(Guest Lecture): April 2024 - Blood Based MRD Tracking

So good morning, everybody. My name is Ola Langren. It's really a great pleasure being here. We love working with Health3. We came here to Miami as a myeloma program. I came here, I was employee number four about three and a half years ago. And before that I served as the chief of Sloan Kettering myeloma program. I was there for seven years before and prior to that I was ten years at the NCI in Washington, D.C. So when I came here, when they tried to recruit me here, I said, if you recruit me, I'm not going to come just for the beaches and the boating and hanging out here. I want to build one of the top three myeloma programs in the United States within five years. So make sure if you give me the offer, if you give me an offer letter, I want to see in writing exactly what the commitment is because I really don't care about my title or things like that. I want to make sure that there is commitment from the institution. So Dr. Nymer said that why don't you write down everything you want and then we take it from there. And I said, why don't you write down everything you think? So he did and I looked at it and I knew that was the lowest level so I couldn't negotiate up from there. And we're very happy that Damien Green, our previous speaker, came to join the university just two months ago. So Damien is leading our cell therapy program and transplant program and I lead the myeloma program. And they are of course very much linked together. So Damien and I go over ten plus years back in time as collaborators and friends. We have had grants together. So we're going to keep on pushing the envelope of cell therapy and immunotherapy here with our programs. Today it was asked to talk about minimal residual disease in multiple myeloma. And as you heard from Jenny, there was a big meeting last week. So I thought that would be very appropriate to talk about what happened there and how will this really change the field to drive drug development faster in myeloma. This is going to impact all patients in a very good way. I'm going to walk you through briefly what happened there. Then I will talk about different types of blood-based tests that are coming. That's the future for testing. And we are setting everything up in our program here in Miami. And then very briefly about also reaching MRD negativity doesn't happen in every patient, but it may not really matter. So there are biological differences also. So what I presented at the FDA on April 12 was the evidence meta-analysis. This work that I worked on for a very long time. So I was a lead principal investigator together with Sean Devlin, who is PhD and statistician. I worked with him for many years in New York. He is at Sloan Kettering. The study is a worldwide collaboration with all the drug companies that own drugs or that they have drugs that they have filed to the FDA and they have all the data from their studies. So as you can imagine, these trials are worth a lot of money because that's how they got the approval. So to get access to these data sets is not easy. This is sort of the core of the business for the drug companies. So I was able to negotiate with every company that had data sets that we got a copy of the database. So there's a lot of trust and a lot of legal language for sure. We finally got everything so we could integrate this and build a meta-analysis. The legal language said that we can only share it with the regulatory agency and we can also share the results like here today and in publications. So when I came to the FDA, the focus of that day was to make sure to the FDA that it's clear to them there is not yet an established curative treatment in myeloma. And also that the most important treatment happens in earlier line, the first line, the second line, the third line. The therapies are getting better and better, but earlier is always better. And with the current endpoints when you try to prove that the new drug is superior to an old drug, you have to use progression-free and overall survival measure. What that means is that you have to benchmark against existing drugs and show that the new drug have fewer patients relapsing and no one is passing away from therapy with a new therapy. But because the therapy is so good, it could take 10 years to make your case. And that means a patient has to wait that long. We cannot wait that long. We need drugs faster. So that was really the objective, asking the question, can minimal residual disease detection serve as an objective and reliable early endpoint for what's called accelerated approval that would facilitate rapid access to new drugs? When I was at the NIH many years back ago, I saw this coming in 2009 and I formed a group of investigators. We formed an interagency collaboration between myself and a couple of other people within the government. So we had the National Heart, Lung, and Blood Institute, the National Cancer Institute, and also the FDA. So we started an internal group pushing forward. What I saw in my clinic at the time, I had access to drugs that no one else had access to that virtually every patient had a response, an overall response. And I also saw that more and more patients received a complete response. So I was thinking in my head, if we don't push the envelope, either we don't have to check because we already know everyone is in a complete response or remission, or we have to do better testing because we knew that in remission there could still be some residual disease cells. And I wanted to know where those cells were and if they were there so I could get rid of them. So pushing that forward, we formed this group. We then had a roundtable at the FDA in 2012. And we invited a lot of people that were patient groups. The International Myeloma Foundation was there. And we had also from academic groups. We had Dr. Gormley that subsequently became the FDA lead for this. We had Dr. Dury from the IMF. We had invited Dr. Paiva and others. And in 2014, I decided to do an annual meeting on MRD to highlight the importance. And I said to the FDA, I will invite you every year till you approve it. We have next meeting on May 9th, by the way. So I was then advised to file what's called an IND, an investigation on new drug application. That's the same exact mechanism that the drug company would use when they want the FDA to consider if this drug could be approved or not. So a drug company has a drug. They go to the FDA and say, we want to do a trial. We want to make this drug for patients with this or that disease. The FDA will say, why don't you write the protocol? And this is what you need to do. And then they put in an application for an IND that becomes a number in the federal government's record. And they would do the study. When the study's done, they hand in the data. The FDA will look at it, and if it's successful, it would be approved. So I was told to put in an application as an individual physician scientist for an IND, not for a drug, but for MRD, which has never happened before. Then we worked for many years. I worked on this for 15 years. So you better be prepared for a lot of work. And I tell the fellows, if you want to have an impact, you really have to make sure that you're stubborn and persistent. You never give up. So I worked on this statistical analysis plan with my statistician, and we worked with the FDA. We set up all the legal paperwork. And as you can imagine, I mentioned these data sets is really what makes the drugs approved or not. So why would a drug company share that with anyone? So it builds really on trust. So we set up a model, and we got data sets over time. And back in 2021, finally, the FDA approved the analysis plan. And I went endless number of times to the FDA. I then submitted everything in May last year, the full report based on the analysis that they had approved, read all the data sets, gave them all the data sets, and also gave them all the statistical code so they could redo all the analysis themselves and double check that everything we had written in the report was true. And we were then invited to come April 12. They told me that the week before the holidays, before Christmas, I had a meeting with them and every time I met with them prior to that, they had said, we want another data set, we want another data set, we want another data set. But last December, I expected them to tell me that, but they said, this is great. Let's set up a meeting for ODEC. So we met April 12. And as you can see, for 15 years, we continued FDA feedback. We worked on this. So what this is all about is to push the envelope forward. I probably can skip some of the background slides here. I put some of these slides because I wanted to show the FDA the importance of it. I just briefly walked through here. So we have over 35,000 patients diagnosed in the U.S. There are close to 200,000 people living with the disease. We know in African Americans and people with Caribbean background, it's two times higher risk of getting myeloma. We still don't understand why. It happens earlier. And as you heard me saying, that progression for survival is really not a good endpoint. It takes too long. So I also made a case for the FDA that we have a lot of drugs. We have over 40 approved drugs. But we still lack a cure for the disease. And that's why we came to the FDA. It's good, but it's not good enough. We have to push the envelope. We need more drugs. We need better drugs. And I also made a case to the FDA saying that in early alliance, that's where we can develop the cure, but we can potentially also do curative therapies, I think, in subsequent lines if we do it right. So I really try to emphasize we need new drugs. So this is sort of a propaganda talk to the FDA, as you can imagine. The progression for survival endpoint was actually approved by the FDA 15 years ago. And prior to that, drug companies had to show survival benefits. When I was in fellowship, I've been a doctor for 29 years. When I was in fellowship, the endpoint of oral survival was to beat an old drug that could only make patients live for two years. So if you could do two and a half years, you could get the approval. But today, patients in our clinic live 10, 20-plus years. And I think many patients will have the same lifespan as a person, same age and gender without the disease. But the problem is that we cannot cure the disease in every person. That's really where we are lacking therapies that can get rid of the disease. With progression-free survival, you capture if the disease comes back. So to illustrate the dilemma here when you design the study is that it takes about two years to identify and enroll patients on a trial. And then you have to wait for all these years to show that your new therapy in red is better than the existing therapy. This is why it takes 10 years. And still, you have not been able to develop a cure. And that eight year, I can tell you I've done a lot of estimations, and I was prepared if the FDA was going to ask me. I actually have data showing it would take 12 to 14 years. So it could be somewhere, say, 10 to 15 years in total. So the FDA has been aware of this for a long time. So they implemented the accelerated approval pathway. So they said, let's not wait till the end. Let's have an endpoint in the middle that you could capture. And if that is successful, maybe we can grant approval through the accelerated approval pathway. They also launched a project called the Front Runner Project, where they said don't develop drugs for patients with multiple relapses. Develop drugs for newly diagnosed patients. Well, the problem is they didn't tell the companies how that was going to happen, because there is no way that can happen. In myeloma, this surrogate endpoint that I was talking about for the accelerated approval pathway is the overall response rate. An overall response means that you treat the patient, and if you get rid of 50% or more of the disease marker in the blood, you can say there is an overall response. Again, that's not how we're going to develop a cure. If there is 50% left of the disease, we know that the disease will probably come back. So we need a better endpoint. If you graph these out, here you can see different regimens over time, and you see a lot of acronyms on the x-axis, VAD, RRD, Cyborg, RRD, DRVD. What this shows you is that in red, more and more patients are having an overall response rate, and on the very right, you see it's very close to 100%. So very few percent to improve upon. But yet, in the red group, you may have 50% of the disease left behind. So this is a really bad endpoint for this disease, because if almost everyone has reached the threshold to say there is a response, and there still is a lot of disease, you cannot do a study. You have to have 10,000 or 50,000 patients in order to show statistically that you made a difference. So it really is a dead end for drug development. That's why we need a new, objective, reliably measured endpoint, and this is federal government language saying reasonably likely to predict long-term outcome and clinical benefit. That's what the federal government says. If you can say that the endpoint does that, they will look at it. And that took me a long time to figure out that you have to talk that same language, so they are paying attention. So what are the requirements for drug development for surrogate endpoints? Well, you have to, first of all, have an endpoint that is linked to the disease biology. Well, MRD actually is. You also have to show that there is a prognostic value. So if you treat many patients, if they reach MRD negative, they're going to have a better outcome versus if they are MRD positive. So you can check that box also. And then you have to do what's called a treatment effect of the surrogate endpoints with a long-term effect. So that means that if you have a randomized study, if there are more MRD negative on the experimental arm than on the control arm, you would like to see that progression for your overall survival is also following the same trajectory. MRD checks that box too. So MRD checks all the boxes in myeloma. So at least we didn't have to have that conversation with the FDA because the MRD already did that. So that's why I was interested way back in 2009 to push forward and develop this study. So I said to the FDA, we will tell you today that our study will give you the evidence to support MRD as this endpoint for early drug approval in the accelerated approval pathway. And I'm not going to bore you with a lot of more slides about this. I just took one slide, and here are a lot of numbers, but I highlight for simplicity arrows on the left. So what this means is that if you look, it's a study. So the studies were labeled by different codes. And then you look at the treatment effect. So that is if there is more MRD negative in the new drug versus the control arm, if that number is 0.00 something, the smaller the number, the more big difference there is in favor of the new drug. And then if you move to the right, if you see the treatment effect on progression for survival, that's the mid column. If there also is a very small number, that tells us that there is much better effect for the new therapy for progression for survival if you move on to the right. And what you can see is that there is consistency between the MRD and the progression for survival. So this is the type of information you need to generate. And there are tons of other slides that I'm not going to bore you with. But this is a very, very strong evidence. So I said to the FDA, we have come a long way. Myeloma used to be a disease where there was nothing really to do. And before I was in fellowship, there were very few options. When I was in fellowship, chemotherapy was very popular. And patients were categorized into transplant eligible or ineligible. But really what's happening right now is that we're heading into the new era of immunotherapy. We already entered it from a drug development point of view. But in order to really push that envelope in the clinic, we want to develop modern chemotherapy free therapies with the potential to offer patients the same lifespan as the general population. And as you heard me saying, I've been a doctor for 29 years. When I was in med school, HIV, there was nothing to offer those patients. Patients got AIDS, and there was nothing we could do. It's just palliative care. Today, I'm sure you all know this, we have for the past over 10 years reached a point where people that have HIV infection have the same lifespan as the general population because the disease is no longer causing severe outcome on people's lives. We don't yet have a cure for HIV, but we have medications to hold the disease away. I honestly think that for myeloma, there are many patients diagnosed in 2024 that have the same lifespan as a person with the same age and gender without myeloma. What we are missing is the access to an objective and reliable endpoint that's reasonably likely to predict this outcome that will allow us to develop trials so we can get drugs approved much, much faster so we can develop this curative treatment for all the patients. That's what we need to do. So Jenny already told you, this was a seven-hour courtroom-style grilling in Washington, D.C. But after 15 years of warm-up, we are ready for that part. So we took this picture afterwards. So this was better than a European soccer game, 12-0. That was in favor of yes, right? So thank you. So this is really a big win for all the patients in the United States. So I should say that we did this, and around 2013 or so when we invited other people to attend, I showed you on the timeline, the International Myeloma Foundation decided to develop their own project. And I think that's great. And I think we have worked in parallel as two independent groups. So they were also part of this presentation at ODEC. So they presented after our presentation. And they confirmed and showed very similar results. And that really gave the FDA a lot of confidence in this. If two groups, independent of each other, show very similar results, that's as good as it gets. So I think that's part of the reason why they also voted yes. What has to happen next is that ODEC is the advisory committee, and ODEC doesn't make the final decision. The FDA asked ODEC to give them advice. No FDA has to, in writing, say what will be the new rule. So everyone is waiting for the FDA to come back and say what the new rule will be. What was discussed at the meeting, and there are records for this, is available online. You can actually watch the whole six, seven-hour show on YouTube if it's a rainy day. It's a very long discussion. Also it was discussed that MRT should be the endpoint for both newly diagnosed and relapsed patients. It was also discussed that it could be either flow or sequencing-based technologies. And also the time point to capture it in trials was discussed. And the FDA wanted it to be very flexible, that you could use pretty much any time point. This is a very technical language. If I had written the FDA's summary, I would not have written it differently from what they did in preparation for the meeting. They were very, very supportive. But I would like to see that in the final document. So we are all waiting for it. So how will this impact the new trials for myeloma going forward? It's going to change everything. Everything is going to change for the better. So you can think of here is a newly diagnosed trial for patients with myeloma. A randomized trial could capture MRT, say, one year into the game. So you enroll the patients. If that takes two years, and after one year you check MRT, if there is more MRT on the new treatment, that could give approval to that new therapy. Is it waiting for 10 to 15 years? We could shrink it down to three years, which is amazing. The FDA would then grant accelerated approval. The company would then have to capture progression-free and oral survival. And once the study is mature, when the data has been collected for, say, over 10 or 15 years, they would get the full, the regular approval by the FDA. The company will have to show progression-free and oral survival, all the safety data at the time of MRT as well, because we want to make sure that the drugs are safe. We're never going to lower the bar in terms of safety. This is really a way to shrink 10 to 15 years down to three, no more than five years. And this is how we can push the envelope and develop curative treatments. The same study design would probably become the new reference for many of the relapse indications. So here you have relapse refractory disease, and it looks exactly the same. The only thing I changed here is moving newly diagnosed to relapse refractory. So the question here is, what would be an appropriate control arm? I think that there could be randomization between different dosing levels. So you could have a higher dose or a lower dose. And if you can capture MRT, you could get accelerated approval as a company for this indication. You capture the data going forward, and you get your full approval. So really what this is is exactly what we have here in Miami. It says 60 miles per hour on the highway, but everyone drives 180 miles per hour. So drug approval gets three times faster. So it's the Miami model here, really. So now I will switch topic from MRT as a tool for drug approval. So I will talk about MRT in the clinic. So everything that was discussed at the FDA were bone marrow-based assays. There was one FDA-cleared assay with adaptive clonal seek or adaptive biotech, the clonal seek assay where you can capture next-generation sequencing signatures. This is the same exact assay when they looked in the blood. So if you look in the blood of someone who has myeloma, you can actually find the same signature as you find in the bone marrow if you do it at the time of diagnosis. But if you pay attention to all the details here, you see that the dots are not showing one for bone marrow and one for blood or 100 for blood and 100 for bone marrow and so forth. There's a little drift to the right. So what does that mean? Well, it means that there's much less disease in the blood, which is sort of obvious because if the disease lives in the bone marrow, you probably will find less of it in the blood if you check. So it's 100 to 1,000 times less. But although that is the case, there is data that you could use this very assay to track patients going forward. If you remain negative in the blood with the adaptive clonoseic assay, you are much more likely to not have a progression event. So the point here is that you can use S-PEP and IFE. You can use light chains. We have used them for a long time. But if you use this adaptive clonoseic assay in the blood, that's a more sensitive tool than just the protein assays. It's less sensitive in the blood than the bone marrow because there's less disease in the blood. But it is still more sensitive than the regular protein assays. So all the other ways to do it, yes, there are many other assays out there. So you can look for something called circulating myeloma cells. So the adaptive assay looks for DNA is in the blood and comes from the myeloma cells. But you can actually try to capture a single free-floating myeloma cell in the blood. You can also capture DNA and not only focus on what the adaptive assay does, you can actually try to sequence the whole genetic code, the whole genome from the blood. So there are a lot of assays that have been developed for this purpose for many years. And it's not only for myeloma. It's for a lot of the solid tumors, colorectal disease, and other diseases people have done this. So if you look in myeloma, here's data I got from one of our collaborators up in Boston. We have been in the field for many years. We work with all the other groups. So here is from Irene Gourbriel's group in Boston, a data she has presented where she compared circulating cells with bone marrow assays in the same patients. And what she shows is that all the changes that you can capture in the bone marrow, you can actually see them in the blood at the time of diagnosis. Now, what this slide doesn't show you are all those cases where there is nothing in the blood. So if you find something in the blood, it's the same as you see in the bone marrow. That's great. But the full story is that up to half the patients in the Boston study has no information in the blood. There is nothing there. You miss every other patient. And that's because this assay is not sensitive enough. When it works, you can characterize the disease cells and you can study how these cells are changing over time. We know that you treat with a sort of therapy and it works very well. If there is resistance, what happens is that the cells are acquiring new mutations, new changes that make them resistant to the therapy. If you switch to another therapy, you can kill them, the majority of them. They may over time acquire new mutations. So now you have to switch back to some other therapy. So this is a way to sort of increase it beyond just checking, is there disease, yes and no, MRD. Here you try to characterize if there is something, what does it look like. We have set up this exact assay here in Miami. And we will offer all patients that come to our center testing with the blood-based tracking of circulating cells here in Miami. This is the Menarini system. Here you have an example of how the disease in blue changes. There is more of the blue on the right and there is less of the orange. So these are like sub-clones of disease that come and go. We are also setting up assays for protein tracking. So SPEP and IFE and light chains have been around for a very long time. But you could use other type of platforms. You could use lasers and you could buss very small amount of serum. So if you have a little plate, it's a very small little plastic plate. They come in 96 well plates. And you can put just 10 microliter of serum, which is very, very minimal in each of these wells. You have five wells for one patient and you let the laser buss each well for 10 seconds, which is 50 seconds. You have five little drips from the same patient, well one, two, three, four, five. You buss each of them for 10 seconds. If you do it, it's going to look like this when you're done. So in less than a minute, you increase your sensitivity by say 100 or so times compared to SPEP and IFE. So this is another way. We already have this technology and we're going to offer this for all patients coming to our center in the coming few months. We are working to set up another technology, which is an integration of sequencing and protein. So if you remember from biology in high school, all the cells run on genetic code. That turns into RNA and the RNA turn into protein. So you can track these different levels. And of course you can look for structures, surface markers and things like that. So the Clonocic assay is DNA based. The protein is sort of the end result. So could you link those two in some way? Yes, you can. So what would be the benefit? Well, the benefit is that if you're looking for disease specific proteins and you know exactly what to look for, you don't have to worry about any background proteins because there's so many background proteins. So this is work I did in New York with Ahmed Dogan and Jessica Chapman when I was at Sloan Kettering where we took tumors and we sequenced them and we look at the sequence to see with these sequences what would be the actual proteins that would be cranked out that we can look for in the blood. So we could look for patient specific peptides. We're now working on a very, very sophisticated assay that's called Clonic Peptide Mass Spec where we can bust blood similar to what I told you about the wells. We can bust the blood and we can look for very specific peptides. We don't have any background to worry about like we have with the other technology and here we can increase the sensitivity not 10 or 100 times. We are over a thousand times more sensitive. So if we are trying to see if these potentially can replace bone marrow biopsies, we are setting this up as well. So my philosophy is that we run the race track and we let all the cars come and drive on the race track and we will find which car is the best. We don't have any preconceived notions. We just let all the cars in and they're going to drive there and we're going to see. So we're going to test for the circulating cells, the MALDI, we're going to do the clonic peptides and we will just keep on adding more and more assays. And we will use internal funds to fund all this. So if patients come, we can test very small amounts of blood and in one year, last year we had over 8,000 visits for myeloma. Next year we're probably going to have 9,000 and next year we're going to have 10,000 and we just keep on growing as a program. So within one or two years we will have the database that will answer the question how this is going to work. That's how you advance science. We're in this for the long run. I told you I was employee number four. I checked our list because we had a social event. We are close to 60 people on the team right now. So we're going to keep on pushing the envelope for this. The last thing I'm going to say before I wrap up is that myeloma biologically is a very complicated disease. We do fish and cytogenetics. We have done that for a long time. That's just the surface of capturing the disease. If you do whole genome sequencing, meaning that you sequence every single base pair in every myeloma cell, you will see that myeloma is shaped up by eight distinct signatures that we don't really understand how that works. One important signature is the Applebeck signature. We see that some patients have very high Applebeck activity that causes a lot of the problems when the disease becomes resistant to therapy. Copy number changes in the middle is what you get when you do fish and cytogenetics. There are some chromosomes that have additional copies, the odd chromosomes. They are commonly increased in 50 percent of our patients and there are other changes as well. You also have the structural variants that involve chromosome 14. There are partner oncogenes that partner with chromosome 14, 414, 1416, 1114 and so forth. And then there are the complex events that are completely not really investigated yet. We have started doing work and we show that up to a quarter of patients with myeloma have something called chromatripsis. That's also very important for prognostics. We published a paper a few months ago where we integrated all these things and we're going to keep on pushing towards precision medicine but we want to tailor the treatment for every patient towards his or her disease. And our goal is to try to seek curative therapies. We also done a lot of work. You heard Dr. Coffey in the morning. He was talking about the immune microenvironment. This is a paper. Dr. Coffey was the lead author. I was the senior author. We published this a few months ago where we show how the immune system actually normalizes in people who achieve MRD negativity and sustain MRD negativity. It looks very similar to a healthy individual. People that lose their MRD status, their immune system doesn't really revert back to normal. And we think that maybe this is something we need to pay more attention to, maybe come up with strategies not only to go after myeloma but also to help the immune system to recover, which I think is probably the next wave of thinking for us. The last few slides here, people have sort of thinking about stopping therapy. We are not yet at the point where we can say this is the time to stop therapy because we don't really have the data. This is one out of several studies, the master trial where patients were treated for up to 12 cycles with a transplant and then they stopped. And they showed that very high rates of patients achieve MRD negativity. And if you followed them for a couple of years, the majority of patients didn't relapse. The latest update from this is three years out, 85% of patients remain free from disease. So that's pretty good. We would like it to be 100% or 99%. So how are we going to get there? I think we need to partner the profiling with MRD, with characterization of the disease and the immune system. So can some patients stop therapy? I think we will come to that point and that's where we are going to keep on pushing the envelope. So Dr. Diamond, who's going to be the next speaker, did a study published in the Lancet Hematology where he showed that there are patients, this one doesn't work, there are some patients that have just a little bit of disease and it just could stay like that for many years. So we have patients who are a little bit MRD positive and 10 years later there is no progression. So there could be cells that could be hanging around that really are not planning on proliferating and causing trouble. So some patients go into MRD negative, many patients do. In our clinic a very high number of patients do. Some of our patients they don't and we keep track of those cells and make sure that they are not going in the wrong direction. So I would like to thank everyone on our team. I want to show you the very last two slides here. So our team, we have now close to 60 people, very big clinical trial program, we have a very large computational oncology program. We have seven, we are just recruiting the eighth faculty. I'm extending an offer letter next week for the eighth doctor and we were very small when we came here. Our goal, as I said, is to be one of the top three myeloma programs within five years. I think two years from now we're going to be the same size as Sloan Kettering was the day I left the job. And we're right on track for that and we're going to keep on pushing the envelope. If you're interested in MRD, I showed you this very last slide here, that we have this annual meeting with the FDA. If you have your cell phone, you can just take a photo of this little QR code there and you can register now for free. You can also find it online. You can type in Miami myeloma MRD 2024 and you can register online. It's going to be a four-hour program. It's going to be May 9th between 9 a.m. and 1 p.m. And the program, I think, is very, very relevant. We have four speakers talking about the newest trials where MRD is integrated. We have four speakers talking about new assays for tracking. And the last session is about stopping therapy. The master trial will have an update. MSK study will have an update. The University of Chicago study will have an update. And also the UK 11 trial will have an update. What happens if you stop therapy after you have been on maintenance for a long time? There will also be a fireside chat with the FDA. So I intentionally scheduled this meeting after the ODEC so I could ask them what's going to happen next. So I'm going to ask them that particular question. And we also have Health 3 Myeloma Research Foundation and International Myeloma Foundation part of this. I'm very happy. This is really a joint project with all the organizations. With that, I thank you so much for your attention. Thank you. Thank you.