Priya Menon – Good evening and welcome to CureTalks. I am Priya Menon, Scientific Media Editor of CureTalks, joining you from India on CureTalks 115th episode. On CureTalks today, we are talking post transplant outcomes in high-risk multiple myeloma with Dr. Parameswaran Hari. On the panel, we have myeloma advocate and survivors, Gary Petersen and Jack Aiello. Gary is also your co-host for today. I extend a very warm welcome to the panel and Dr. Hari. Dr. Parameswaran Hari – Hi! How are you?

Priya Menon – Treatment of patients with myeloma has changed dramatically in the past years due to development of new agents and myeloma-specific targets. Despite these advancements, long-term benefit remains less clear in high-risk multiple myeloma patients. Myeloma is classified as high risk based on presence of cytogenetic abnormalities and poor treatment outcomes. In the next hour, we will be talking to Dr. Parameswaran Hari on his recent research on post-transplant outcomes in high-risk myeloma patients. Before I hand over to Gary to introduce the expert and begin with the discussion, just reminding the listeners that we will be addressing questions sent in towards the end of the discussion. If you have a question you would like to ask, please press 1 on your keypads and we can bring you on air to ask them. You can also email the question to priya@trialx.com or post the question on curetalks.com. With that, its over to Gary. Gary, you are on air. Gary Petersen – Yes. Thank you very much. Appreciate all the efforts that you and TrialX have put together to bring these outstanding people on this program to benefit those of us with multiple myeloma, me included. I love the way that you say Parameswaran Hari, its far better than I do. You say it so nicely, Priya, but Dr. Hari, is the Armand J. Quick – William F. Stapp Professor of Hematology at the Medical College of Wisconsin. Dr. Hari serves as the Director of the Adult Bone and Marrow Transplant Programs for Froedtert Hospital and Section Head for Hematologic Malignancies and Transplantation in the Division of Hematology and Oncology in the Department of Medicine. He has gotten his medical degree in India. He completed his training in Internal Medicine and Hematology at premier institutes in United Kingdom and Medical Oncology Transplantation at the Medical College of Wisconsin. He is also the Scientific Director of the Plasma Cell Disorders and Lymphoma Working Committee of the CIBMTR, which is the Center for International Blood And Marrow Transplantation Research, but in addition to that, Dr. Hari is what I would consider one of the best myeloma specialists in the world and has shown some outstanding survival statistics for multiple myeloma, those being some of the best, the very best in the world. So, not only does he have a tremendous background, but he has the results, some of the best in the world that signifies just how great a myeloma specialist that he really is. So, thank you so much, Dr. Hari for coming on this program again and…, and being able to share with us some outstanding results that you have achieved, that you have shown have been achieved with post treatment for transplant patients, but to begin with, The Center For International Blood, Marrow, and Transplant Research, what is this and, you know, what are the purpose and goals of the organization and what types of things are and what data is part of this registry? Could you do that for our listeners, Dr. Hari? Dr. Parameswaran Hari – Sure. Absolutely! Thank you, Gary, and thank you, Priya. Thanks for having me on again. So, to get to your question, Gary, the CIBMTR stands for Center for International Blood and Marrow Transplant Research. So, CIBMTR has been in existence not with this same exact name, but since almost the mid 1970s when bone marrow transplantation was just being invented, and one of the pioneering places was the Medical College of Wisconsin. So, the institutions that were doing bone marrow transplant that time such as Seattle and Minneapolis and Medical College of Wisconsin decided to track every single patient’s outcome. Obviously, now, we have come a very, very long way. There are almost 40,000 transplants being done annually in the world, almost 20,000 in the US. So, even now we do that. It has become the CIBMTR now. It used to be called the IBMTR and we track essentially everybody who gets a donor transplant in the United States, that is by law, as a law passed by the Congress saying that outcomes after a bone marrow transplant from another person, a donor transplant, have to be reported to the CIBMTR and its the CIBMTR’s job to disseminate that information about the results and so you can go to the website and find out what the survivorship of each transplant program is, but that only applies to donor transplant. Now, as you know, in multiple myeloma, majority of transplants, the vast majority are auto transplants with other patient’s own stem cells. There is no legal requirement to send the data to us for everyone, but about 80% of the country does, including all the big centers because they have to report their donor transplants, so they might as well report the auto transplants too. So, we have data on essentially the majority, a vast majority of transplants happening in the country. We also get voluntary reporting from Europe, rest of the world, and more than 500 centers report to the CIBMTR these days. Dr. Parameswaran Hari – In terms of myeloma, the autologous transplant outcomes for myeloma have been tracked by the CIBMTR from the very beginning of auto transplant and then, as you know, the auto transplant still remains one of the most powerful tools for transplant-eligible patients to get into a good deep remission and with some post transplant treatments that just we are going to talk about. We have achieved very, very long progression-free survival periods in patients with newly diagnosed myeloma and we have been able to track this over time, look at various combinations of treatments that have worked, whether induction treatment matters, whether post transplant treatments matter, what type of transplant, how to transplant, all that. So, we have the Plasma Cell Disorders Working Committee of the CIBMTR is entrusted with that job and we have excellent myeloma experts from the world who are the chairs of that committee and I happen to be the Scientific Director of that committee. So, we have published numerous studies and one of which caught Gary’s attention recently. Dr. Parameswaran Hari – In addition, the CIBMTR also runs something called the BMT CTN which is a cooperative group performing prospective trials. That stands for Blood and Marrow Transplant Clinical Trials Network. So, the largest ever transplant study in the US was called the STaMINA trial and that was just completed by this group and we have results coming out at ASH about the STaMINA trial. Then, currently the DETERMINATION trial which is the trial comparing early versus late transplant, which is also done by the French, also known as the IFM/DFCI trial because the French started it, then the Dana-Farber Cancer Center took it over and now its being run through the CTN2. So, that trial is about to finish in the next few weeks and that’s another large trial that the BMTCTN is running and the CTN is a group for which the CIBMTR serves as the data coordination and most of the trials are run through this organization. Gary Petersen – Okay. Thank you very much. How does multiple Myeloma has been known to provide a poor life expectancy, something around two years; however, the CIBMTR has conducted analysis of autologous transplant data and found hidden in the data real survival breakthrough. Would you please give us an overview of…, of this retrospective study? Dr. Parameswaran Hari – Yes. So, this was a study that we just published and it looked at people getting auto transplant between 2008 and 2012, so that’s the period when initial treatment for myeloma changed quite a bit in this country. Regimens such as RVD which lot of people get, we call them modern triplet, starts with lenalidomide or Revlimid, and Velcade or bortezomib, and along with dexamethasone. So, this triplet therapy became very popular during that period and whenever you do a retrospective study, one of the times when we…, really we should be doing the studies is when technology changes, so we can go back and see how the change in technology affected or improved our outcomes. So, that’s why we decided to choose this period between 2008 and 2012 when the country really switched from doing things like thalidomide-dexamethasone or just doublets like Revlimid-dexamethasone or Velcade-dexamethasone during triplets. Dr. Parameswaran Hari – So, there are a bunch of patients who are getting doublets, bunch of patients who are getting triplets, and also another technology change that happened is that people started getting maintenance treatment in that period. This is the time in which lot of the maintenance studies reported their results and the doctors were switching people to maintenance right after the transplant. So, we looked at patients who were high-risk patients and we had to be absolutely certain that these patients were high risk versus low risk. So, we only looked at… Out of the thousands of patients we had in that period, we only looked at about a thousand people who were, we had exact data whether they were high risk or low risk. So, the high-risk patients were about 125 patients classified as high risk based on the presence of certain chromosomal markers. So, everyone knows about the 17p deletion, the translocation of chromosomes 4;14, the translocation 14;16 and then hypodiploidy where the myeloma cells don’t have the full complement of 46 chromosomes, but they are like 44 or less and then couple of other markers such as chromosome 1 amplification or 1 deletion and these abnormalities were all put together as high-risk markers and there were 125 patients with these high-risk markers, some of them having more than one high-risk marker and we had 715 patients who were absolutely certain to be low-risk markers. Dr. Parameswaran Hari –So, we actually compared outcomes between these two groups and the interesting thing was that when patients were identified to be high risk, they were much more likely to get a triplet in this period. About 60% of the patients who were getting…, who had known high-risk disease got triplets, and they were also more likely to get bortezomib or Velcade if they were known to be high risk. So, this is…, you know, since this is a retrospective study, we looked at what happened to them, not like we didn’t decide what to give them or treat them with. We just saw what people did and then tried to make inferences about the outcomes from what they did and again this was for patients in the high-risk group who were much more likely to get maintenance treatment such as, you know, and some of them actually got triplet maintenance, including bortezomib-Revlimid, Velcade-Revlimid, and dexamethasone. Dr. Parameswaran Hari – What we discovered was that high-risk patients actually did better than anybody expected them to, suggesting that, you know, the outcomes after transplant have improved dramatically because of the initial therapy getting better and the post transplant therapies getting better and this is a common theme which we found in many other studies too. So, 60% of patients in the high-risk group had a very good partial response or better and three-year progression-free survival in the high-risk group was 37%, it was about 50% in the non-high-risk group, but the three-year survival overall was 72% in the high-risk group versus 85% in the non-high-risk group, so which means that, you know, that the…, it is definitely not two years as we believe. It is at least…, you know, when we say median survival is two years, it means 50% of patients are essentially gone in two years. In our study, we found that only about 25% of patients were gone at three years, which is quite a bit better and one of the things that made a difference was being on post transplant treatment with either lenalidomide or lenalidomide-bortezomib combination. So, if the patient had a transplant and then stayed on a maintenance treatment, there were 81% three years of overall survival, which was outstanding, whereas if they didn’t get the maintenance treatment, that was only about 50%. So, without the maintenance, they kind of behaved like the literature says they did, but with maintenance it was about 81% three-year survival. So… Gary Petersen – Equal to the low-risk group, correct? Dr. Parameswaran Hari – Sorry? Gary Petersen – Very close to the low-risk group? Dr. Parameswaran Hari – Very close to the low-risk group. Yeah. The low-risk group was 88% and importantly, the low-risk group had 79%, you know, if you are low risk and you did not get maintenance, your three-year survival was 80%. If you are low risk and you have got maintenance, it was 88%. So, difference was quite narrow there, whereas in the high-risk, if you didn’t get maintenance, it was only about 48% and if you got maintenance, it was 81%. So, it was quite a bit better if you were high risk and you got maintenance. So, one of the messages of this paper is that high-risk patients should be improved, should get better or catch up quite a bit if you do maintenance after transplant. Gary Petersen – And how is the length of maintenance? Could you… Dr. Parameswaran Hari – Unfortunately, we can’t find that from the data. We only know that the patients were put on maintenance. Gary Petersen – Okay. Dr. Parameswaran Hari – And the length of maintenance is something that we don’t know about from this database, mainly because, you know, the intention, as you all know, is to continue until progression for most patients, but, you know, if some patients came off, for example, with toxicity, we wouldn’t know that from this database. Gary Petersen – Okay. Well, for a while, there was in that period, there was probably a lot of patients that were just told to take maintenance for one or two years. Right? Dr. Parameswaran Hari – It was quite possible, yes. Gary Petersen – Now, its until progression. Dr. Parameswaran Hari – Indefinite maintenance at least in the US, that’s what most people recommend. I am not sure we have, you know, strong data to go either way, but indefinite maintenance at least in the high risk is what most people recommend and in Europe, especially in France, the maintenance is again, you know, is limited to about a year. Gary Petersen – Great! Well, obviously, you know, that’s very, very great news for high-risk patients, you know, because they were always considered to be having about half the life expectancy of the low-risk patients. So, high-risk patients certainly have something to look forward to based on this information. Dr. Parameswaran Hari – Absolutely! Gary Petersen – So, did you also find any one regimen which was the best in total or ones which worked better by specific high-risk features? Dr. Parameswaran Hari – Unfortunately, I don’t think we can say one or the other separately, but, you know, there is a lot of thought about what would work better and to an extent it depends on how you get to be high risk. So, some of the agents, for example, bortezomib and carfilzomib are proteasome inhibitors and they have been used in high-risk regimen, high-risk myeloma much more than, for example, IMiDs and because of feeling that or the data that people with translocations mediating the high-risk nature of their disease such as translocation chromosomes 4:14, translocation 14;16 and even some people with deletion 17p and similar deletions, these agents, the proteasome inhibitors seem to abrogate that high risk better than the other agents. On the other hand, there is also emerging data that pomalidomide might be able to abrogate the high-risk situation in patients with 17p disease, for example. There is some data emerging for ixazomib and combinations too. The combination of carfilzomib, pomalidomide, and dexamethasone or KPd, again in patients with extremely high-risk disease, multiply relapsed disease was shown to be very effective in producing deep remissions and that was another…, that’s another regimen that might help. However, you know, from my analysis or our database, we actually couldn’t distinguish this because statistically when you have so many different ways in which a person can be high risk, its very difficult to show statistical differences with the…, with the limited data set. We, you know, it really needs to… Yeah. Gary Petersen – Yeah, we are 125 people only, so…. Dr. Parameswaran Hari – Exactly. Yeah. Gary Petersen – …understandable. Were there any other important findings from the study that… Dr. Parameswaran Hari – I think I would use the study in two ways. One is that, you know, if you have high-risk disease, you should probably try to achieve a transplant…, try to go for a transplant-based strategy for your initial therapy. You know, we always think whether we should do a transplant or not and whether for a while we used, you know, there was a thought that in patients with high risk, nothing makes a difference, so why do a transplant? Well, you know, transplant has gotten better. Many places even do it as an outpatient and its a limited amount of time that you have to give up for getting through the transplant, but it seems like if you combine the various types of treatments that we have, good induction, transplant, and then post transplant therapy, you are, we are much more likely to get people into deep remissions and the nature of high-risk disease biologically, what does it tell us? It tells us that this is the type of disease that’s not likely to stay quiet in the body and tries to get active and attack the host. So, we need to get it to as low as possible so that the relative value of getting a deep remission is more for a person with high-risk disease than for a person with standard risk or low-risk disease. So, that’s #1. So, you should use all the tools at your disposal, get modern triplet induction, followed by a transplant, followed by some form of maintenance to get, if you have high-risk disease. #2, the post transplant treatment is important, in that even if you did achieve a good remission, either VGPR or a CR or stringent CR even or even a NextGen sequencing-mediated deep CR, molecular CR, you still probably should require maintenance unless otherwise proven. We have not been able to prove that, you know, any group can do without maintenance, but if anything, the group that should do maintenance and should…, seems to benefit the most seems to be people with exceptionally high-risk disease. So, that’s one of the big messages of this paper, I think. Gary Petersen – Okay. Fantastic! I certainly was excited to hear about it. There’s currently a number of programs which will be used for data mining – the MMRF CoMMpass study with a thousand patients, Celgene has 3,000-patient study called Connect MM, and a team sponsored by Takeda Pharmaceutical will follow 5,000 patients and its called INSIGHT-MM. Dr. Parameswaran Hari – Yeah. Gary Petersen – How many patients are in the CIBCR database…, CITMBR? Dr. Parameswaran Hari – We have 6,000 patients per year that are reported to us with myeloma. So, we have a much bigger database than any of these other databases and of the 6,000 patients, these 6,000 patients, we get essentially all the information, like when was…. We don’t collect deep level of information on everybody, but the lowest level of information that we collect on patients itself is pretty good, in that we get data on their age, demographics, those kind of things. About the myeloma, we know the date of diagnosis, we note the type of paraprotein, we note the type of responses they got before transplant, we actually, and the type of transplant that was done, whether maintenance was done or not, when they relapsed, and when they passed away. So, this much data is available on every single patient. So, that’s about 6,000 patients every year. The data that we collect on a subset of patients, probably about 15% of patients or about a thousand a year is much more deeper level data like in any other…, anybody going on a clinical trial. We get every bit of information, the exact levels of paraprotein, the exact treatment, the drugs that were given, the doses that were given, the cytogenetics, everything, essentially everything you need to know about the patient and then those data are audited. They are like very high level data. So, we have that level of data going back to, say, 1992 for myeloma and so the number of patients with that kind of data is about upwards of 25,000. Gary Petersen – Well, that’s…, that’s much larger than those that are being developed right now by some.. Dr. Parameswaran Hari – Right. Gary Petersen – …of the drug companies, so that, you know, you know, this seems like then this mining of your data, its…, its, you know, the sky is the limit that you could do so much with this raw data and… Dr. Parameswaran Hari – Correct and so one of the ways in which we use it is to actually design clinical trials for the future. So, we have the myeloma intergroup that kind of talks between the transplanters who do myeloma and the big cooperative groups that do myeloma, like ECOG and SWOG and CALGB. So, we all get together and talk about what to do next and some…, and sometimes these data become very, very useful. So, one of the strategies that, for example, that we have talked about recently is for patients, especially patients who have had a long, say, if somebody with high-risk myeloma gets three to four years from their first transplant, they are doing okay, and then they relapse. So, what can you do next? So, in the past, we have actually just approached relapse as if, you know, once you relapse, you are…, you are essentially done. We keep doing some drugs. We keep doing combinations and then as each combination fails, we just kind of, you know, look for something that keeps the patient going rather than actually going after the disease. Dr. Parameswaran Hari – So, our approach to induction and transplant and maintenance in the first line setting, we don’t really do for patients who relapse. So, we have actually thought about changing that and going after relapse the same way. There is nothing that tells us that that should not work, so we should be thinking, especially in people who have had a response that lasted for a little bit, like two to three years. We are thinking about a re-induction with a new three-drug combination. We have very good combinations now, especially with antibodies and new proteasome inhibitors, etc., followed by another transplant because most people have self-stored and then followed by another form of maintenance. So, basically use the triple sequence of induction, transplant, maintenance again one more time and many people are doing it already. We have…, at our center, I actually offer this strategy to almost anyone who is fit to get a transplant even a second time and that might be the better way of using cells than doing tandem transplantation, especially since the drugs have gotten a lot better. Gary Petersen – So, have you gotten some results from this strategy that you can share? Dr. Parameswaran Hari – Yeah, So, we have actually not published yet, but we have very promising early results. The question really is, you know, so, we have looked at the CIBMTR database for this again and we found that for patients who do get a second transplant compared to any other strategy that they do, if you relapsed more than two years out from your first transplant, almost nothing else beats it than getting a second transplant. So, essentially that’s something that’s very interesting that I found, but there is a little bias there, you know. To get a second transplant, you have to be fairly in good shape. So, if you relapse and you are not in good shape, you may not get a second transplant and that always detracts from the finding, but a prospective study looking at a second transplant at relapse is now needed. Gary Petersen – Okay. Well, obviously this is exciting that you are doing a little data mining here and coming up with some real jewels. So… thank you so much for that and hopefully, you know, there will be more of this for some of the high-risk features and, you know, how do you attack kidney failure, bone damage, etc., you know, same kind of thing… Dr. Parameswaran Hari – Absolutely. Yeah. Gary Petersen – But for the high-risk patient, you know, who has always been told, its two years and sorry about that, there’s nothing we can do. Well, obviously, this changes that and thank you so much for, you know, this very positive and encouraging news. Jack, are you online? Jack Aiello – I am online. Thanks for inviting me to be part of this. Just to let you know, Gary, I am on the CIBMTR Consumer Advocacy Counsel and there are lots of papers that are summarized for patients that are available on the CIBMTR site and there’s lots of good research that goes…, comes from many of these…, from this large database of information. Dr. Hari, thanks for being part of this. I am wondering if the CIBMTR’s database actually includes whether or not a patient received consolidation between his transplant and before maintenance and if not, because I am not sure its part of the database, what do you do in terms of recommending consolidation? When do you recommend and at what dosage, is it based on the response of the transplant, is it based on high-risk factors or something else? Dr. Parameswaran Hari – Thank you, Jack. Then, thanks for serving on the CIBMTR Consumer Advocacy Group. So, the consolidation is very interesting. So, its, you know, the line between consolidation and the maintenance is often called its very, you know, its arbitrary. So, if somebody gets a transplant and then you give them full blown treatment like induction treatment for a few months and then stop and then give them maintenance, which is lower intensity treatment, that we call consolidation. We just… As I was saying before, we just finished what we call, or we just have the results of what we call the STaMINA study which is going to be presented at ASH, so I can’t discuss those results, which looked at exactly the same question. What is the value of consolidation? So, the study involved three arms. This is a prospective study, a clinical trial, in fact. So, patients getting initial therapy, transplant, and then lenalidomide maintenance or Revlimid maintenance, that’s the first group, which is the standard group. The second group got transplant followed by consolidation for four cycles with three drugs, which is Velcade, Revlimid, dexamethasone, that used to be the best combination at that time. So, we used that, then Revlimid maintenance, and the third group got a first transplant, a second transplant as the consolidation or they got tandem transplantation and then got Revlimid maintenance and the objective of the study was to compare progression-free survival between these three groups. Dr. Parameswaran Hari – So, we are going to have some results presented at ASH, hopefully at ASH, because we just submitted the results today to ASH. So, we will know if they are going to be accepted as late breaking abstract or not, but its a study that people have been waiting for because nobody has actually formally compared consolidation with any other strategy. In actual practice, here’s what people do pending the results of these kind of analyses is if you…, if you have high-risk disease, its everyone’s desire to get those patients into as deep a remission as possible. So, we get… Once you do a transplant, the immediate question is, what sort of remission did the patient get into. So, you do a post transplant disease check and if the patient is in a complete remission, you should perhaps go ahead and do a minimal residual disease check at that point. If they are not in a VGPR, then there is no, you know, point doing a minimal residual disease check because, you know, it only applies to people who have no overt residual disease and after that, the question is if they have not achieved a VGPR or a CR or even a minimal residual disease-negative state, you need to amplify the treatment at that point to get them to that situation. In Europe, the practice is to do a second transplant. In the US, for the vast majority of centers as far as I can see from the CIBMTR database is to go for consolidation which means three drugs for a limited amount of time, for six months at the most, followed by some sort of maintenance. Now, Dr. Lonial’s group at Emory have done a very interesting phase II study, which is a small study, where they took patients with high-risk disease and they put them on what you would call consolidation or I would call consolidation, three-drug regimen for a long period. They…, they continued the three-drug regimen for three years and at that point backed off. So, this is…, and they essentially again showed that the high-risk nature of the disease was completely gone by amplifying the treatment in that way. So, its a very interesting question and I think the value of consolidation perhaps is mostly for people with high-risk disease as a strategy to get those patients to a deep remission. Jack Aiello – Thank you. That’s really interesting. That’s a very long-term consolidation. Dr. Parameswaran Hari – Well, yeah, you could call it maintenance too. But its three-drug maintenance, yes. Jack Aiello – Is there any circumstance where you might recommend for a newly diagnosed patient to get an allo as a first line treatment rather than auto? Dr. Parameswaran Hari – Yes, there are. Its not a common thing to recommend, but there are some patients for whom a newly diagnosed, even a newly diagnosed patient should think about an allo. The obvious situation is plasma cell leukemia. That’s probably the highest of the high-risk patients and the problem in plasma cell leukemia often is that these patients can’t even get two transplants because the disease course is so rapid and so difficult that they don’t even get to a good remission to get into…, get two transplants. So, those kind of patients, if they can get into a decent remission and if they are eligible to go for an allogeneic transplant or a donor transplant, I do recommend that. The next group is for the patients who are extremely young. So, I have patients who are, you know, in their 20s with multiple myeloma, which is something that we didn’t used to see it, say, 15 or 20 years ago and again, those patients I usually recommend that they should do an allo transplant, perhaps not even wait until the first relapse to do it if they have high-risk features, especially 17p deletion, etc. Dr. Parameswaran Hari – Now, allo transplant is the poor man’s way of doing immunotherapy. It is quite possible that in the future we will get very sophisticated, better, less toxic ways of doing immunotherapy and that may completely eliminate the need for doing it. The bottom line with high risk is, you know, why is it high risk. It is high risk because the treatments that we have today don’t work. We know we may come up with better treatments in the future that make these same high-risk patients low-risk patients of the future, you know, if we find a better way of treating this disease, you know, maybe people who have these kind of deletions are better treated with immunotherapy and our immunotherapy drugs are especially useful for them, say that happens. If that does indeed happen, then the high risk suddenly becomes low risk. So, that can change in a matter of…, you know, its our inability to control the disease with our current technology that makes the patient high risk. So, patients with high risk who are chemorefractory again, you know, those patients I do recommend allo transplant. That’s because, you know, by being chemorefractory which means the initial induction treatment doesn’t do much, the disease doesn’t move much at all, or sometimes even grows in the face of this treatment. It means that standard chemotherapy, cell killer type of methods are not working and you need to get a new immune system to go and fight the disease. You know, the fighting of the immune system is organic. It is adaptable, it learns about the disease, and it kind of changes. As the disease changes, the immune system also, you know, ramps up, whereas the drugs cannot do that. So, in that kind of situation also, I recommend those patients should consider an allogeneic transplant. Dr. Parameswaran Hari – And then finally, one other group of high-risk patients are patients who relapse very soon after an auto transplant. So, they get an auto transplant. Everything looks good. The patient’s got good remission. Then, you do an auto transplant, they get into an even better remission. They are in really good shape, but within, say, 18 months of doing the transplant, they relapse. For those patients, that is actually people who we didn’t know had high risk, but then time is telling us that’s high risk. its a very powerful indicator of high-risk nature of that disease. So, those patients I usually try to get them into a complete remission again and then consider an allogeneic transplant, especially if they are fit. Jack Aiello – Thank you! Earlier this year…. Gary Petersen – Just a point of note is that Dr. Hari also publishes his allo transplant information and it goes from, you know, and his is some of the best in the country, in the world for that matter as compared to others which are, you know, still at 50% survival in one year, Dr. Hari’s is well above that, in the 80s. So, its pretty remarkable, the success he has had with allos. Dr. Parameswaran Hari – Thanks, Gary. Jack Aiello – From those lines, Dr. Hari, you are differentiating between, you know, what patients will call a mini allo versus a full allo when you talk about those figures. Dr. Parameswaran Hari – Oh, yes, yes. So, a mini allo is what is applicable to the vast majority of patients with myeloma who are thinking about an allo. Because myeloma is a…., you know, patients with myeloma have significant organ dysfunction and myeloma is a disease that happens to people in their 60s, 70s, 80s age group. So, mini allo meaning, you reduce the intensity of the conditioning chemotherapy. So, the chemotherapy that people get before transplant is what’s called conditioning chemotherapy and when we do mini allos, the intensity of that treatment is actually even less than what you get with an auto transplant and so, you know, many of my…, most of my mini allos are actually done as an outpatient where patient doesn’t even spend much…, any time in the hospital, in fact, whereas a full allo or an ablative allo is a technical word, is where you get a full blown treatment which basically gives you mouth sores, diarrhoea, hair loss, all that and very low blood counts for a period of two to three weeks. That type of allo is less commonly done in myeloma. The only situation where I would do that is a young person with, say, plasma cell leukemia. At that point, I treat them as if they have regular leukemia and try to do a curative intent full allo transplant and that’s very rare. It happens maybe once a year, twice a year, whereas a mini allo is what we do for the mass majority of patients. Jack Aiello – And I think when Gary mentioned 50% mortality is, he is talking about mortalities from full allo as opposed to mini allos that you just read. Dr. Parameswaran Hari – So, yeah, so things have changed quite a bit. So, one, so, national one-year survival for every program is published by again by the CIBMTR and it has…, its a publicly reportable event by law. So, again, you know, there is a lot of variability in that and that’s…, I think that’s what Gary was referring to, but again, you know, we tend… So, when you do an allo transplant, the real issue in myeloma when a patient is in front of me with a high-risk disease that needs an allogeneic transplant, the real question is, how likely is it that the treatment will harm them. So, the key number is treatment-related mortality. So, if we have a patient with myeloma that’s really bad, has relapsed maybe within two years of auto transplant or 18 months of an auto transplant, for example, we know that things are going to be difficult from there on just because of the myeloma. We do an allo transplant, we are trying a completely different approach to treating this disease by putting in a new immune system and asking the immune system to take care of the myeloma. So, if that whole procedure itself causes significant mortality, its…, its obviously harmful to the patient and will reduce their lifespan. If after the allo transplant the myeloma returns and then we are dealing with the myeloma again, say, a year from then or two years from then or five years from then, then it is…, the procedure did something, but it did not do the whole thing by curing the patient. So, what I often say to the patient is that the big question is how much is it likely to harm you and that number is the treatment-related mortality. Again, in our hands, with mini allo transplants, it is less than 5% and it varies all the way from 5% to 20% across the country. Jack Aiello – Earlier this year at the tandem meeting, I heard you speak about various benefits of using something called Evomela instead of melphalan for the high-dose chemo used for an auto transplant. Now, I am beginning to hear some patients at least ask about such, so can you share a little bit about this Evomela and should patients be asking their doctor for using that for the high-dose chemo? Dr. Parameswaran Hari – So, obviously, so there is a conflict of interest here. So, I did the Evomela study. So, I have to put that out front, upfront. So, we don’t have any head-to-head data for Evomela versus regular melphalan, but having said that, regular melphalan has certain problems, in that, regular melphalan, you know, so melphalan is a drug that…, one of the most powerful drugs in myeloma. The only problem, its been around for a very long time, so we don’t think of it as a myeloma drug, but its…, you know, if you just give somebody melphalan, its a desert island drug as I call it, because if I have to go to a desert island, never get anymore drugs again and I get to choose one drug to go with me to treat patients with myeloma, I might end up taking melphalan or dexamethasone because they are still very strong drugs. So, melphalan is a drug that doesn’t go easily into solution. So, the way in which we make it into solution normally is by mixing it with something called propylene glycol, which is very similar to ethylene glycol. Its a glycol that’s not good for the body. It does increase your lactic acid levels. It gets excreted through the kidney but kind of slowly and, you know, its not something that the FDA likes in a…, in a…, in a drug. Then, there are some certain…, there are certain limits at which you can give this propylene glycol and the most important thing about regular melphalan and propylene glycol is that… Gary Petersen – Isn’t it antifreeze? Dr. Parameswaran Hari – Sorry? Gary Petersen – Isn’t it antifreeze? Dr. Parameswaran Hari – Yes, its similar to antifreeze. Gary Petersen – Ethylene glycol. Dr. Parameswaran Hari – Ethylene glycol is antifreeze. Propylene glycol is kind of a cousin of the ethylene glycol. Gary Petersen – Okay. Dr. Parameswaran Hari – So with this PG or propylene glycol, the melphalan starts degrading the moment its mixed and if you have ever seen somebody mix melphalan, its takes a while to mix it up and then by the time it gets to the patient, we actually, probably have lost 10% of the melphalan already and melphalan is a drug that has something called a dose-response effect, which means that you have to give the correct top dose that you can give the patient. So, because of all this, its a clumsy drug to make and it is a drug that doesn’t get into patient the same way we want it and we don’t know how much each patient gets when they get it. So, Evomela kind of gets past all this because it is solubilized, not in propylene glycol but in something else called beta-CD and in a couple of different studies we were able to show that it got very stable levels in the body and right now we are actually trying to perfect that technique. We have a study ongoing where we give Evomela and then we measure the amount of melphalan in the person’s body for about four hours afterwards with blood test and then I am hoping to get these findings done by the middle of next year or by March of next year and then we will see what are the safest and best levels of Evomela for patients and then there are colleagues at the Memorial Sloan-Kettering who are doing a very similar experiment. They are giving patients a test dose of Evomela couple days before the transplant and then they measure the levels and then they can tell you, that test dose will tell us what exact dose of melphalan to give to the patient on the, you know, the day before transplant. So, we are trying to make it so that the variability in melphalan should not be a reason for somebody’s transplant not to work. Jack Aiello – Thank you! And I had one last question, because of the study for high-risk patients showing such a benefit of maintenance after transplant, the progression free I think you said was from 48% to 81% improvement if you use maintenance. Is there, you know, studies that also show that type of result for non-transplant-eligible high-risk patients? Dr. Parameswaran Hari – Actually, off the top of my head, I can’t think of a study like that in the non-transplant patients. You know, the concept of continued therapy in non-transplant kind of solidified after the first trial, as you all know. Its the trial where patients got lenalidomide-dexamethasone for 18 months versus for continuous therapy and we know that patients who stopped at 18 months had a…, they started declining and getting relapses straight afterwards, but what we really need is a study in high-risk patients. So, again, you know, its the high-risk patient where we don’t want to stop treatment, but I can’t think of a study where, you know, this was looked at specifically for high-risk patients. Jack Aiello – Thank you very much for your very clear answers. Thank you! Dr. Parameswaran Hari – Thanks. Gary Petersen – Thank you, Jack. Priya, do we have some callers online that would like to ask their questions? If not, I’ll start going through the questions. Priya Menon – Gary, we can go through the questions. Gary Petersen – Okay. Priya Menon – Yeah, they have just sent in some new questions. Yeah. Gary Petersen – Okay. Dr. Hari, you know, you’d mentioned plasma cell leukemia tends to be lumped in with the high-risk multiple myeloma, yet its own unique, its own unique disease. Have you seen any evidence of outcome changes among PCL patients using specific treatments or sequencing, that’s stem cell transplants, tandems, autos, auto-allo with intense maintenance? Dr. Parameswaran Hari – So, there are very few prospective studies in PCL. So what, like I said, when we…, when we look at our own database and what we have done, we have seen that patients who do get to a transplant after PCL tend to do well and most of the time the transplants that are being done are still auto transplant because of the, its again like myeloma that primary plasma cell leukemia is more common in older patients and most of them are not eligible to get an allo transplant. Having said that, this year, we have a study from France, I am just trying to pull it up right now as I am talking to you, about which did look at an initial therapy including bortezomib-containing regimens and followed by an auto transplant, which did show the best possible results in PCL so far and I think one of the things that can be said about PCL is that this is a disease where we try to combine as the best possible agents in myeloma together and then, so the patients in France received bortezomib, doxorubicin which is standard chemotherapy after the VAD regimen or VDT-PACE regimen, cyclophosphamide and dexamethasone. So, basically they got four drugs including two standard keyboard drugs followed by an auto transplant. Dr. Parameswaran Hari – So, they enrolled 40 patients and their median progression-free survival was 15 months, but overall survival was 36 months, but again the biggest problem was that many patients could not get to the auto transplant. So, the response rate to induction, which means, you know, how many people had a benefit to the initial therapy so that they could go on to the transplant, that was only 70%. Now in myeloma, we expect anywhere between 95% to 100%. So, that’s the difference with the first step of failure in a person with PCL, is the first initial induction treatment. At that point, we are losing about 25% to 30% of patients from getting to where we want them to be and for, my approach in younger patients is to actually admit them to hospital and give them initial induction therapy with multi-drugs. I usually combine these same drugs, bortezomib, doxorubicin, cyclophosphamide, and an IMiD such as lenalidomide or Revlimid and sometimes thalidomide in some cases that we use the VDT-PACE regimen and that usually again gets about 75% to 80% of patients in remission and at that point we think about a transplant. I try to do an auto transplant, followed by a second allo transplant with reduced intensity if the patient is in a complete remission. Gary Petersen – Well, I do know a couple people who have been with your program with PCL and, you know, they are some of the few that are still alive today. So… Dr. Parameswaran Hari – Yeah, we do have a lot of six and seven years of PCL who have never relapsed, which is… Yeah. Gary Petersen – Yeah, You’ve got some great results as a matter of fact. Yeah. I know there are a couple of guys that are following and you’ve had some outstanding results treating in the younger and certainly they are very thankful they are still alive. One patient says, I was almost five months post auto transplant and having to switch my meds over to Kyprolis, dex, Pomalyst due to large skull plasmacytomas and elevated proteins. I am curious if you found that there is a better sequencing of drug regimens for high risk. In other words, do patients do better following a specific order of drug changes? Does one specific regimen have more success after another specific regimen? Dr. Parameswaran Hari – Well, that’s a very insightful question actually. This is something that we are all struggling with right now. Unfortunately, we don’t have any prospective data to answer this question. In other words, the question is, you know, if you say drug A before B, then C or if you…, if the drugs went A, B, C, is that better versus going B, A, C. We don’t know that. We don’t know the answer to that. When we choose drugs, we usually try to avoid drugs of the same class as much as possible and there are people, you know, actually we have colleagues at the Moffitt Cancer Center in Florida who actually look at drug sensitivity in the lab. So, they have patients who are getting four-drug combination for relapse disease and they look at the relative contribution. They have a very cool assay by which they can tell the relative contribution of each drug to the control of myeloma and they found that when we give people four drugs, most of the work is done by one or two drugs, just like in any team, you know, 80% of the work is done by two or three heavy hitters. So, same thing in…, in the myeloma too. Dr. Parameswaran Hari – So, if we knew the answer to that question, we would definitely be able to sequence drugs better. Having said that, the most important thing to remember is that when you have a good drug, that is best used earliest in the disease course. So, for example, we have very powerful drugs in each class of disease now. So, we have proteasome inhibitors. We have the first generation one, which is bortezomib. We have a second generation, which is carfilzomib. We have ixazomib, which is another oral agent. So, we have three drugs in that category. With IMiDs, we have thalidomide, Revlimid or lenalidomide, and/or pomalidomide. We have three drugs in that category and then we have a chemotherapy category. We have melphalan, cyclophosphamide, doxorubicin, agents such as that and each one of them is a different. The way it works is different. When we come to antibodies, we have approved antibody with single-agent activity, daratumumab, and then we have elotuzumab, which really doesn’t have single-agent activity. So, if we confine to the drugs which have single-agent activity, we would use the most effective drugs upfront and at this time, it is a tossup between the two combinations. One of the most powerful combinations is daratumumab-IMiD combination. Another one is carfilzomib-IMiD combination. These are approved in the second-line setting at this point and at some point, they will move into the first line setting, perhaps even in a combination of a quadruplet, rather than a triplet because again, all of us expect a good drug should work even better in the first line than it did in the second line, so…, and I wouldn’t hold back a very powerful drug, saying that, okay, let’s use it when you relapse because most of the time it works…, doesn’t work as well as it should have worked when you use upfront. So, the whole philosophy, especially for people with high-risk disease, is to use the best drugs available at that particular point in time and the other thing to say is, you know, patients with high-risk disease should always consider clinical trials. Its even more important to think about clinical trials when you have high-risk disease. Gary Petersen – Okay. We… Another question and we have answered it, I think. Its maintenance therapy post stem cell transplant. Your thoughts on the length of therapy. I am on a two-year maintenance plan. My last oncologist mentioned something about indefinitely because I was tolerating it well. MY new oncologist says, no more than two years max, and your thoughts. Dr. Parameswaran Hari – Again, you know, there is no good… I think I would say both oncologists are right. So, if you are an young patient and if you are tolerating the maintenance really well and you are in a complete remission or going towards a complete remission, most oncologists in the country, the majority actually, would be…, would not stop the maintenance. On the other hand, if you are older, if you are unable to tolerate the maintenance and if you were already in a good remission even before you started the maintenance and it is difficult to say how much the maintenance is added to you, then many of the…, many oncologists would say, so probably okay to stop maintenance. So, I use the two-year rule to stop maintenance, especially in people for whom I think there is a high risk of second cancer and the maintenance is lenalidomide because the lenalidomide is definitely associated with a risk of second cancers, not very high, but its about 4% to 5% and some of them are not life-threatening cancers. So, overall, the risk is there. It is better. Its more than the baseline but is not as bad as we think, but that is something that we need to avoid having…, happening to our patients. So, I try to limit it if I think the risk is higher. So, it turns out that men, people above the age of 70, people who have low blood counts on lenalidomide, those are the people who tend to have the second cancers. So, especially, in that kind of setting, I stop it, but if you are tolerating it good and if you are young and you have a long number of years to live with the myeloma, its better to stay on it continuously, which is the current paradigm, at least in the US. Gary Petersen – Okay. Another caller asked, I read an article online about new categories for assessing a patient’s risk factors – high, intermediate, and low risk. I guess its kind of a male thing and a lot of people also categorize them differently, although new protocols include delaying of a transplant maximized advantages of improved chemotherapy. I guess the question, you know… Dr. Parameswaran Hari – The early versus late transplant question? Gary Petersen – Late transplant, yes. Dr. Parameswaran Hari – Right. So, we have four different studies that have been reported in the last two years. We had a large study from Italy. Dr. Palumbo reported it in New England Journal of Medicine, which looked at early versus late transplant and that study in the people who got a delayed transplant got lenalidomide-dexamethasone or Revlimid-dexamethasone followed by melphalan and Revlimid combination orally, whereas the other group went on to have transplant and in that the people who got a transplant actually lived longer. There was an overall survival benefit for transplant. Although about 68% of the patients who took a delayed transplant did…, did end up getting a transplant after the relapse, but still it didn’t catch up in terms of the time they lived. The second study was reported by Dr. Gay and that what she showed was the…, is again with the transplant versus maintenance using initial therapy followed by maintenance using cyclophosphamide and Revlimid. They again showed the same results with better PFS and it was for people who got a transplant and then we had another European study which was reported by the EMN Group at ASCO meetings in June, where they showed a combination of melphalan, prednisone, and Velcade. Everybody started off with a Velcade-based induction with cyclophosphamide-Velcade and dexamethasone, then melphalan-prednisone-Velcade versus transplant and the people who did not get a transplant and stayed on the melphalan-Velcade combination could actually get a transplant later. Dr. Parameswaran Hari – Again, there was a progression-free survival advantage for transplant and then finally we had the big French study that was reported at ASH in December of 2015, where they showed Velcade-Revlimid-dex versus transplant and the people on the Velcade-Revlimid-dex could actually get a delayed transplant, where again the PFS or progression-free survival was better for transplant. So, at this time, as the chemotherapies have improved, the outcomes after transplant have also improved. Now, its very difficult to… So, if you look at people who got a transplant in the early 2000s, their median progression-free survival was about two years or 24 months. Now, the median progression-free survival is easily 48 months, four years, we have doubled it with transplant and maintenance. The reason I think is because more people are getting two transplants in a very good remission because of the initial therapy being better and then second reason, what we are getting in terms of a graft from those patients is actually probably a better quality graft because there is very little myeloma left in their body and then we don’t lose many patients during transplant. The average mortality from an auto transplant in this country is 0.5% or less. So, its very little. You need to get to 0, but its, you know, its as close to 0 as you can get, at 0.5% or less and then the maintenance treatments have obviously contributed too. So, I think delaying a transplant unless you are on a study doesn’t make much sense. Gary Petersen – Okay. One last question and we’ll wrap this us, why is IGD myeloma considered more aggressive? What are the survival rates for IgD patients after stem cell transplant? Dr. Parameswaran Hari – So, there’s only one paper which was published about.. There are several papers about IgD myeloma. The large paper that looked at IgD myeloma and transplant was published by the CIBMTR again. I think I…, we published it quite a while ago actually before the modern treatments came. So, one reason for IgD myeloma being considered… You know, we actually don’t know the exact chromosomal changes or biological changes that accompany IgD myeloma in every case. Some.. Many a time IgD myeloma is not diagnosed because nobody does an IgD. When you do a standard serum protein electrophoresis and followed by an immunofixation, people are only looking for IgG, IgA, and IgM myeloma and unless you specifically ask the patient, ask the pathologist to do it, it might get diagnosed as either a light chain myeloma or, you know, a nonsecretory myeloma. Dr. Parameswaran Hari – So, we have looked at the IgD and IgM myeloma and published in 2010. At that time, we showed a three-year survival of, I think, 69% or 70% for IgD myeloma, which was about this…, you know, slightly worse than what you would expect for IgG and IgA subtypes, but remember this is only about 2% of the entire cohort of myeloma. Again, statistically, its very difficult to show anything, unless we have a specific study showing the biological risk. Most people don’t look at the phenotype of the myeloma anymore or the factors like IgG or IgA. Those things we don’t look at. We more…, we look more at the genetics of the myeloma, either by standard FISH test or what we call gene expression profiling and there are many tests available right now and even more coming round the pike. So, ultimately, we will all be looking at people’s gene expression of the myeloma, meaning what genes are driving the myeloma cells forward and what genes can be shut down and that really will give us the answer about how to deal with high-risk myeloma. So, if you have IgD myeloma, I think the first thing is congratulations to the doctor who picked it up and the second thing, don’t think that this is, you know…., you know, I am not sure if the era of IgD myeloma is showing bad outcomes versus previous era where we didn’t know as much about the biology of myeloma as we do now. Gary Petersen – Okay. Well, doctor, you have again provided an excellent presentation of the material we asked you to look at and I have to thank you so much for all the work that you do for the myeloma patient community and like I’d said long time ago, I said, it seems like you didn’t hear that much about the, you know, the Medical College of Wisconsin and it was a little secret for Wisconsin, long ago that secret has made it out of the bag because your program is one of the best in the world and I thank you for all that you’ve done, including all the work that you’ve done with the CIMBs…, that you know… Dr. Parameswaran Hari – Thank you. Gary Petersen – Yes. Dr. Parameswaran Hari – Thanks, Gary and Jack. Gary Petersen – Priya, you are on. Priya Menon – Yeah. Thank you, Gary. Thank you, Jack, for your valuable inputs and your participation. Dr. Hari, as usual, its a pleasure to actually listen to you and so much of information you shared, I think this is one of our best talks so far and the talk will be put up on CureTalks’ blog site for playback along with its transcript. Dr. Parameswaran Hari – Thank you. Priya Menon – So, please visit curetalks.com for details on upcoming talks. Thank you, everyone. Gary Petersen – Thank you, Priya, as always.