Dr. Philip McCarthy, MD Roswell Park Cancer Institute Interview Date: August 3, 2016

 Stem cell transplant continues to be a strong treatment in multiple myeloma. Based on clinical trials, early stem cell transplant vs. later transplant showed longer progression free survival (an eight month benefit). There was no difference in overall survival (based on the current time frames) and Dr. McCarthy says that overall survival rates will take longer to assess now that newer treatments are being added and patients are living longer. Tools like minimal residual disease testing to see how patients respond to induction therapy will also help determine how transplant timing relates to overall survival. He suggests that triple combos are more powerful as induction therapy for stem cell transplant instead of doublets. Dr. McCarthy reviews results from several clinical trials with over 1200 patients to see whether lenalidomide maintenance is beneficial. According to those studies, there is a 26% reduction in the risk of death and a roughly 2.5 year increase in life if lenalidomide maintenance is used. With all the new treatment options, they are now considering doing a doublet for maintenance therapy (len plus daratumumab, elotuzumab or a HDAC inhibitor), watching for impact and quality of life. For how long should maintenance be used? According to Dr. McCarthy, there is not enough data to give a definitive answer. Some experts are saying "until progression" while others are looking to assess specific time frames (2-5 years?) but until more studies are performed, the right answer is unknown. When they looked at specific myeloma genetic features in a subgroup analysis, it looked as though high-risk genetic features were not completely overcome by lenalidomide maintenance while bortezomib maintenance worked well for del 17 patients but did not have impact for 4;14 patients. Dr. McCarthy discusses additional stem cell transplant strategies (natural killer cells, vaccines and checkpoint inhibitors) that are being evaluated in myeloma.

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 hope you’re having a great summer, and we are enjoying ours and we’ll be looking forward to a busy fall with more Myeloma Crowd Roundtables. You listen to this program because you want answers from myeloma experts and the Roundtables or live meetings are where you can listen to live myeloma experts in person. The Myeloma Crowd Roundtables cover new treatment options and hot topics like immunotherapy, but also focused on relapsed and high-risk disease because these patients need help the very most. We will be announcing our next Roundtable meetings shortly. Now, what we’ve heard from the major conferences covering myeloma is that even with all the new therapies, stem cell transplants are still key in myeloma treatments. Drugs or other treatments are now being added on the front and back end to make transplant even more effective. So joining us today is Dr. Philip McCarthy, who is a stem cell transplant expert, and he joins us to share his findings from recent research just completed at the Roswell Park Cancer Institute. Welcome, Dr. McCarthy. Dr. McCarthy: Thank you, Ms. Ahlstrom. I apologize for being late. Jenny: You are totally fine. Perfect timing. Let me give an intro for you before we get started with our questions. Dr. McCarthy is Director of the Blood & Marrow Transplant Program at the Roswell Park Cancer Institute. He’s Associate Professor of Medicine, a member of the Graduate Faculty and Professor of Oncology and Internal Medicine. Dr. McCarthy is a community member for local, regional, and national groups, including the Core Member and Associate Chair of the Multiple Myeloma Committee, Core Member of the Transplant Committee, Cancer and Leukemia Group (CALGB), now called ACTION, Alliance for Clinical Trials and Oncology. He is a FACT, Clinical Standards Committee Member on the Blood & Marrow Transplant Clinical Trials Network for myeloma, an ASH Scholar in the clinical studies section, a member of the NCI Myeloma Steering Committee, and the Myeloma and Lymphoma CIBMTR working committees. So extremely involved in creating the direction for myeloma transplant. Dr. McCarthy has been Clinical Investigator in Oncology, particularly, in bone marrow transplantation for more than 20 years. And his research interests are devoted to helping new auto and allo treatments for hematological disorders or blood cancers, including myeloma that will lead to improved patient outcomes and to decreased toxicity. Dr. McCarthy, thank you again for joining us. Dr. McCarthy: Thank you for the kind invitation. It’s always great to speak with patients about all the new ways we can treat this disease, and hopefully, someday cure it. Jenny: Oh, I agree. So let’s talk about transplant because I know in the news recently was one of the papers that you presented at the recent ASCO conference. But maybe you want to step back for a minute and give us an idea of the role of transplant in the new therapies. I know patients all the time think, “Well, if we have these new drugs, will stem cell transplant eventually go away?” At ASH, this last December, we heard about lots of new therapies, but we also heard a key message that transplant was still a core and valuable treatment. Dr. McCarthy: Yes. There were actually two recent studies. One was the French-American study. Michele Attal, from the French group, presented data looking at an upfront treatment of transplant versus transplant at first progression after a primary therapy. Now, all the patients in the French group and in the United States received similar upfront therapy. There’s a difference in maintenance which I can talk about in a second. So he presented the French portion of the study. They had about 900 patients who received either lenalidomide, bortezomib, dexamethasone. Everybody got that, but then followed by either transplant or collect stem cells and then transplant at progression. So it was three cycles of so-called RVD (len-bortezomib-dex) And then stem cell mobilization with cyclophosphamide, which we don’t always do in the states nowadays but it was done to make the study more homogeneous. Again, the patients who are assigned to high-dose therapy, they received melphalan, stem cell rescue, and then the same RVD consolidation, and then followed by len maintenance. For the other arm, it was eight cycles of RVD and then len maintenance. In France, they did only a years’ worth of len maintenance. There’s a whole discussion about secondary cancers, we could talk about that in a second, but what they showed in this study was that the patients who received the upfront transplant had a superior progression-free survival, and I think that is one one of the question you posed - the differences. What that means is that it took longer for the disease to come back if you received a stem cell transplant, whereas, if you got RVD or chemotherapy alone, the disease came back sooner, and there was a significant difference. However, when you look at the overall survival, it was essentially the same. There was no difference between the two arms. That meant that the patients who had progression of disease were still alive and were able likely to receive salvage therapy and then potentially go into transplant. They didn’t present that data. But they did show that the three-year survival was over 80% for both arms, which really had been unheard of. This is really an advance. Now, you want the three-year survival to be 100%. We’re not there yet. But this showed that transplant was still a valuable option in terms of preventing the disease from coming back sooner relative to, say receiving chemotherapy. Do you want me to talk about the ASCO presentation from the Europeans? Jenny: Sure. Dr. McCarthy: That’s EMN-02. That is the European Myeloma Network Trial. That was presented by Michele Cavo on behalf of the European Myeloma Network. They had a little different one. They started with a bortezomib-cyclophosphamide-dex, called VCD, and in the States that’s sometimes called CyBorD, cyclophosphamide-bortezomib-dex. And there are different flavors of how it’s administered with different dosing and things like that. But they would have fairly standard dosing schedule. Patients got three to four cycles of VCD, and then high-dose cyclophosphamide to mobilize stem cells. And then they were assigned to randomize to either bortezomib, melphalan, and prednisone for four cycles from low dose where they got high-dose melphalan for one or two transplants. If there wasn’t a good enough response, they got two transplants. And then there was a further randomization to a consolidation with bortezomib-len-dex, VRD or RVD as you want to say. That’s for two cycles versus no consolidation. Then all patients got lenalidomide maintenance until progression, that’s a schedule of 21 days on, 7 days off. So 21 out of 28 days every four weeks. That study showed that there was a significant benefit to the transplant arm in that patient who got a transplant, had a superior progression-free survival again. There was about an eight-month difference at three years in terms of progression-free survival so that the transplant arm, it took longer for the cancer to come back. Again, there was no difference in overall survival. But again, in both this study and in the French-American study, they’re early. Just because now that we’ve gotten much better therapies, people are, fortunately, living longer. So it’s going to take longer to see if there really will be an overall survival difference between the different treatment modalities. Plus, because people can get salvaged with newer drugs because there are lots of new drugs, it’s harder to see an overall survival difference because it’s not like if you progress after chemotherapy, there’s nothing you can do, there’s actually many things that can be done. And then one last thing, the French and American study, the Americans led by Paul Richardson are doing a little bit different maintenance strategy in their patients. Instead of getting maintenance only for a year, there’s maintenance until progression. We think that is probably better and that leads into the study that I was involved with that was presented at this year’s ASCO. We also re-presented it as similar one at EHA, the European Hematology Association. That was right afterwards, a couple of weeks later. And what we’re able to show there is we took the three studies. We took the French study that was published in 2012, IFM 0502, the New England Journal of Medicine paper that we presented, CALGB 100104, and the GIMEMA trial, which is the Italian study. The three studies all looked at lenalidomide maintenance until progression versus either a placebo or no therapy, and each study showed a progression-free survival benefit. In other words, those patients who received lenalidomide, it took longer for the disease to come back. The French study did not show a clear overall survival benefit, and the Italian study is the same. They had a trend. Whereas, in the U.S. study, the 100104 study, we did see a survival difference. What this meta analysis did was look at all three studies. So we pulled the data from all three; the French, American, and the Italian studies. So now we have over 1,200 patients, 605 who received len maintenance, 604 who are control patients, either placebo or no treatment. What we’re able to show, the bottom line was that the control arm, those who did not get maintenance, had a median overall survival of 86 months. So that meant that at 86 months, half of the patients had died of their myeloma but the other half were still alive. And if we look at those who got lenalidomide, the median overall survival has not yet been reached. We could do an estimate that is probably going to be close to 116 months. And the hazard ratio between them showed that it was 0.74. What that means is there is a 26% reduction and the risk of death in those patients who got lenalidomide, and this translates roughly to about a 2.5 year increase in median survival. Obviously, we want to make it so that everybody is alive for a prolonged period of time, but this we think is a big step forward. When we look at seven years from the start of the study, the seven-year overall survival is 62% for the lenalidomide patients, and 50% for those who got placebo or control. This to us means that the lenalidomide maintenance can be considered a standard of care in all of these studies it was until progression. There is lot of controversy. Some people are saying, “Do you need it for only two years, three years, five years?” We don’t know that answer yet but we at least know that lenalidomide maintenance does prolong survival when you looked at the three studies together. Jenny: What you said was dramatic, so I just kind of want to call it out because the original studies were just looking at how long did it take for progression-free survival. And then your analysis that was just announced was looking at just the overall survival. You said you saw 26% reduction in risk of death, and a two and a half increase in overall survival by using lenalidomide maintenance until the disease progresses again. So that’s very significant. Dr. McCarthy: Yes. We’re pretty excited about this because as you pointed out, all three studies were PFS studies. In other words, they were designed to show a difference in progression-free survival. The secondary endpoint on all three studies is overall survival. So they weren’t really powered. In other words, to do some of these studies, you have to have several hundred patients to be able to see a difference, especially in overall survival. For PFS, you need smaller numbers, but even then, the CALGB 100104 study was like a 460 patient study with half going to len maintenance and the other half, placebo, and the French study was over 500 patients. The GIMEMA study was about, I believe that was around 250. Either way, you have to have large number of patients for just progression-free survival differences. Now, we’re seeing that because we have better therapies, than let’s say ten years ago, we now need to have larger number of patients to see if there’s going to be an overall survival benefit. And as you can see, it took many years to see the difference. So now, what we’re trying to do is develop -- are there earlier endpoints that we can use to help us predict long-term outcomes? So the sole concept of minimal residual disease by flow cytometry or next generation sequencing. If you can go into what we call MRD-negative state, in other words, there is no minimal residual disease, is that it appears to predict for a better progression-free survival, and probably, overall survival. But still, people who are MRD-negative have progression of disease. So there are other factors that are involved with long-term control of disease, and we just need to understand those more. Jenny: One question is when you have these hundreds of patients, because there’s a lot of patients and a lot of data to look at, can you go retrospectively and when it comes to maintenance, is there a difference in a particular type of genetic feature of the myeloma? Or for whom did this work the very best and for whom does it not work? Dr. McCarthy: Yes. That’s a good question. On 100104, we did not have very good cytogenetic data because when the study opened, unlike the French who have been a little bit ahead of us on this, a lot of places did not do what is called CD138 selection of the marrow to pull out all the plasma cells. Plasma cells express CD138. So you pull out all of the plasma cells and some are malignant at diagnosis. And then the laboratory can look to see what kind of chromosome abnormalities are associated with the myeloma, and that helps with prognosis because there’s certain chromosome abnormalities that are poor risk, and then some of it are better risk. On the French study, they have not completed this. They had an ASH abstract a few years ago but they have not actually officially published it. They mentioned in the paper that they saw a benefit even in high-risk cytogenetics. What they actually had in their ASH abstract, it said that deletion 17, which is a poor-risk abnormality benefited from len maintenance. But again, that’s only in abstract form. There is controversy about 4;14, which is another one. So at least right now, it appears that some will benefit. When we looked at subgroup analysis, we still see though that adverse cytogenetic risk is not completely overcome by len maintenance. This is called a subgroup analysis. And that showed that it was probably not as beneficial as somebody who had better-risk cytogenetics. So it points out the fact that we have to do better in this patient population. For example, like in the HOVON-65 trial where they looked at two years of bortezomib maintenance, deletion 17 also benefited, but again, 4;14 did not. There’s been some phase 2 studies, sort of non-comparative studies that have shown that you can retrospectively look back and say “RVD or len-bortezomib-dex, lower dose,” the Emory group published this. For a long period of time, it controls disease for an extended period of time, but they didn’t have a comparator. So we need to start looking at newer modalities, newer treatments for controlling disease long-term, thus, we’re very excited at some of the newer drugs. For example, like daratumumab, the antibody. There are studies now that are examining it as part of maintenance therapy long-term. We’re very excited because we do know that this type of antibody seems to work against even high-risk cytogenetics. Will this be part of how we can control the disease long-term even in bad-risk cytogenetics? Jenny: And going back to what you first started out with when you were talking about the different studies, the transplant studies, if they had better progression-free survival, if someone does a transplant upfront or early in the course of their disease, would one of the strategies be to do that regardless of the overall survival? Because so many new things are coming out, and you can say, “Well, gosh, if I kick my myeloma out in three years, it’s likely that I’ll have a lot more options than if I try to take it easy and not do the transplant upfront.” As a transplant specialist, what do you suggest? Because you see many, many patients and you have deep expertise here. Dr. McCarthy: Well, that’s a good question. A lot of it is personality-driven. Some people are incredibly risk-averse. So we present both pros and cons. I am a transplant physician, so sometimes I’m a bit bias. Like I say, “When you go to a baker, you always get bread.” But I too try and be balanced. I often will pull up a PowerPoint slide where I will show the curves from the different studies, both the French and the Italian, and say, “Well, this is what we see now.” And as you just pointed out, if you are relatively fit and you don’t know what may happen in the future so that you may not be able to get that salvage transplant. In the Italian study, for example, I think about 60% of patients who got chemotherapy instead of transplant upfront were able to get a second transplant, but 40% did not. So there are variety of reasons: Their disease progressed, they weren’t fit, there are a whole bunch of other reasons. So if you are otherwise physically fit, it’s not fun to have a transplant but it is a relatively short period of toxicity. Most people feel pretty well by 30 to 60 days following it and they’re usually by 60 or 120 days, they are usually back to their usual self and they’re able to resume a regular life. So we do think about that. Again, we have some people who say, “No, I just don’t want to do it,” and we will say, “Well, at least you need to store your stem cells.” So we strongly recommend that everybody get their stem cells collected after their induction therapy, treat to best response, collect stem cells. We do recommend early transplant because of the whole idea of controlling disease for a longer period of time because as you pointed out, there are new drugs. We had four new drugs in 2015, and we may have some more in 2016 and 2017. So there’s a very exciting time at least in terms of having multiple things that we can do to help treat patients with multiple myeloma, both upfront and with relapsed disease. Jenny: And let me go back to something else because one of the other doctors mentioned the same thing you just did when we were talking about genetics, and you said some of the people didn’t study the CD138 selected cells. One doctor mentioned that when somebody is newly diagnosed, they should always ask their doctor or even the lab if they can actually do this, if they can actually select for CD138 when they’re getting their testing done so that they are testing the right sample. So you have this really valuable information about your own kind of myeloma. Do you want to elaborate on that or is that something that’s done just at diagnosis, at relapse? Because this is something patients need to know to go ask. They don’t know that the lab is not doing something right or is doing something deeply or not. Dr. McCarthy: Yes. This is not a standard. It’s become more of a standard, and we really need to make it so that everybody is doing this. In fact, I have a Twitter account, and Rafael Fonseca from Mayo tweeted about the fact that he had just seen a patient in consultation who had not had CD138 selected cytogenetic analysis or FISH, which stands for Fluorescence in Situ Hybridization. It’s a way of painting the chromosomes to look at chromosome abnormalities within the plasma cells themselves. This is really very important because if we don’t get that information, it doesn’t help us risk-stratify. A well-informed patient would be able to say, “When you do my bone marrow test, are you going to send it to a lab that will do CD138 FISH, CD138 selected FISH to look for specific chromosome abnormalities associated with multiple myeloma?” And you brought up another good point, which is sometimes there is something called clonal evolution where when the disease comes back, if this is suspected, it would be important to check, “Are these chromosome abnormalities still there or there are new ones present?” Because sometimes that will inform us about the best treatment. For example, deletion 13 is thought to be best treated, as well as 4;14 with a bortezomib containing regimen, or at least a proteasome inhibitor. So this type of information is incredibly helpful with regards to telling us what may be the best way to approach this disease. Now, there’s some genetic testing, Signal Genetics has something called a gene-expression profile (GEP) that right now identifies a high-risk patient population, but so far, it doesn’t tell us what to do about it. In other words, we know this patient has a higher risk but we don’t have a regimen that’s dedicated to knocking out this risk. Hopefully, we’ll have better understanding as time goes on. There’s a company called FoundationOne. They’re doing it more in leukemia and lymphoma, especially leukemia, and they’re just trying to do it now in multiple myeloma. And that is a way of looking for chromosome abnormalities that are associated with higher risk features in myeloma. That’s early and there’s now a new polymerase chain reactions to test to look at the RNA and DNA in the cells that may identify, in larger amount, the multiple chromosome abnormalities associated with multiple myeloma and how these change over time. So this is all very exciting and this we somewhat new - the PCR and or the molecular testing. But the cytogenetic testing should be considered standard. Jenny: Well, it just seems to be if you’re running studies and you have hundreds of patients enrolled, if you really had this at the beginning of those studies, you could eventually and quickly personalize treatment based on the results of this large scale phase 3 type studies. If you have that at the beginning, it would just be so much easier. Dr. McCarthy: Yes. I mean part of it is technology evolved so that sometimes we see what is standard today will be outdated a year from now. I don’t think it would be quite that fast but the field is moving quickly. So we’re trying to keep up. So part of it is we store samples and then go back and look at them later. We incorporate new ways of understanding the genetics of the disease so that it helps us predict the best treatment. Again, with some of the new drugs we have, what we’re really interested in doing is looking to see how drugs like elotuzumab, daratumumab, ixazomib, how well do they impact outcome for not just lower risk patients but for all risk patients. Jenny: My main question about this show is, as a transplant expert, you could do a typical transplant. But with all these new therapies, what’s advantageous to add on the front end and what’s advantageous to add on the back end? So you talked about lenalidomide maintenance and that really makes a big difference. And in some patients, you mentioned that proteasome inhibitors might be used as a maintenance therapy. So as a patient who might be seen by a local oncologist, how do they go about (and we always advocate they see a myeloma specialist) but how does that doctor or how does a myeloma specialist choose the right maintenance therapy or new drug ad on in the mix with transplant? How do you come to those conclusions for each patient? Because it seems very difficult. Dr. McCarthy: That’s a good question. Well, I think we’re moving away from doublet for a transplant eligible. So if you’re somebody who’s young and fit and would be considered a transplant candidate, in the old days, we used to do things such as lenalidomide-dexamethasone, or bortezomib-dexamethasone as doublet. And I think there’s enough data that suggests that we really should be looking at triplets. One of the triplets was bortezomib-cyclophosphamide-dex, and the other was lenalidomide-bortezomib-dex. Just recently at the last ASH meeting, the French studied -- it’s a little different. It was bortezomib-thalidomide-dex, and they compared it to bortezomib-cyclophosphamide-dex. So it’s called VCD versus VTD. What they showed was the patients who got the thalidomide-containing regimen had a little bit better responses. There’s no difference in PFS but they weren’t asking that question yet because it’s early. They were only looking at response to induction therapy. So that made us think that perhaps the addition of the IMID, the thalidomide was a little bit better when combined with the proteasome inhibitor. So at least now people then extrapolated, “Well, lenalidomide is a little bit better tolerated than thalidomide.” So there’s so-called RVD regimen or lenalidomide-bortezomib-dex. A lot of people are using that now because it appears that using a triplet gives you better responses than using a doublet, and that you can deepen the response. So the thought is that the more you can drive the cancer down, it allows the melphalan the ability to kill off less cells. In other words, there’s less cells that have to be killed off when you actually come to a stem cell transplant. In other words, patients who achieve a CR or even a stringent CR where you can’t detect it by flow or molecular testing, they seem to do better than those who have a lesser response to the induction therapy. So right now, that’s sort of where people are moving towards with the sort of standard FDA approved approaches to treatment. Now, there is a study being done in Europe looking at daratumumab with VTD, the bortezomib-thal-dex, and they’re comparing dara VTD versus VTD stem cell transplant, and then a consolidation afterwards. That study is still ongoing and that will give us some information. The only problem is it does use thalidomide which we don’t use as much now in the states. So in the ALLIANCE, which you mentioned in the intro, we are going to be studying RVD dara versus RVD -- Peter Voorhees is leading that trial for the ALLIANCE. That’s a phase 2 study. So it’s going to give us a signal that we hope we can translate into a phase 3 study where we can have a definitive comparison. So we think that, for example, that would be one other way of incorporating some of the newer drugs. There’s an interest in doing the same thing with elotuzumab as well, or substituting ixazomib for bortezomib. In that way, you’d have a triple drug regimen that’s all oral. Jenny: So these are triple combinations as induction therapy, right? Because right now, daratumumab is only for -- I saw they just change with the designation. So now it is being fast tracked so you can get it after you had one therapy in that combo but that would be upfront before transplant, right, that’s what you’re saying? Dr. McCarthy: Yes, that’s going to be tested. I’m not saying that’s not standard yet but it’s currently being tested right now. Jenny: Okay. Dr. McCarthy: Yes, they’re all clinical trials. And it is exciting because daratumumab, as you know, it was initially approved as a single agent. But after both the EHA and the ASCO presentations, combining with VD or RD, it’s going to be incorporated as part of a triplet for salvage therapy for those who have relapse after their original treatment. Jenny: That’s a quad therapy, so you’re moving well beyond the doublets, right? Dr. McCarthy: Yes. In the old days, when they tried the quad therapy, there was a study called the EVOLUTION trial where they compared VCD, RVD, and RVD plus C, it’s an RVCD. That was the quadruplet. Then it was a little too toxic because they had a little too much cyclophosphamide, lenalidomide, bortezomib, and dex. And the combination of probably the len plus the cyclophosphamide was fairly tough on the marrow. So sometimes you got to get the right drugs together to get the right quadruplets. And you have to study it. I’m not saying that daratumumab-len-bortezomib-dex is going to be standard but it’s going to be tested to see if it will become standard. Jenny: And elotuzumab usually works well with Revlimid. So you can combine that into that quad therapy and that might be equally effective or you’ll just have to test it and see. Well, it’s exciting now that these drugs are available now and that you can do all the different iterations. Dr. McCarthy: Yes. We’re excited about studies, and really, it’s just going to be a matter of having enough patients who are willing to participate in clinical trials because that’s critically important. And we are grateful that people are willing to participate in trials because it offers some access to the new agents. But also, it allows us to be able to best position ourselves and we really rely on the goodness of people's hearts to participate in trials so that five years from now, we’ll know what may be the best way to do things and just as somebody did this five and ten years ago, they help us today decide what’s the best approach to the treatment of both upfront and relapsed disease. Jenny: Well, this program was created to encourage clinical trial participation because this is a way patients can help weigh in to help accelerate their own cure. So I would say after you have a drug that’s been approved and it looks like it’s working well, I would hesitate to just do a standard transplant anymore. I would want to add all these different new agents into the mix and see how deep my response could potentially get. The same thing in a relapsed situation. Personally, knowing what I know now, I don’t think I would ever do just a standard second transplant. I would look into a clinical trial and find something else that was added to that transplant to make it even better. Dr. McCarthy: Yes. In fact, we do know that second transplant, say the disease comes back and some people can get a second transplant, and the British has a study where they compared it to just cyclophosphamide alone and found that second transplant was better because there really was no standard for what to do after re-induction and a second transplant versus just doing re-induction and following the patient. So we know a second transplant works. That was published just recently in Lancet Hematology where Gordon Cook is the first author. But we are in the middle of trying to sort out what’s going to be the best maintenance, say approach after a transplant, both upfront and then later on after, if its the second transplant. For upfront, we now have a bunch of different drugs that we could potentially look at. There’s some HDAC inhibitors, histone, deacetylase inhibitors that are being tested or looked at. There’s daratumumab, elotuzumab. There’s even checkpoint inhibition with the pembro, which is another drug, pembrolizumab. What we need to do now is sort of figure out what may be the best way to do this. So we’re actually trying to develop a trial in the alliance to look at sort of a pick the winner. We would do smaller phase 2 studies to see which one gave us the best signal and then try and look at that in a larger phase 3 study so that we can then pick which would be the best approach for maintaining disease control. There’s some cellular therapies going on. There’s a variety of cell products, off-the-shelf products that are being developed to maintain disease control. Some of them are natural killer cell, some are T cells. We have a vaccine trial that’s through the BMT CTN and it’s a randomized show looking at dendritic cell vaccine where the patients own cancer cells are fused with something called a dendritic cell to create a vaccine where the patient responds to their tumor cell. You make it into an antigen. So this would potentially allow this as a platform for long-term disease control by allowing the patient’s own immune system to get revved up to attack the cancer. These are all sort of new studies. This one is called BMT CTN 1401 that is just opening in a variety of centers throughout the states. These other maintenance trials that we’re talking about developing, adding on to lenalidomide, whether it be lenalidomide with dara, lenalidomide with elo, lenalidomide with HDAC inhibitor. What will be the best platform from moving ahead so that we can potentially look at say a doublet for controlling disease as maintenance as opposed to a single agent. So these are all questions that we needed to answer. We need to make sure they’re not toxic, that the patient is able to maintain their usual quality of life without having toxicity. We don’t know enough about scheduling and we don’t know enough about how long. So these are all questions that we need to look at, and we appreciate patients who are willing to participate in these trials to be offered. As you pointed out, the opportunity to be able to have a new drug that might be able to control their disease long-term. Jenny: Right. It sounds like you talked about multiple strategies. So one strategy is to add something as you’re doing transplant like this dendritic cell vaccine. And then the maintenance, what you talked about earlier, is a whole separate idea. I think this study opened just barely, like last week or something that you’re talking about the dendritic cell vaccine. It’s open like its 15 locations. So there’s a lot of different facilities. I did talk to Dr. Avigan just a little bit about that one, and it sounds like you’re doing the transplant and then several days later, you’re not waiting a long time. It’s not like its maintenance therapy but you’re doing it with the transplant pretty much. Dr. McCarthy: Right. So what happens is the patient’s cancer cells are collected early, then they fuse the cancer cell with the patient’s own normal cells to create this vaccine, which is administered subcutaneously as a shot. I can’t remember the exact period but it’s 30 or 60 days after the stem cell but it’s relatively early. And then it is given with lenalidomide and the drug called GM-CSF to rev up the patient’s immune system so that the patient would potentially attack any residual cancer that still might be in their body. Jenny: And just a point of that, the doctors have said vaccines aren’t that great if you just use them by themselves or you need to have a really low tumor-burden. This is a way of using stem cell transplant to knock down the tumor burden and then use a vaccine that could extend the effectiveness of the transplant, but also do something plus. I think those types of studies are really exciting. Dr. McCarthy: Definitely, and this is one of them. We are working with one of the companies, Celgene. They have an off-the-shelf natural killer cell product where it’s derived from placental cells where they put the right cocktail of cytokines, which are molecules that help the cells grow. And they create what are called natural killer cells, which are a type of immune cell which will kill tumor cells. And they have a trial looking at in something called acute myeloid leukemia. And they’re also going to be looking at natural killer cells and think about five or six centers after auto transplant from myeloma as a platform for further drugs development because these cells right now last about two weeks. You give a drug called Interleukin 2 to help stimulate them. But eventually, they sort of go away, and this is a third party. Well, it’s derived from a placental cell from placental blood. So this can be grown up and expanded and potentially used in multiple infusions to control disease long-term or there’s some new cytokines. There’s a drug called Interleukin 15, which might simulate NK cells to live a lot longer. That cytokine IL-15 is still not FDA approved. So this is a whole new area of cellular therapy to, again, help maintain response in a minimal residual state after a stem cell transplant where it’s easier to potentially control or kill off any residual disease. Absolutely, there are multiple different strategies that are being tested to see how we can control this disease long-term, and as we talked about, someday eradicate it completely. Jenny: And as you go after these residual cells, I’ve heard some doctors and I think there’s some disagreement about this, about cancer stem cells or at least precursor cells that might be lingering around. That’s what transplant or the other drugs may not be getting to. Do you have an opinion on that? Dr. McCarthy: Well, that’s a big question. I’m not sure. Jenny: Is that opening a can of worms? Dr. McCarthy: No. I’m pretty agnostic on this one. I don’t know. There are a variety of strategies. Some people think that you’re right, it is a primordial stem cell that doesn’t have the features of myeloma from which the myeloma arises. Some people feel that the myeloma cell is pretty much the beginning as opposed to stem cell. There’s data that suggest both. So we’re not certain because we do know, for example, there are certain markers that are present on some myeloma cells and not others. There are certain genetics that are associated with one myeloma and not another. So I’m taking a wait and see approach because I am still not sure which is the right answer. We need to be looking at it though and studying it so that if we think we’re in a minimal residual disease state, can we be looking for other cells within the bone marrow that might be something that could be a precursor or the stem cell that’s lying there dormant and then all of a sudden goes malignant, as opposed to we’ve killed them off and we just want to make sure we keep eradicating them with our current strategy? So I don’t feel strongly one way or the other. I think we just have to see what the data tells us. And because myeloma is a pretty heterogeneous disease, I think we even may see both. Jenny: Well, it makes sense that some of the cells might just not respond to the drugs that have been given. And then there might be something else happening around that we don’t know about yet. Dr. McCarthy: Right. Well, it’s a good example. I’m sorry, there’s one small point. You know, the CAR T cell study that was done. You probably had Ed Stadtmauer on to talk about where they manipulated the patients own T cells to attack CD19. CD19 is really not expressed that much on myeloma cells but they had one patient in whom a CD19 CAR completely eradicated the disease. That didn’t make quite a lot of sense but it sure did work. So there’s a lot of stuff that we don’t understand, and the same thing with -- there’s another CAR T cell that Dr. Kochenderfer presented at the last ASH meeting. It’s something called B-cell maturation antigen, which is also expressed by myeloma cells but also some precursors. For a lot of patients, it didn’t work, or else it just stabilized disease. But there was one patient in whom this cellular-directed therapy completely eradicated the disease. So we still don’t know everything that we need to know to help us understand yet completely, how we control the disease for all patients. Jenny: We’re helping to fund the CAR T cell research project that’s targeting CS1 and BCMA. But is this CAR T cell stuff being used with transplant, or potentially, could it be? I know right now it seems like it’s using it alone. Dr. McCarthy: Right now it’s being used as a salvage. So in other words, somebody is resistant, usually, the multiple lines of therapy. CAR T cells, say the CS1, and it’s also called SLAMF7, that’s one type of CAR. BCMA is another type of CAR. There’s actually antibodies being developed to BCMA. So you may not need to develop the CARs because the one problem with the CAR T cell technology is you have to take the patient’s own cells. You have to grow them up with the modified chimeric antigen receptor to attack the antigen of interest. It’s fairly laborious. What would be great is if you could have an off-the-shelf, something that’s sitting in the freezer that you can administer to the patient right away without having to go through growing it up. Whether or not that will ever be practical, we don’t know. But these are all things that are currently in development, and there are many centers both in the states and in Europe who are looking at different strategies for CAR T cells. The natural killer cell therapy I talked about earlier is relatively non-specific. In other words, you don’t have to have the patient’s own cells, but it’s an off-the-shelf and it’s a relatively, it’s somewhat non-specific but that may be enough to kill different types of myeloma cells in the patient because myeloma sometimes mutates -- they have different expression, different molecules, different genetics within the patient themselves. In other words, there were several clones that are abnormal and you have to figure out a way to target all of them. So these are all questions that we have to answer by clinical trials. Jenny: Now, you talked a lot about maintenance therapy and lenalidomide, and we talked a little bit about proteasome inhibitors. When people get refractory to lenalidomide, what do you suggest to extend the life of the transplant that they just had without the Revlimid? Dr. McCarthy: Good question. If somebody has progression of their disease on lenalidomide, then -- usually, the lenalidomide is given in low dose. So if it’s a slow progression, you might be able to get away with increasing lenalidomide to treatment dose with dexamethasone. So that’s one possibility. But now that we have newer drugs, there are other things that you could do. If it’s a relatively slow relapse and you’re seeing it progress over time, then there’s a position where the patient makes the decision of when to treat. Here are some of your options. One is to use elotuzumab with len/dex because the elo combined with the lenalidomide has good activity against the myeloma cells. It doesn’t have the infusional toxicity associated with daratumumab. And daratumumab now is being moved up, so now you’re going to have that option. Ixazomib is another drug combined with len/dex for progression. For somebody who’s not having a very aggressive progression, if you have somebody who has an aggressive progression and they’re otherwise fit, then carfilzomib combined with len/dex, it’s reasonable. Some people are combining with pomalidomide as well. Pomalidomide often will allow you to rescue somebody who was len resistant because it will salvage patients, probably, via the cereblon pathway. And that pomalidomide is less affected by this type of resistance in a patient who no longer responds to lenalidomide. And then daratumumab, now that we’re going to start bringing that up more because it used to be for more than two lines. It's going to be now something that you can bring up sooner. So right now, we’re in a position where we have multiple choices. There’s also panobinostat combined with bortezomib-dex. That has activity as well. So I think that we’re just going to have to wait and see how this all shakes out because we have lots of possibilities to get the patient back into response and then control the disease for a prolonged period of time. Jenny: And I guess if you become refractory to lenalidomide, what you just said, you have pretty much an active disease control using these different combinations. Dr. McCarthy: One thing that’s interesting too is that the lenalidomide makes antibodies work better. So even if you have a patient who is resistant to len, if you add len not to have a direct myeloma effect but potentiate or increase the activity of the antibodies, we’re seeing that it makes elotuzumab work better, it makes daratumumab work better, probably the same thing with pomalidomide. So we’re very interested in how these small molecules, these IMIDs enhance the activity of antibodies. Same thing with pembrolizumab. The pembro is a single agent and sort of mediocre, but when you combine it with len-dex, you get more activity. Jenny: I’ve heard before that it activates your immune system. So they use lenalidomide a lot with some of these other strategies too. Dr. McCarthy: Absolutely. Jenny: Now, talking about a very big -- well, I guess mid-transplant, so we’ve talked about kind of pre-transplant and what’s going on in clinical trials that either adding some of these quad therapies as induction therapy. I did a show with Dr. Bartee, who talked about cleaning up the stem cells before they were given back during transplant. Is there any other work that you think is significant that’s being done to help make the transplant process better itself? Then I think we’ll open it up to other caller questions. Dr. McCarthy: Sure. I went and read about his myxoma virus, which seems to be able to target the myeloma cells that potentially might be in the stem cell graft. We, most of the time, treat people to best response. So they shouldn’t have tumor contamination in the stem cell product. But if they did, this would be a potential modality to completely guarantee that. We think that most of the time when disease recurs, it’s because there’s residual disease in the patient. So as you know, there have been some strategies trying to use a viral mediated therapy. There was a measles virus study from the Mayo group where you actually target the measles receptor. It’s kind of cool, which is expressed on myeloma cells so that you actually get the measles virus and then kill the virus and kill the plasma cell. These are all sort of not quite ready for primetime but these are very interesting avenues of research. I think the most important thing is still control of disease in the patient that we can probably get a pretty clean stem cell product if we can drive the disease into a way and have the patient now, have a stringent complete response so that we’ll collect stem cells that would be relatively clean. I think it would help guarantee a clean stem cell product but I think the big problem we have to face is the disease that’s still in the patient that we need to figure out a way. The high-dose melphalan knocks it down further. But what can we do to eradicate those clones where they are not there hiding out as stem cell precursors or they’re lying dormant as plasma cells and are not as affected by the medications that we currently use, or maybe they will be by such things as the antibodies, which will allow the immune system to target these cancer cells and get rid of them. Jenny: And then when you reviewed all the different international studies and you saw one of the arms comparing single versus tandem transplant, does that provide benefit? Dr. McCarthy: That’s still not quite a clear question because all the earlier - the EMN-02 study does look at single versus tandem, but they didn’t report on that. They suggested that maybe if you got two, you did a little bit better, but that wasn’t a primary point of his presentation. So we’ll have to wait and see from that study. As I mentioned earlier, BMT CTN 0702, that will give us some pretty good information in the modern era of the utility of two transplants. It’s tough to get through two, it’s hard to get through one, but some people are able to do that. And the issue becomes, “Do you need to get two back to back or can you save it for later on?” Those are questions we don’t have the final answers to. We do know that for patients, in Europe at least, the standard is if you don’t have a good response or if you’re not at least a very good partial response at least a 90% reduction with one transplant, you should get a second. So I think that again, that’s done more often in Europe. Some places in the states do that as well. So I think the data is not completely in, especially now that we have these new drugs which drive people into better responses. We may not necessarily need to do two transplants but it’s still an open question. Jenny: Well, that’s great. Now, do you have any other comments about add-on strategies that could be adopted? I mean, we’ve gone over a lot. The time goes so quickly and there’s so much to talk about, but I want to leave it open for you to make some final assessments before we open it up for caller questions. Dr. McCarthy: No. I think the most important thing we did touch on is we are so happy that people participate in clinical trials. And I’m glad that you’re sponsoring one because I think this is what will allow us to advance the field and come up with the best strategy for someday completely eradicating this disease. Jenny: Well, I completely agree. As a patient, I want to come to conclusions as fast as possible and help people like you and the researchers who are doing this incredible work come to their conclusions faster and because it's really in our self-interest to do that. So it’s great. The work that you’re doing is truly great and incredible. Dr. McCarthy: No. I appreciate the opportunity. Thank you. Jenny: Well, we’d like to open it up for caller questions. So call 347-637-2631 and press 1 on your keypad if you have a question. So we’ll start with our first caller. Go ahead with your question. Caller: Hi, Dr. McCarthy. Thank you for being on the show. My question is about when do you use a second transplant or not to. How long should the first one have worked in order to consider a second? And there are some doctors say, “Why do a second if the first didn’t work well?” Maybe you can help me out understand a little better. Dr. McCarthy: Sure. A lot of it has to do with length of time. So in other words, as a rough rule of thumb, if the disease progresses, recurring in therapy, especially after 18 months and even longer, two years, three years, four years, a second transplant probably will be of some benefit. If the progression is early like within a year, in particular, it’s less likely to be a benefit to do a second transplant because this disease came back fairly quickly after the high-dose melphalan. So everybody has a slightly different place where they cut it. Some people do it at 12 months, some at 18 months, some at two years. So I think that’s what people are thinking of that if took long time for the disease to come back, thus, a second transplant may be a benefit because again, there was a good response to the first transplant. Caller: Okay. Thank you. Dr. McCarthy: Sure. Jenny: Okay, great. Thanks for your question. Our second caller, go ahead with your question.   Caller: I have a question about your thoughts on allo transplant. Where does that fit in all of these? And there are a few clinical trials. I know that there’s one at Johns Hopkins and I think there are a few that were opened at MD Anderson that seemed to overcome the mortality rate from graft-versus-host disease. So thoughts on that. Dr. McCarthy: Sure. There was a trial that had been opened. It’s going to reopen again, called BMT CTN 1302. That is a reduced intensity allo transplant, and there’s a backend randomization to ixazomib versus placebo to see whether or not the addition of ixazomib could help control the disease in an allo setting. As you’ve pointed out, the major toxicity that we face in an allo offer that for allo transplant, it’s usually in patients who have diseases such as a plasma cell leukemia or very high-risk multiple myeloma. So for example, I have a patient, he’s 32 years old. It took three different regimens to finally have a semblance of control over his disease. So we’re going to do -- for example, unfortunately, 1302 is closed right now. We would have offered him that trial, but we’re going to offer him an allo transplant just because we are so concerned that his disease won’t respond to the other transplant. So we don’t do a lot of them. The vast majority of the patients that are centered undergo in autologous transplant because they often do so well with it. But for patients that we’ve identified with our team as being very ultra-high-risk, we will offer them an allo transplant. But as you’ve pointed out, nobody has the right way of doing it. So there are variety of different clinical trials that are being developed to see what may be the best approach to controlling the disease and minimizing the toxicity associated with allo transplant. Caller: Okay. I have a follow-up question. If a patient elects to do an allo transplant, forgive my ignorance on this topic, but how much sicker -- to control the GVH, how much sicker or more awful will a patient feel with that type of transplant? Dr. McCarthy: Well, I have this discussion a lot with patients because sometimes we cannot predict who’s going to get bad GVHD, for example, and who doesn’t where the donor cells attack not just the cancer but they also attack normal tissue. And when they attack normal tissue, you can get very sick from that. So we don’t yet have a way of predicting who is going to get bad GVHD and who is not. There are some strategies now that may suggest the early onset of GVHD so we can intervene early, but they’re still not ready for primetime or universal acceptance. So we don’t know yet which is the best approach but we do know that we are trying to develop what are called reduced intensity transplant so that we get the patient to his best response as possible, take them to the allo transplant where there’s as little disease around as possible, because if there’s too much myeloma around, it makes it very difficult for this graft versus -- myeloma factor graft versus tumor effect. So you can get fairly sick from this, but then we have some patients who they sail through it because there’s minimal toxicity. So until we better understand all the predictive factors, we can’t say with 100% to a patient, “Oh, you’re going to do just fine” or “You’re going to have a fair amount of toxicity,” just yet. We’re getting close. A lot of it depends on the age of the patient, how much disease they have, what kind of donor they have. But we don’t have it nailed completely where we can say to our patient, “Oh, we can really guarantee that you’re not going to have that much toxicity.” Caller: Okay, all right. Well, thank you. Thank you for taking my question. Dr. McCarthy: Sure. Jenny: Well, thanks for your question. Well, Dr. McCarthy, thank you so much for joining us today. We’re just thrilled that you’re working on all these different iterations to make transplant better and to extend outcomes and potentially cure patients. We’re very, very grateful for your daily work and dedication for us. So thank you so much for all you do. Dr. McCarthy: I think it’s so wonderful that you have this radio program because it’s part of getting the word out to patients so that they can best understand what their treatment options are and be an informed patient so that they can know the best strategy for trying to control and someday eliminate the multiple myeloma. Jenny: Yes, I agree. And if we ask better questions, we’re going to get better care because it’s better to tap you when we come into our apportionment and ask those important questions rather than not when we have your valueable time. Dr. McCarthy: Absolutely. Jenny: We’re so thankful for you. Thank you so much for joining us, and we thank you for listening to another episode of Myeloma Crowd Radio. Join us for future shows to learn more about the latest myeloma research and what it means for you.