Sagar Lonial, MD Winship Cancer Institute Interview Date: July 19, 2017

Recent meetings held this summer had important updates in multiple myeloma therapy. Renown myeloma expert Sagar Lonial, MD of the Winship Cancer Institute joins Myeloma Crowd Radio to share the latest in developments for newly diagnosed, relapsed/refractory, elderly and high-risk patients.  He stressed the importance of using both the immunomodulator and proteasome inhibitors in combinations - typically in triplets as induction therapy. Dr. Lonial also stressed the need to keep stem cell transplant in the mix of therapies to potentially get the "cure fraction" of patients to a higher percentage. He noted the introduction of quad therapies - or the addition of one of the monoclonal antibodies - and the need to balance treatment with toxicities. The nice part about adding a drug like elotuzumab or daratumumab is greater impact with minimal extra toxicities. He noted the excitement around the CAR T cell therapies with BCMA as a target. He emphasized the need for genetic testing at the beginning of diagnosis because he sets a 5-10 year strategy for his patients based on their type of myelolma. For high-risk patients, this would mean a longer maintenance period. 

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Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom. This is our 101st show, and I'd like to thank our episode sponsor, Takeda Oncology, for their support of Myeloma Crowd Radio. Before we get started with our guest today, I'd like to let you know that we have now raised $477,000 for the Myeloma Crowd Research Initiative. Our goal is to reach $500,000 for this program, and once we hit that target we will first jump up and down with joy and then run this process again. About the process, it was very important how we went about choosing these projects. We invited investigators worldwide to submit their proposals for high-risk myeloma because these patients need it the very most. And we received back 36 proposals. Our Myeloma Scientific Advisory Board narrowed that down to a top ten. So after hearing from these ten investigators on Myeloma Crowd Radio, both our MCRI Scientific and Patient Advisory Boards selected two project participants: one is the CAR T cell research out of the University of Würzburg in Germany targeting CS1 and BCMA, and the second is the MILs Research at Johns Hopkins with Dr. Borrello. Both are immunotherapies. And based on the recent news that we'll be hearing about more in today's show, I can, with great confidence, say that our process worked. This method of crowdsourcing and crowdfunding is helping to advance leading edge and incredibly effective treatments for not only high-risk patients but all myeloma patients. Additionally, 100% of the money you've donated to the MCRI is going to these two projects. So congratulations for making a difference in all of our care and helping us speed along a potential cure. Your support matters greatly. Now, recently, several major meetings were held, and our show today is with one of the myeloma greats, Dr. Sagar Lonial, at the Winship Cancer Institute at Emory University. Dr. Lonial spoke both at the American Society of Clinical Oncology, or ASCO meeting, as well as the European Hematology Association meeting and has graciously joined us today to review the advancements which are significant. I am so thrilled that he could join us today. So welcome, Dr. Lonial.

Dr. Lonial: Thank you so much for having me. I think congratulations are due to you for all the great work you guys have done in terms of educating and now getting into the research business. It's a really amazing work for such a short time.

Jenny: Well, you're doing so many great things, so we're thrilled to just support what people like you are doing. It's amazing. So let me introduce you before we get started. Dr. Sagar Lonial is Chair and Chief Medical Officer of the Department of Hematology and Medical Oncology at the Emory School of Medicine at the Winship Cancer Institute. He's Professor of Medicine in the same department and Founder and Course Director for the annual updates in hematology and oncology at Emory as well. Dr. Lonial also serves as Director of Translational Research for the B-Cell Malignancy Program at Emory, and Dr. Lonial is Committee Chair of the Multiple Myeloma Research Foundation Steering Committee, the Eastern Cooperative Oncology Group, also known as ECOG, which constructs and coordinates large national clinical trials, and is on the IMF Scientific Board of Advisors. Dr. Lonial sits on the PANORAMA-1 Steering Committee for Novartis and is on the International Myeloma Society Board of Directors. He is also a Myeloma UK External Advisor. He is so incredibly busy. He is Associate Editor of the Myeloma Section and Editor of Clinical Lymphoma and Myeloma and is on the Editorial Board of the Journal of Clinical Oncology, Leukemia and Lymphoma and Clinical Cancer Research. Dr. Lonial is internationally recognized as a leading authority in multiple myeloma treatment and research and is invited to speak regularly at major meetings where updates are held. So Dr. Lonial, thank you again for joining us. We have a lot to talk about today.

Dr. Lonial: Yes, let's get started.

Jenny: So what I heard (I didn't attend the ASCO meeting, but I did attend the EHA meeting) is a lot about the art of treating myeloma. So why is treating myeloma not a simple task?

Dr. Lonial: I think that's a great question, and I think part of it has to do with two pieces. The first is that the assessment of a myeloma patient or a potential myeloma patient is a moving target. The reason I say that is that the evaluation, the diagnostic workup, the genetics workup, all of that is continuing to move forward as we get newer and better technologies. And so I think knowing what to do at any given time point may be different than it was six or 12 months ago. The second piece I think that makes it perhaps not quite as cut and dry as many other malignancies is that there's such an age range in the patients that can get this disease that the treatments can sometimes need to be tailored based on other co-morbid condition, things like hypertension, severe diabetes, functional status, what we call performance status in the US as well as renal function, hepatic function, all those other things that go into making decisions about what to do for a myeloma patient. So based on those significant variability, deciding what to do for a garden variety 50-year-old with myeloma is different than what you do with a garden variety 80-year-old with myeloma, and even all 80-year-olds are not the same. So I think that's what adds a level of complexity in a disease where the average age of presentation is 65 to 70.

Jenny: And I know a lot of patients don't see myeloma specialists. I don't know what the percentage, what the real percentage would be, but I know it's a significant one and I know there is a great advantage to seeing a myeloma specialist or at least consulting with them and maybe even getting your care locally.

Dr. Lonial: Yeah, I think that's really important. This in no way is intended to say that every myeloma patient has to be receiving their direct care from a myeloma center. But even something as simple as the staging system, I know that I still see notes from physicians where the Durie-Salmon staging system is quoted in the original diagnostic note, and we haven't used Durie-Salmon for over a decade now. ISS, which was the previous staging system has now been replaced as of 18 months ago with R-ISS. I think that just keeping up with how to do this stuff in the modern era I think really is important. As something as simple as staging has changed, the treatments have changed even more dramatically, not just in terms of what am I going to do first but as I tell most new patients that I meet, I have in my head a five-year and a ten-year plan for what I plan to do for that individual patient. I may only show or describe certain parts of that five or ten-year plan, but you need to have that five or ten-year plan because myeloma patients are living for a really long time, and it's not just about can I get this drug to work now and then I'll think about it tomorrow tomorrow. You really have to think about tomorrow today.

Jenny: Well, I totally agree with that because I think what's done up front really is critical for the patient. When you say you're having a five to ten-year plan for these patients, what you're doing is you're looking ahead at what potentially could work effectively or what could go wrong, and making sure they had the most durable outcomes based on what you're doing at the very beginning. What you said about, not just the staging but I think also the testing because I know a lot of patients will go to a doctor, a general oncologist, and the testing has changed so much, so they may not be running the right type of testing up front. I just think this is an important point for patients to understand. That's really critical for them to be seen and diagnosed by a myeloma specialist.

Dr. Lonial: Yes. And just to speak to the testing point, there's a lot of controversy over whether FISH or sequencing or gene expression profiling should be done on patients with diagnosis, and that's not a debate that I think we're going to settle certainly at this moment right now. But even something as commonly performed as FISH testing on a bone marrow can be done in a number of different ways, only one or two of which will actually give you usable results. I'm constantly surprised by how often I see FISH results done at a lab that does not select out just the plasma cells. So you end up potentially getting a false negative result thinking I've got standard risk disease because my FISH testing was negative. Well, not if the FISH testing wasn't done on myeloma cells. Something as simple and subtle as that can make a big impact on how patients are maintained and what their approach to long-term outcomes are.

Jenny: And maybe even not the right probes being run. From what I understand about the FISH test is that you get what you test for. If you don't run the right probes, you're not going to get the right tests. I had a translocation the didn't show up on my FISH test that did show up on genetic testing. So maybe we want to we transition into testing. With all these different varieties of the FISH testing, and I agree that if you're not selecting the plasma cells, you're going to get a very good result, but even beyond that and these other next generation sequencing or the gene expression profiling testing, how important today is genetics in myeloma? When I was diagnosed in 2010, hardly anyone was doing any kind of genetic testing.

Dr. Lonial: So I think understanding the genetics is really critical to identifying the risk group that a patient is in. We really struggle when patients don't have that testing done appropriately at the time of initial diagnosis in trying to figure out what is our maintenance strategy going to be. I know that several years ago there was a lot of controversy over should standard risk patients be treated differently at the outset from high risk? And in my view, that approach that was favored by a couple of large institutions suggested you could undertreat a standard risk patient because they were going to do fine, and that it was really the high-risk patients that you wanted to focus on aggressive induction therapy. Well, we now know from randomized trials that that is incorrect, and that what's good for high risk is even better for standard risk in terms of depth of response, progression free survival, and overall survival. So that testing piece at the outset is really critical, in my view, not to deciding what am I going to do at the very first moment I'm treating a patient because that's going to be standard across high risk and standard risk, but how am I going to maintain that patient. Because that's where it's key. High-risk patients need much more aggressive and more intensive maintenance therapy, whereas standard-risk patients, if they've achieved a good response, can probably get away with less intensive maintenance therapy.

Jenny: That's an amazing point. I think patients need to understand that. I think a lot of patients don't even know that if they have started treatment and they no longer have some myeloma cells and that information is lost, so what you're saying about doing something from the get-go and doing the right testing and the appropriate testing on the right type of cells is critical.

Dr. Lonial: Yeah, absolutely, because if you don't have it a diagnosis, the next time you're going to get it is going to be in relapse. You want to head that off if you can. So you're right, I think you do need to know it early on.

Jenny: So with the FISH test and now the next generation sequencing kind of being used in some clinical trials and the gene expression profiling, what do you suggest at your facility? What do you typically do for patients?

Dr. Lonial: I think at our place we are continuing to do, for routine clinical care, we're continuing to do a FISH panel that's got about 10 or 12 different probes in it, so we're able to get pretty comprehensive data, and it's done on sorted plasma cells. Now, I will tell you that I suspect that in the next few years, we'll probably be talking about RNA seek-based approaches which are able to give you mutational analysis, potentially translocations through copy number assessment as well as expression profiling. So I think with one or two tests, you're going to be able to get huge amounts of data. We just need to understand what the best panel for these patients are going to end up being, and what's the most efficient way to get it done in a CLIA- certified lab environment. That actually I think is an important subpoint to make. What CLIA mean is it's basically a national laboratory testing standard. When we do investigative testing, so if somebody were to come and get sequencing done in my lab or somebody else's lab, not the clinical lab, that can be used for research basis but it should not be used to make decisions because that's not been done in a clinical grade lab. I think that the reproducibility and all the other pieces that go in to a clinical grade lab is an extra hurdle, but it allows us as clinicians to feel much more confident in the data we have and allows us to really use it for decision making. I touched on high risk versus standard risk is one important piece of information that we get from the genetic testing at the time of diagnosis. Now, in 2017 where we've got potentially drugs such as venetoclax that are very active in a subset of myeloma patients alone or in combination with steroids and that's the patients with (11;14) translocation, you really want to know who has (11;14) translocation early on because that will be a critical piece to managing their disease either in the maintenance setting or in the early relapse setting as well. It will have therapeutic implications as well.

Jenny: And it's so exciting to see, because when I was first diagnosed, there was a lot of the opinion just seemed to be, well, it's not going to change my practice at all. So that may be interesting in the future, but I'm not sure why I would capture it now. I think it's super exciting to get that much information out from patients. Are there ways the patients can get the RNA sequencing right now or is that just all in clinical trials?

Dr. Lonial: I think there probably are a few centers that are doing it early on. Many clinical trials are not doing it as part of the standard diagnostic workup for entry into newly diagnosed myeloma trials. The CoMMpass trial that you may know about now has a database of over a thousand patients with RNA sequencing data on I think at least 800 of them now. I think there are potential ways to get access to it. But again, much of that data on expression profiling from RNA seq does need to be -- I won't say validated, but it needs a little bit more depth and experience to help us understand how best to use it. It doesn't have that large data set that many of the gene expression profiling send-out tests already currently have.

Jenny: Do you see the gene expression profile test as is being valuable right now while the RNA sequencing ramps up?

Dr. Lonial: Yes, I think that's a good question, and I know that there are a number of sites certainly from my colleagues that do use that fairly consistently. I think, in my mind, sometimes high risk and standard risk is not as simple as a line, either you are or you're not. I think that there can be some subtleties that come along with it. I think that my biggest issue with the current gene expression profiling platforms that are out there is that the report will often say your result is either high risk or not high risk. I think for me I like to know a little bit more in terms of what's up, what's down, what does that mean for certain subsets of patients and how to apply that. I like a little bit more information from a broader category of patients from sources. But certainly, gene expression profiling data does have a role and it can be used to define high-risk myeloma even now.

Jenny: Great. Well, I heard a lot about different drugs coming in like venetoclax and other drugs that I'm sure you're going to talk about today's show. And a lot of that I heard one of the doctors discussing the idea of balancing all this new impact or efficacy with possible side effects. I don't know if you want to talk about that first, or if you'd like to do that after we talk about all the new things that are coming up.

Dr. Lonial: No, I think we can address that balance. I think one of the important taglines that you'll hear over and over again in many myeloma talks is one that's very near and dear to my heart, and that's the idea of combination therapy.  I think that for the most part, except in the truly frail patients, I think we've demonstrated with multiple large randomized trials that the question of sequential single agent versus combination has been put to rest, and that is combinations are clearly better across the board in terms of response, depth of response, duration of remission, and now even overall survival; we have a lot of data that says that. But the balance of that combination of factors, what is the price you're paying in terms of toxicity? In my mind, the only way that the toxicity balance can work out is if the benefit you're getting when you combine drugs is more than one plus one equals two. I'm going to try and make this non-mathematical. One plus one equals two to me is two drugs that work well together, they're additive in their benefit. If you give drug X and then you follow it by drug Y, you'll probably get the same result in the long term because they're not synergistic; they're additive in their benefit. The combinations we look for in myeloma are actually synergistic combinations. We're looking for one plus one equals five. When you get one plus one equals five, when you put IMiDs and proteasome inhibitors together or you put IMiDs and monoclonal antibodies together, what you end up getting is not just additive benefit but synergistic benefit. In that situation, the benefit on the clinical side outweighs the toxicity because the toxicity is the most additive as well. I think that's really what we need to be striving for in myeloma and in other diseases as well. That's where the science comes into play because the preclinical science, the lab work can give us clues about what combinations are going to be synergistic versus what combinations are just going to be additive. I think certainly at our center, we focus a lot on the synergistic combinations.

Jenny: That's a great way to answer that question. Well, let's talk about some of those therapies. I know that some of the talks were organized around the patient group, and some were just organized around the new stuff. I know you spoke at one of those about emerging therapies. Maybe we want to start with that because a lot of exciting data came out of ASCO and was talked about at that European meeting.

Dr. Lonial: I think as you begin to talk about emerging therapies, there are a couple of targets that I think have a fair amount of interest in them, and probably the one that every patient I saw in clinic yesterday asked me about was about CAR-T cell data. And we now have at least three different sets of CAR T cell data in myeloma that focus on what I would argue is probably the best target in myeloma, and that's BCMA. I know that everybody is out there saying to me, well, there's target CD38 and that is really good. Why are you saying BCMA is the best target? The reason I think BCMA particularly for something like a CAR T cell is such a great target is that it is almost exclusively expressed on plasma cells, whereas many other targets that we use or look at in CAR T cells or other antibodies may have expression on other tissues. When you're looking at the off-target effects or the on-target/off-target effects of a given immune therapy, you want to keep that as tight as you can on the tumor cell itself. I think BCMA probably is one of the best potential targets in that aspect. We saw data at both ASCO and EHA talking about either updates of data or new sets of data from a couple of different groups. Now we've seen data from the Bluebird group, the Novartis UPenn group as well as the Chinese group on BCMA as a target. If you were to add up in aggregate all the patients who were treated with the BCMA CAR T cell from those three trials, it would still be less than a hundred. I think it's important to put those numbers in some perspective. There are thousands of patients around the country and around the world that are either trying to get on or on waiting lists or are on screening lists for trials of this type, and yet we've only seen data on less than a hundred. What that tells me is that the proof of principle of this technology is very good. The response rates are incredibly high. Some patients are achieving MRD negative complete remission, and some of those remissions appear to be quite durable. But we haven't really compared it apples to apples like we have every other treatment that we have, meaning I got a patient in the clinic that has relapsed disease, can I pull something out in the next two weeks and treat them successfully with that treatment approach? Because CAR T cells take a little bit of time to manufacture. Not everybody can potentially have CAR T cells made from their product, and not everybody can wait the amount of time you have to wait potentially to be able to get access to that CAR T cell product as well. There are a lot of variables that I think we need more data on to fully understand it, but there's no question it's an incredibly exciting data set. And whether one of the companies is going to be better than the others is hard to know, but more is always better because with more you have more choice. You hopefully get a little bit of competition in there, and competition is always good. I think we will see a place of this technology in the near future.

Jenny: Oh, I think what's happening is just totally incredible. What you think is the timeline for expanded numbers of patients in these studies? I have a lot of friends who are trying to get into these studies, and so I know the numbers are low and you want to be cautious and things. You want to make sure everything is safe. But how fast do you see these studies opening? Because you're on the ECOG board, and I know you're working with Novartis and other companies, and here you have your finger on the pulse of all this. In your mind, what will happen as far as expansion?

Dr. Lonial: I think you're going to see trial access begin to open in the next few months. There's the three that we've already talked about as well as a potential two more may begin to open up BCMA programs in the context of CAR T cells for myeloma. But many of those trials are still going to be relatively small. The number of patients treated will grow. There's no question, and I think we'll get corroboration of the early data we've already seen that looks so good. But I think it will be a while before you're going to have thousands of patients treated with BCMA CAR T cells because there just is some limitations in terms of how many products you can make at any given time. The same technology is being used for ALL, diffused large B-cell lymphoma, and other diseases, CLL as well, where CAR T cell technology is clearly very important, very active. I don't think it's going to be something that within six months you're going to be able to walk down to your neighborhood oncology office and get it. I don't know that it'll ever be that easy. My suspicion is it'll probably be something that's offered at specialized centers that are used to dealing with cellular therapy. For the most part, that will probably be bone marrow transplant programs. That sort of circles back to your earlier discussion about making sure that you're connected with a myeloma center because almost all myeloma centers are cellular therapy and transplant centers, and so that will give you the highest and most success in terms of potentially getting on those trials and getting on those waiting lists.

Jenny: Absolutely, and access to clinical trials. One of the reasons that I started this show is to help, encourage patients to join clinical trials because this is how -- I mean it's clear to see with this BCMA product just as a single example that this is how we move things forward. If we want things to get to the clinic faster, I think this is important idea to go to transplant centers, go to myeloma academic centers that are actually performing the research as well.

Dr. Lonial: I absolutely agree. When patients come to me and say, well, why should I do a trial instead of taking the standard of care? I have two answers to them. The first is that their standard of care came from a clinical trial, and so we won't ever advance the field if we don't do it. The second is every patient in every phase of their disease should think about a trial as a potential solution for them because again that's how we move the field forward. Not every trial is going to work, that's true. But I will tell you, in plasma cell disorders and in myeloma, we've been very fortunate that we've managed to use science and genetics and the experience of many of our colleagues to raise the bar and to have a pretty good batting average in terms of being able to offer new and effective therapies for our patients.

Jenny: I think what's happening in myeloma is just stunning. And going back to the BCMA, I think the manufacturing may be an issue right now in terms of speed. I think that will get faster over time, don't you?

Dr. Lonial: Yes, I think you're right. I think it will get faster over time. You can probably get CAR T cell products in less than two weeks or on an average in around two weeks which I think would be better. The capacity for manufacturing is going to be really the issue. That's something I know that each of these companies is really working hard on because I think the last thing they want to do is have an effective therapy and not be able to get it to patients who need it.

Jenny: Well, what's happening is really exciting and all the data that came out is just really amazing. Do we want to go through different types of patients? So maybe for newly diagnosed patients, what you saw as a major theme in treating these patients or suggestions or recommendations?

Dr. Lonial: I think when you talk about the average newly diagnosed myeloma patient, I think that one of the themes that has arisen is that an IMiD and a proteasome inhibitor plus dexamethasone probably represent the standard of care at this time. There again are a number of trials that have spoken to this. But I think there's no question that an IMiD-PI combination likely the one with the most data is RVD, Revlimid with Velcade and dexamethasone.  The one that's vying for equal billing, if you will, is KRD, carfilzomib in combination with Revlimid and dexamethasone. Also in that same competitive group is IRD, ixazomib with Revlimid and dexamethasone. I think each of these three have various arguments that I think make them more or less attractive to patients, more or less attractive from an investigator perspective. I will tell you I think that in my view the standard continues to be VRD. And there is a current ECOG trial ongoing comparing VRD with KRD which I think is really an important trial because KRD has clearly demonstrated very significant activity and efficacy in a number of small Phase 2 trials, and I think we need that Phase 3 validation to understand what it brings to the table over VRD in a randomized trial comparison. If there are newly diagnosed patients that are out there, I would encourage them to think about participation in that trial.

Jenny:  I was wondering how long it would take to find the results from that? How long do you have to wait for that type of study to know which one would be more effective long term?

Dr. Lonial: That's a great question, and it's at least a year and a half to two years before we really have some of that information. You know, until that time, everybody's got to make their judgment and best judgment in terms of what the optimal options are. I won't say that anyone is right or wrong. What I would say is find a regimen that you feel comfortable with, that you can give, and that you understand the potential side effects that come up so that you can anticipate them or manage them in an efficient way and use that regimen and get comfortable with it. If that regimen is KRD for you and there are many centers that are doing that, I think that's okay. Just know that there are certain things you're going to experience with KRD that you may not necessarily experience with VRD. And just be prepared to anticipate that and help patients deal with it.

Jenny: Good to know. Sorry to interrupt you.

Dr. Lonial: No, that's okay. I think the other piece about newly diagnosed myeloma that I want to touch on is the role of transplantation. There's been a lot of discussion about replacing transplant and transplant is outdated. We have all these great new drugs. We don't need transplants. I guess what I would caution people about thinking is that transplant continues to remain a really active and important and underutilized approach to treating myeloma. And when you and I were speaking early on about the idea of having a big long-term plan, transplant does play into that big long-term plan. If you look at the most recent IFM study that came to us from the French group where everybody got RVD induction and then were randomized to early transplant or continued RVD and both groups were followed by lenalidomide maintenance, what we know is that at two years two-thirds of the patients who were MRD negative were in the transplant group. So to say that I don't believe in transplant or transplant has no role I think underplays the importance that transplant can play in getting patients who may already be in complete remission into MRD negative complete remission and then sustained MRD negative complete remission. This is really important because I think that gives us the best chance of long-term remission, and it also gives us the best chance to put patients in what I would call the “cure fraction” of myeloma. That's not a phrase you probably typically hear very often from people, and it's not one that I'm going to use cavalierly. What I want to say is that I think even with data from ten years ago, there were about 10% to 15% of patients who would be what I call cured, meaning ten years continuous remission, no evidence of relapse, ongoing complete remission. I think with the drugs and the technology we have, if we put them together in an adequate way, that number can at least double, if not triple. I think in order to do that, we have to have a defined treatment approach that at each stage tries to hit the myeloma from a different perspective, and that's how we're going to get to ultimately curing more patients with myeloma. But in that situation, we shouldn't say, well, can I delay a transplant or should I do it early? If the results are equivalent, there's no reason to do the transplant. That's not moving the field forward. I don't want equivalent. I want better. In order to get better, we’ve got to get more patients into MRD negative complete remission.

Jenny: Well, it sounds like from what I've been reading that MRD negative status is a better indicator of your progression free survival or your overall survival than some of the current designations like complete response or very good partial response, that it has more to do with the length of life and how long you can go without disease than those standard type of designations.

Dr. Lonial: Yes, that's absolutely correct. What we know from retrospective studies is just what you described. Patients that achieve MRD negativity have a longer overall survival and longer duration of remission. What we don't know, and sometimes this gets confused when we when we talk about MRD, is if you take a patient who's MRD positive and change their therapy and potentially make them MRD negative, have you changed their natural history? And that's actually a really important question because the presumption is if you take an MRD positive patient and make them MRD negative, they're going to fall on the MRD negative curve, but we don't know that. So what it may be is that MRD at certain time points is a prognostic factor. It tells you who's going to do well no matter what. But it may not be a factor that you can use to predict who you should change therapy on. Those questions are being tested right now in large trials. So we will have that data in the next few years.

Jenny: Yes, like if I'm MRD negative and I've been that way for two years, so can I stop therapy? Or I'm MRD negative after two months, should I stop maintenance? Probably not. You're saying that you don't have the data yet.

Dr. Lonial: Absolutely. Not only if your MRD negative can you stop because we know that the MRD negative curves don't hit a plateau yet. There will be patients that potentially relapse. I'm very nervous about the "I'm MRD negative, can I stop?" argument because you could argue that was like I’m CR, I'm conventional CR negative, can I stop? We had our heads in the sand. We didn’t know how low we could go. The same token, just because you're MRD positive doesn't mean that the game is over. There are many subsets of patients who can potentially remain low level MRD positive or even overtly MRD positive and do well for a long period of time. What we need to understand is biologically what's different about those patients so that we can not try and drive people that are never going to get to MRD negativity by changing treatments if they're going to be fine and stable even if they are MRD positive. It's a bit complicated.

Jenny: Yes, it is complicated, that's why you have you to go to a specialist. I don't know, every time I think about it I don't know how a general oncologist can keep up with all the nuances and all the details behind it. It's just really stunning. So for newly diagnosed, transplant is still important up front. What I also heard you say is triplets are better than doublets (which are kind of out the window now in terms of induction therapy). So how about clinical trials using quad type therapies?

Dr. Lonial: We saw some data at ASCO and the EHA combining daratumumab with KRD, combining elotuzumab with RVD. I think this to me really looks like the next big wave of induction therapy. We tried for a number of years to go to quads when we had IMiDs and PIs as our major backbones of therapy. The problem was that the fourth drug we were adding in was a conventional chemotherapy drug like Cytoxan or cyclophosphamide. When you add in the fourth drug and it has a lot of baggage in terms of adverse events, that's where the toxicity that you mentioned earlier on really begins to balloon out because now you've got three drugs, or four, depending upon how you put the dex in, that each has their own concomitant set of side effects and they really do start to add up and steamroll over a period of time. What the antibodies bring to the table is a new mechanism, a novel mechanism without a lot of the adverse event baggage that many other fourth drugs brought. As you know, when you bring in a monoclonal antibody, the most common adverse event you see is infusion reactions with the first few doses, and that's pretty much it. You may see a little bit of attenuation of neutropenia perhaps with daratumumab and the IMiDs, but that is something that's relatively easily managed particularly by the hematologists because that's what we do. But that is nothing compared to the toxicity of adding in Cytoxan or other chemotherapy drugs as a fourth drug. I think this really does hold pretty significant promise. What we don't know right now is what happens after transplant in terms of depth of response. Does it make everything better after transplant? Most of the trials we've looked at have been very early time points like responsive cycle 4, and that's a pretty early time point to be able to see very much. What I think we really want to understand is what's the MRD negative rate post-transplant, what's the MRD negative rate post eight cycles, and how do all these factors play into each other to understand which patients would gain the most benefit from adding in an antibody early on.

Jenny: It seems that class of drug is the perfect add-on to me.

Dr. Lonial: Yes, absolutely. Jenny: So that's exciting and I know future studies will help us understand that situation better. Thank you for participating in helping run those studies. I think these are critical questions to ask.

Dr. Lonial:  I go out and actually thank our patients for going on these trials because they are being a bit on the edge to do that. And to participate in a trial, when you know something is pretty good, a three-drug regimen, they go out on a limb and say, "I want to risk the adverse events and the toxicity because I think it's the right thing to do." I think the credit really should go to the patients.

Jenny: Well, that's true, very true. I mean it's both, right? We need the patients to participate in order to answer the questions that are trying to be asked. It's really exciting to see these monoclonal antibodies. It seems like they're just adding power and have lower toxicity. That's incredible when you find a whole new class of drugs that does that.

Dr. Lonial: Yes, it's exciting.

Jenny: So for relapsed/refractory patients, now that we have these monoclonal antibodies and other types of things in clinical trials, how as an expert do you pick? I mean it's so confusing. Earlier in the show, you talked about how you're making decisions based on age and fitness and any other co-morbidity kind of things like liver issues or kidney issues or heart issues or whatever someone might have. But is there a general theme that you're saying in terms of relapsed/refractory patients?

Dr. Lonial: Yes, this is probably the biggest area of confusion not only for patients but for docs about how to manage and go through the litany of Phase 3 trials we have in myeloma to decide what to do for a given individual patient. I will tell you that just as I mentioned, there were factors that we use with newly diagnosed to try and parse through how to approach that given patient. Those same factors and in fact a few new ones begin to arise in the context of early relapse. The categories or things that we begin to think a little bit about is what did the patient get at their initial treatment, and did they get it at full dose, did they get it half dose? So do we consider that they were effective treatment regimens, or can we recycle some of those drugs that we used before? The second is, what were the adverse events that a patient experienced with those drugs that might help decide what we should do for second line therapy? For instance, if a patient did get pretty significant neuropathy with early therapy, we might want to try and go away from drugs that would give neuropathy in the setting of a first relapse. By the same token, if a patient had very sensitive blood counts to the use of IMiDs, that might sway you away from potentially using an IMiD in the context of first relapse. These are some of the disease and patient-related factors that play into the mix. How long was that first remission? Was that a six-year first remission or was that a six-month first remission? Patients with shorter durations of remission, particularly less than a year, are by definition high risk, and so you might want to think about a different strategy for that patient if you know they're high risk early on than if they have a four or five or six-year duration of remission after their initial induction therapy. Finally, where and how far away from the clinic do patients live? So being in Atlanta, we have a number of our patients that live in our backyard in Atlanta, but we also have a number of patients that come to us from South Georgia, North Carolina, South Carolina, Tennessee, Alabama, Mississippi and other areas within the southeast. And so for those patients, thinking about a treatment that brings them into the office once a week may not be the most practical approach to managing their disease. So those are all some of the factors that go into deciding how to manage a patient in early relapse. What I'll tell you sort of as a general principle I think now in 2017 is that the data that we see from the CASTOR and POLLUX trials in terms of duration of remission, hazard ratio, subset data, almost across the board suggests that if a patient has not seen daratumumab in their first relapse, or in their original treatment approach, that we should probably be thinking about daratumumab-based approaches for their first relapse. And whether it's an IMiD combination or a PI combination depends on what they got, what their maintenance was, what their side effects were, all those factors that I mentioned just a moment ago. That's certainly the way we approach it at our center that we try and expose patients to dara in the first relapse setting with a partner that they may not have seen before based on their previous therapy.

Jenny: I was reading something too about some daratumumab patients who relapse, and they lose the CD38 signal on their cells. I was reading somewhere that the HDAC inhibitors might actually boost that CD38 signal. Have you heard about that?

Dr. Lonial: There's a paper out of the group in Germany that suggests that panobinostat and other HDAC inhibitors may upregulate CD38. We've looked at that same data in our own lab and patient samples and cell lines. There is a modest increase in CD38 expression. Whether that translates into resensitization, we don't know. But what's really actually even more powerful at impacting CD38 expression is actually data from the Dutch group. What they found was that on the gene for CD38, there is a binding site for something called ATRA. An ATRA is all-trans retinoic acid. An ATRA is a drug that's used in a certain kind of leukemia called APL, or acute promyelocytic leukemia, where they're incredibly sensitive to that basically vitamin A in a different form. So that is being tested in a trial in the Netherlands to increase sensitivity to daratumumab. There are suggestions that in patients who become resistant, adding in ATRA or vitamin A may actually offer some benefit. We actually use a lot of vitamin A in our center based on some of these data. Again, it's very soft. At least the vitamin A stuff from our group is a small set of data that we've not published yet, but the ATRA data is out there and published and looks very, very encouraging, at least from a pre-clinical perspective.

Jenny: That's so interesting. Okay, well, we'll do some more research on that and share it with patients. That's really exciting to be able to upregulate that I guess or make it come back if it loses the signal, right?

Dr. Lonial: Yes, absolutely.

Jenny: So other strategies for relapsed/refractory patients, besides adding the monoclonal antibody, might be some of the targeted therapies, and you talked about venetoclax earlier.

Dr. Lonial: Yes. I think in terms of other potential therapies, obviously carfilzomib is one that we haven't talked a lot about. There's clear data from the ASPIRE trial looking at carfilzomib with lenalidomide and dexamethasone or high-dose carfilzomib from the ENDEAVOR trial that demonstrate not just longer remissions than their comparator arms but actually improvement in overall survival. These data I think are really important and suggest that carfilzomib should be an important part of how we manage patients in the relapse setting as a second generation probably more potent proteasome inhibitor than Velcade. Venetoclax is another drug as you were mentioning that I think is really very exciting and very active. I think it's exciting for a couple of reasons. First is that it's a new mechanism in myeloma, and we're always looking for new mechanisms because IMiDs and proteasome inhibitors are great, but if we can get new targets and new approaches, I think it will really help us put a larger number of patients into long-term remission. What we know about venetoclax is that it appears to have pretty significant activity in a subset of patients that have a translocation called (11;14) translocation. That's where a piece of chromosome 11 breaks off and trades place with a piece of chromosome 14 that then results in this abnormal fusion protein. We in our group and others are working on why venetoclax seems to work so well in the (11;14) translocation, but alone it looks like 40% of (11;14)'s will respond, and with dexamethasone it looks like over 50% of patients will respond to venetoclax plus dex if they're (11;14) positive. There was data presented at ASCO and EHA looking at venetoclax in combination with Velcade. What they suggested from that data was that the response rate was much higher when it was combined with Velcade, and that it seemed to work even in patients who were not (11;14) translocation positive. Which would be really exciting data if we could broaden the use of venetoclax to a larger patient population by coupling with the drug like Velcade or potentially carfilzomib or even ixazomib. That is a work in progress but certainly a very exciting approach from a targeted therapy treatment approach for venetoclax and dexamethasone.

Jenny: All right, how exciting. That's wonderful. Well, we're getting close to the end of our time, and I know we have a lot still to talk about, plus some caller questions. So maybe I'll ask you to touch on things for elderly myeloma patients just briefly, and then let's finish up talking about the high risk, and then I'll open it up to see if anyone has any questions. Optimal ideas for elderly or more frail patients?

Dr. Lonial: So the theme that you probably have heard from me over the last 40 minutes or so is the idea about the importance of combination therapies. The truly elderly frail patient is a one group where I would make an exception to that concept, and that is because the truly frail elderly patient may not be able to tolerate some of those adverse events or toxicities that come part and parcel with full-dose combination therapy. So the one group that I might think about sequential therapies would probably be the older, frailer patient. Now, I don't use age as the measure here. I actually use functional status as the measure, and I actually saw a couple of new patients in the last day or two who were in their mid to upper 70s both of whom a transplant was not discussed as part of their initial therapy. I brought it up when I saw them in the context of early relapse saying we should really think about this because you're well enough and fit enough to get through this process, and why throw away a treatment that could offer you pretty significant benefit? I think transplant is important even for older patients, but those are not the truly frail ones. The truly frail ones tend to have not as good performance status, no matter what their age is, or they're patients over the age of 80. And in there, those patients I think you have to be very, very cautious.

Jenny: And one thing I did hear about that is if you're going to sequence things and one other study talked about should I alternate things or should I just put them in order and sequence them? It sounded like it didn't matter.

Dr. Lonial: Yes, that's a hard one to really address. There's one trial from the Spanish group that would give alternating cycles, so A and B, A and B, A and B. And that looked to be similarly effective to six months of A followed by six months of B. And so I think it's a matter of what you can do. Sometimes those really complicated regimens are harder for older patients, so you really got to think again about what's the optimal way for deliver therapy in a patient population where travel, coming back and forth, access, those all may not be equal. So figuring out what's best for your individual patient might be the right way to go.

Jenny: Right. Okay, great suggestions. Let's end on high risk. I know you talked a little bit earlier about high risk, that you need to know if you're high risk because it's going to change your maintenance plan. But what other things should high-risk patients consider and what are you hearing?

Dr. Lonial: I think the first is that high-risk patients should again get IMiDs and PIs together. So whether it's bortezomib or carfilzomib with lenalidomide, that's probably going to be the optimal induction therapy for those patients. There's a big controversy between Europe and the US about the role of tandem transplant in this patient population. I think it's an important one to understand. The reason it came up is that in the US trial, we actually did a randomized trial of tandem versus single transplant and did not find a difference across the board in how long patients stayed in remission or in how long they live even in high-risk or standard-risk patients. The European trial is same thing, but they did find a difference in how long patients were in remission and in how long patients lived. The reason for that difference is I think access to drugs. In the US, most patients got RVD as their induction therapy, whereas in the European trial, most patients got Velcade with Cytoxan and dexamethasone. We know that VCD or Velcade-Cyclo-dex is not as good as VRD. So if you don't have access to the best treatments, then you might need a second transplant to try and overcome that. But if you do have access to the best treatments, then I don't think the second transplant really adds anything. Most major myeloma centers are not doing that as their standard approach for high-risk myeloma.

Jenny: Right, I knew it was more common in Europe versus the US, and that's interesting. I've never thought about that before.

Dr. Lonial:  Yes, it really does come down to access.

Jenny: Interesting. And then I heard a little bit about using something else as a maintenance therapy like maybe a proteasome inhibitor instead of an iMiD, because everyone now says, oh, I'll just go on Revlimid or some kind of IMiD type maintenance. But then maybe a proteasome inhibitor might be better for high-risk patients?

Dr. Lonial: So there is pretty significant data now suggesting from the Dutch group that bortezomib or Velcade as a maintenance approach is more effective in the high-risk cohort than thalidomide and certainly historical data from Revlimid as well. What I'll point you to is data that has now I think become relatively standard in many centers, and that's data that came from Dr. Nooka in our group where he published data on triplet maintenance for high-risk myeloma, showing a period of survival for patients with 17p deletion. And that's actually become a standard in many different sets of guidelines and recommendation that patient receive not just a PI or just an IMiD but the combination together for a sustained duration of time. In our center, it's three years in order to try and overcome those high-risk features.

Jenny: Well, that's important because you need to do everything you can for those patients. So that's really important. Wow, that's really fascinating. Interesting. The other question that I had was should it be doublets? But I guess for high risk, you're thinking about triplets, so that's great.

Dr. Lonial: We're moving beyond doublets.

Jenny: Yes, that's great. Well, I want to leave just a few minutes for some caller questions. So if you have a question for Dr. Lonial, you can call 347-637-2631 and press 1 on your keypad. Go ahead with your question.

Caller: Dr. Lonial, just a quick question. You mentioned ATRA, and I'm on dara and the result is kind of flagging. Is there any way I can give myself enough oral vitamin A to get the equivalent sensitization?

Dr. Lonial: That's a great question, and I can tell you what we recommend. Again, I'm going to preface this by saying there's not a lot of clinical data out there. We're sort of flying by the seat of our pants here. I don't want anybody to think that this is a high-level evidence-based recommendation. What we end up recommending is that patients take 8,000 units of vitamin A for about a week, and then what we worry about is long-term vitamin A toxicity because it is a fat-soluble vitamin. So after a week, we then recommend going down to a regular multivitamin that has vitamin A in it. Those are easy to find. But I think that certainly would be one approach that we would take. I don't know that there's a downside to doing that.

Caller: Got it. Thank you.

Jenny: Okay, great. Thanks for your question, and thanks for responding. Our second caller question, go ahead with your question.

Caller: Hi, my husband has multiple myeloma, and he was diagnosed three years ago at stage three, which I understand is the aggressive type, but he's very sensitive to medication. He was on RVD for a long time. Then for 18 months, they took them off and then his numbers start going up slightly. So they had him on Kyprolis and dex. But the Kyprolis made him break out and he's so sensitive, so they took him off for a while so he got that treated. But in the midst of starting the Kyprolis, he got up two plasmacytomas: one on the breast and one above the right eye. I just wondered how serious these plasmacytomas come into the picture while he's starting the medication.

Dr. Lonial: Patients who present with plasmacytoma-based disease particularly in the context of relapse represent essentially a functional high-risk group. That's really important. And those are patients that if they can tolerate it, we try and treat with aggressive triplet-based therapy to try and get that under better control. These are patients where the IMiDs alone probably don't offer a lot of benefit. The proteasome inhibitors probably do offer pretty significant benefit, and the antibodies probably offer benefit as well. So using that information to sort of concoct the next regimen I think is really important.

Caller: So Kyprolis is not in that? And he got bad side effects from Velcade, so it's so hard to know --

Dr. Lonial: Without having all the information in front of me, it's hard for me to make a recommendation. But having disease that grows outside of the bone marrow, in my mind, means that you need to really think carefully about making sure the treatment you're using is particularly effective in those types of relapses.

Caller: And they're doing radiation for the plasmacytomas along with the chemo, that's fine. They're doing it together.

Dr. Lonial: Yes, that's okay.

Caller: That's okay. Okay, thank you so very much.

Jenny: Okay, thanks for the question. Our final and last question, go ahead with your question.

Caller: Hi, Dr. Lonial. I have a quick question. If stem cell transplant is so key for newly diagnosed patients, why are they underutilized and what can be done to increase its use?

Dr. Lonial: I think that the reason it's underutilized is that patients have or their doctors have an idea about transplant from 20 years ago. And 20 years ago, an auto-transplant was likely in large part attained from the bone marrow instead of the blood now. And the toxicities of a transplant were pretty significant. When I talk about a transplant in a myeloma patient, it's really just one drug. It's melphalan. It's fairly well tolerated. Patients don't spend more than a couple of weeks in the hospital if it's a hospital-based transplant program. It's tolerated much better than every other kind of transplant across the board. I think education around the morbidity associated with a transplant. The mortality at our center, the mortality is less than 1%. We do over 220 transplants a year for myeloma. I think just getting more information out there about it would be a key part of getting more patients who are eligible to go through the transplant.

Caller: Great. Okay, thank you so much.

Jenny: Okay, thanks for your question. I think it's important. Again, the Myeloma Academic Center is really critical and key. They have a lot of expertise in the bone marrow transplant area. They're going to feel pretty comfortable with that recommendation if that's appropriate for you personally I think as a patient. Well, Dr. Lonial, we are so grateful for your participation today. We know you have a lot going on, so we'll let you go, but what a valuable summary of everything that has come out in the last few meetings. You're very clear and concise and very easy to understand. So thank you so much for helping us understand what's the latest. We are going to look forward to what you have coming out also for the ASH conference in December.

Dr. Lonial: Thank you again for your time. Again, we appreciate all that you and your group are doing on behalf of patients and education and research, and thanks for your efforts.

Jenny: Okay. Well, thank you so much. All right, thank you for listening to Myeloma Crowd Radio. Tune in next time to learn more about the latest in myeloma research and what it means for you.