 My name is Paola van Henig. I work at the Dutch regulatory agency, so the Medicines Evaluation Board. And I'm one of the two Dutch representatives in the European Committee that deals with marketing authorization in the EU. Today I will talk about minimal residual disease in multiple myeloma and the European regulators review on this. Next slide, please. My presentation has actually two topics. The first one is about MRD itself. How is it measured? How it can be used? And what is what we do not know about MRD? And the second topic is the email's position on the use of MRD in multiple myeloma. And is MRD a valid endpoint for drug approval, which is a very important question. And I guess I would not be here if this would not be a matter of discussion. So that leads me to the second part that I would like to discuss with regard to this topic. And it is what would be needed in terms of other information from a regulatory point of view to make MRD indeed a valid endpoint for drug approval. Next slide, please. So how to measure MRD? Perhaps this has also been addressed by other speakers before me. So just a brief recap is that, and it is that currently MRD is measured by next generation flow cytometry or next generation sequencing, which are both very sensitive methods, which means that they can detect a very low level of cancer cells among normal cells up to one in a million even. And that is of course a very helpful for its purpose in saying that you want to measure as low as level of disease as possible. It is of course important to realize that each test method has its own limitations and also its own strengths, but also indeed the limitations and that has to be considered when you're thinking about what you want to use it for. Another aspect in relation to MRD that is important to realize and is that it's repetitively measured in bone marrow and considering that it is an invasive procedure, it is very important that there are indeed, there's a necessity to develop tests that can measure MRD in peripheral blood. And in case that has been done or will be done, and there's quite some interest for that both from the clinical perspective as well, I guess from pharmaceutical companies is that when you test for MRD in peripheral blood, this needs to be validated so that we need to be sure that what we previously measured in bone marrow represents the same type of information as when you measure MRD in peripheral blood. Next slide, please. So how can MRD be used or potentially be used? First of all, it is used to determine whether the treatment has eradicated the myeloma or whether traces remain, but that is of course already captured in determine itself minimal residual disease. Also, it enables us to compare the anti-disease activity of different treatments and monitor the patient's remission states. That's sort of a consequence of being able to understand whether the drug has effectively reduced disease in a patient. It also helps detecting the recurrence of the myeloma and at some point choosing the treatment that will best meet the needs. However, what is still under debate and not particularly used in clinical practice is that at least MRD is not used to make treatment decisions. So when to start next treatment? Next slide, please. An important and interesting aspect of MRD is that it has predictive value in terms of progression-free survival or overall survival and that is shown on this slide. On the left side, you see a graph with information regarding progression-free survival and on the right side overall survival. On the x-axis, you see the time and on the y-axis, either PFS or overall survival on the right side. And the different lines in this graph shows you the difference in progression-free survival or overall survival. When for patients that have obtained minimal residual disease, so are MRD negative or have still residual disease in their bone marrow and are MRD positive and then comparing two types of chemotherapy. So within the chemotherapy type, you should compare the red with the blue one line and the green with the purple line. And what you can see is that independent of the chemotherapy, the progression-free survival for patients that have obtained MRD negativity, so are red or green, sorry, are blue or purple, they have a better survival in terms of recurrence of the disease or on the right side overall survival in comparison to the patients that have still residual disease. And in summary, this means that if you obtain minimal residual disease, so no disease is any more detected in the patients, then you have a better prognosis. This is what we call patient level surrogacy. It has predictive, MRD has predictive value. Next slide, please. So what is what we do not know about MRD? And this is a list, it's quite some things we do not know. I want to highlight a few topics. The first one is the optimal timing for MRD assessment during and after treatment. I must say that over the past years, there has been increased, insight has increased in this. And what we see in clinical trials is that the timing for MRD assessment is getting more and more standardized among between trials and when compared, when comparing different types of patient populations. The other thing that we're not sure about is what the meaning is of MRD negativity in specific subgroups, for instance, high risk psychogenetics has the same sort of value if you like for this kind of patients in comparison to patients with less aggressive disease. And I already told you that the use of MRD to alter therapy, so treatment decisions is not without debate. So whether you could use MRD to determine the duration of maintenance treatment or the change of treatment or add agents that's just not known. And then I come to actually the topic of my presentation that is that whether MRD is a valid endpoint for drug approval. Next slide, please. So the current position that we as European regulators have is that this far, it is recognized that the available studies have reported indeed a correlation between MRD and progression free survival and overall survival. So we know it has predictive value. We call it like I said, patient levels for ROGACY. However, it's currently not possible to define what order of magnitude for MRD negativity would be needed to be associated with a minimal clinically relevant effect in terms of overall survival and PFS. And in other words, this is rather formal, but in other words, it means that we're not sure, we don't know, that's how I should say it, is what we're not sure about the quantitative relationship between MRD negativity and the clinical endpoints of overall survival and PFS. And this is what we call that trial level for ROGACY is not known. I will elaborate on that a little bit further on the next slide, please. So patient level ROGACY, I've mentioned this several times now. It means that with for MRD negativity, it predicts a favorable effect on progression free survival or overall survival. Trial level ROGACY means that the treatment effect on MRD reliably predicts the effect size of PFS and OS. And if you focus on the graph on the right side of this graph, you can see what we actually mean. So what is actually needed to conclude on this. So that across various trials, we should have a positive relation between the extent of MRD negativity, which is shown on the X axis and the extent of PFS and overall survival gain. Next slide, please. So in the absence of properly conducted validation studies, any assumed extrapolation of an effect from MRD to overall survival PFS should be carefully justified on a case-by-case basis. And there, of course, there's a little bit of a problem because of course, what would be exactly the criteria which you use to determine what type of data are convincing to make such a decision in considering that we're not actually, we do not know the quantitative relationship between MRD and overall survival PFS. So that is a matter of debate and often a topic for discussion in both CHMP, so that's the committee where I work in as well as in scientific advice. The solution to this all is that the surrogacy of MRD for overall survival and PFS is investigated in a systematic way using appropriate statistical techniques, using a collaborative effort to maximize the inclusion of trials. And this is a very perhaps formal way to say that we should all work together because a vast amount of data is needed to do this. And it has also to be done in a systematic way. So people have to agree on how to collect that data. That would, that is, I think the only way or we think it's the only way to be able to compare and pull results. So measure MRD at the same time point after start of treatment in comparable situations. And the comparable situations would be related to type of patients, patient characteristics, treatment naive or relapse refractory with or without being eligible for transplantation and such things, such considerations, I should say. The other aspect that's important for this is our statistical techniques. We have to, there have to be made reasonable and relevant clinically relevant assumptions. And that is of course based on the information that we already know. For instance, the graphs that I showed you on the relationship between MRD and PFS and overall survival, I think that gives you an hint on what type of effect you can expect. And then of course that is something that should be investigated and validated. And like I said in the beginning of discussing this last topic, it requires collaboration between stakeholders. I think that's the only way to guarantee that there's sufficient data for initial analysis, but also for external validation. And that is needed considering the heterogeneity in the prognosis of patients and the treatment settings. And well, this is something that, well, like I said, we should all work together in order to establish this because that I think is the only way to progress on this topic. And with that, in my presentation, and please ask me any questions if you have so. Thank you.