 Good evening, everyone. This is Nicole Wickey from Myeloma Patients Europe. Thank you all for joining us this evening for this webinar that's part of the Myeloma Patients Europe annual general meeting master class. So today's webinar is focused on minimal residual disease and multiple myeloma and ALM lidosis. Paula, maybe just before you get started, I just want to let the participants know that the webinar today will be approximately 45 minutes of presentation from Paula, our exceptional guest speaker today. Thank you so much for taking the time to run through this content with us today Paula. So we'll have about 45 minutes of presentation followed by approximately 15 to 20 minutes of questions and answers. If you guys have any questions throughout the presentation to be asked at the end, you can feel free to use the questions option in the go to webinar menu and you can send your questions over to me. Or you also can use the raise hand function and you can raise your hand and then I can unmute you later on in the call and and you can pose your questions to Paula. So just that everyone is takes a look and finds out where they can raise their hand and where they can type their questions in. And we will address all the questions at the end. My name is Paula van Henik. I'm an alternate CGP member for the Dutch agency. And which means that I'm one of the two representatives in the European Committee for Human and Medicinal Products. So we discuss and decide about marketing authorizations for medicinal products for human use for the European market. And today we'll talk about minimal residual disease in multiple myeloma and in amyloid light chain amyloidosis. I will go to the next slide. See how that works. So on the second slide, you see the item of the presentation of the day. I will first talk about normal blood cell production. I will briefly touch upon multiple myeloma, the disease itself, as well as on amyloid light chain amyloidosis. I will discuss MRD, minimal residual disease, how it can be used, how it is measured, and what it is that we do not know about MRD. I will also touch upon in this position on the use of MRD in myeloma trials. And I will refer to the regulatory guidance as is available by the FDA. So on the next slide, slide number three, there's a graph, a very nice drawing actually of normal blood cell production, which in other lives takes place in the bone marrow. Where the hemopoietic stem cell, you can see that the cell in the middle of the graph, which is actually the mother of all mature blood cells, produces every day and every day of the week and every year mature blood cells, like the red blood cells and the platelets and the white blood cells, including the lymphocytes and the graded lymphocytes. And this hemopoietic stem cell and the progeny of that is kept very well in a very nice house, if you like. It's called a bone marrow microenvironment, which is formed by the osteoblast, the stromal cells, sorry, the stromal cells and the adipocytes. In case of malignant hematological malignancies, something goes wrong in one of these cells, varying from hemopoietic stem cells in case of leukemia, to the more mature cells, so the B cells in case of multiple myeloma or the amyloidosis disease. So on multiple myeloma, some facts about epidemiology. It is a rare and incurable disease that accounts for approximately 10% of all hematological malignancies. And the incidence of Europe is four and a half to six per 100,000 people per year with a median age diagnosis between 65 and 17 years. The course of multiple myeloma is highly variable and clinical behavior is heterogeneous. And in general, the disease is characterized by a chronic phase lasting several years and an aggressive terminal phase. And most patients with this disease need multiple lines of therapy. So on the pathology of the disease on slide five, multiple myeloma is characterized by marrow plasma cytomas, which is a complicated name for plasma cell tumors and an overproduction of antibodies or immunoglobulins. These can be of various types. So you have ITG, IGA, ITG or IGE. Now we'll get back to that in the next slide. Or by an overproduction of Bench-Jones protein, which is a monoclonal copper or lobda and copper or lobda life change. So there's only a part of an immunoglobulin. And important is that it is all of one type. So one patient, one cell that actually goes wrong and creates a monoclonal disease. And this coincides with impairment of the production of normal antibodies. On the right side of the slide, you see the structure of an immunoglobulin with the dark yellow part with the orange tip being the heavy chain. And the light yellow with orange tip being the light chain part of the immunoglobulin. And these are connected together with the particular types of chemical bridges. The exact mechanism of why a myeloma cell does not differentiate is not known, but the disease is associated with chromosomal changes and clonal evolution. And on the right side of the graph, you see a smear of a bone marrow aspirate puncture. And the cells are stained with a particular dye and shows you that the big cells that you see here, the blue ones with the purple nucleus, those are the myeloma cells. And normally these kind of cells are in a bone marrow, but not just as many in case of myeloma. If we go to the next slide, a little bit more about antibodies or immunoglobulins. On the left side again, the picture of the structure of the immunoglobulin with the dark yellow is the heavy chain of the immunoglobulin and the light yellow is the light chain. Both of the heavy and the light chain, there are two of them in one immunoglobulins. And you can see that IgE and IgD look very similar in terms of structure. However, IgM is composed of five separate immunoglobulin molecules, which you would normally recognize as IgE or DE, so the same structure, but then five of them. And IgA is connected making a sort of twin immunoglobulin. And this isotype is normally secreted and can be found in saliva or in the gut. Abenz-Jones protein is an immunoglobulin consisting of only the light chain, either the copper or the labda. So this is only this part of the immunoglobulin. And of that light chain, you have two isoforms as you may understand, the copper or the labda. You cannot see it very easily. You should look at the amino acid sequence in very much detail in order to see the difference between copper or labda. On slide number six, I will tell you something about clonal evolution, because if you may remember, I mentioned that my multiple myeloma is a monoclonal disease, but how does it happen? So you have a particular, you have a B-cell in a particular state of differentiation. And at some point during the course of life by accident or by external factors like irradiation, the cell gets a mutation or translocation, which means that the chromosomes are reshuffled, which normally doesn't happen. But sometimes it happens by accident, like I said, or by an external factor. And that makes the cell proliferate faster or give it a survival advantage. And that means that it can, that there will be more of those particular cells in comparison to the rest of the, in comparison to the other cells in the bone marrow. In the end, you get an increase in the bulk of the disease. This is normally associated by getting of the cell, getting additional mutations. And that also often coincides with differences in the micro environment because the cell starts producing particular growth factors or other kinds of substances, which either stimulate the immune system or inhibit the activity of the immune system. And that together, so both the changes occurring in the B-cell itself, as well as the effect that it has on the micro environment, cause the disease to develop in over the course of the time. And in the end, there is often the emergence of the high risk state. And that is, of course, a very, has a very great diagnosis. So it's important to understand that in case of multiple myeloma, it's not only about the B-cell that is, that is changing over the time and getting more and more aggressive, but also the environment is affected by that. And that those two together lead to the type of disease that multiple myeloma actually is. If we go to the next slide, slide number eight, there's actually the same information and differently depicted. If you look at the middle of the slide, you can see the changes from the B-cell to in the end multiple myeloma and the extra medullary disease. So that's part of the high risk stage with the changing in the cells occurring, leading to clonal competition and also effects on the tumor micro environment. And like I also just explained, is that during the disease developing, there's more and more remodeling of the tumor micro environment, which in the end also contributes to the disease being there. So on the one hand, this doesn't sound good, of course. On the other hand, you can also, you can also turn it around and saying that, okay, because it's not only about the multiple myeloma itself itself, but also about micro environment. You can say, okay, these we need to, we need to target both aspects in order to have an efficient treatment of the disease. So on the one hand, we can target the immune cells that surround the multiple myeloma cells. So we do immunomodulation, as we call it in combination with targeting the multiple myeloma cells by themselves. For instance, by increasing, sorry, this should not be here, increasing the cell death. So the cells going to die and the cells being targeted by inhibiting the proteome zone pathway. And the proteome pathway is sort of the garbage disposal mechanism of a cell and if you inhibit that, the cells get sort of overwhelmed with the amount of garbage in the cell and causes also the cell to go into program cell death, so die. And of course, like I said, targeting the micro environment can also help. So you can see that, and I think that is also recognizable in the treatment of multiple myeloma. It's important to target the various aspects contributing to the existence of the disease and development of the disease in order to have to increase the chances of a good response to the treatment. Next slide, a little bit about amyloid light chain amyloidosis, the pathology of the presentation, I'm now on slide 10. The normal plasma cells produce antibodies that fight infections. If a plasma cell becomes cancerous, it may produce extra light chains. These light chains circulate in the bloodstream and can deposit in organs throughout the body causing organ damage. And this is what is causing the amyloid light chain amyloidosis. So most common organs affected are the heart, kidney, nerves, guts, skin, soft tissue, the tongue, and that of course causes the symptoms. And the presentation, because of the various organs can be involved, the presentation is diverse and can vary from vague symptoms such as weight loss or fatigue to kidney failure, heart failure and liver failure. The incidence in Europe is 5 to 13 cases per million patients, sorry, per million persons per year, which is really rare. And the median age is 60 years. On slide 11, there's some information on the pathology. There's a picture of a heart muscle. On the left side, you see a normal heart. On the right side, you see a heart muscle from a patient that suffers from amyloidosis. On the left side, the pink circles actually with the purple dots, those are the muscle cells in the heart. You see that they are very close together and rather well organized. On the right side, there the heart cells are pink and the purple, sorry, the light purple staining is the amyloid. What you can see is that the structure of the muscle is completely different, not to say that the structure is gone. And you can imagine of course it has an immediate function, sorry, immediate reflection on the function of the heart. So this is the immediate consequences of overproduction of the light chains in case of amyloidosis. So the treatment of amyloidosis has two goals, improve the function of the involved organs and decrease the production of normal light chains. And the most effective treatment is autologous bone marrow transplantation with stem cell rescue. And other treatments involve therapies similar to those used in multiple myeloma. On slide 13, it is about the difference and overlap between the two diseases and considering the pathophysiology of both diseases, you can understand that these diseases are closely related because they are both a disease in which identical clones of antibody producing cells grow rapidly. In multiple myeloma, the main problem is the growth of abnormal cells in the bone marrow while in amyloidosis, the main problem is the buildup of the light chains produced by the abnormal cells. And this causes also of course the differences in presentation. But indeed, there can be overlap between the two diseases and 10 to 50% of the patients with multiple myeloma may also develop overt amyloid light chain amyloidosis. Now we come to the topic of MRD. So minimal residual disease is the name given to small numbers of cancer cells from the bone marrow that remain in the person during treatment or after treatment when the patient is in remission. It is the major cause of relapsing blood cancers, including multiple myeloma and leukemia. And ultrasensitive molecular biology tests can measure renewed levels of cancer cells in tissue samples, sometimes as low as one cancer cell in a million normal cells. So how to measure this? This is shown in slide 15. This is a graph showing the development actually of MRD measuring from 1995 already to 2015. So in the beginning, there was demanding really looking at the chromosomes. And since a few years, there's a next generation sequencing, which of course gives you a very high level of sensitivity. So the thing that is not on this in this graph, but is used in clinical trials is next generation flow cytometry, which means that by means of four to six markers, but it can be up to 10 to 12 markers, cells can be detected among many other cells to see if there's indeed MRD, yes or no. So it is, it's not as sensitive as next generation sequencing, but it can be sometimes quicker. It is important to know though that each test method has its own limitation. And what an addition what is what is really actually needed is that because MRD is repetitively measured in bone marrow, there's the need to develop to develop possibilities to test in pierce or blood, because that would of course be of much comfort to patients. Next slide please. So on the definitions on slide 16 definitions for depth of response and MRD. So in the light blue text you see complete remission stringing complete remission and next generation flow cytometry and DNA sequencing. And in the black letters you can see how sensitive these methods are. So just by looking at cells from bone marrow you can see, sorry, the definition of a complete remission is a one cancer cell in a thousand while by means of next generation. So cytometry you end up in one cancer cell per thousand and next generation DNA sequencing you can detect one cancer cell in a million cells. So very different sensitivity. This the same information is actually shown in this in this graph with on the x axis the time and on the y axis the depth in in remission. So at some point we start with a patient within certain amount of tumor cells. And if this patient is treated but does not respond then the number of cells increases. If the patient responds a little but not too much, you end up with a stable disease. And if the patient responds, but a little bit more than stable disease, then we talk about a partial responder. So the dark blue gives the level of tumor bulk under which we talk about complete responders. And within that, that that part of complete responders, there is also the level of response that refers to having an complete MRD. And this patient will probably have the longest time before the disease returns. And and of course what we all hope would hope for that it does not. But that is, of course, a very rare in multiple myeloma as it is in principle and not curative disease. These these explains these slides explain the the the the principles if we go then to slide 18. So how can we use an MRD? In principle, we can use to determine whether treatment has eradicated the myeloma or whether traces remain. We can compare the antidease activity of different treatments and we can monitor patient remission status. Also we can detect the recurrence of the myeloma and choosing the treatment that will best meet its needs. There's a debate on whether MRD can be used to start when to start next treatment. So if the disease is resurfacing, whether that would be the time to treat already or would be better to wait. There's debate about that. If we go to slide 19. This shows you actually the effect of having an MRD being MRD negative or positive following treatment in relation to progression free survival or overall survival. So for both graphs, there's time in years on the x-axis and the percentage on the left graph on the y-axis is percentage of progression free survival. And on the right side is percentage of survival. CTD and CVAD are different treatments. But if you compare the red and the green lines and the purple and the pink, you can see that as soon as there is MRD negativity, then the chances of having a longer progression free survival is higher as compared to when there is MRD positivity. So red and green lines. So this shows that if you are MRD positive, the chances that the disease will return is higher as compared to when the disease is not there. So when you have an MRD negative. So the time to that at resurface, I should say it like that. And that same correlation you also see overall survival, it's less strong, but of course there are often more treatments which affect in the end overall survival. Next slide. So what is it that we do not know about MRD? In principle, the list is quite long. We do not quite know what the optimal timing for MRD assessment is during and after treatment. Also, we do not quite know what the meaning of MRD negative is in specific soup groups. For instance, the high risk cytogenetics or whether there's a different meaning. And also whether we can use MRD to alter therapy. So in duration of maintenance, change of treatment, add agents, those kinds of things. And in relation to regulatory approval, drug approval, we're not quite sure whether we can use MRD as a valid endpoint. And I will talk about this in the upcoming slides. Because in the upcoming slides, I talk a little bit about what current position is on the use of MRD in ultramarilloma for regulatory purposes. So this far available studies have reported a correlation between MRD and PFS and OS. That's what I showed you on the graphs. Try to explain. If something is not clear, we can go back there. Currently, it's not possible to define what order of magnitude for MRD negative would be needed to be associated with a minimal clinical relevant effect in terms of OS and PFS. So this is rather complicated. But what does it mean is that we do not know how deep your response would be in terms of MRD in order to have a certain amount of PFS or OS benefits. And I will get to that a little bit in the upcoming slides, a little bit more in the upcoming slides. So what we think is that the surrogacy of MRD, because that's what we're actually looking for of MRD for overall survival and PFS should be investigated using appropriate statistical techniques using a collaborative effort to maximize the inclusion of trials. Because one trial is not enough. So in the absence of properly conducted validation study, that's how you call them, any assumed extrapolation of effects from MRD to overall survival or PFS should be carefully justified on a case by case basis. So if we if we use this means that if we use MRD, we we should be sure that it can be done on that in that particular case that it actually means something. The example that I would like to refer to is that often we say when one of the texts we have once written is that we call it dramatic effects on MRD. So to increase the likelihood of a positive effect on a clinically relevant outcome, being PFS or OS should be shown. But then of course we can talk about what is really dramatic. And like I just said, this should be decided on a case by case basis. And this is all at least as long as trial level surrogacy has not been established. So what is that actually? I'll show you in the next slide. So this slide explains patient level versus trial level surrogacy. So patient level surrogacy means that if you're a patient is MRD negative or positive, this predicts a favorable or not effect on PFS or OS. So if you're MRD negative, then you know that has that the time to that disease returns is going to be a longer in comparison to patients that are MRD positive. And that also saturation with overall survival. Trival level surrogacy is that the treatment effect on MRD reliably predicts the effect size. So how long PFS will be or how long the overall survival benefit will be. And this is also explained in these two graphs on the left side to see patient level surrogacy and on the right side trial level surrogacy. On the XX MRD on the YX PFS OS. So for trial one, you can see that for this patient, the MRD difference gives you a long PFS OS and within this trial this correlates. And so if you have a shorter, sorry, lower MRD level MRD level, then the PFS is shorter. So you can see that there's a correlation and the same is true for trial two. However, in order to have the qualitative correlation between MRD and PFS, you should correlate this among different trials. Because you can see that the circumstances in trial one for those patients correlate, but not for when you combine trial one and trial two. Well, it is the case when you combine the data for trial one, two, three and four, at least with the results obtained in these trials. So this type of analysis can help us understand or can help us show, can show that MRD reliably predicts the effect size of PFS and OS. And that is what we need in order to have MRD as an endpoint to be used in regulatory approval. So on the use of MRD in amyloidosis, there's indeed scientific interest, that's for sure. And the limitations that I have described for myeloma are also there for amyloidosis. Also, it should be noted that there are different treatment goals for this disease as compared to myeloma. The reduction of the plasma cell clone is not the only goal of the treatment. So because indeed for this disease, there's the improvement of the function of the involved organs and the decrease of the production of the abnormal light chains. So additional goals. This link shows you to, would lead you to the regulatory guidance of the FDA. And there's the similar position as IMA currently has for the use of MRD for regulatory approval. And I must say that there has been a lot of debate and probably you are aware of that as well within regulatory agencies and within those agencies and IMA and within the IMA about the use of MRD for regulatory approval. And what we have learned is that during the course of this year, there will be additional data available, probably able to show trial level surrogacy for MRD, which would of course be very welcome. Both for patients, physicians as well as the regulatory authority because that would indeed enable MRD to be used as an early endpoint in clinical trials and that would speed up drug development, which of course is what we would all want. And with that, I think I want to thank you for your attention. I hope it's clear. Please ask any question you like and we can go back to the particular slide. Thank you. Thank you so much, Paula. That was a really exceptional presentation, really informative. So for those on the line, if you have any questions, you can feel free to use the raise hand option or you also can type your questions in the question box and I can pose them to Paula on your behalf. So our first question is from Hans. Hans, I'll just unmute your line and you can go ahead. Thank you, Nikola. Thank you very much for the insightful presentation with a lot of context. So we understand the concept of MRD much better. Although for me it was very interesting to see what, in what context this discussion is happening around MRD. I was wondering, we only talked within this area of me alone, my doses and recommendations for new treatments about MRD endpoints. Why didn't we have the discussion around complete remission or very good partial response? For example, aren't they also predicting overall survival in the end? Yes, that is a very good question. And I think with complete response you would have, as far as I know, you would have the same discussion there. So you would very much, there you also understand that if you have a complete remission, for you as a patient, as an individual patient, this is very good news. The question is that it is very difficult to predict how long the disease will be under control. And also it's very difficult to say how long your survival will be. So in principle you would have the same discussion there, I believe. But I don't know why we didn't have it. Sorry, I can't answer that question, that part of the question. Okay, thank you. I was just wondering, because we have this intense discussion around the position of MRD. And one of the things we as a patient often are worried about, MRD is of course absolutely an improvement in the technique of diagnostics to look at that detail of the remaining disease. On the other hand, when it would be approved, wouldn't that be encouraging the pharmaceutical companies in the end to create also in the induction states very heavy treatments to reach MRD instead of a long-term health situation? So is that taking into account too? Please clarify a little bit your question, because you were wondering, you would say that... What I meant, maybe I didn't explain it, what I meant that well, but at some moment the CBT or the EMA or FDA would approve MRD as an endpoint to recommend a new treatment. Isn't there a risk that when we have a situation like that, that in the end pharmaceutical companies will focus on MRD. So they will hit the disease as hard as possible to reach that MRD instead of looking at long-term effects of it? Yeah, sorry, now I understand. So what I... it's very good that you raised it, because I should have explained it actually. So the effects that you reach MRD should always be confirmed by BFS data and overall survival data. And at least there should be no detriment for overall survival. It's not a myeloma. So if your fear will be that indeed companies will develop drugs that are very toxic to reach MRD, then they can be approved. But in the end, people are actually getting very sick because of the adverse events or even have increased chance to die because of the treatment. Because of the toxicity, then that's of course not of any value for no one. So that's why MRD data should always be confirmed by data of BFS and overall survival. So that means that probably the regulator will recommend MRD as an endpoint in combination with overall survival and quality of life data? Yes, exactly. So MRD will be used as an early endpoint. So what they can get is, for instance, conditional approval based on MRD and then the specific obligation, as you call it. So there's a requirement that they provide PFS and overalls, progression free survival and overall survival at the latest stage as soon as available. That's true. And of course, this is surrounded by specific recommendations or agreements that they cannot stop the trial early. So you should have enough events for overall survival and PFS to be informative. So be able to say something about what the effect is on those parameters. Thank you. Thank you, Hans. So I have a couple additional questions that have come through Paula. So first is a question with two parts. So first is, is MRD measurement able to be performed in most conventional hematology clinics, so in most hospital settings? So that's part one. And second part is whether the price of MRD testing would maybe be something that would have an impact on whether or not hematologists would utilize MRD in their regular practice. Okay. Thank you. That's clear. So it depends with regard to which type of MRD testing is available where. I think what often, at least as far as I know, and I know a little bit about the Dutch situation, I don't know how it's organized in other countries that well, is that there are a few central labs in which there is the next generation sequencing done, and also the next generation sociotometry, so with up to 212 markers. And that's done in centralized laboratories. And let me see if I... So to answer the question directly, not every MRD testing method will be available in every hospital. But that doesn't mean that it is unreachable. What I understand, at least again for the Dutch situation that the hematologists send samples to the central laboratories await and await the test results. Whether the MRD testing price would impact the availability. Yes, that's a difficult question, at least for me to answer, I must say. In principle, you can look at it from a bigger, as a bigger picture. Because if you would know if the MRD, sorry, if the disease is resurfacing, as I call it, then that's very valuable information because you can discuss with the patient whether to start treatment now or later. And that of course can in the end also contribute to lower costs. So I must say that further than that, I find it very difficult to answer this question. I would assume and hope it doesn't, but I of course am not sure to talk about the whole of Europe. Okay, thank you Paula. So another question is really round. So for now, the current approach to MRD testing is really reliant on bone marrow aspiration with this being potentially the gold standard. Do you think that this will be, so based on your knowledge, do you think that this will be maintained as the high standard? Is there any possibility for there being a blood test available, for instance, in future to be able to test for MRD? Yes, that's also a very good question. And I think the bone marrow will remain, bone marrow aspiration will remain the golden standard until the protection of MRD and peripheral blood has shown to be as sensitive and as specific as the MRD testing in bone marrow. So there have to be validation studies. So that is the next level effort, I would say, that needs to be done by both the companies as well as the human collaboration with academia. Okay. It will not be short. It will not be soon, I'm going to say, sorry. Yeah, but are there currently blood, so peripheral blood assays that are under investigation that you know of? You can do next generation sequencing on your blood. That's technically that's possible, but you have to show that the correlations that you see in the bone marrow are similar in the peripheral blood. And that has, so you have to do in several trials, you have to show the same pattern in bone marrow and blood and people just need to do that. Okay. So technically it would be possible. Great. I think that's something that patient advocates can advocate for in future research. Yes, of course. And of course, there's the advantage for, not only for patients, but it's also the advantage for companies as well, right? And also for physicians as well. I think it's a triple win situation if you can do it by peripheral blood. It costs less effort for the physician to do, to collect peripheral blood. You can do it much more frequently, which is interested of interest for companies as well. And for the patients, I mean, there's a big difference between drawing blood and getting bone marrow, getting a bone marrow aspirate. So, yeah. Thank you. Another question is around MRD and with the aim of MRD as a surrogate endpoint with having the aim to speed up drug development. So the question is around which stage of development would be, would be sped up per se. So it seems that MRD data would be used in conjunction with trial data. So there would be still considerable time given to trials to test for toxicities and side effects is what the asker has put to add some context. So. Yes. Yeah, it's a very good question as well. So I mean, which aspect of drug development would be speed up? And I think it would be the part, so the basis. So the basis for regulatory approval would be in whatever line of treatment that would be, of course, depends on if surrogacy has been established in the different settings, which of course are clearly there in multiple myeloma treatment. But and the question touches upon a very important point, of course, and that's the safety because I mean, the drug can be very efficacious. But of course, it can also be very toxic in that you have to have sufficient exposure. You should call it so sufficient number of patients should be exposed to the drug for sufficient duration in order to get a good feel about the safety profile. And there are guidelines for that. And of course, if you have a drug approval based on an early endpoint that would that would that would you bring about a risk that you have an indication that it works but not sufficient safety information. There's that is indeed something that we should be, you know, be on the lookout for that that doesn't happen. Of course, it takes several months in order to see if patients respond. And also, you need to have quite a number of patients to actually, you know, get a good feel. Oh, Paula, I think your audio is cut out. Can you hear me now? Yes, I can hear you now. Oh, sorry. Yeah, I got disconnected. Sorry. So it is about the balance between efficacy and safety that is of course clear that needs to be established and confirmed. I think you were able to really stress that point. So, but we've wrapped up the webinar now. So I've sent everybody off for the evening. So thank you once again so much for a really great presentation. Have a really nice evening. We really appreciate you and do this webinar and really regret that we couldn't have done this face to face at the AGM would have been great to have you with us. But as always, you've explained this stuff really brilliantly. So we appreciate your time. You're welcome.