 Hi, everyone. Welcome to this webinar on minimal residual disease testing in Myloma, organized by Myloma Patients Europe. I am Cylentin Saldan, a research assistant at MP, and before we start, I would like to go through some of the technical aspects of this Zoom webinar. So first of all, you should be able to see and hear all presenters, but you will not be able to see or hear any other attendees. If you cannot hear presenters, make sure that your speakers are not muted and that the volume is set high. The gallery view setting in Zoom enables you to see all the presenters in a tiled format on your screen, and the view setting can be changed in the upper right corner of your screen. And please use the questions and answers feature, which is found in the toolbar at the bottom of your window to ask questions to the panel. And please do this throughout the whole event. And you can also click the like button for specific questions to upvote certain questions, which will let us know which ones are more interesting to you. And you can also use the chat feature with other participants to share your experiences or comments on the current discussion. And if you are experiencing any technical issues, please let us know about it in the chat and one of our colleagues can help you. If you are having any troubles with poor video or the signal cutting out, please consider attending this event in audio mode only this webinar will be is being recorded and will be available on our website and social media channels. Thank you all again for joining and I will now briefly introduce MP and the agenda for this event. So Miloma Patients Europe is an umbrella organization of Miloma and AL amyloidosis patient organizations across Europe and MP currently has 48 members based in 31 countries. And our mission is to provide education and information, and to support our member groups. Our project we are presenting today is part of MP's patient evidence department, which was established to better understand what research gaps exist within the Miloma landscape, and to generate evidence that seeks to influence decision makers, and to definitely improve treatment care and access for all Miloma patients and their families. And over the past year and he have conducted research to better understand the patients and hematologist perspectives of MRD testing in Miloma. The rationale and results of this project on MRD will be presented shortly by myself. And then we will present I will present the panelists for the day, and that they will share with you their perspectives of MRD and debate different questions that arose through our research. I would like to thank all our panelists for joining today, and we will finish off the event with questions and answers session as well. So before we begin, I would quickly like to give a brief overview on what minimal residual disease is before going into the rationale and methods of our research project. MRD refers to a very small number of cancer cells that remain in the body during or after treatment. MRD testing such as flow cytometry and next generation sequences uses advanced laboratory methods that can find one cancer cell amongst one million normal cells in the in a bone marrow sample. And these remaining cells often cannot be detected through traditional tests of treatment response and may cause no physical symptoms. So positive MRD results indicates that cancer cells were identified. However, if a patient is MRD negative, meaning that no Miloma cells are found at that sensitivity. It means that there's a very deep response. And if this continues over time, it can potentially indicate a better prognosis. So there is a wide range of scientific articles exploring the application and use of MRD. There is a very limited number of studies assessing the qualitative perspectives of patients and clinicians on the current current and potential impact of MRD. And before this research project was designed to understand the patient and clinician experiences and perspectives of MRD and its potential use in clinical practice. Our research explored the current and future uses of MRD and how the understanding and expectations of the potential align or vary between patients and clinicians. And we also gathered with some perspectives on the use of MRD as a surrogate endpoint in clinical trials and in regulatory and reimbursement decisions. So for this project, we conducted a non systematic literature review to identify themes related to MRD that then underpinned our discussion guides. And we then conducted individual interviews with nine European hematologists and held to focus groups with 14 European Miloma patients. And the interviews were then transcribed and thematically analyzed and the results were written up in a report format. The project's development was also followed and reviewed by a steering committee, which comprised of patient experts, hematologists, researchers and regulators. And I would just like to take a moment to thank everyone who took part in this research project, whether it was by taking part in interviews or by reviewing documents throughout the project. We really appreciate it and this project would not have been possible without you. So moving on to the results. To begin with, we wanted to understand how familiar patients were with MRD. And we found that there was quite a wide range of familiarity. Some patients were completely unfamiliar and one patient had never heard of heard of MRD before joining the interview. Other patients were familiar with MRD testing, but had no personal experience with it. And only three patients had firsthand experience with MRD testing. Two had undergone MRD testing as part of a clinical trial. And one had undergone MRD testing in clinical practice. So patients found that MRD testing in clinical practice is very promising and stated that it would be particularly useful if research showed that it is an indicator that maintenance therapy can be stopped. Most patients stated that they would be open to more frequent bone marrow tests, provided that the information was useful for treatment decision making. They also agreed that they would undergo more frequent MRD testing if the methods were less invasive, such as through blood serums. And patients also stated the importance of considering the potential cost of MRD testing and the implications of potential cost savings to health care systems from potentially stopping maintenance treatment. So all hematologists who participated in interviews were optimistic about the potential use of MRD testing in clinical practice. Some hematologists stated that their hospitals are increasingly requesting MRD testing among patients who have had maintenance therapy for several years and are considering stopping treatment either due to side effects or personal circumstances. And in future MRD testing may assist hematologists in reducing the over treatment of patients. One healthcare professional mentioned that they use MRD testing to determine whether or not to perform a second stem cell transplant. So if a patient was MRD negative after the first transplant, they would maybe decide not to do a second transplant. And hematologists also emphasized the importance of being transparent with patients and explaining that MRD testing is experimental and that evidence is still being collected. So without specific guidelines, hematologists decide individually or as an institution when to request MRD testing and how to use the information. So we gathered some of the key questions that patients and hematologists have regarding MRD and the main questions are regarding treatment milestones or time points. So when MRD testing should be done, whether the location of a biopsy matters in terms of accuracy of the results and what additional tests or risk assessments patients should undertake to inform whether they can feel comfortable stopping maintenance therapy. There are multiple barriers to MRD testing in clinical practice. First of all, hematologists noted that MRD testing for MRD testing to be implemented, implemented equitably across European countries, laboratory capacity needs to be expanded. And many hematologists stated that laboratories conducts reliable and consistent tests. However, one hematologist had observed that different laboratories produce different results for the same sample. Hematologists also stated that they would need additional training on when to use MRD testing, how to apply the findings to guide decisions and on what to do with MRD results if it conflicts with other relevant tests. And lastly, hematologists commented that MRD testing is not covered by all insurers in all healthcare systems. And in some countries, patients need to go out of pocket to get MRD tested and may not fully understand why they need to pay extra for these additional tests. We also asked patients and hematologists about the impact of MRD testing on patients and their families. And patients stated that their emotional responses would be unique to their circumstances. Several patients stated that waiting for results could be extremely stressful for them and their families. And on top of that, patients pointed out that the MRD biopsy technique themselves can be burdensome for patients as these methods are quite invasive. However, some patients did not anticipate a negative emotional impact and stated that the MRD results could be useful for planning their personal lives, for example, whether to go on the holiday or not. And patients did emphasize that a positive result would be much worse if no alternative treatment option was available in their country. So we did ask interviewees about strategies to managing the emotional impact of MRD testing and found that clear communication from hematologists is key. Hematologists should discuss the purpose of MRD testing and how the results may or may not guide treatment decisions. They should discuss what to expect during MRD testing and give information about how to interpret the results. It was also suggested that this should be delivered through a telephone call or during a visit to allow patients to discuss the results and plan next steps. And alongside this, hematologists need to make sure that patients are provided with timely support, for example through peer support groups or through professional counseling. So in our research, we also explored the perspectives of patients and clinicians on MRD as a surrogate endpoint. And patients thought that if researchers demonstrates that MRD status is a reliable surrogate endpoint for survival outcomes, it would be an important advancement. However, some patients emphasize that they saw it only as additional information and not as a replacement for other lab tests. And several patients were concerned that if MRD status becomes a common outcome measure in clinical trials, it could be used by government agencies and insurers to deny maintenance treatment or withhold new and potentially expensive treatments. Hematologists also saw a role of MRD testing in clinical trials, especially as an opportunity to make new treatments available sooner, but also showed some concerns. They stated that MRD testing should be a co primary endpoint or support conditional approvals, but that larger and longer trials are needed to validate MRD as a surrogate endpoint. And consensus is also needed regarding when and how often MRD testing should be conducted. And Hematologists also stated that researchers needed to understand minimal clinically relevant differences in test results between negative and positive MRD results and how MRD status correlates with long term effects of relapse. And lastly, although MRD testing is useful for many patients, there are some patients for whom it doesn't work and it is important to explore this and how genetic profiles may potentially contribute to this. So in conclusion, our research generated multiple recommendations. The first being that more research needs to be conducted and that the results need to be communicated with patients. There needs to be clarity on how frequently MRD state a test should be done and how the results should guide this treatment decisions. Additionally, as mentioned before, there needs to be better clarity on why MRD testing is predictive of improved survival in some patients, but not in others. The second recommendation we have is that it is crucial to place the patient needs at the center of MRD testing. Hematologists need to provide timely and convenient emotional support for patients and their families and deliver MRD tests with the potential for patients to discuss next steps. The last recommendation we have is to develop training and resources for patients and healthcare professionals. As a myeloma community, we need to develop introductory materials for patients and their families on what MRD is, how it is tested and what the results mean. And we also need to develop information for healthcare professionals about when and how to, how MRD results should guide treatment decisions and also develop training for laboratory staff. So following the recommendations, we have worked closely with stakeholders to develop educational materials as a first plan of action. Firstly, we have written up an advocacy report on this project, which is well as well as an extensive questions and answers document. And we have also created an educational video on MRD, which have been sent in the chat or should be sent now. And you can find all these resources on our website and our virtual exhibition room, which again should be sent in the chat now. And after this event, we plan to continue to engage with the myeloma clinical community to discuss the direction of MRD. And we will also continue to engage with FPA on surga endpoints and develop further educational materials for our members across Europe. So I would now like to take some time to introduce our five panelists for the day. Welcome. First of all, we have Hans Schruer, who is a myeloma patient and the chair of the workgroup of European Cancer Patient Advocacy Networks. Next, we have Dr. Martin Kaiser, a hematologist at the Royal Marsden Hospital and Institutes of Cancer Research in London. Next, we have Dr. Bruno Paiva, researcher at the Clinica Universidad de Navarra in Spain. We also have Veronica Calzada, who is an oncology novel endpoints representative at the European Federation of Pharmaceutical Industries and Associations. And lastly, we have Paula von Hennig, who is the director of regulatory sciences at Pro Pharma. I would now like to pass the floor on to Eric Lowe, who will be moderating our panel discussion today. Thank you. Thanks, Lynne, and thanks for a great, great presentation. It's definitely stirred up a bunch of questions and emotions for me, so I'm sure it's done the very same with the panel. So I'm sure we're in for a really dynamic and robust discussion in the next hour or so. So first off, this is my name is Eric Lowe. It's a great honour to have been asked by MPE to moderate this webinar on MRD. I'm a huge fan of my patients Europe. I have a huge respect for their work. And also, it's an honour to be moderating the discussion between some really brilliant panel members. So the first thing that we're going to do is just give each of the panel members two or three minutes just to respond to the findings of the MPE report and just sort of give some commentary on reflections from kind of their perspective. I'm not sure what the best order to do it is whether I look at my sheet and copy it, but I think we should start with the hands. It's always good to start and end with patients. So hands, I'd be interested in your reflections and thoughts on Celine's presentation and the findings of the report, and then I will just go back to my list and follow it in the order I was given. Thank you, Eric and Celine for introducing this interesting webinar on MRD. And thank you for inviting me to join the MRD panel discussion to be able to provide a page perspective that is also captured in the research project itself. First, I would like to express that innovation is not similar to improvements of myeloma care and cures. It only depends on the use of the innovation and where to it is used and what questions or needs are addressed. So in the case of MRD testing, it is more or less, although from the patient perspective seen a fine tuning of the remission. That is when having a complete remission, I would say when you are in a complete remission or a string and complete remission the MRD test is the finest test to show that to show how deep your remission is and that is more than a nice to know. When in a deep remission MRD negative, no malignant plasma cells detected on the MRD test level. It is a very deep remission. This means for the patient, the treatment was remarkable effective. It killed almost all my cancer cells. That is what you want to hear from your doctor for sure. It contributes highly to your to your mood, your spirit to continue the quality of life. Also for the family around the patient. The other thing is when you reach every negativity. It means mostly that within your bones, there's no now plenty of space to grow healthy bone marrow. And that means that your blood normalizes. And with that, you get back energy over time. And there is more space for your body in general to recover parts that were affected by the malignant cells before the treatment. So yes, knowing that you are Emily negative has many positive implications for the patient. It's about the impact on the daily life and life perspectives. The third and last aspect I would like to mention is that everybody is measured by bone marrow function. And many patients fear that the important measure points to detect how treatment is working can solve this, looking at the use in clinical practice. It might be good to just do the regular checks through blood serum, where you can look at the levels of M protein and light change, etc. Besides all the other indicators that say something about your health. And it's a no brainer to state, I think that MD testing is not very eligible for daily, weekly monthly checks. You need to define specific moments to put in MD testing to check the status of the disease. There are more treatments to have a starting point and appoint a few months later, maybe three months later that depends on a treatment difference from treatment to treatment. When you could assume that a remission is reached. So, you use everybody fine tuning of the state of the disease on meaningful moments that are for sure meaningful moments for the patient and its family. In this research is that patients responded that they are not against the MD testing in clinical practice. If they understand what it adds. So explanation is important. If it's used before start of the treatment and a few months later after start when reached a complete or string can complete remission. These are moments that are important and for sure for patients. I think results of everybody testing should therefore be shared with the patient and the family when known. It says, look, this is what my treatment did with me. Knowledge is few for a positive spirit to adapt to your patient life to your perspective. The point MD testing is in the blood is in development, not reliable yet as the bone marrow puncture method, but a promising future looking at the lesser impact on the burner for the disease. There is more to say to this but I would like to leave it this to this for now. So we have enough points left for the discussion. Thank you for listening. Thanks, Hans. I mean, you raise a number of great kind of points there. We will come back to you later because what I really want to explore with you is the decisions that patients need to make in their life beyond just that treatment decision because there's this is a bias towards just this treatment decision has been to be on be all and end all but of course it's not like that when you're a patient. So I'd love to explore that and a bit more depth with you later on in the webinar. So I'm going to move now to Martin you're next on the on the list Martin so we'd be interested in your reflections on the MPE report. Yeah, I think there's, you know, lots of excitement and I think generally when we have new ways of assessing the disease. This is always, you know, really exciting and a good prospect but I think one of the things of course that has come through to me and the results is that question what to do with the results. And there is still a lot to be learned. This is not meaning that, you know, we will never get these results. We will get these results. There's lots of research going on. But in daily practice, I completely, you know, can resonate with what Hans has just said. Just the flip side is one of the comments I've seen in in the report as well as a patient voice. It's, it's nice when your MRD is negative, but what what is it if it's not negative. And that's a difficult one. I think I'm feeling, you know, definitely Bruno will contribute here far more and there are more and more exciting areas evolving where it could be of much use. And Bruno's most recent work on CAR-T cell MRD, for example, is really stunning. But the error where we're using it most is, for example, after an autologous transplant because we're doing a bone marrow biopsy there anyway. And that's the one indication where our hospital gave us the permission to do the test which I just had an email about today actually. It takes six times longer to use the machine to do an MRD test which is flow based at our laboratory than the normal standard flow system. So they want from us to know exactly which patients we want to test because ultimately it's a capacity question in our healthcare system, unlike in public in private healthcare systems as in the US where the test might generate an income for the hospital. It doesn't in our hospital, we have to say, you know, what is the best use because there's only a certain limited capacity. And we're doing it in those after transplant. The interesting question there is, of course, I always like to transmit the result of a negative test result in MRD to a patient, which is always great. But even if I transmit the result of a positive result, I have to tell the patient I don't quite know yet what that means because at that point they have just had their transplant, they're still starting consolidation, they're still starting maintenance treatment. They might well still turn MRD negative and we know that again from work. I feel like I'm the minor contributor here. Bruno has generated most of the evidence, but there is for example data from a number of trials from one that you six out on it where a lot of patients that were positive still early after transplant, even with even when they took placebo turned out to be MRD negative six months or 12 months later. So it's a bit that question. What to do with the information and for us to really find a sweet spot where we can use test best, I think is probably what came through to me in the in the answers as well from the patients. Thanks. Thanks, Martin. I'm trying to contain myself here for not jumping in and asking questions, but that conundrum is true to a lesser or greater extent with existing tests, even a par-protein test is the same jeopardy, the same unpredictability potentially. So so patients are still having to go through that difficult discussion of your power proteins drop this much or that much and then is it the magnitude of response or the duration of response and how it pans out over time and although we've got more, I think, clinical practice on par-protein, for example, it's still, it's still jeopardy there for patients. It's still, and I think with tests like MRD, it's the context that surrounds it as much as it is the result itself. But anyway, Bruno, you are the main man when it comes to MRD. You're next on my list and it looks like that's perfect because Martin has set you up brilliantly for your reflections on the MPE report. Thank you so much, Eric, for the kind words and introduction. First, let me thank the big efforts and an important point to conduct this initiative also for the questioner. Very, very important. And in my view, it reflects very well where we are at the moment and what efforts should be done for the future, particularly to provide the lights and answers to some of the questions that remain and resolve and that we very well have been in the slide presented before. And also, following on Dr. Keithard's words, I should say that in my opinion MRD has been one of those fields where we have been blessed by seeing so many and valuable contributions coming really from all over the world, the UK group, one of the groups contributing the most to this field in myeloma and beyond. And I think that's one of the reasons why we are here today, talking about MRD, the fact that we have seen diplomatically across the years and across the globe. Informative, reproducible results. And this is not trivial from the perspective of laboratory diagnostic to see a biomarker, a test that from study after study, cooperative group after cooperative group, we continue seeing the same positive sound results. And this is why in my opinion MRD is one of the most informative, prognostic factors in myeloma. Now, this being said, it's not perfect. In fact, it's far from perfect. And I think that MRD alone, and perhaps this applies to virtually all biomarkers, is capable of discriminating different groups of patients that may have different expected progression through survival, but it's very hard to predict at the individual patient level. And to really predict outcomes at the individual patient level, MRD is just another layer of information that should be integrated with all other patient and tumor features. And I think that Dr. Kaiser highlighted this extremely well, particularly given the dynamics of MRD status that may well fluctuate over time and thereby also its prognostic value. So, a final comment and to avoid searching too much my time, from the laboratory, we hear the patient perspective, and we understand and think that already a few years, we and others around the globe are working hard towards developing more minimally invasive MRD tests. Definitely to avoid those invasive and painful tests for the patient. This was well pointed out in the first part of today's meeting. And secondly, because we believe also that to provide better information that can be potentially used to pine tune the management of the patient, you need to rely on frequent testing. And frequent testing can only be done in a minimally invasive sample. This is where we are aiming in the next few years. Thank you. There are some really, really excellent points there at Renault. And I think it's just, it's complex myeloma, predictability, risk stratification, it is so challenging. And I can't help thinking that we need to look to the next five or 10 years rather than the past five or 10 years, because I think as cell and gene therapies come online and decisions about who gets them and who doesn't get them, and what happens next. We need to have, I think, really spectacular information to do that and MRD could be one way in which we could do that. So there's lots to think about there, but we'll move on and Veronica, you're next on my list. So we'd love to hear your, your, I mean, obviously you can introduce yourself as well. I got an interesting title novel and points representative so it looks like this is this is in your sweet spot here from an endpoint perspective so we'd love to hear your perspectives. Yeah, indeed. Thank you so much. So good afternoon to all. Thank you to MP for this opportunity. It's a pleasure for me today to represent the European Federation of Pharmaceutical Industries and Associations perspective. We like to initiate by highlighting what the findings reflect to us as FPA. So first and foremost, most ensuring that we hear the patient perspective connected to the science. And how both intersect is meaningful to this community. The report shows the potential use and implementation of MRD, as well as flags important considerations that may influence the approvals and reimbursement decisions in certain populations. There is a big opportunity to amplify the use of MRD as a tool to guide decision making and the value in combining MRD with patient reported outcomes to enable greater correlation with overall survival, as well as measuring, you know, outcomes of high importance for patients living with multiple men. What we have seen all across, you know, our discussions is that one of the main barriers to use MRD as an endpoint in regulatory and reimbursement decision making is the level of uncertainty about the long term, clinical and economic outcomes associated with implementation and interpretation of the results. As pointed out in the research, we shall address this uncertainty by providing guidelines and standardizing MRD measurement across hospitals and countries as much as possible. Addressing this uncertainty will be key in ensuring, you know, the adoption of MRD status as an endpoint in clinical trials and beyond that can be used to support regulatory and reimbursement decision making. I would like to finalize by mentioning like FPS stands for the recognition and valuation of these endpoints beyond overall survival that will give the benefit that can bring to patients and the wider healthcare system. It is now important for stakeholders to work collaboratively and ensure that reimbursement decision making evolves to include the use of novel endpoints as well as to paving the way for the innovation that is coming. Thank you. Thanks, thanks Veronica. Some really important points and I think you kind of and we'll get into this a little bit and I should really be quiet but I think that, you know, even existing endpoints such as PFS, for example, in myeloma is somewhat uncertain, right? The jury is out about whether it predicts for overall survival and you know the FDA are making changes to their guidance around making sure that there's follow on trials for OS and things. So, again, for me it's not sort of singling out an endpoint, it's looking at them in the round and thinking how they collectively contribute to painting a more certain picture for response and risk in myeloma. Because there is a lot of uncertainty and I'm interested in what's a novel endpoint versus not a novel endpoint, right? What's important is what is the endpoint that's needed to whether it's novel or not, you know, so there's lots to unpick there in terms of what do we mean by novel endpoints but that's that's for later. Paula, last but not least, we're over to you for your perspectives then we're going to come back to your hands. Yes, so good afternoon everyone. Well, the way I read important is indeed there's a general interest in MRD from both patients and physicians, as already also stated by the other panelists and I also saw in the reported patients who have the knowledge of MRD also see the potential of use in particularly in relation to making treatment decisions. It's also clear that there's inequality of knowledge and access to MRD between and within European countries. In addition, it seems to be there seems to be shared understanding that there's currently not enough information to use MRD either for treatment decisions and or regulatory decision making and I want to sort of relate to what your comment to your comment just now is that I think it is very important to decide what information is necessary to use in which particular situation, whether it's for treatment decision or regulatory decision making or anything else. So I think that determines the requirements and I will get to that later I guess during the panel discussion. My impression from the report is also that patients and physicians and sponsors, and I took the letter from from other meetings are in general very eager to get to the point indeed to use the potential of MRD. At the same time, and that's also already been mentioned some patients are quite skeptical towards the use of MRD. So that is, it's going to be used to deny access to relatively expensive treatments rather than providing the best treatment for the right patient at the right time, while that is actually of course, why we are all here. In my view, the first so so you trying to use MRD for regulatory decision making requires large quantities of patient level data collected in a standardized manner. The letter so really to address the skepticism with patients, I would say that requires building of trust by being transparent on rules and requirements plans and results, every step of the way. And I must say that the plans that are laid out laid down by NPA, I think are a good, good step in the direction. Thank you. Brilliant Paula really excellent points there and I can a good, a good reminder at the end of the day that this is all about making good decisions for patients right patient right treatment, right time and just making sure we've got the right information to do that of which end points are part of it holistic needs assessments all kinds of things should feed into that for that decision so it's a nice segue into our sort of first question for the panel which is around the role of MRD in treatment decision making and the utility of MRD in in clinical practice. I'm going to start with you hands and Martin for the first kind of question and it's very much around looking at it through a sort of patient, a patient lens in. What what the impact potentially is on patients and their carers and their loved ones about knowing their MRD status, whether that's positive or negative. Whether you want to know or not hands as a patient and, and you know you can very well think about the impact of MRD positivity but what's the impact of MRD negativity and both you and Martin touched on that. So so hands, what we'll start with you just to sort of shine a brighter torch, a little bit on on the your perspectives and the patients that you work with annoying their MRD status. Yeah. Well, that's an important point and also I think Martin raised that point as well. I think for most patients, it is important to know how deep the remission is it was also it is also before we had MRD that you wanted to know if you are had a partial remission or a good to mission very good partial remission, complete remission shrink and remission and what that means that you had to explain that as a doctor. And that's the that's important information to also support shared decision making between a doctor and a patient. And not every patient wants to know but I would say, put it on the patient portal and let the patient decide if he wants to know his results, or rather wait until he speak as doctor and give info so that that might depend on the one patient and the other. So I think it's for patient importance, where he stands, what's the disease. Also, when it is negative, because you need to the cancer diagnose was already a negative message, but it is just how it is the reality. You need to adapt to that. And you can only adapt to a situation when you know where you stand. So that is why I'm in favor of just sharing it with the patients. Tell him him or her what what it means. And discuss what what the options are. And could you just give us a flavor of because I don't want this just to be about treatment decisions because patients live complex life, right. Myeloma may not be the only challenge they have there may be comorbidities there's things going on financially at work stress mental health there's all kinds of things that go on in in normal day to day life. So what is the flavor of what types of non treatment decisions that patients have to make, and how important it might or might not be knowing their MRD status. But that's a pretty broad and difficult question because it depends from one to another, like you already said, but to know that, especially of course, when you reached a very deep remission that that gives fuel for filling in the perspective of the life you have. So that's for sure important. And also, for I think you afforded that point but I think treatment decision is also important in that sense to that's maybe for for later because it needs a lot of research. If an MRD point means that you can, for example, have a treatment free interval, or choose for maintenance therapy. Those are things you need to discuss with your patients. Do you feel secure for that. And if, if you have done a very deep remission measured. It's extra information for the patient to help make a decision with with your doctor on having for example, a treatment free interval so you can recover a bit and you for its unnecessary toxicity. Brilliant. We're slightly over time, which is my fault because I'm doing things I wasn't told to do until not to do so. So we'll, we'll move on to you kind of Martin and obviously you like many doctors see patients in clinic of all types all shaped sizes ages perspectives. And what's your, your feelings around the potential impact of knowing patients knowing their MRD status. I think it can be very useful. But I think it is something that has come through already in the comments but also from the previous discussions is a tool amongst several and in some sense, it will be the most powerful if you are really having detailed conversations with an expert team about what the result means. I think it is very clear also for more recent evidence that on its own, it is a result that can be useful but the interpretation of it what it means for you will be sitting best with you personally if you have multiple areas on multiple inputs of information so one of the things that we have for example learn through through a trial that was performed in in the US, where people stopped treatment after they had continued MRD negativity was that the disease had very high risk features. It was still at risk of coming back earlier, even if they were a muddy negative and it was quite an interesting study because it showed that those with this high risk features had the same rate of a muddy negativity so that they say a number of patients when they might be negative as others. Of course that is a subgroup a smaller subgroup of patients and for the majority still you know the finding did translate into a long treatment free period but I think it just shows that that it is I think going to be one of the things that is happening anyway is this specialization of my teams and think especially when thinking about an MRD test, it sits best for you if you are under a team that has lots of other inputs and lots of other insights into your disease as well. I think I think that's the nature of things across many cancers. That's not my own specific but I think it will be developing into a very powerful tool the more and more people are knowing how to integrate it with other areas of information. It makes perfect sense. Thanks Martin. Bruno we're going to come to you next if that's okay and I'm going to combine two questions into one. So I don't know we've covered some of this but from your perspective what are the potential benefits and risks of using MRD testing to make treatment decisions. And the second part to the question is how far away are we from realizing the potential benefit of MRD testing in clinical practice. Very difficult questions for which I think there is no right or wrong answer. I think that let me say something different. Being myself a patient not with my aloma but with arthritis I would like to have myself all the information that I could on my disease and I would definitely want my physician to have all the information for whatever decision she makes from now on. And I think that it feels reasonable to ask and to understand as often as from my patient perspective. Now regarding the remission I know from the information on my articulation that I'm not in remission happening more techniques to know that. But I do and we had discussions about this. I'm sorry for for engine giving to another disease but I do understand that you really want to have all types of information to make an informed decision. And on the other hand, I do realize that despite the robustness of one biomarker to inform on the patient status of a certain metric of the disease, and despite all the evidence that may or not be accumulated. Still, at the end of the day, there is no link between a result and a decision. And at the end it could be the best judgment of the physician to do in consensus with the patient what is best next. Now, regarding where we were when we are and what we can next. I think that for MRD myeloma. I do believe that we will learn quite significantly in the next few years, because in the next few years, I'm confident that we'll see a lot of scientific contributions from many groups around the world with MRD assessment in clinical trials. Some sort of treatment question about intensity or duration, where MRD was systematically measured using the best methods, standardized and optimized and endorser by the international myeloma working group. In other words, we will learn from many many many trials in the next few years trials that have a design that was not there in the past and trial that they've been using the same MRD methods meaning that we can learn from one study to another. So I think that in in in comparison to the last few years, the next few years will have sent in you have additional value that we haven't had until now. Brilliant, but that that makes perfect sense Bruno thank you so in the interest of time we're going to move over to questions around MRD as a surrogate endpoint and they're mostly going to be directed towards Veronica and Paula, but others can kind of pitch in if they want so. So I guess we know there's some some issues around MRD as an endpoint. And it's kind of plausibility I mean I think there's challenges with endpoints. Not only but there seems to be a strong push from the community the MRD should be an endpoint. A regulatory endpoint and I'm aware of conversations that I guess the great in the good of my loam I've had with FDA and others about making the case for MRD as an endpoint. So some unanswered questions from the report around sort of the cadence of MRD testing now all that kind of stuff which needs to be to be addressed so Veronica I'll come to you first so from your perspective. What are the main unanswered questions or evidence gaps or sort of trip hazards that are still in place that they are hindering the approval of MRD as a surrogate endpoint. Thank you, Eric. I believe they're both Bruno and Martin have outlined very clearly on on the gaps that we have different levels among laboratories technologies, you know, having in place different protocols. I mean, in general in a nutshell the standardization process is something that we need to ensure it takes place for decision making processes within all the steps that we as manufacturers follow meaning from regulatory to you know, and then it comes you know also the the data uncertainty translated to payers and what is the data generation needed to demonstrate this correlation so everything is is connected. I mean, I will probably like to comment more in the sense of, we have outlined right now, they still you know uncertainty and the data gaps that from the clinical perspective we need to all together come through. And all of us as industry is really to take an active role together with the community on this evidence generation on the value of MRD in clinical trials to make this breach of improvements of MRD negativity and the long term feasibility and how this translated to quality of life. And we have also as Bruno was saying on this learning that industry has also a role to play on disseminating this evidence through different platforms and how we bring all the stakeholders together on really, you know, our experiences in clinical trials also together with the the scientific community and patients for sure on on discussing the still the unmet needs as Hans was mentioning. Great. Thanks, Veronica. And Paula, what would your response be to to that question? You know, actually, of course, I've been thinking about this form for some time, but I'm actually a bit unsure on whether there is sufficient agreement among the stakeholders on what will be required to use MRD as an registration endpoint. I mean, and stakeholders are the patients, the physicians, the payers, the HTA, the regulators, and of course, and pharmaceutical companies, right. And then of course, there's the challenge, because interests are not the same, so there should be put effort to find really the common to common ground in that. And I'm actually convinced that it is possible, of course, because in the end, I mean, if you can use MRD as a registration endpoint, it means that you have also sufficient information to make treatment decisions, which could be a benefit of the patient. And it can also allow patients to decide whether they want to buy a new house or not at this point, right. The same as that payers can say there's sufficient evidence to reimburse this treatment for this patient at this time. So I really think that, you know, the requirements for decision making that is something that I would hope you could be could be answered in a sound way. And that, and because that will also shape the data collection. And I must also say that another thing that what I've always sort of, you know, missed in all the discussion is, is the impact of the durability of MRD, having a deep response may not just may just not be sufficient to say that this is the best predictor for long term benefit. I think the durability of MRD may fit in as well and that can also help in understanding why an MRD in for patients with a high risk profile most of myeloma is not has not the same value as a patient with a with a lower risk type of myeloma. Yeah, raise some important points and I'm just sort of as I'm thinking through through this as a sort of average Lee smart layperson I'm sure that that you guys the panelists could have a two week congress on MRD and and it still wouldn't be enough time to talk through all the different layers and complexities that that we have hands you very kindly very politely put your hand up to jump in so we'll come to you next. I just wanted to add something what Paula said, the, I think the true ability is also for patient groups we discussed this also more than often because we are approached to have an opinion on MRD and that's why we have this research done anyhow, but that's also the patient group very important. I mean, one of the concerns patients, patient groups had when MD was coming up is that it's on one hand, it says something on the power of a new treatment, looking at for example, in the real respiratory myeloma patients in the latest stage, you have to those immunotherapies and you suddenly saw that where the stage where the disease is very aggressive. You will get MD, MD negative results, which are spectacular, I must say, but when MD would be an endpoint, and you look at for example at the first stage where people just have, have had the, the diagnosis, and you focus on getting MRD results as a company to get to get your market authorization. We feared that the treatment will be too toxic for patients just to get that MRD results so very heavy. So that's why we said, well, we are very much in favor of putting MRD in the spotlight. Also for for patients is important to know how deep your responses but it goes hand in hand with knowing what the long term toxicity is, especially when we know that myeloma patients live longer with myeloma it's important to also keep an eye on the long term effects. Really important points, hands. Paula, you raised a really crucial or you said a crucial word there, consensus. And it would be good just to explore that for the next kind of couple of minutes because I think getting consensus is absolutely critical to the next steps in MRD. Easier said than done. I think that, you know, sometimes on the outside looking at the impression I get is different stakeholders, even different people in the same stakeholder group. It's like we're all on jet skis zipping around the lake a little bit all different directions, but we all actually need to be in the same row and row in the same direction and I think MRD, if we and it sounds like there is this energy and this vision for MRD to be to be there. And but unless we get consensus unless we take a very strategic and thoughtful and collaborative stepwise approach to it and come out the other side with sort of implementable and transactable solutions we we might miss the goal a little bit and that would be devastating I think for all of us. So, how do we get that consensus I mean all groups are represented on this kind of panel. How do we get consensus what are the steps that we, we need to take in order to get consensus. I think that was a direct question to me right. Yeah, yeah, so I think it is. It is, I think that the common ground that I referred to is really about the topics that we can agree on, but it's also about the uncertainties that we can accept. Because I think if you collect data from from different different trials, and even in a standardized manner and you do a meta analysis that is I think it would be a very good start. I think for, and that would be of interest to all stakeholders mentioned I would say, however, it was very possible that, you know, for some stakeholders there will be remaining uncertainties and I think it would be good to to lay those down and describe, you know, this would be acceptable to us in relation to reimbursement, for instance, by also being flexible in the type of reimbursement given like give a conditional form in that respect. And depending on the longer term results. You may change that to, let's say a full reimbursement similar as you have a conditional and a full approval in the regulatory system. So I think it would be acceptable pragmatic Martin. And I think that's sorry that's just indeed the word pragmatic right I think there's a lack of data we need to collect data. And let's then see what what we have do this in the best possible way, and then see what we have but except uncertainties, which may be fulfilled in the longer term. Thank you. And I think there's a difference between volume of data versus the right data. And I think that volumes of data can actually be counterproductive. You know, we need to be rational and thoughtful in in not just throwing spaghetti at the wall and hoping some sticks but be very thoughtful and aligned about what the remaining questions are, and what research, what the best research are to get the answers with all stakeholders involved in that research design, especially downstream decision makers. Martin, over to you. Yeah, I cannot agree more but I actually really want to make a case here for the excellent work that people like Bruno, Dr Piva, you know, have been doing which it looks like he even might have MRD data on his screen actually. In the corner of the image here. What I'm trying to say is actually, you know, the work that that Bruno has done, and others are doing and, you know, and in other categories, a lot of researchers are doing should not be underestimated and this is actually including for example, developing the methods, sharing the methods, making the methods into tests that people can use and clinicians and researchers can use everywhere that is not a small feat here and it has been I think one of the things that have been. We're not in the focus of the drug producing industry, and as such, I think have been underfunded for quite a long time, I think we're fortunate that we're seeing more and more attention and this and I think this webinar is one of the, you know, important signals of that but the work that has been going on has been really Herculean and I think you cannot do a meta analysis if people haven't thought about already 10 years ago, you know what methods, everyone could access and everyone could use in the future and I think this is really, you know, fantastic to be on such a panel together with one of the people that have been working towards this for such a long time amongst with many others but I think it's it's actually something that I would say is important to realize what contribution academic research is doing. Because that would not have happened had there been only the research that was ultimately incentivized and I think there's not no moral judging but you know the people that are producing drugs they only can address what producing drugs actually entails. I think I think the a lot of the other research came from other areas and of course enclose and tell a lot of patients as well that participated in that research. Yeah. So all roads and all things lead to Bruno. So I hope you've got big shoulders Bruno because I think, you know, I think Martin's right and I've been working in Milo my entire career I'm scared to tell you how long that is. But when I think about MRD I think about you. So, so what what's your thoughts around how we get consensus and how we address the outstanding questions. Well, start this is really a team effort and and picking up on the last sentences, Martin. It's true that we need to we need support. And the community work from everyone to produce high quality data and I believe it was the way that said it's not that much about the amount that the quality, and that particularly applies to this issue that I'd like to briefly address in my comments. And we can always improve but I would even say that fortunately in the last few years we have seen how perhaps stand 15 years ago. We in academia that we're making the effort of developing the methods and the testing them in the prospective studies. More recently we have we have seen how this testing is really present in, I would say 99% of all new prospective studies regardless of these are from academia or pharmaceutical companies. I think that this is something of high value it's not. I would say it's not unusual but at the same time I would say my advice is special example across the community methodology, we are we're seeing this kind of collaboration and combine effort, can always improve but I would be on the positive optimistic side. And as Martin said, the fact that this has been ongoing for the past few years. has enabled all the data that can be analyzed and met and I see fashion for other. There are some contributions, beyond what they might be can offer in terms of pronouncing value and eventually treatment decisions that is the value of sterilizing. Now, to answer to provide my comment on the service that this was addressed before. Again, investigating is a immense value without knowing what would be the results of that, in my opinion, at the moment it's highly unpredictable what will happen, but he's given immense value, because having the possibility of knowing very early on, let's say, six to 12 months, what is the added value of a new scheme or a new travel scheme and compared to the standard of care. I think it's extremely valuable and it's the direction I'm saying this because of one sentence I saw before in the beginning of our webinar. Ideally, it's to accelerate the access to new drugs for patients and it will never preclude or exclude the access to those drugs. However, it could also be information to identify or to detect a signal very early on that this new iteration on treatment is not really or will likely not improve progression free and eventually the overall supply. That is equally important. Now, it's a completely different mindset when compared to the classical role of MRD as a prognostic factor. I believe it's really to make sure whatever difference we see in MRD negative rates in two different treatment strategies will correlate in the benefit to what is most important to a patient that is survival. So as you can imagine, this is very important and not easy to establish about predicting the future in what is most important to a patient based on the result that is being measured six or 12 months after treatment was initiated. This is why we need huge amounts of data, high quality data. In my view, we are only at the half of that process because all the data may not have the enough quality for this kind of meta analysis. So, without knowing what the future will tell us about results, I think that because of what I said in the beginning, it is the most valuable list, try and see if there is some role out of it, even now, or potentially in five to ten years based on continuous accumulation of data. I had a final, oh yeah, as always, and as I was saying at the beginning and many have mentioned this, that it will never be isolated and MRD will never ever provide 100% final answer because a certain schema may not induce prolonged progression through survival and in my side that may improve the quality of life of the patient. This is very important as well and cannot be measured on MRD. So MRD may help but it would never ever be sufficient for all of us. Yep, yep, that makes perfect sense. Hans will come to you and then there's a couple of things we've got to do in the last 10 or 15 minutes. One is have a little bit of a Q&A. I'm looking at the Q&A box and there's a few questions, not many, not enough to fill 10 minutes. If there are any questions in the audience, please pop them in the chat or the Q&A function now, that would be massively helpful and I want to make sure that everybody gets at least 30 seconds for closing comments and then I will try and summarise things which I'm not looking forward to, I can tell you now, but Hans, you kindly put your hand up. I just want to react on one aspect of what Bruno said on the prognostic value of MRD tests and Martin also mentioned in the beginning of our meeting, for example, the treatment exazumib. I thought maybe you could think with me on this and what the clinician and research perspective is but wouldn't it be good to first have pilots piloting some treatments where you for sure can say that MRD testing would be of higher value than others. I could imagine for example exazumib has a different meaning in the treatment pathway, it has a low toxicity, you can take it or also it's especially for the older people very valuable but not so many people reach a really complete remission or a very deep remission. But looking at Dara Tumamap or Dara Lenelindemite dexamethasol for example is a very effective one, many people reach a complete remission besides that Dara Tumamap has a very long half life of about five, six months. So the question there could be could you, is it possible that you could have a treatment free interval to recover for example and then you would need MRD. So wouldn't it be good to pilot MRD testing in a clinical practice for specific treatments where you now already can see that it might have value. How do you look at it as research or as clinician. Yeah, Bernard Martin do you want to respond to that. Yeah, I think you know this is a very good point as everything and I of course research costs money. So if we go back to the very initial development of these drugs, these questions came already up when the trials were running that were leading to the current trials and I think at the time, understandably I have to say I'm really also raising understanding here for for the, you know, industry that developed these drugs you know that they made their whole financial plans employing people on the basis that the drug is used indefinitely until progression. So unless there is actually a movement in in how drug pricing is done how you know all sides find an agreement I'm coming back to that consensus question that maybe a price could be renegotiated if you find a way of using it better for a shorter example, they will just never be an incentive, for example from drug producers to run such a trial, especially when they're early in the development of note they don't know yet at that time what their revenue will be over time I completely understand why they want to plan this at the later stage like now where the drug or the treatment is used and standard of care, a trial due to the regulations that we have to follow is very expensive to run and pay for the drugs it's still something where you need to monitor safety where you need to do lots of occur lots of central funds now that's a question for the public payer and we have unfortunately seen over the last years that all of the public countries have reduced trial funding, which is, I think in this circumstance short sighted. And I still also feel the public shouldn't be only putting itself up into seeming as an as an industry unfriendly environment as well so if you if you for example start such a trial you should have an idea of how you may also incentivize people in the future, developing things in your country, so I think it's it's a very fine balance but you're completely spot on. I completely agree with you, you know, you probably realized I think your questions absolutely valid but there have been the environment at the moment has not been designed to necessarily support the studies, although there have been some in the making as Bruno said, the next coming years will be actually showing some interesting data and some of these areas. Excellent. Okay. So, I'm conscious of time. Seven minutes left. Now the questions are coming in. We've got no real time to answer them all, which is silly of me. So, I'll just pick one one question. MRD tests being based on bone marrow biopsy. And obviously the implications for patient experience and consent, etc. is not, you know, simple. And hands you mentioned, or somebody mentioned the prospects of liquid biopsies in the future but is there any prospects of any other biological samples, such as Venus or a heretic blood samples is there any other way to do it basically, what's on the horizon in terms of trying to overcome this issue of bone marrow sample. Bruno, do you want to go for that one? Yes, I would say that's a question for Bruno. And what I'm, part of what I'm saying, what I'll be saying is, this indulgence would be somehow hypothetical, because it's made, it's based on predictions of what we could potentially achieve, according to results that feel very written and proven. I believe that to some extent, similarly to other immaculatical malignancies, the bone marrow will remain a backbone of sample for evaluation of treatment efficacy. Particularly early on, during the more intensive stages of therapy. Because there is where most tumor cells accumulate, and therefore is the easiest sample to see if there is residual disease in patients otherwise in remission, according to their immunophilic patient status. I believe that this will remain for the next few years, however, based on current data. If there could be, and what is currently an hypothetical scenario, where at late stages of treatment, for example, during maintenance or observation if treatment is not until this is progression. Also later on if treatment is identical until this is progression, constrictive cycle and moving to, there could be a role for minimally invasive tests. The view, replacing the marrow, by a minimally invasive test, demands a lot from a methodological point of view. And it could well be that it's not about replacing the same technique in one sample versus the other, and moving from the marrow into the blood, you need a combination of methods. And along that combination of methods. I do believe that high sensitive measurement of the M protein, for example using mass spectrometry, and an even more sensitive assessment of individual cells, either through sequencing or flow cytometry slightly more sensitive to the methods that we currently have, would achieve both a high negative and high positive predictive value, and therefore replace some bone marrow aspects at late stages of online treatment. I believe that this could be particularly attractive in those scenarios where, for example, treatment free interval may be considered, and where you would like to rely on frequent testing to see the outcomes of such a treatment free interval. Again, I insist this is only an hypothetical scenario based on preliminary recent data, we and other groups are generated. It sounds very pragmatic. I mean, I quite like the word pragmatic, but it sounds a pragmatic approach. Martin, just very, very quickly question for you. If a patient was to raise the topic of MRD testing with their clinicians tomorrow, what type of response would they expect? A very individualized one, I would say, it really depends on what they expect. I think it for me personally, it always means in a clinical setting now. Yeah, we're not talking about episodic setting in a clinical setting, understanding what they expect they get out of it, what I can offer as, you know, anticipate as potential answers after I have done the test. I'm definitely trying to get clarity before and not just jump into the test because, you know, that there might be a lot of disappointment otherwise at the other end if the patient does not get as much information out of it. But there are definitely situations where I feel it's a very valid question and it's actually hopefully going to become more and more evidence we have based on how we can base our decisions on it. Thanks Martin. So I'm going to try and sum up in 30 seconds. So I think that there is, I think, strong support for and an understanding of the potential utility of measuring MRD in clinical practice. I don't think anybody is disagreeing with that. And I'm also convinced that MRD not just is here to stay, it's going to become more and more significant as the data and the need for it increases. We already have lots of data, not all of which is necessarily at the right quality. But there's a lot of good stuff out there already. I mean, I was at Ash in December and it was everywhere. But there are unimportant unanswered questions and gaps to fill and it's incumbent upon us all to work together to make sure that we get consensus on these. We take a collaborative approach and we ensure that the research is of high quality moving forward. So we can't trip up moving forward as best we as best we can. And we need to recognize that we're operating in a complex system. So myeloma the myeloma system ecosystems complex, but the systems complex between regulatory HDA pair, etc. And that's challenging to navigate because as everybody has said, there's different incentives, there's different vested interests and different rewards, which makes it very difficult for us all to get in the same boat and row in their same direction. Paula recognized that but you also said Paula that we can do it. It's possible. So we should take heart and hope from this that it's challenging, but possible. And what we have is MPE, which I think is the strongest possible honest broker in the system we could hope to have. And I'm sure MPE will take MRD forward and push for the consensus push for unification in thinking about it and making sure that we identify and get consensus on the research question and ensure we deploy our best, the best we can to get to get that research done. And I think it's important because after all, we care about patients and patients are waiting. And I think that we owe it to them to make sure we've got the maximum amount of information available to support these incredibly difficult decisions that, that they have to make but also clinicians have to make but also health systems have to make about how they allocate scarce health care resources to new, new, new treatments. So really this is over to MPE to take this forward. I wish them luck. Thank you MPE for having the foresight to pick up the MRD batting to do that great but of research and report and point us all in the right direction. Many thanks to the excellent and wonderful panel. You've been absolutely brilliant. And thank you to everybody who took the time out of their busy day to participate in the webinar. And I'm sure MPE will be following up with everybody. So thank you all very much and enjoy the rest of your day.