Full Show: The Latest in Amyloidosis Research With Heather Landau, MD, Memorial Sloan Kettering Cancer Center
Thanks to our episode sponsor Heather Landau, MD Memorial Sloan Kettering Cancer Center Interview Date: February 28, 2017 Summary Many multiple myeloma patients can also have amyloidosis - or protein buildup in specific organs. Dr. Heather Landau of the Memorial Sloan Kettering cancer center explains the different kinds of amyloidosis, current treatments and exciting clinical trials for these patients. These trials include myeloma drugs such as Ninlaro, carfilzomib, daratumumab and other standard treatments, but also a new drug called NEOD001 that can reverse amyloidosis in certain organs. This is a very informative show for amyloidosis patients with or without multiple myeloma. To find clinical trials for amyloidosis, click here:
- Study of Dexamethasone Plus IXAZOMIB (MLN9708) or Physicians Choice of Treatment in Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis
- A Dose Escalation Study of Carfilzomib Taken With Thalidomide and Dexamethasone in Relapsed AL Amyloidosis (CATALYST)
- Daratumumab for the Treatment of Patients With AL Amyloidosis
- Trial of Venetoclax (ABT-199) and Dexamethasone for Relapsed or Refractory Systemic AL Amyloidosis
- NEOD001 PRONTO study
- NEOD001 VITAL study
Dr. Heather Landau on Myeloma Crowd Radio
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, and are grateful for their support of the Myeloma Crowd Radio Show. Now before we get started, I'd like to invite you to participate in this year's Muscles for Myeloma Program. This is an online program. You can join to help you get fit in honor of Myeloma Awareness Month which is in the month of March. This program runs through March and to the end of April. We're doing this because fitness matters for everyone, but it's especially important for myeloma patients who are segmented into fit, unfit and frail categories. There are some treatments they can't receive if they're not fit. This is a national effort. We're teaming up with academic myeloma centers. We have over 20 teams in place where myeloma researchers reside like Memorial Sloan Kettering, MD Anderson, Mayo Clinic and Dana-Farber, to name a few. As you get fit, you'll set your own goal, you'll post your goal on your page and encourage your friends and family to support you to reach your goal. In doing that, you'll be supporting the research centers, myeloma academic research of the team that you joined. It's an easy program to join. It helps you build new and better habits. It can be done at any level of fitness that you're at whether you're just coming out of transplant or you have been in a remission for a while or you're currently undergoing treatment. It's really for everybody. Go to our homepage on myelomacrowd.org. At the bottom of the page, you'll see the links to get started for the Muscles for Myeloma Program, and we're just really excited to get that going tomorrow. (https://give.crowdcare.org/muscles2017) Now onto today's show. At the recent ASH meeting in December, I met with Dr. Heather Landau who mentioned that amyloidosis -- and that may be a tongue twister for me this whole show -- patients are in need of a little more attention. She's an experienced myeloma specialist at Memorial Sloan Kettering Cancer Center and also treats disease that can be associated with myeloma but not necessarily so. Though I know little about amyloidosis, she knows quite a bit. We are thrilled that she can be our top expert on today's show. Welcome, Dr. Landau.
Dr. Landau: Thank you very much for the warm welcome. I have to say that I agree with you entirely about Muscles for Myeloma and getting fit. I think that one thing patients can do for themselves to help their body tolerate both the disease and the treatment is actually keeping their muscles strong. I really strongly encourage all parties: amyloid patients and multiple myeloma patients especially pre-transplant and post-transplant, to really get on an avid exercise program at whatever level of fitness could be achieved, it's a benefit to you.
Jenny: Yes, we completely agree. Coming out of transplant for me, I didn't feel like exercising at all but the more you do it, the better you feel and the happier you are and the stronger you are. Especially with long-term maintenance therapy and the need for transplant in the many cases. Well, before we get started, let me just give a brief introduction for you, and then we can dig into the questions. Dr. Landau has a shortened timeframe. I think we are going to have to skip patient questions at the end and let her tell us when she needs to go. Dr. Heather Landau is Associate Member at Memorial Sloan Kettering Cancer Center and Assistant Attending Physician at the Memorial Hospital in the Division of Hematologic Oncology and Memorial Sloan Kettering Cancer Center Myeloma Program. Dr. Landau serves as the Outpatient Autologous Stem Cell Transplant Service Co-Director and the Amyloidosis Multidisciplinary Group, and she's the Co-Founder and Director. She's Associate Professor of Medicine at the Weill Cornell Medical College in New York, and she teaches at the Memorial Sloan Kettering BMT fellow lecture series both about high dose therapy and stem cell transplant for myeloma as well as risk-adapted stem cell transplant for light chain amyloidosis. Dr. Landau has been involved in innumerable research publications and is a member of many groups for hematology in addition to being a founding member of the Amyloidosis Research Consortium Collaborative Network. Her recent awards include the Post Master's Foundation in Hematology Course for Advanced Providers sponsored by the Oncology Nursing Society and the Donald C. Brockman Memorial Research Grant from the Amyloidosis Foundation. Dr. Landau, we're so thrilled that you're here. I know patients listening are probably amyloid patients, but maybe you could give us just an overview of that as it relates to myeloma, as it relates outside of myeloma, as it relates to light chain version and just introduce it that way.
Dr. Landau: Sure, my pleasure. Light chain amyloidosis is part of a bigger spectrum of diseases called the systemic amyloidoses that is that the end result of a misfolded protein which forms an amyloid protein, and that amyloid deposits in organs and disrupts organ structure and function and causes morbidity and mortality. As it relates to plasma cell diseases, light chain amyloid is the result of a similar underlying plasma cell disorder as multiple myeloma. There are too many abnormal plasma cells. More often two abnormal plasma cells exist but not as many as we see in multiple myeloma, but they can make an abnormal light chain protein that then misfolds and causes this disease called light chain amyloidosis. The difference with respect to the other systemic amyloidoses is that another precursor protein unrelated to plasma cell disorders can also misfold into this substance called amyloid. Most commonly, the protein can be a hereditary variant or as a result of a mutated protein or just the result of long term as in the case of another common disorder which used to be called senile systemic amyloidosis, now it's called wild-type transthyretin amyloid. That is as patients get older or as persons get older, the wild-type non-mutated form of this protein called transthyretin can misfold and deposit in places such as the heart and the nervous system. When we look under the microscope, those patients have amyloid deposits in their heart. They can't necessarily be discerned from amyloid related to light chain amyloid or amyloid as a result of light chain amyloid, but then we can type it and find out if this is caused by a plasma cell protein or this transthyretin protein or a variety of different hereditary mutated proteins which we're finding many, many more of. Does that make sense?
Jenny: Yes it does. As I was doing some homework about amyloidosis in myeloma patients, it looked like it was like a 10 to 20% of myeloma patients could develop this. Are there certain causes or possible risk factors that could go on to develop this? It sounds like what you were saying is what called the light chain amyloidosis is called AL amyloidosis instead of just regular.
Dr. Landau: Yes, light chain amyloidosis. The confusion starts with the semantics. Light chain amyloid is also AL amyloid. It's also primary systemic amyloidosis. All of that is the same thing. It means that you're starting out with a plasma cell problem in the bone marrow that's making this abnormal light chain that's misfolding into this substance called amyloid. Indeed, about 10% of patient with multiple myeloma also, as far as we know, the incidence is probably higher but as far as we know about 10% to 20% of patients with myeloma have true systemic amyloidosis, meaning just like multiple myeloma has previously been defined by the CRAB criteria, meaning having a plasma cell disorder that causes end organ damage, meaning it causes kidney failure or anemia or bone disease or hypercalcemia as I'm sure you're familiar. Because we also know that there is precursor diseases to multiple myeloma such as MGUS and smoldering myeloma where you can have abnormal plasma cells but no manifestations of the disease, meaning no organ damage from it, just having a significant burden of these abnormal plasma cells. So having multiple myeloma with end organ damage plus amyloid deposits causing end organ damage, the true incidence of that is about 10% of all cases with these plasma cell diseases.
Jenny: And are there patients that are more prone to having that?
Dr. Landau: That's a good question. We don't really understand both the driving - whereas those that have lambda as their precursor protein but it does not exclude patients with kappa light chain from developing amyloid.
Jenny: Interesting. I was reading that there is some kind of significance with the IgM. You always have IgG or IgA, but IgM seems to be significant in some way.
Dr. Landau: Well, again, light chain amyloid is the end result and in 98% of patients, the light chain is produced by a plasma cell disorder and in about 2% of patients, there is an underlying lymphoproliferative disease much like Waldenstrom's, like a lymphoplasmacytic cell is making the precursor protein that then folds into amyloid, and that's often associated with an IgM paraprotein.
Jenny: Okay. Well, maybe you want to go over what treatment options are in today's clinic. What is the standard to treat this? I don't know if you're treating patients just with multiple myeloma and amyloidosis or just amyloidosis alone. But maybe you can give us an idea because it looks like some of the standard myeloma therapies are also used for this disease.
Dr. Landau: Yes. I think that the biggest issue is again thinking about the diseases distinctly. They both have an underlying plasma cell problem in the bone marrow that's making abnormal proteins and causing organ damage, and the damage from myeloma patients are distinctly different from the damage that amyloid patients get. And again in 10%, patients will have end organ damage from both of the entities. The difference is for the amyloid patients, when the amyloid deposits in organs such as the kidney, the heart, the liver, the GI system, it causes different pathophysiology. When the myeloma protein deposits in the kidney, it often deposits in a certain place in the kidney and causes acute kidney failure. And if we treat it, that's very reversible. In patients with amyloid, the amyloid protein, the misfolded light chain can deposit in a different place in the kidney and cause what we call proteinuria, loss of protein through the kidney. It starts out very subtle and often goes unrecognized until it's quite advanced. There is different pathology. Again, in myeloma patients, the myeloma protein doesn't necessarily affect the heart. In amyloid patients, about 50% to 60% of patients will have heart involvement. When the amyloid deposit is in the heart, it causes heart failure. Especially as the amyloid becomes more advanced, it's a very difficult problem to recognize because the disease itself is underrecognized and these patients present not to the hematology clinic but to the cardiology clinic. There is lots of other more common reasons for heart failure so these patients go unrecognized. If we think about the pathophysiology of the patients are very different, patients with amyloid having kidney problems in a different way than myeloma patients do and manifestations of heart failure, then treating the disease becomes a little bit different because the amyloid patients tend to be a little bit more fragile in terms of what they can tolerate and how the drugs affect them. So the drugs themselves that are active against the plasma cells, because the first step in treating amyloidosis is shutting off the factory that's making the amyloid protein which is plasma cell directed therapy which is similar to what we do for patients with multiple myeloma, the drugs are similar. However, dosage and schedules and what patients can tolerate and there are subtle differences of what seems to be more effective or less effective in amyloid patients than in myeloma patients. But one of the most common regimens that patients with multiple myeloma patients receive is Revlimid or lenalidomide, as you know, and often as induction therapy, Revlimid will be given to patients with multiple myeloma at a dose of 25 mg a day during their cycle. Amyloid patients in a Phase 1 study, patients only tolerated up to 15 mg a day. So the maximum tolerated dose was quite different. If you just look at a patient with amyloid and say oh, they both have plasma cells and their bone marrow will treat them like multiple myeloma and give them 25 mg of Revlimid, they suffer a lot of toxicity.
Jenny: Interesting. How about stem cell transplant, is that typically used as well?
Dr. Landau: Yes. A stem cell transplant, again, before all these novel drugs were available, stem cell transplant was first used for myeloma patients and subsequently used for amyloid patients, and actually is very effective therapy can result in complete responses in about a third of patients. And those responses tend to be durable if you can get a complete response because the underlying plasma cells, there are limited underlying plasma cells, it's a less proliferative disease. But again, because these patients are fragile, you can use stem cell transplant which is effectively using high dose melphalan but because these patients are fragile, we use risk-adapted dosing of the melphalan in order to ameliorate the toxicity. If we gave everybody melphalan at high doses without paying attention to what organs are affected by their amyloid, we would cause a lot of mortality or death from the treatment itself. In terms of stem cell transplant while all myeloma patients and amyloid patients should be treated at experienced centers, it's even more important for amyloid patients to be treated with stem cell transplant at very experienced centers that are familiar with amyloid patients in particular. There is a lot of supportive care that's necessary to get patients through a stem cell transplant.
Jenny: I think this is just a general point. I mean multiple myeloma is a rare disease by itself. We always recommend to have a myeloma expert on your team, whether you get local care by your oncologist and you're getting infusions closer to home, but you still need to be treated or have your care crafted really by a myeloma specialist, in my opinion. It sounds like just because it's so difficult to diagnose, that this is even more important, like you're saying, for amyloidosis patients that they really have to have this because something could creep up on them that they don't -- and if somebody is not watching it, just because they're not familiar with it, that might happen.
Dr. Landau: Yes, I think it's a necessity to have an amyloid expert on your team if there is a diagnosis of amyloid. I agree with you, multiple myeloma patients should seek expert care as well.
Jenny: I was reading something too about allo transplant. Now it's not used very frequently in myeloma. Is it used in the same sort of way in the amyloid diseases?
Dr. Landau: Because again patients are so fragile, the use of allo transplant has been quite limited. Really only in Germany is it more - I wouldn't say routinely - not even there as used routinely, but they have the largest area there that's been treated with amyloid.
Jenny: You mentioned Revlimid which is one of the immunomodulators and like thalidomide is in that same family. It looks like both of those were being used. It looks proteasome inhibitors like Velcade or I don't know if you're using Ninlaro or carfilzomib or some of these others in there. Is that standard care in the clinical sense?
Dr. Landau: Yes. So actually, the proteasome inhibitors which really their function is to inhibit the garbage pail of the cell which is important in protein processing disorders, patients with amyloid seem to be exquisitely sensitive to the proteasome inhibitors including bortezomib and carfilzomib and the oral proteasome inhibitor Ninlaro is actually the first drug that there is currently a Phase 3 trial ongoing in relapsed patients and is the first drug that is seeking FDA approval for this disorder.
Dr. Landau: There are actually no approved drugs independently approved directly for light chain amyloidosis.
Jenny: So they're all combination therapy approvals?
Dr. Landau: There is not one drug that's approved for this disorder. We borrow drugs from patients with multiple myeloma. Unless you're on a clinical trial, carfilzomib, Ninlaro, daratumumab, these are very difficult to get for amyloid patients who don't also have multiple myeloma.
Jenny: Oh, I see.
Dr. Landau: Again, in the amyloid community, again, it's 10% a patients who will have disease manifestations from both multiple myeloma-related complications and amyloid related deposition, but 60% of patients won't qualify or will have less than 10% plasma cells in their bone marrow. They neither have enough plasma cells to qualify them as smoldering myeloma, and then they don't have access to drugs. If they have greater than 10% plasma cells, they can be considered for the purposes of really obtaining drugs to have multiple myeloma even though pathophysiologically they don't have end organ damage for myeloma. Does that make sense?
Jenny: Yes, it does.
Dr. Landau: Then they have more access to drugs but the 60% of patients who have less than 10% plasma cells really are challenged in terms of getting novel agents.
Jenny: As a specialist, because you have expertise in this disease, do you just use off label type of combinations for individual patients? I mean you were just dosing like you were saying earlier with some of these therapies.
Dr. Landau: Actually, I encourage all patients to go on clinical trials so we can actually understand what we're doing.
Jenny: Yes, that makes sense.
Dr. Landau: At my center, I'm fortunate to have several clinical trials available for patients. We have been studying Ninlaro. We have been studying carfilzomib. We are starting to study daratumumab. We are studying the very interesting drug, NEOD001 which is actually not plasma cell directed therapy but is amyloid directed therapy. I'm not sure if you're familiar with that.
Jenny: No, I'm not. I think you should talk about this because you have two studies open. It looks like one is called the VITAL study and the other is called the PRONTO study that are using this drug. I think this is really a key for patients to understand. Maybe you just can explain more about what drug is and how it works.
Dr. Landau: Yes. This is a really novel and exciting time for amyloid patients because even though again, I said that in order to treat amyloid, you have to shut off the factory that's making the amyloid protein and that's with plasma cell directed therapy. Once we get rid of the plasma cells, there is no longer any more light chain deposits, but it does not get rid of the resident amyloid that still exists in organs. For patients with amyloid to get better, you have to shut off the factory and then then over time, meaning months or years, the organs can recover sometimes. The kidneys usually do. The GI tract usually does. The nervous system can also recover. The heart is the one organ that doesn't typically recover even if you shut off the factory that's making the abnormal protein. The antibody that we're studying is called NEOD001. It's an antibody against the amyloid protein. It binds to the amyloid that's already been deposited and it’s thought to neutralize circulating precursor proteins so that the immune system then can recognize those proteins as foreign and clear the proteins from the organs and from circulation so that the organs can improve. In the initial trial, the Phase I/II trial where we treated 27 patients on the Phase I dose escalation study, and 42 more patients in the expansion cohort, these were all patients who had their disease controlled initially with plasma cell directed therapy, and then we gave them the antibody as a single agent because there was no safety data yet for the drug, and we can study it in combination. This is how the trial had to be designed. When we gave them the antibody, we saw organ responses in over 50% of patients with heart disease using cardiac biomarkers which is the established biomarker to test organ improvement. So over 50% of patients with cardiac involvement and over 60% of patients with kidney involvement had improved organ function when we used this antibody in patients who already had their disease controlled with plasma cell directed therapy.
Jenny: That's impressive.
Dr. Landau: The PRONTO study is a randomized study placebo controled in order to prove that it actually works and that it wasn't just because of the prior therapy that the patients received. You have to do a randomized study so half the patients are getting the NEOD001 drug and half the patients are getting placebo on that trial, and that's almost fully accrued. The VITAL trial is using the NEOD001 along with combination chemotherapy with the CyBorD regimen or Velcade-based therapy to plus-minus the NEOD001 in the upfront setting. I would encourage patient who may be eligible for either study to reach out to centers that are conducting these studies. It's often again challenging for drugs to get approved because of the rarity of the condition. Patients who are eligible for studies not only get access to the most novel agents but also help further the research so that we can understand the drugs that have potential promise for this population and also seek drug FDA approval for the first time.
Jenny: And this is one of the reasons that I started this show is because I wanted to have patients join clinical trials because that's something that we can do to get things done faster.
Dr. Landau: Exactly.
Jenny: One of the myeloma doctors pointed out to me at the beginning that the difference between adult cancer patients are joining at a rate of 3% to 5% participation rates and kids with childhood cancers are joining at 85% rates and how much faster the research happens just because of participation. We will definitely add links to those two studies when we post this show. We partnered with a clinical trial finder for myeloma (SparkCures) that helps people ease them through the process because it's not an easy process to find and join the clinical trial. I saw for amyloid patients that other drugs like carfilzomib, like you mentioned, and daratumumab and I was also seeing venetoclax. How is daratumumab being used right now? And then how is carfilzomib and venetoclax being used in clinical studies?
Dr. Landau: Let's start with carfilzomib because it's the only drug that has been studied in amyloid, and we completed a Phase 1 study where we treated 28 patients with amyloid with carfilzomib at escalating doses and that was presented as an oral presentation at ASH this year by Adam Cohen. The response rate was upwards of 70%, and the depth of response was high as well. The issue with carfilzomib is that there's some cardiac toxicity associated in myeloma patients and as well in amyloid patients. So understanding the safety in that population is really key. While we think it's effective based on the preliminary data, we also would like to get a better sense of who is going to suffer toxicity, and that's the real challenge with that drug. Daratumumab is the anti-CD38 antibody that's now recently been improved for multiple myeloma patients and it's really been a boon for that population. Again, there are limited data in patients with amyloid. Actually, at the International Amyloid Symposium in Sweden this summer, Michaela Liedtke presented 18 patients and the response rates were upward of 80% within a very refractory patient population with a single agent. We do think that this is a very effective drug for this population, but it is not yet available. As I understand it, Janssen will have a company-sponsored Phase 3 randomized in newly diagnosed patients up and running by the second quarter of 2017. So newly diagnosed patients can also be looking out for that trial.
Jenny: Are there open clinical trials for relapsed refractory patients?
Dr. Landau: Not as of yet. There are two that are soon to be open, one at Boston, one at MD Anderson, I believe. We are going to have one in combination with the IMiDs shortly thereafter, but not readily available.
Jenny: Okay, I see why you feel passionate about this patient group. They need extra attention.
Dr. Landau: Yes. Lastly, venetoclax has shown incredible activity in multiple myeloma particularly in the patients with translocation (11;14) by virtue of the mechanism of action of venetoclax. Because that's a common translocation in amyloid patients (the most common translocation in amyloid patients), it's being studied by Dr. Comenzo at Tufts, and I would encourage patients that his study is for relapsed patients and that has recently been open. Relapsed refractory patients can see if they're eligible for his study in Boston.
Jenny: You would suggest that just for the 11;14 translocation patients with myeloma and amyloid?
Dr. Landau: I don't think we know that yet.
Jenny: Maybe you could explain that a little more.
Dr. Landau: Yes, I think that the study is actually available to patients who have both the (11;14) translocation and not because the pathway is upregulated, we believe, in light chain amyloidosis. But I'm not positive if Dr. Comenzo's study is limited to patients with (11;14) translocation. I think that he is accepting all comers.
Jenny: Okay. That makes sense.
Dr. Landau: And the myeloma patients that were studied were all comers as well. There is some activity albeit less, but some activity in the patient population who does not have a detectable (11;14) translocation.
Jenny: All right, that makes sense. I also saw that you had a study open for Captisol-enabled melphalan. Maybe you want to explain that because I'm not familiar with that.
Dr. Landau: Yes. Actually, that is a new formulation of melphalan called Evomela. It's really the same drug, the same melphalan that's packaged differently. When we give high-dose melphalan, it's a very unstable molecule so it has to get in the patient within 60 minutes. There is breakdown and there's risk of underdosing. We don't typically measure the level of the melphalan; we haven't been able to. We typically don't know how much drug is being delivered to each patient. So Captisol-enabled melphalan is packaged differently. It's a more stable product. It's supposed to be safer because it's propylene glycol-free which is what regular melphalan is packaged in. It's more stable and potentially less toxic than regularly available melphalan. We are doing a study in both myeloma patients and amyloid patients. We are trying to target a specific concentration in each patient in order to kind of target a sweet spot of where in using high-dose therapy, patients have the most efficacy and the least toxicity. We can do that using this product. It's more stable and we can measure it in the blood of our patients so that we can have PK or pharmacokinetically directed dosing of the drug in order to try to improve safety, tolerability and balance that with efficacy.
Jenny: Great. Well, it sounds like you have so much going on at Memorial Sloan Kettering. It's exciting what you're doing. I know you have a hard stop, and I know we have some caller questions. But what I think I'll ask them to do is email me with their questions, and then I'll email them to you and maybe you can respond and then we'll add them to the final show post. But is there anything that you want to leave amyloid patients with in terms of recommendations of what they do or watch for or what type of treatment that they get before we close?
Dr. Landau: I think really what we started with is what I'll leave you with. Number one, stay active and again the best thing that you can do for yourself is keep your body strong in order to be able to tolerate the disease and the treatment if possible. The other thing is to seek treatment at an expert center by an expert who has access to what may be available and also the supportive care that's necessary for patients. There are subtle differences, as I mentioned, in treating patients with multiple myeloma and light chain amyloidosis. It really takes some expertise to really understand that and treat patients with heart failure and protein loss and use tricks of the trade like compression garments and certain diuretics and things that we don't often think of as oncologists who are just treating oncologic problems but not the same pathophysiology as patients with amyloid have.
Emailed Question #1: If AL Amyloidosis is under recognized, why not test all Smoldering Myeloma patients to detect it at its earlier stages? I know Dr. Comenzo's SAVE trial is trying to do this for Lamdba Light Chain SMMers, but why not Kappa Light Chain SMMers as well? Many kappa smoldering myeloma patients have reported that they were misdiagnosed.
Dr. Landau: At our center we do routinely test all newly diagnosed patients with MGUS, SMM and MM with cardiac biomarkers and urine studies to look for manifestations of AL amyloidosis. Dr. Comenzo's effort is most valuable since it will help define the true incidence of AL in this population. Certainly if there are patients with kappa SMM or even MGUS and have typical symptoms- or are just feeling more unwell than expected we promote looking for AL (for patients in the community).
Emailed Question #2: What are the most common early symptoms to be aware of?
Dr. Landau: The issue is that AL mimics other more common conditions and can often present with such symptoms as fatigue, shortness of breath (more pronounced on exertion), poor appetite, weight loss, lower extremity swelling, lightheadedness. But there is no one constellation of symptoms that manifests in all comers.
Emailed Question #3: What are the most common cytogenetic abnormalities associated with AL Amyloidosis?
Dr. Landau: The most common genetic abnormality in the plasma cells of patients with AL is t(11;14). However we also see other chromosomal abnormalities (such as deletion 13q or excess 1q) that are common in MM patients and are being recognized more frequently. There are some data to suggest that t(11;14) is associated with inferior outcomes, especially when treated with bortezomib-based therapy. On the other hand, patients with gain of 1q have inferior outcomes when treated with melphalan and dexamethasone. Of note, cells with the t(11;14) abnormality have a high expression of BCL-2 and may be more sensitive a drug called venetoclax which is now being studied in AL amyloidosis patients by Dr. Comenzo at Tufts University.
Emailed Question #4: Do you forsee a combination trial of Darzalex and NEOD ?
Dr. Landau: I do foresee a trial with Darzalex and NEOD001 in the future which is good news…But not in the short-term. So I would really encourage eligible patients to enroll on the currently available trials including the NEO trial for newly diagnosed patients with cardiac involvement (VITAL), the NEO trial for previously treated patients who do not require plasma cell directed therapy (PRONTO) or the Ninlaro/Dex study for relapsed patients who have never been exposed to bortezomib. Lastly, along with colleagues at NY Presbyterian Columbia and Mount Sinai, we will have a trial for newly diagnosed patients using the all oral combination of Ninlaro, cytoxan and dexamethasone opening shortly.
Jenny: Well, great. We are so grateful that you took time to talk with us about this important disease. I would stress again that it's true. I mean especially with the situation where they are not a lot of clinical trials being run or not a lot of approved drugs yet for these patients. It's absolutely critical that they join clinical trials so that you can do your work more quickly. Instead of taking 10 years to come to conclusions, you can come to conclusions in one or two years. Thank you for all your doing. Thank you for joining our show today.
Dr. Landau: As you mentioned, the VITAL study and the PRONTO should study are accruing. I think that anybody who is eligible for the Ninlaro study which is the oral proteasome inhibitor that's been difficult to accrue to that study but it's a very important study because if you are an amyloid patient but have not had bortezomib or Velcade before, then that would be a great trial for you. Any other studies that you are eligible for, I think that it's really a win-win for both the patient and the field as a whole.
Jenny: Wow, terrific. Well, we will include links to all those studies in our final show. We just are so appreciative for what you're doing for this patient group.
Dr. Landau: Thank you, Jenny, for all that you do. Have a great day.
Jenny: Well, thank you and take care. Thank you so much for joining us today. Thank you for listening to another episode of Myeloma Crowd Radio. Join us next time to learn more about what's happening in myeloma research and what it means for you.