and they have the anti-po-BNP of more than 1800 are troponin, T is more than 0.025. And the difference in the free light chain is more than 18 milligram per deciliter. So patient who has none of these that stage zero, if one of these is present that stage two, if two are present that stage three and if all three are elevated. So that's a stage four disease. And the prognosis of these patients depends on the stage and we can see here from stage one to stage four, the median overall survival goes down from 94 months to less than six months in these patients. So it's imperative to get these patients diagnosed early before they develop stage four cardiac failure because those patients when they're diagnosed at the stage four disease then the prognosis is poor and most of these patients are not even eligible for therapy at that time because they are so frail and not even able to tolerate the treatment when they have the stage four amyloidosis. So this is just one slide discussing on how we can target the amyloid in most of these patients. So most of the treatments that we have available so far are directed against the plasma cells. So the therapy that we are using mainly the anti-plasma cells are directed. We don't have any good drugs that can target the amyloid fibers that have already deposited. So again, coming to the point that if we try to diagnose these patients early, we might be able to detect them early and can offer them treatments because once the amyloid gets deposited it's very difficult to recover from that damage. There are some newer anti fiber treatments that are in the clinical trials. There's one KL-101 that is showing some good progress. So hopefully if that shows some good results we might have some anti-fibrillator therapy but so far the therapy that we have is directed against the underlying plasma cells. So there are different components. So there's a chemotherapy drugs, immunomodulatory drugs and then there are monoclonal antibodies. So chemotherapy, we use Melflan cyclophosphamide and then we have proteasome inhibitors which is what is the most important drug there that we have immunomodulatory drugs, IMAIDs, lanolidomides and then we have the newest modality of the monoclonal antibodies. CD38 is one of the target on the plasma cells that we can use to target the plasma cells and Diatumumab is one of the drug that has shown a very good efficacy in these patients. So this was the Andromeda clinical trial published in NEJM in 2021 which studied the VCD or the cyborgy combination and they randomized patients to two arms, one arm got the cyborgy, another arm got just the cyborgy and but this trial excluded patients with stage 3B cardiac disease, amyloidosis but we have shown here that the Diatumumab addition improves the outcome in these patients significantly as compared to just the cyborgy. So most of the patients, the standard of care for the first line is if they're able to tolerate, we start them on the combination chemotherapy with Diatra, Velcade, cyclophosphamide and dexamethasone based therapy. And with this treatment, there was significant cardiac and renal responses and this is the response rate at six months and 12 months and we showed that with the addition of Diatra cyborgy, there was a 42% cardiac response as compared to 22% just with the cyborgy and the same with at the 12 month the response rate even improved to 57% in the Diatra cyborgy as compared to 28% of the patients in the cyborgy. So it's important to get those patients started on the combination of the Diatra cyborgy treatment once we diagnose them with light chain amyloidosis. So treatment options start with Diatra cyborgy, consider stem cell transplant if transplant eligible, if transplant ineligible then we continue them on the Diatra cyborgy until we have able to achieve a very good hematological response or better. If they have a relapse to factory disease then there's some other treatment options available like pomalidomide, dexamethasone lidomide, carfilzomib and patients who have 1114 translocation with consider venatoclax which is another targeted treatment that we can use in these patients that has shown some good results in patients who have 1114 translocation. So the take home message here is that consider amyloidosis in patients light chain amyloidosis if patients have non ischemic cardiomyopathy and they have LVH on echo findings then we start with the workup with the ASPAP immunofixation and free light chain ratio. If patients have cardiomyopathy autoimmune dysfunction corporatinal syndrome, peri-orbital PEPA, macroglossia that phenotype is more consistent with light chain amyloid. So we check CMG in electrophysicist immunofixation free light chain ratio. And if monoclonal protein is present of abnormal free light chain present then we need to get hematology involved for bone marrow and biopsy in fact by aspirate before ordering a PYP scan. I think because the PYP scan sometime can give you false positive rates and in those patients I think it's important to rule out the light chain amyloidosis first before we jump on to the next step. Now with this I would like to conclude and thank you everyone for your attention.