Dr. Ola Landgren, MD, PhD Memorial Sloan Kettering Cancer Center Interview Date: November 20, 2015

Two new drugs were announced in a single week for myeloma treatment and the pace is ever increasing. Dr. Ola Landgren at Memorial Sloan Kettering Cancer Center shares more about the recent daratumumab and ixazomib announcements. He also shares trends from a recent myeloma expert conference in Rome - giving the best therapy possible for newly diagnosed patients up front, using minimal residual disease (MRD) to make sure that happened and using good drugs for relapse, which can potentially have the same outcomes as a newly diagnosed patient. He also tells us what to watch for at ASH - the French study of upfront vs. delayed transplant, the pipeline of new drugs, the CAR T cell immunotherapy work and many other topics. Dr. Landgren reviews the clinical trials that are open at MSKCC (links provided below) and the wide range of research that is happening to further improve outcomes for myeloma patients.  Clinical Trials Discussed in This Show Ixazomib, the new oral proteasome inhibitor with allo transplant for high-risk patients Pomalidomide and dex with or without ixazomib Higher Carfilzomib Doses without Transplant Smoldering Myeloma Daratumumab VLX1570 - an upstream proteasome inhibitor The Myeloma Crowd Radio Show With Dr. Ola Landgren

This episode sponsored by Takeda Oncology

Jenny: Welcome to today's episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. We'd like to thank today's episode sponsor, Takeda Oncology, for their support of Myeloma Crowd Radio and all that they do for multiple myeloma patients. Takeda recently sponsored us for the Myeloma Crowd Research Initiative 12-day Challenge. Over the course of just a few days we, as myeloma community of patients, family and friends, performed 12 challenges that would help get the word out about myeloma. At the end of days full of challenges we had over 60,000 shares which resulted in over 500,000 impressions on social media which is completely incredible. Takeda sponsored us for $1 each share, up to $50,000, and we clearly reached that target. So together we did it. I'm so proud of us. Signal Genetics also participated for $1,000 in addition to giving free MyPRS test. So we raised $51,000 towards the Myeloma Crowd Research Initiative Projects, which is so very exciting. Now, speaking of Takeda Oncology, just a few minutes ago the FDA approved the very first oral proteasome inhibitor, ixazomib, now named Ninlaro for myeloma patients who have received at least one prior therapy. According to the FDA the approval was based on a trial of 722 patients where they either tried ixazomib, lenalidomide and dexamethasone or just lenalidomide and dex. The study showed longer survival, and this introduces a more convenient oral option for patients. So for the first time patients have access to all oral combination therapies. I know we'll be hearing more about proteasome inhibitors later in today's show with Dr. Landgren. This is very exciting news. Now, for our Myeloma Crowd Research Initiative Project, we have reached out first milestone of $100,000 towards these two projects, and we are ready to hit our second milestone before the end of the year which is $200,000. All of the proceeds will go to the doctors that are raised for $100,000 each so they can get their project started and will keep raising funds up to $500,000 goal until these projects are completely funded. We will be having an online silent auction on December 1st for Giving Tuesday for 24 hours. So if you have any items you would like to donate or services, please send an email to me at info@crowdcare.org. We will be gathering your items and your service or they can be included in the auction to help the Myeloma Crowd Research Initiative. We just showed what we can do together through the social media challenge so we're going to keep it going. There is so much happening in myeloma. We have on the show today one of the very best in myeloma who helps craft the direction of the research both nationally and internationally. Dr. Ola Landgren of Memorial Sloan Kettering Cancer Center joins us today to help us understand the recent announcements at the Rome myeloma conference, the upcoming ASH conference and a preview there, and recent announcements like the approval of daratumumab, and now today, another announcement of ixazomib. So Dr. Landgren, welcome.

Dr. Ola Landgren: Thank you very much for having me, Jennifer. It's a great honor. Thank you so much.

Jenny: Let me introduce you just before we get started. Dr. Landgren is Chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center, and Professor of Medicine at Weill Cornell Medical College. Formerly, he was a senior investigator in the Metabolism Branch at the Center for Cancer Research, the NCI in Bethesda, Maryland, and also was head of the Multiple Myeloma Section of the Medical Oncology Branch. Dr. Landgren is from Sweden and received his degrees in Sweden at the Karolinska Institute, and joined the NCI in 2004. His major research interests are in the causes of myeloma and how myeloma is diagnosed and treated particularly in the early stages like MGUS and smoldering myeloma. He was a pioneer in defining the standards for minimal residual disease testing in myeloma, and was a very key figure in the IMF Black Swan Research Initiative. In collaboration with colleagues at Memorial Sloan Kettering as well nationally and international, he helps develop new strategies including cell-based, molecular-based and imaging-based strategies to implement advanced MRD testing in clinical trials and minimal residual disease. His research also includes how the immune system both affects myeloma and how it is affected by myeloma. The number of papers he's written or been included in are innumerable, and recent awards include an NCI Bench to Bedside Award and NCI Research Highlights Award and American Society of Clinical Investigation Award. Dr. Landgren, we are just thrilled that you're here. I consider you one of the leaders in myeloma. There is so much to talk about.

Dr. Ola Landgren: Thank you again for having me. I think all your efforts, all your hard work is just amazing, and all the work you do for patients and helping people like me to do all the work for patients, moving that forward is just amazing. You should have so much credit, Jennifer. Thank you so much again for having me on the line here today.

Jenny: Well, thank you for joining us. You're very kind to say that. I feel that the doctors are working so hard and you need help getting the word out sometimes of the great things that you're doing. So it's my pleasure and privilege to be able to do that. Now, let's start with the recent International Myeloma Workshop that was held just a month or so ago, maybe two months ago now, in Rome. Maybe you can describe the purpose of the meeting and maybe your key takeaways.

Dr. Ola Landgren: We have this International Myeloma Workshop meeting I think every two years now. Last meeting was in Japan prior to this meeting. As you pointed out, the most recent meeting was in Rome. The intent of this meeting is to bring all the myeloma key opinion leaders, all the experts both clinically and scientifically together at one meeting, and to go over all the accomplishments that have been completed, and try to identify the gaps so we can move forward. So having these meetings every two years is a way for everybody to get together. I think what's striking to me is that two years for a meeting used to be a very important step but I think with all the increments now are happening in six-month types of chunks. So I wonder how this is going to change the agenda for these meetings. When we come and we talk about was we did two years ago it feels that's almost forever ago. The field is moving so quickly forward.

Jenny: I agree. I think so much is happening. So what were the key topics that were discussed at this meeting?

Dr. Ola Landgren: There were many topics. So if I were to synthesize what I heard, I think key trends were the importance of delivering good therapy for a newly diagnosed patient and not to save good drugs for later, the importance of doing a good job right away and to assess that. And that takes you into the topic of minimal residual disease testing to really make sure that the job is done well. I also think that similarly for patients who do have recurrence of the disease, to go after the recurring disease with effective drugs can actually result in extremely good outcomes. So just doing one drug or try to string it out, which used to be the way it was done in the past, is not really modern treatment for recurrent disease either. Using good drugs for early relapse can almost have the same outcome as you have for someone who is newly diagnosed. There was data presented for people who were recurring that the disease could stay away for years even in the relapsed setting which is fantastic. There was a lot of information on the new drugs. Coming back to what I started off saying with the time scale, the meeting happened two or so months ago. This week two drugs that were presented at this meeting as new drugs have been approved in the United States. So we are flying full speed forward. So at the meeting the daratumumab drug and ixazomib drug were described as future drugs. This week we can just say they are now part of the available options. So there was a lot of talk about these new drugs and there were a lot of other topics also but I think these were the key pieces that I picked up at the meeting.

Jenny: Let me ask you some follow up questions before we move beyond this meeting because there is quite a bit that we need to talk about. When you say good therapy for newly diagnosed patients and you want to make sure that they receive the very best upfront, are you thinking transplant upfront or are you thinking combination therapies upfront? What's the overall strategy for the newly diagnosed patient? Because I have a friend who is newly diagnosed and she's quite confused.

Dr. Ola Landgren: At this point transplant is still considered standard of care. As you know, there have been a lot of discussions whether transplant really adds a whole lot. If you now use the more modern drugs, that seem to be so much more efficacious and they're much less toxic. So what could a transplant with melphalan really add to that? That's the question that has been on the table for quite some time. There is one study that will be presented at this upcoming ASH meeting only a few weeks away from now. This is the study that was initiated by the French group, the IFM group. They combined Velcade, Revlimid and dexamethasone. They gave three cycles. They harvested stem cells and gave another five versus they gave three cycles, they harvested and they transplanted and then they gave two more cycles of the same therapy. After they did these two approaches for the two arms in the randomized trial, they put patients on one year of lenalidomide maintenance. From what we have heard and what's available online, it will be formally presented at ASH but what's available at this very moment online is that the patient that received these drugs with the transplant, they had the longer progression-free survival. So for people who believe in transplant they would this study shows that this arm was the winner. Now, if you look at it from another perspective, that was not the intention of the trial design, but if you look in these two arms you will that patients will have a very good response to these three drugs without a transplant, and there are patients who have a very good response in the arm with the transplant. There is a higher proportion of good responders in the arm with the transplant, and that's what drives the progression-free survival benefit for that arm. Now, if you only take out those patients who have a good response in the two arms, they seem to be super imposed, meaning that there is no difference in their outcome. They have an equally good outcome. So another way of looking at the data is that if you have a good response, it might not really matter how you have that response. So the transplant may not be required to have. People who think that transplant may not be needed, that's how they look at data. So which what is the right way of looking at data? This is something that will be discussed at the meeting. I'm pretty sure this is going to be a very hot topic.

Jenny: Well, I think it's a burning question for everyone and for patients who are trying to decide what to do right up front. Well, that kind of takes us to what you said, minimal residual disease. Can you give us an update on minimal residual disease and what you're looking for and how this bar, I guess, is being reached by a variety of groups and how it's being measured?

Dr. Ola Landgren: So minimal residual disease was initially developed for multiple myeloma probably 15 or more years ago. It was initially done by the group in Leeds in the United Kingdom - Andy Rawstron and colleagues. At that time the therapies were quite inferior for myeloma. So there was quite little interest in minimal residual disease detection in myeloma. Today, we have such high response rates, we have done studies at the NCI where we showed up to 60% of patients reaching a complete response even without a transplant, that really motivated us to go back and try to use minimal residual disease tools. So we pushed that out about five years ago and right now the field is going very fast into this dimension of minimal residual disease detection. I think what we have learned these past five years is that out of the three main platforms for testing that probably two of those platforms are going to help us into the future. One is probably no longer valid. The one that's no longer valid is the so called ASO-PCR which is a quite complicated technology where you have to take out the individual patients' cells and you have to do a lot of work in the lab, but each patients' sample is going to be processed in an individualized manner and still does not really deliver high sensitivity. The two technologies that seem to be the most reproducible and more valid is either the flow cytometry-based or the sequencing-based. At this very moment I think that the flow cytometry-based is probably the best one because most centers have access to flow cytometry machines. So as long as they set up their lab panel with antibodies so they can do it the right way with the right antibodies and the gates and they use the right number of cells for the determination of the test, et cetera, I think that is probably the best test out there for the high volume number of institutions. The last test, the sequencing test, has higher sensitivity. It's probably 10 times more sensitive than the flow test. The problem with the sequencing test is that it's not available everywhere. In fact at this time it's a pretty centralized type of test that requires that the institution send it out to one or two centers that do exist currently in the world. I think this technology is going to become available for centers around the world in their local labs probably in one to two years because this technology is not very difficult to package and you could run it on instruments that do exist in pathology departments. But the technology needs to be approved by the FDA. What I know, I think that the technology that is currently available in decentralized labs, that technology is currently undergoing FDA review. So I think in one to two years from now that technology, I think, would replace flow cytometry. Flow cytometry for now is the best as far as I'm concerned.

Jenny: I know that the IMF effort and your effort in joining the Black Swan Research Initiative was really to help standardize this testing and to deploy it through lots of different facilities worldwide. Do you feel that you've achieved the success that you were looking to achieve?

Dr. Ola Landgren: I was invited by the IMF. I think it was three or four years ago at the European Hematology Association meeting that occurred in Amsterdam in the Netherlands. Brian Durie invited me and Vincent Rajkumar and Jesús San Miguel and Michael Kauffman to form the Black Swan group. So the five of us we started that group. We decided to try to work together to standardize and roll out a platform for MRD testing. We agreed that flow was the method. As I pointed out in the very beginning of this talk today, the field is moving so fast forward. For me, six months is so much time. I feel that for the past six months there were so many new opportunities. We are now working in the blood. We are working to see if we can replace the bone marrows with blood tests or even urine tests. So if a patient could pee in a cup or we could do a blood draw and determine MRD, that's what I'm trying to accomplish right now, that's what we are doing in our research lab. It's not yet available. It's going to probably take us another two years to fully standardize that but that's what I'm working on. So I think from a practical note, with all the flow work we have accomplished very much standardization, there is software, there are antibody panels. We have agreed on that. I'm very much a supporter of the Black Swan roll out. I think that's needed for the field but also we cannot stop development. Development has to go on. So these are two parallel processes.

Jenny: That makes sense. I've seen the chart that talks about minimal residual disease. It's really a picture of an iceberg. It's like seeing the tip of the iceberg or maybe your M-spike and then digging below and getting deeper to see how much disease is really left. Is there anything you want to describe about the MRD testing that would be helpful for patients to understand?

Dr. Ola Landgren: The whole concept of minimal residual disease testing, ultimately it would be a way to say that there is no disease left, you are cured. That would be the ultimate goal. It's important to know that at this time there is no such test available that reliably can say that. The tests that we do have, they are tests that can rule out with a certain degree of sensitivity that no cells are there that are abnormal. The sensitivity varies quite a lot. There are assays with sensitivities of 10-4, 10-5, 10-6, that's the best we currently have. So 10-6 means that you can find one tumor cell out of 1 million cells that have been assessed. That's what the sequencing can do. The flow cytometry typically do 1 in 100,000. That's 10-5. The older flow cytometry, they did 10-4 or even 10-3. So now we are down to 1 in 10,000 cells. What every study that has looked into this shows is that for each improvement of sensitivity, each log, meaning each 10-fold sensitivity improvement, that translates into longer both progression-free and overall survival. So what we are trying to do is to develop new assays that are so sensitive so we cannot find any residual cell. I think in two years we probably, at our institution here, will have blood or urine-based testing up and going. At this very moment we have fully implemented minimal residual disease testing for every patient that come to us, and that's based on bone marrow testing. So every patient that comes here, if they reach complete response, we do MRD testing both on protocol and outside protocol. Every patient will be offered that. So we are quite aggressive moving this forward.

Jenny: Getting it from blood or urine would be absolutely fantastic.

Dr. Ola Landgren: I just opened a study a few months ago where I offered patients who are treated either here or elsewhere if they come here and they go on maintenance therapy. This testing is integrated. Part of the research is to use the samples from the blood and the urine to study MRD. I really hope we can deliver this in the coming two years. We are working extremely hard to move this forward.

Jenny: Well, it's fantastic. I'm wondering, from your perspective, because you're really in the thick of driving some of the directions of research, why do you think things are happening so fast in myeloma?

Dr. Ola Landgren: There are very many pieces. Having access to all these new drugs obviously changes the whole landscape. From my perspective, I think Velcade, lenalidomide, carfilzomib, they really started pushing things forward. Now with daratumumab and also ixazomib coming out and being approved this week, that's going to drive the whole field. We need more sensitive tools to assess responses. When we start having those needs we will have the need to monitor it over time. And if we monitor over time we have to go away from the bone marrow testing then we have to have the molecular testing. For patients who don't have the full benefit, then we start asking why, so then we have to study the clonal signature for the disease. So I think the drugs are very much pushing everything forward. That's one thing. The other thing is that all these technologies that we can use and study the disease and do things in the lab, they are becoming more and more available. They are much cheaper to do. So the technologies to study the disease, they are also exploding at the same time. I think those are the two main factors in the field. I also think what you are doing maybe is even the number one driver. You are informing people about the disease. You are educating people. People come and ask me questions where I may not know the answer. I have to go and find the answer. That motivates people like me to design studies. So I think patients asking us and putting pressure on us to advance the field, that may actually be the number one, and then having the drugs and the technology could be number two and three.

Jenny: It seems like there's a very collegiate community of doctors as well, that there are a lot of people really going after myeloma research.

Dr. Ola Landgren: There are a lot of people going after it. We have the working group where we meet, and there are a lot of other forums as well. We are trying to share. I think with the fast moving field, if you don't work together with other people you get lost. So I'm positioned geographically in Manhattan, in New York. I meet with Mount Sinai, I meet with Cornell, I meet with Columbia University, I meet with Hackensack. We have a very nice collaboration, the New York consortium. And then we participate in the international collaborations. We also have collaborations between our institution and maybe one or two other institutions for certain projects. I work with University of Heidelberg for imaging. I work with University of Reykjavikc on MGUS studies. I think the whole opportunity with the internet has opened up a whole new possibility for us to do all these studies even if we are in different cities.

Jenny: Absolutely. Before we get to ASH and what we're looking ahead to in the next few weeks, maybe you'd want to spend some time talking about the recent announcements of daratumumab. I know a lot of patients have a lot of questions about that, like when would you use it and with what combos and when should they be asking their doctor about it.

Dr. Ola Landgren: Daratumumab was approved on Monday this week in the United States. I think it was accepted to be reviewed by the Canadian authorities this week. The approval here in America is for patients with more than three relapses, I believe. I think that's the label. It was approved, as far as I know, as a single drug. It came out of the phase II trial. So for patients who have had several relapses that would qualify for that, I think it's a very good option. It's an infusional therapy and it's given weekly for the first two months and then it's biweekly for another two months and then it can be given monthly thereafter. In terms of tolerability, we know when we give monoclonal antibodies that people will have a reaction typically the first time. The drug that we have most experience from is rituximab or Rituxan. We have used that for 15 years in patients with lymphoma, and I used to treat patients with all types of hematologic diseases. That was one of the new hot drugs that I remember that we were working on. We learned how to deal with these infusion reactions. With daratumumab, the Infusion reaction is a little bit different from Rituxan but they share some of the same features. So it's almost like an allergic type of reaction with upper respiratory type of symptoms. The way it's handled in the clinic is that we turn off the infusion, and immediately the symptoms, they go away. We also can give medicines to cool it off with antihistamines and steroids and things like that, and then we start the infusion again. If it works better when we start then we can even increase the infusion rate or we can go with a lower infusion speed. Typically after patients have received daratumumab the first day, the subsequent doses usually are without any reactions at all. It's not entirely clear why this happens but, again, we saw this when we started using Rituxan 15 years ago. This has been found with other monoclonal antibodies as well. The infusion times are quite long the first time, the first dose. With this drug, daratumumab, I think it's five to seven hours or something like that. For the subsequent doses it can be much quicker but it still would probably be in the range of around two, three-hour infusion times with the current development of the drug. This may be shorter in the near future but for right now I think those are the infusion times. It's very tolerable. This is the dosing the schedule.

Jenny: General oncologists who maybe don't know about this recent announcement or don't know much about daratumumab, as a patient if you're kind of educated and you see this announcement come out, when do you say, "Doctor, I'd like to have this drug. Would you consider this for my treatment? Are you considering this for my treatment?" At what point do you say that? You can't do it if you're newly diagnosed. I thought it was three prior treatments, not three relapses but maybe I'm wrong.

Dr. Ola Landgren: I think it's three prior treatments. You're right. Three prior treatments it is.

Jenny: Okay. Let's say you've been through transplant or something and now you're relapsing, how is this used in combinations? Which combinations is it better with? What are your thoughts on that?

Dr. Ola Landgren: There are a lot of ongoing development for the drug. Right now it's approved as a single drug. That's how the label is. The company is combining it with very many different types of drugs. They have Revlimid, dexamethasone and daratumumab for newly diagnosed. That's an ongoing study they have. They have a Revlimid, dexamethasone also with this drug for relapsed and refractory patients. They have a study going on in Europe with Velcade, thalidomide, dexamethasone and the drug. They also have in Europe Velcade, melphalan, prednisone and this drug. They're looking into, as far as I know, to combining it with ixazomib. I think they're also looking into combining it with carfilzomib. Those two, I have not yet seen being launched by the company but they are looking into this other I mentioned. These are the companies sponsored by the protocols they have written themselves. I think in addition they are opening up what's called investigator initiated trials where people like me can propose to the company "Let's do a study for this and that combination." And if they approve it that could open at that single institution or it could be more than one if they agree to do that. I don't know if they have opened any yet but I know that they are looking into other combinations. The last study I know they have is a trial for patients with high-risk smoldering myeloma. They have three different dosing schedules with a single drug, with only daratumumab for people with high-risk smoldering myeloma. I'm on the lead for that study. So we will open that study I would think in a week or two here at Memorial Sloan Kettering, and we will offer patients with high-risk smoldering myeloma to be treated on that trial. So the bottom line is for patients who have three prior lines of therapy, they could receive this drug as a single agent. It seems to be highly efficacious. 30%-35% of patients that were heavily pretreated had a good response to it in the approval package they sent to the FDA. So it's probably much higher if you had earlier relapses. It's very tolerable. Ongoing combinations need to be filed in order for that to come through and for reimbursement. I think if we were to prescribe this drug with another drug, I'm not sure they would approve that. So it probably will have to be a single drug for right now but that would probably change quite fast, I would think so.

Jenny: Yes. I know that it has single agent activity especially compared to elotuzumab which doesn't but looks great when combined with other things. It seems like myeloma treatment is all about the combination that's why I ask that question.

Dr. Ola Landgren: Yes. I think that the field for sure will use multiple drugs in combinations for all different stages, if it's newly diagnosed or relapses. I think that's how it's going. I have requested here at our institution to have the drug available for patients. Five minutes after I saw the FDA approval I requested that they put it in right away. I have not yet prescribed it but I will see next week when I have clinic if I can prescribe it. I will also see if I can combine it with other drugs. I don't know if that will be approved or not or if they will only do a single drug. So I will know next week probably.

Jenny: For those patients who have not ever heard of daratumumab or know what it does, it's a monoclonal antibody that targets CD38 on top of the myeloma cells. Maybe you want to kind of just give us a quick explanation of how it works.

Dr. Ola Landgren: So it seems that the drug has even four different mechanisms of action. The first one is targeting CD38 which is expressed as a protein on the surface of myeloma cells. That's what it was developed to do. When it binds there it attracts immune cells to come and join the antibody. And then those immune cells when they come they kill the myeloma cell. So that's called ADCC, antibody?derived cytotoxicity. The second mechanism of action is that it has a complement-derived cytotoxicity, meaning that when the drug binds to its target it activates other mechanisms in the body, not only immune cells, it activates these complements that are also present in the body, and the complement kills the tumor cells. The third mechanism of action is when the antibody binds to the surface of the myeloma cell, just by binding and binding to these very structured 38, that is not something that the myeloma cell like. So they actually can die from that directly. It can cause damage to the cell. Now, there is a fourth mechanism that is much less understood, and there's a lot of research going on. It seems that for reasons that we need to further explore, that the drug also alters certain enzymes that trigger other sides of the immune system, T-cells. And these T-cells, based on what's some preliminary data suggests, can become very active and independent of the antibody binding or not. The antibody by itself seems to proliferate and activate these T-cells. You have a very active immune system that goes after the myeloma cells. So that actually potentially could open up a whole new avenue for a drug like this. So you could even think of giving a drug like this to diseases where there is no expression of 38s. Maybe this drug could even activate T-cells to go after other types of tumor cells that are not myeloma cells. So that's a side topic. But that mechanism may even work in myeloma. So it's kind of fascinating how a drug can be very specific but has a lot of other activities as well. We don't know if it's a combination of these or if one or many of these are the important ones. This is the current thinking.

Jenny: It seems they have a broad impact. That's very interesting. I think it will be really interesting to see how it progresses because I know more and more studies will use it. Would you mind talking also about today's announcement of ixazomib if patients are not familiar with that as well?

Dr. Ola Landgren: Before I say that, I will restate. Daratumumab, that's the first monoclonal antibody for treatment of myeloma. That was approved Monday this week. Today, ixazomib, which is the first oral proteasome inhibitor, was approved for multiple myeloma. Ixazomib targets exactly the same parts in the tumor cells as Velcade and carfilzomib does. Velcade and carfilzomib are also called 20S proteasome inhibitors. In every cell throughout the body there are proteasomes. When a cell is doing its job every day, there are a lot of proteins that are being produced inside a cell. Unfortunately some of these proteins are not done the way they are supposed to be, so they are so called misfolded proteins. The cells what they do is they throw these proteins into the proteasome and the proteasome can peel them apart and they become free amino acids, and then the cell can use these and produce new correct proteins. So it's a recycling feature in the cell. For reasons that are not known, myeloma cells are very sensitive if you interfere with this proteasome. So if you block that, myeloma cells, they die. They are much more sensitive than other cells, normal cells and probably also if you compare with any other known cancer. Why that is is not clear, but that's just how it is. So what Velcade and carfilzomib do is that they block a couple of the subunits in this 20S complex of the proteasome. Ixazomib, again, has exactly the same mechanism of action as Velcade has and is similar to carfilzomib. It's an oral formulation. It's given as a tablet once a week. So from a dosing perspective it's extremely convenient. It will be presented at ASH in more detail. There are ongoing trials in combination with Revlimid and dexamethasone and it's compared to only Revlimid and dexamethasone. The data shows that there is a benefit which is the reason why the FDA approved it.

Jenny: Well, we're excited that things are getting easier for patients. I think once a week, that's incredible.

Dr. Ola Landgren: It is an incredible drug. I think for patients that have historically been treated with two drugs, the Revlimid and dexamethasone, I think that, in my opinion, is quite an old way of treating compared to what's available now. Six months is a lot of time. I think two drugs is, in my opinion, an old paradigm. So having access to ixazomib moving forward, that would make it possible to receive three drugs even for patients who cannot go into the clinic and receive infusions or things like that. I think it's a fantastic opportunity, fantastic.

Jenny: You mentioned that it will be previewed at ASH. Are there other things that you're looking forward to at ASH? I want to make sure we get to talk to about your clinical trials.

Dr. Ola Landgren: The highlights that I'm looking for are the study I mentioned before with the transplant upfront versus delayed because that's a key questions. Patients I see in clinic who have extremely good responses with good combinations with the new modern drugs, they ask "Do I really need a transplant or not?" If you look at different pieces of data, that question is very difficult to answer. I think ASH will be important when it comes to trying to address that question in the future. It will open up the data from the French study and we will have to dig into that, and I think it could potentially change the field.

Jenny: A question about that. What do you consider upfront? Are you talking like in the first year of starting treatment or are you just saying they consider upfront to be "Well, we're not going to wait five or six years until you're down the road with all these different drugs, and then we're going to do transplant," saving it as a last option? What do you consider to be upfront?

Dr. Ola Landgren: Thank you for asking that so I can be a little bit more clear. So what I mean with that is that I think that the field historically has been very rigid. Every patient got the same number of cycles and then they go to transplant independent of what their response to therapy was. So I think that has to change. I think the response should guide us what the next step would be. So what I mean is that you give four cycles of therapy and then you automatically by default just go right to transplant. I can see that that could change in the near coming future. I think that the response could guide much more on the next steps, so to speak. In plain language, if you get some good therapy and if you have a very good response you may choose to not go to transplant and you could harvest the cells and you could be on some maintenance therapy. If, God forbid, the disease became active again, one of the options to cool it off could be the transplant but it could also be many other drugs. I could see that a lot of patients could end up not getting the transplant ever but there could be patients where the transplant could be a good option. Now, for patients who are treated to begin with and the response is not that good, I think that the transplant could be a way to improve the response if the other drugs don't really deliver. So I think a more differentiated and more personalized way of treating the disease and that the response is guiding what the next step will be, I think that's kind of what I see the field is going but these are obviously controversial topics and there are people with opposite opinion that think you should transplant every person whatsoever. So there are different opinions here.

Jenny: Well, that makes it tricky for patients to have all the different opinions because sometimes your treatment us just going to be based on who you're seeing and what their philosophy is, which is frustrating from a patient perspective. I think patients would like to say, "Show me the data and then I'll pick the best option."

Dr. Ola Landgren: If you review the different opinions, we have these opinions of two versus three drugs, for example. There's no data to back that up that has been published. There is no generated study that backs that up. That's completely made up by people who think that's how it should be. The transplant story is being evaluated in clinical trials. You are absolutely right. There are a lot of pieces where we don't know the answer. You can go and talk to different doctors. I think the bottom line, in my opinion, that patients should do is to at least have one second opinion to hear more than one answer, and ask the doctor how could it be that there are these two different schools of thought. Unfortunately, there are a lot of questions where we don't have the answer, and then you have to use your judgment. I think if there is one aggressive and more conservative approach -- I think people are different. If the doctor is very transparent and explains that these are all the options and these are the situations, I think that's as good as it gets and I think patients can make informed decisions based on the information. I think patients going to a doctor who's not up to date and being told something that may or may not be right, obviously that would be the bad decision. We don't want that to happen.

Jenny: I think this disease is so complex. I think you really have to have a myeloma specialist on your team even if you're not getting your day-to-day care there. Anyway, I interrupted you when you were talking about ASH. You were saying that the first thing you were interested in seeing is that IFM study about transplant versus delayed. Then you want to continue about the other topics that you're looking forward to.

Dr. Ola Landgren: Yes. So the IFM study, the French study with transplant, I think that's important. I also think important pieces will be to see more data on the drugs that now were approved to really go through the details. So having drugs approved is fantastic but it's almost like the first day you get your driver's license. You could go out and drive but you may not be a perfect driver. You need some more practice. I think having these drugs approved is fantastic but I would like to see more about the details from the studies and what are the lessons learned from these studies which is more sophisticated analysis, and talk to people that have worked on them. So that's something I'm going to do, try to talk about it. The third thing is I also want to look into the pipeline of the future in terms of new drugs. A lot of new drugs are being developed also. There are immunotherapies with CAR T-cells. There are new modalities that are in development. So that's something I also will spend time looking into.

Jenny: It will prove to be an exciting conference.

Dr. Ola Landgren: Absolutely.

Jenny: So let's talk about your clinical trials. You have one that we can talk about but I'm sure you have a lot at your facility. So I'll just let you kind of decide what you think is the most important. You have a clinical trial called VLX1570 which is in the proteasome inhibitor category. Do you want to share a little bit about that?

Dr. Ola Landgren: We do have a new trial with a drug that currently has no name. It's VLX1570. It is a drug that targets the proteasome but it targets the proteasome in a different manner than Velcade, carfilzomib and ixazomib do. It targets the upstream of these three drugs. So if you look at this proteasome I was talking about before, they hit in the middle. This one goes in the top of the proteasome. The reason I say that is because when the protein misfolded, when they go through the proteasome they go in the top and then they go through it and then they leave in the bottom of the proteasome. What has been found is that patients who become refractory to Velcade or carfilzomib or ixazomib, if you have those cells -- these are not in patients yet. These are from experiments that we have done in the lab from cell lines and also in mouse models, in xenografts. If you have cells and you expose them to these drugs that are available they become resistant. If you block upstream, then you still deactivate the proteasome. So it's a way to overcome resistance to these drugs. You still take advantage of the proteasome which is so vital for myeloma cell-killing but you trick the cells so they cannot kind of use their resistant mechanism from the 20S. You go above that. So that's the rationale for using this. So we have a new drug on a new trial. We are treating patients for relapsed myeloma. You have to have been treated with an IMiD and you have to have been treated with a proteasome inhibitor but you could be on just one of each. So you could Velcade and Revlimid or carfilzomib and Revlimid or you could do more than one of each also but at least one of each. That's what make patients eligible. It's a combination with dexamethasone. It's the same dosing schedule as we have for carfilzomib. We have opened it here at Memorial in New York. It's open for enrollment. We will open the same study at Dana-Farber. So I work closely with Ken Anderson and Paul Richardson. Paul and I will move the study forward together. They probably will open it up there in January or so. So patients can be treated at either of the two sites. So far I've not seen, actually, one single toxicity. There have been zero. There's no neurotoxicity as far as we have seen. There is no cardiovascular toxicity. In terms of duration of the response, it's a little bit too early to say how good that is and how deep the responses are. So it's in early development but so far from what I've seen, it seems to be extremely well tolerated and patients do very well but it's in early development. So that's where we are with that study.

Jenny: Okay. That's terrific. I know there are a lot of different strategies trying to be used to overcome resistance to existing drugs that we already have. People don't fully understand why they're becoming resistant. I know a lot of studies are working on that. So this would allow, even if you were resistant, to try another method - just hitting it at from the top-down. It sounds very interesting.

Dr. Ola Landgren: It's a rational approach trying to go after a target that we know is important - proteasome - but instead of hitting exactly where the other drugs go, it goes a few steps above molecularly, and we know, there is proof that it works. So it's cool work by the scientist who developed this molecule.

Jenny: Are there other studies that you want to talk about? You have a lot of myeloma researchers at your facility. I'm sure you have a lot going on.

Dr. Ola Landgren: We have a lot of studies. So are opening a new strategy. It's in the same vein as the work that I led at the NIH when I was there. So we are opening a new carfilzomib, Revlimid, dexamethasone study where we use higher doses of carfilzomib. The end point of the study is to become MRD negative. My projection is that we probably can deliver MRD negativity in maybe up to 75% of patients when treated on this trial. The study does not include transplant. So patients come and they can be treated on the protocol. If they turn MRD negative or if there is still residual disease the study does not mandate the next step. So patients who want to go on to a transplant, they can do that. Patients who don't want to go for a transplant, they can be collected and they don't have to go through transplant. We would offer patients to go on maintenance with Revlimid which is another trial we have. We have a trial with continued maintenance with Revlimid on this trial for three years. We monitor MRD assessment over time. This is where we're building this new blood and urine-based MRD testing. We also have trials with daratumumab for smoldering myeloma. We're opening in January a study with ixazomib, that was approved today for relapse myeloma. We are using ixazomib with low dose of dexamethasone for smoldering patients. So that's a new smoldering trial. We're also working on new other smoldering trials with carfilzomib but those are not yet open. For relapsed disease, we have several monoclonal antibodies that go after other targets. We have something called BCMA antibodies. We also have checkpoint blockade inhibitors, various types of immune markers. We have a protein transport inhibitor for nucleus protein transport inhibitor for relapsed disease. That's going to open also next year. So there are a lot of small molecules and monoclonal antibodies. We have a program that goes all the way from smoldering myeloma to newly diagnosed myeloma and for relapsed myeloma. For smoldering the goal is to see if we can develop curative strategies. For newly diagnosed we try to do curative work or at least functional cure, that the disease does not get active again even if it's molecularly detectable. For relapse disease we are trying to find ways to overcome resistance or to develop new targets. The last thing I can tell you is that probably we will have an up-and-going CAR T-cell program open for enrollment I would think in 18 months from now. So we have already selected targets and we are producing all the pieces that we have a full-scale facility. We already have CAR T-cells in the leukemia program here. So we are now rolling into myeloma next summer. Not this coming summer but the following summer we should have a full scale CAR T-cell program for myeloma up and going.

Jenny: That's very exciting. With all these different options how do you counsel your patients to guide them to the trial that's best for them?

Dr. Ola Landgren: So we try to have different trials for different situations. For smoldering trials, for example, we have some oral drugs and we have some IV drugs. Some patients have problems traveling so maybe oral could be better. For patients who could travel then we give them both the options. So we try to have something that could work for any situation. For newly diagnosed we are trying to see if we can reduce the number of cycles and use the dosing a little bit differently so you can reach very good responses very quickly. For relapsed disease we have both oral strategies, we have IV strategies, again, to try to meet different needs. Memorial is just in the process of opening up very many facilities both in New Jersey. We already have facilities there. We opened in Long Island. We also opened north of the city. So we will probably have between eight and nine very large facilities around New York City here in the metropolitan area. In each of these cities, we are rolling out all our trials. Now we have many of these trials I was telling you about available for patients. So patients can come and see us here in Manhattan and then they can be treated at our local facilities and receive these drugs on our trials. They don't have to commute in here for every dose but they may come once a month into the city, for example.

Jenny: That's a great strategy.

Dr. Ola Landgren: Yes, it is.

Jenny: Yes. That's exciting. I want to leave some time for caller questions. I have an emailed in question that I would like to ask also. So let me do that first. If you have a question for Dr. Landgren, you can call 347-637-2631 and press 1 on your keypad. Go ahead with your question.

Caller: Hi, Jenny. Good afternoon, Dr. Landgren. It's a pleasure to speak to you this afternoon. I have a question about a new trial that we've heard about in the smoldering community. Your CRD trial at the NIH for high-risk smoldering was and continues to be successful as we have a few members in our smoldering group who continue to maintain MRD negative response based on, I believe, your MRD tests that you used while at the NIH. So I would think that's the MRD negative 10-6, the 1 out of 1 million cells that you referenced earlier. We watched a recent IMF video where Dr. Durie outlined the Black Swan Research Initiative cure trial. It's an aggressive approach for high-risk smoldering patients. He refers to it as the ASCENT trial. They'd be using carfilzomib and Revlimid with low-dose dex and daratumumab with two years continuing treatment of carfilzomib and dara. The trial, from what he explains, has two randomized arms. One arm would include a stem cell transplant with high dose melphalan, and one arm does not include an SCT. I would really welcome your thoughts as well as any insight as to what parameters the trial will use to define high-risk smoldering myeloma. Because of the backbone of the CRD trial that you held in the NIH, is this something as a trial that you would recommend to your high-risk smoldering patients?

Dr. Ola Landgren: First of all, thank you so much for being here on the call. It's a great honor talking to you on the phone. Well, I think that all the other topics we have talked about, there are very many different schools of thought. I know Brian very well and know the people behind that study very well also. When I look at the data that we generated at the NIH we found 100% complete response rates. When we applied the MRD tools we found close to 95% 10-5 and 90% 10-6 MRD negative. So when I've been thinking about how do you build on something that looks so very good, my answer to myself after thinking about this back and forth many rounds is, if you don't have the tools to measure your success then you have to improve your tools for measurement before you go harder on the treatments because these treatments are quite toxic. So my school of thought would be to try to understand why you don't have 100% 10-6. So how is this different from the ones that you'll have detectable disease? And also try to monitor longitudinally the MRD negativity. So my approach would be to build on what we did and try to understand why it didn't work. For those where it didn't work, maybe add something additionally to those such as antibodies or mechanistically try to carve out the details and use other strategies. This strategy you are referring to takes the opposite approach. So it's more aggressive. So without looking into any of those details you just give everybody a much more intense therapy. You give transplants or you give antibodies and you just add more drugs. Now, if they can cure every person then they were right, but if none of the people that were treated on the existing study who had a good response also were cured, then you could say that they are overtreating. So these are the questions that I don't know the answers to but these are questions that I'm thinking about myself. So either you go very aggressively and you do all these things or you try to figure why there is a subgroup where it doesn't work, then the longitudinal monitoring way did work. So that would be my answer.

Caller: Thank you, Dr. Landgren. Question for you though about your CRD trial at the NIH and success rate. Was it across the board for different cytogenetic abnormalities or was it more for standard-risk patients versus the high-risk to relapse features?

Dr. Ola Landgren: I'm glad you asked that. For the newly diagnosed study we did at the NIH we had 45 patients. I think there were seven or eight individuals with 17p deletions. At about three years of follow up every patient, except for one, has remained non-active disease. They have not recurred. One person did. There were also some people on the newly diagnosed study who had a recurrence who were not 17p deletion disease. So there is no evidence that 17p deletion responded less well, and that's exactly the same as Andrzej Jakubowiak showed in his newly diagnosed study also with CRD. For the smoldering trial, there were some patients who also had 17p deletions. So far, to my knowledge, none of those patients have relapse. These are small series. There are only 45 patients for the newly diagnosed from our series. Andrzej's study was 53. The smoldering trial was only 12 patients. So in my opinion that pieces that need to move forward is to understand why it doesn't work in every patient, and for those where it worked, to make sure that it works longitudinally, also I think to do a larger study. The proposal that you're referring to where you just give very powerful drugs, that's another school of thought. It's good that there are different options.

Caller: Dr. Landgren, how are you moving this forward, your thought process, to try to determine the relapse patients and the reasoning behind that? Are you opening up any studies? Are you considering and contemplating any additional studies for high-risk smoldering patients other than the daratumumab that you mentioned?

Dr. Ola Landgren: So I will daratumumab opening probably next week for high-risk smoldering. I have the ixazomib and low dose dexamethasone probably opening in January. I already have a protocol with carfilzomib, Revlimid and dexamethasone that has been approved internally at Memorial Sloan Kettering but it's still with Amgen and Celgene to approve that we can move that forward. So that does not include transplants. It's a similar protocol to what we did at the NIH but it has improved dosing and it has much more sophisticated MRD monitoring. What I was referring to between the lines when I said try to figure out what's going on, so we are setting up something called single cell sequencing. So we can actually sequence one cell at a time. That means that we can understand the biology of the cells that can escape these good therapies.

Caller: So the remaining cells, the MRD positive.

Dr. Ola Landgren: Correct.

Caller: Okay. Dr. Landgren, from a smoldering patient's standpoint I thank you for your investment in our patient population because, as you know, we're all anxious to try to do something. The watch and wait phase is a tough one to sell to us. So we applaud you and thank you. Hopefully some of us can become some of your participants in your clinical trials.

Dr. Ola Landgren: Thank you very, very much for your kind words. I try my very best. I'm trying to move these things forward. I try to be as transparent as possible so people can make decisions that kind of fit with their own thinking. I think that we are in an era where there are a lot of options, and different options come with strengths and weaknesses. I respect that people do different things. That's kind of the nature of life. I think that's how it has to be.

Caller: Yes, it is. I agree. I think it boils down to, from a patient standpoint, of which treating physician philosophy resonates with us personally. Then we're left with making the choices. Sometimes they're very difficult but with the assistance of someone like yourself who have such background in treating it and have the data and continues to follow it is very, very helpful. So thank you for taking the time today to speak to me and to share all of your insight with the myeloma community.

Dr. Ola Landgren: Thank you so much for having me. Take care. Thank you. Happy Thanksgiving.

Caller: Same to you. Thank you.

Jenny: Thank you, Dana. Sorry. Okay. Go ahead with your question.

Caller: Yes. I wonder if you could comment on the difference between bortezomib and ixazomib. One is obviously oral but are there differences in the mechanism of action and the toxicity? Is it true that insurance would only reimburse it if it's prescribed the way it's been approved by the FDA which looks like it's in combination with other therapies or can you just substitute it for Velcade wherever people are taking Velcade?

Dr. Ola Landgren: So we'll start with the first question. The drug is a 20S proteasome inhibitor. It blocks the same target or hits the same target as Velcade does. It's very, very similar to Velcade. If you look at the other 20S proteasome inhibitor which is carfilzomib, they can be split into two subgroups of 20S proteasome inhibitors, Velcade and carfilzomib can. Ixazomib and Velcade are in the same subcategories. So they are not only two 20S proteasome inhibitors, they are also in the same class of 20S proteasome inhibitor. So they are very, very similar. When it comes to clinical aspects of them, Velcade has, unfortunately, as you probably know well, has the peripheral neuropathy side effects profile. If you give Velcade intravenously, around 14% of patients can have three or higher peripheral neuropathy. If you give it subcutaneously, that number could go down to less than 4% per available data from clinical trials. With ixazomib, there is also a low-grade peripheral neuropathy that has also been recognized with that drug. So that seems to be something that's linked to that class of drugs. Carfilzomib has not been found to have that. So there's a little difference in those classes. The percentage of patients with peripheral neuropathy with ixazomib based on current knowledge, it seems to very low but it is still some signal. Another thing is that all oral drugs that are available, probably across the board for every disease, if you do oral versus IV or subQ, oral seems to be more associated with diarrhea. Ixazomib has some GI problems. Not every patient has it. In those people who have it, it is not necessarily bad. I think based on current knowledge it could be 20% or so that could have something. That number is probably a very loose number. We need to learn more about the drug. Also the dosing is only once a week. So if it's for only a few hours that may or may not be a big issue for people who suffer from it in relation to what the other drug alternatives are. Any oral drug has that component. Also what has been seen is that you have rash as a side effect of the drug. So some patients could develop skin rash. It has been found with Revlimid. But that seems to be transient and seems to go away relatively quickly for most individuals. That could, of course, be a range. I think there is also a little bit of fatigue over time. I mentioned a lot of the problems because you asked me for toxicity and the profile of the drug here. Most patients don't have big problems and very few patients have all these things. So there could be a range of a little bit of some of them or could have a little bit of something else. So I think overall it's quite well tolerable drug. The last question you asked me about is if it's approved to combine with any other drug and can you just replace. I am not 100% sure. I think that the label, the way it's approved is probably how it will be reimbursed right away but I think that probably is subject to change as more data will come out. That would be my guesstimate. I have not yet prescribed it. It was just approved a few hours ago.

Caller: Okay. Thank you.

Dr. Ola Landgren: Thank you.

Caller: It probably can't be just substituted all the time for carfilzomib until there's a bit more experience and insurance companies get more used to it.

Dr. Ola Landgren: Exactly, but this is probably going to change soon.

Caller: Okay. Thanks.

Dr. Ola Landgren: You're welcome.

Jenny: Thank you so much for your question. Okay. We have one write-in question that I'll end with. Jack says, "Concerning the recent approval of daratumumab in Rome, Dr. Anderson mentioned that its usage affects accuracy of the IGG measurements, and this was confirmed in the press release. Does that mean new assays are needed or maybe the M-protein tests are not affected?

Dr. Ola Landgren: Can you please repeat the question again?

Jenny: In Rome, Dr. Anderson said that with daratumumab that its usage affects accuracy of the IGG measurements. So his question is, does that mean new testing is needed or maybe the M-protein tests are not affected by that.

Dr. Ola Landgren: The issue is that for multiple myeloma by the response criteria you check the protein levels, and if they go down to zero you do bone marrow and then you confirm or you call it complete response. If you have a drug that is a monoclonal antibody and you give that to a person and you check the blood you will, if that drug has a long half-life, be able to see the drug in the blood. Now, it happens to be so that these drugs are monoclonal IgG kappa drugs. So what happens is that if you treat with these drugs, daratumumab, the SAR drug or other drugs as well, you will be able to quantify them and see them in the blood. So when you see that, if the lab is not aware that the patient received this drug then the question is "Oh, is it residual disease?" but, really, it could be the drug. Right now there are ways to overcome that or to figure that out in the lab but you have to use additional antibodies. So the lab needs to do more.

Jenny: And the lab needs to know what they're doing.

Dr. Ola Landgren: The lab needs to know.

Jenny: Yes, when they're looking at the results.

Dr. Ola Landgren: Right.

Jenny: That's a great answer. Dr. Landgren, we've kept you way over our time, I know. I know how busy you are. We're just so thankful and grateful that you took the time to talk to us today about your thoughts on these new drugs that are coming out and on the work that you're doing. We hope and pray you continue your excellent, excellent work.

Dr. Ola Landgren: Thank you so much. Well, I'm trying to work hard. I wake up every morning and I run to work. I work long hours. I'm trying my very best, I promise you that. Thank you so much for having me.

Jenny: Well, we really, really appreciate you taking the time out. We look forward to all the things coming out at ASH and your future work.

Dr. Ola Landgren: Thank you so much. Take care.

Jenny: Okay. Thank you.

Dr. Ola Landgren: Bye.

Jenny: Thank you for listening to Myeloma Crowd Radio. We believe that patients can help support the discovery of a cure. We encourage you to listen, learn and become involved