 Good afternoon, everyone. My name is Ana Vallejo. I'm the communications manager for Myeloma Patient Europe, and I will moderate this webinar today. I would like to welcome you all to this online session on personalized medicine in Myeloma, and I would like also to thank you for joining us today. For your information, this webinar will be fully recorded and uploaded to Myeloma Patient Europe website, which is www.npeurope.org, and also to the MP YouTube channel, so it will be available in case you would like to share it with someone or to watch it again. Before we start, I would like to make a small summary of the webinar dynamics. As you know, this webinar is scheduled from 6 to 7, so the presentation will last about 40, 45 minutes, and then I will open the session for questions. There are two ways to ask questions to the doctor. One of them is using the microphone in your computer. Just press the right hand bottom that you will see on your screen, and I will unmute you so you can ask the question to the doctor. And the other possibility is to do that in writing in the question and answer window that you will see also in your screen. I will receive those questions and I will read them so the doctor can answer them. This talk will be given by Dr. Annemiek Royiel, Department of Hematology Erasmus M.C. Cancer Institute in Rotterdam, the Netherlands. So Dr. Royiel, on behalf of Myeloma Patient Europe, I would like to thank you for your kind collaboration and also for your time to prepare and also to give this webinar today. Thank you very much, and the floor is yours. You can start whenever you want. Good afternoon, everyone. My name is Annemiek Royiel. As I said, I'm situated in the Erasmus M.C. in Rotterdam treating myeloma patients doing research, and I will give you some information about myeloma and about personalized medicine. So I will tell you about the diagnosis of multiple myeloma, the variety in the disease, the person of medicine, and also examples of personalized medicine. So to give a short introduction, multiple myeloma is a type of cancer that comes from the plasma cells. A clone of plasma cells arises, gives one type of M-protein, so an IgA Kappa and IgG Lambda, which actually has no useful function, but also gives the problem of a lower other immunoglobulins that gives problems in kind of infections. As we know, that's all kinds of multiple myeloma are preceded by a precursor state, AMGUS, then a smaller myeloma, and then multiple myeloma. And AMGUS is a situation in which there are still low percentage of plasma cells in a bone marrow, a low M-protein, and no myeloma-definy events. In smaller myeloma, the clone of plasma cells is already larger, giving rise to a higher M-protein, but no myeloma-definy events. In a situation in which a patient has myeloma, then there is an M-protein, plasma cells in a bone marrow, and an important thing is that there are myeloma-definy events. So we see that globally, there are 0.8% of all the cancers are myeloma, and we see that around 140,000 people each year get diagnosed with multiple myeloma. The problems in multiple myeloma are mostly bone pain, but also the current infection because of the low immunoglobulin status and the unfunctional M-protein. There are sometimes kidney damage and there is fatigue. So the original myeloma-definy events when we started to treat patients with myeloma are when patients had osteolytic lesions, had anemia, hypercosmia, or renal failure. But there are some other features that also were found to predict for as soon multiple myeloma did kind of cure. And that is around 80% within two years when patients have an involved versus un-involved seropropylgene of more than 100, rich of more than 100, have a high plasma cell potential of more than 60%, and more than one focal lesions. These patients were found to have myeloma, to develop the myeloma in around 80% within two years. So also this ultra high risk, first named smothering myelomas are now defined as having multiple myeloma and are therefore being treated. So to have the diagnosis multiple myeloma there are some blood draws and evaluations that we have to perform. And first of all we look in the blood laboratory results if there is an M-protein, if there is anemia, hypercosmia for example. Furthermore we look at the M-protein level and the free life-chain levels. We look in the urine for the life-chains and we do a bone marrow test. And this bone marrow test is necessary to give the diagnosis of multiple myeloma. The bone marrow is required for the diagnosis. When there is an M-protein we search in a bone marrow for a plasma cell monoclonal plasma cell population. Sometimes it arises also from a plasma cytoma but most of the time there is a bone marrow in which there is a high percentage of plasma cells, monoclonal plasma cells. We also perform fish and fish is done to look at chromosomal aberrations which I will talk about a little bit later. And also we perform now extra genetic profiling. This is not done in each enter yet but gives much more extra information about prognosis of the patient. So to show most of the patients who have multiple myeloma have an high M-protein or have an M-protein, there are some patients with multiple myeloma in which the plasma cells do not secrete an M-protein. A lot of patients, 60-70% have anemia, around 62% have bone lesions, 20% with renal failure and some patients like around 10-12% have hypercalcemia. So myeloma is characterized by showing, by being occurred or the cause of the disease is mostly due to genomic abnormalities. We see that half of the patients are characterized by having a hyperdiploid, which means that they have an extra chromosome copy of chromosome 3, 5, 7, 9, 11, 15, 19 or 21. So they have to not be there all, but at least some. And we see that it's not of the even but of the uneven chromosomes. Then we see that most of the patients or health of the patients are characterized by having translocation. And these translocations always occur with 14q32. So we see the translocation 1114, translocation 414, 1416, 614 and 1420. Each time an oncogene is attached to a very active point of 14q32 and that gives rise to an extra expression of an oncogene, which helps the myeloma cell, the plasma cells to survive. Some of these are conferring a poor prognosis, especially the translocation 414, 1416 and 1420. 1114 translocation is preferred for extra neutral prognosis. What we now see is that all the patients or the different patients are characterized by differences in myeloma characteristics. So one patient has, for example, on translocation 414 or other genetic features than the other patient. That is the first thing that we have found and we have found before that you can subdivide myeloma patients into like 10 subgroups showing different characteristics in their gene profile, for example. And we see that like 20% of the patients have a translocation 414 while also a number of patients like 15% have a deletion 17p. So we have the differences between the patients. Then we also see that there are different clones within one myeloma patient and that is important for something that I will show a little bit later. So the patients will have like maybe three or four clones with one clone. For example, having a translocation 414 in a low percentage, which is maybe not detected, or different genetic features. So we see already that the translocations in myeloma there can already be seen in a precursor state. But the further you have the myeloma, the longer you have myeloma or the more advanced myeloma is, the more problems you see. So at a time that some patients have a plasma cell leukemia, which is really an end stage, or sometimes also occurs in the primary setting, but most of the time it is in an advanced stage. Then we see that there are multiple, there could be more translocation, there could be a translocation and a deletion 17p. There could also be one Q gain, which is an extra copy of a short arm of chromosome one, and it can be acquired mutations. And very known mutations are from the KRAS and RAS genes. What we also now know, and that makes it even more difficult, is that there was this research that has been done before, and multiple three or more sites were punctured and bone marrow cells were analyzed. And we saw that at different sites the clones can be different. So at one point at one site there can be a clone showing the different genetics than another clone. That makes also the treatment of the disease very different, very difficult. What we have seen that in the state of the Amgust, that you can see some clones, some different clones already, then there will be in one way or the other due to microenvironment changes, one small clone that develops into a myeloma. This myeloma will then be treated with chemotherapy, and three things can then occur. You see in the part C that, for example, even a precursor clone that was already there in the Amgust state but didn't grow out to a myeloma can have the chance by, for example, getting rid of the other clone to grow out to the myeloma. On the other hand you can also see that myeloma that has been treated, there's still some cells left that are not attacked by the chemotherapy that grow out again to be the myeloma. And one of the clones that is by being treated, a small clone when it was myeloma, but also has the chance to grow out to a myeloma when the disease is treated in the first place. So in the newly diagnosed setting. So three of those situations can occur. And very nice research has been done in the past in one patient who had multiple bone marrow functions each time that the disease occurs. So that you can see in the more left side of the picture the circle with different colors reflecting different clones. So at the largest clone of 72% is a clone with certain genetics, certain characteristics. The patient is treated with Lenalidomydexamethasone. Then the disease re-develops again. Then you see that another clone comes up and that is the green clone of 64%. This is another clone with different genetics. Then another treatment is given. In this case it was carfilzomib. That gets rid of the green clone, but an orange clone comes up with different genetics again. And so you see, based on the different chemotherapies that you give, that different clones can come up and different clones are sensitive to treatment. And this is one of the examples. You see that this patient had like four clones at the start of the treatment. We also know that in more advanced disease there are more clones and more in the early stage of myeloma sometimes only one or two clones or maybe one clone can be seen. So it also depends on when treatment is started. If this is already an advanced myeloma or it was a myeloma which is already conferred with a prognosis, sometimes based on having the deletion 17b which is also correlated with having multiple clones already as diagnosis. So the translocation for 14 as I already said is one of the chromosomal aberrations that is conferring for more prognosis and that is also shown in the left picture. So the blue line, the patients having the translocation for 14, they develop earlier succumb to the disease than the patients without the translocation for 14. Also on the right side you can see patients with the deletion 17b have a poor prognosis than patients that don't have the deletion 17b. That's the red line. So what is shown already by all these researches is that we can see that multiple myeloma is really a heterogeneous disease. It varies between patients, it varies between locations in the body and it varies over time and also due to chemotherapy. So what can we do with this information? We always and still actually do treat the patients with the same therapy. So all the patients actually get in the first line kind of the same therapy. In our country, for example, in the Netherlands, but in most other countries, VTD, botasomib, telomide, dexamethasone is an induction therapy for younger patients or patients that are eligible for a high dose melvanistensal transplantation. So we give every patient the same treatment and that doesn't help every patient. So we see already, of course, that some patients respond to treatment and some do not. And most of the time we do not really know what was different about this patient than the other patients. We have, happily, we have many new agents that can be used in the treatment of myeloma. We have the imid, the immunomodulatory agents, thalidomide, lenalidomide, and pomalidomide. We have the proteasome inhibitors, botasomib, carfilosomib, exasomib, monoclonal antibodies, which is one of the last latest developments already now known for a couple of years and also been implemented in standard treatments, daratumumab, elotizumab. And we have the alkylates that are still very important in the treatment of myeloma, myelofilum, for example, encyclophosphamide. So what we actually want to do in the future is to go towards personalized medicine. We want to tailor therapy to have the patients get the best response, achieve the best response, and also give a safe therapy and also to keep on giving a good quality of life to the patients. We have now all kinds of features to look at the patient, to look at the characteristics, for example, to look at genomics, the gene expression, but also the protein expression and all kinds of plasma cell features that confer for prognosis. And with this kind of biomarker signature looking at the gene expression profiling, we develop an algorithm which could help in looking at the characteristics of the patients of the myeloma, maybe in the future also of the environment in which myeloma is growing, to see the difference between the patients and to treat according to their difference. So what do we already have now? What do we already use now to treat patients based on their characteristics? We have the high-risk multiple myeloma. I will tell you a little bit more about this. Then we have the minimal residual disease and we want to implement later on personalized medicine into clinical trials. So high-risk myeloma is defined based on different factors. We all know and it's all still used the ISS stage. The ISS stage is actually more based on the tumor burden. So the higher the better to make microglobulin, which is also a marker for the bulk of the disease of the patient and also the albumin, which is lower when a patient is quite ill, shows that patients that have a low albumin, and especially in high better to microglobulin, have a high tumor burden and also have a poor prognosis. We have the translocation 414 and the lesion 17p that confer poor prognosis and defined high-risk myeloma. We have also a combination of the risk stratification of the fish data plus the ISS stage and also like the gene expression profiling and the mutation status that can be used to confer for risk stratification. Also the H still plays a role, but even more the availability of new agents in the treatment of myeloma, which are not available in each country in all the countries, so that also plays an important role in virginity. The myeloma profiler with the SKY92, this is a high-risk profiler, which identifies patients based on the genetic characteristics of their myeloma plasma cells. So based on a number of genes, 92 genes, which in each have a certain amount that they contribute to the signature, will show whether a patient has a high risk or not. So when they have the SKY92 gene signature positive, it shows eventually what we have seen in a number of studies that they have a lower progression-free survival and eventually also a lower overall survival. And we have tested that in many patients. So we have tested that in the newly diagnosed setting, which is the left picture on the top. We have also shown that in the relapse setting, we have shown this in the elderly setting, and also in some different study cohorts, so study cohorts in the States and study cohorts with one agent, so that actually we see that this high-risk signature defines or identifies the myeloma patients with a high risk. But it also shows in this case that it doesn't matter what kind of treatment you get if you're young or old, if you're newly diagnosed or relapse, this high-risk signature will find the patients with a high risk, and it is not dependent on age or treatment. That is what we have found then. We have further found that if you combine the high-risk signature with the ISS stage, if you combine that, then it is the strongest identifier of patients with high risk. So what can we do with that? That I will show a little bit later, what we can do with that. First, I will mention the mineral residual disease, which I think is also known already by many patients, is mostly used actually in clinical trials, but will also play a very important role in the clinical trials, but also in the future to tailor therapy. We see that we have different techniques, so looking at the flow or looking at the genetic clove, and then you can, with the sensitivity of one cell in 100,000 cells, you can find if there's still myeloma present or not. That sensitivity shows that if you are negative, then if you are MRD negative, then that confers for good prognosis. So the goal is now more and more to really get all patients MRD negative, and not only one time between you really see a sustained MRD negativity, which means that you have bone marrow after one year, one and a half, two years. If it stays negative, then it really confers for a good prognosis. So also that can be used in prognosis. So what do we do now with the SKY 92 or the translocation status? We still don't know actually what will help the patient with the SKY 92 positive risk signature, and also had troubles with finding what helps the patient with the translocation 414 deletion 70p. What we do know already with the patients with the translocation 414 and deletion 17p is that there was one research, one clinical trial that found if you give patients with that chromosomal aberration two times the high-dose melvanin and stem cell transplantation, that they have a better prognosis, which could even be comparable to the patient that do not have those chromosomal aberrations. So that was actually one of the first usable features and methods in which we have used the chromosomal aberrations in how we treat patients then differently. The next is that we are looking into clinical trials, how we can better treat those patients. So we know that based on the normal or on the normal on what has been done until now, that patient with the SKY 92 positive high risk signature performed poorly. So then it is already found that actually double therapy with potassium indexamate zone was once very active, but then we found that triple therapy was more active. Then already we are now in the times that we are giving quadruple therapy with daratumab and proteasimab thalidomide indexamate zone from a trial that found that it was the casiopeia, that it was very active. And now even we think that with quadruple therapy or sorry, PENTA therapy that we can even help those patients with a high risk better. So this is a Mach 9 trial which looks at those patients at a high risk. So having the SKY 92 positivity and adverse chromosomal lesions. And those patients will get therapy with daratumab, cyclophosphamide, proteasimab, linolyte, linolyte indexamate zone. So PENTA therapy to get these patients also into an MRD negative state and then with high dose melformin and consolidation cycles gets also these patients into a better prognosis. So this is one of the first ways to, and it will be done more and more to get extra, more intensive treatment for patients that have a poor prognosis based on their translocation or on their genetic stages by the SKY 92 signature. And more and more trials are now looking in this. One of the other utilities using the characteristics of the plasma cells is for example the Translocation 1114. I have said before that the Translocation 1114 does not really confer for prognosis but what has been found that venetoclux, which is an agent that attacks the patients with who have a high BCL2, low MCL2 ratio, have a good response on the venetoclux. And especially the patients with a Translocation 1114 who gives this high BCL2 ratio, sorry, BCL2 MCL ratio respond very well on the venetoclux. So this is also a very nice way to use the data of the plasma cells to really give targeted therapy with also better response than the patients that do not have the Translocation 1114. So personalized medicine that will indeed enable their tailored therapy and will actually achieve a high response but also will give the best treatment to the patients with giving no extract or trying to decrease or minimize the collateral damage by giving agent that do not really have a good effect on the myeloma plasma cells. So really find a therapy that will achieve the best response in this patient. And we use now this genetic information in the different studies to stratified patients but indeed we have no, in a clinical practice, no current treatment that will give the patients when they have certain chromosomal abnormalities except for what I just stated, the patient with a Translocation 414 and deletion 17B which in some countries an extra high-dose myeloma and stem cell transplantation is offered. Then there are now interesting projects ongoing and one of these projects is the Horizon 2020. In this project there are multiple centers involved. The Skyline, a business we have developed the Sky92, University of Turin and Erasmus MSE, the Erasmus School of Health and Policy and Management and also the myeloma patients in Europe. And in this project we will look at the data of the data that we already have, look at the genetic signatures of the patients and we will look at what genetic signature of the patients will do for a myeloma doctor in a sense of that it could help the myeloma doctor to base his therapy choice on and what would be eventually the best treatment to give. So we will search for new, also for new predictive signatures that will help us to define which treatment will help which patients and even better than what we have now. So we have the translocation 1114 that really triggers the myeloma doctor that this patient would be best treated with, for example, for natoclex. This is all still in clinical trials and not outside clinical trials. But in the end in the future we will have the patient, we want to have the patient before us look at their genetic profile, of course, also the patient itself, also the wishes of the patient and the comorbidities, but offer the best treatment based on the clinical, sorry, based on the genetic characteristics of the myeloma. And we hope to have this predictive signatures of these patients looking at their genetic up make of their different clones. So there were already quite some efforts done with the SKY-92 signature and this is shown also in this slide in which we have seen that if you look at the right picture that patients were treated with vinkistine which is quite an old treatment, adromycin and dexamethasone, or with portesimib adromycin and dexamethasone and we see that if you look at the whole picture that there is a little bit of a difference between when patients were treated versus control with the portesimib or with the vats. So the vinkistine, adromycin or dexamethasone. But especially if you look at the risk state of the patient then you see that when patients are standard risk so do not have a SKY-92 high risk signature then it doesn't really matter if you give or portesimib or vinkistine. But if you give a patient with a high risk signature vinkistine adromycin, dexamethasone then those patients are really not given the best treatment. Those patients seem to do much better on the portesimib adromycin, dexamethasone. So that would mean that in the future if you have a patient with a SKY-92 high risk signature that those patients will not get vinkistine adromycin, dexamethasone but will get portesimib for example. So this is one of the efforts that was done. Other efforts is that we look at the patient that are for example treated with in this case VMB, portesimib melvalent prednisone or high dose melvalent. This was done in a trial that has run in the past years and we see that the ultra low risk patients that get or VMB or high dose melvalent they are not too large different. There are some differences when they get high dose melvalent or VMB and those patients show that the ultra risk patients are better off not getting the high dose melvalent but the VMB which is nice for a lot of patients because high dose melvalent means an admission to hospital means high toxicity. So we rather and the patients rather go for treatment in which they can stay at home, come to the outpatient clinic but are not admitted to hospital. But if you see the high risk patients on the right side then you see if they are offered only portesimib melvalent prednisone and not a high dose melvalent that are worse off. So those patients that have a high risk signature should get treatment with high dose melvalent instead of a VMB. So that really makes very clear that it is necessary to know what is your high, what is your risk signature in the beginning. Are you better off getting no high dose melvalent and just portesimib melvalent prednisone in the outpatient clinic or are you better off getting the more intensive treatment. And that is also what we see if you look at treatments like we all know the lanolidomide and telidomide and what we see looking at the not, how do you say this, the straight lines and the lines that are more in dots then you can see that the MPR patients that get melvalent prednisone lanolidomide is the first red line which you can see in the second one you see that if patients are, sorry, a little bit of a strange figure because it has colors and it has different lines. But what you can see is that the patient that are sky 92 high risk, if they are treated with telidomide they really have a poor prognosis. If they are treated with lanolidomide the prognosis is much better. When patients do not have a sky 92 risk signature so they are low risk then it does not really matter if they are treated with telidomide or with lanolidomide. So again, to know the high risk signature, to know the risk you know that patients should not be treated with lanolidomide but should get lanolidomide. So already two of these utilities are now shown. First of all the patients with high risk in all kind of clinical trials show that they have benefit from high dose melvalent instead of getting out patient clinic therapy with, for example, melvalent prednisone and mortazomib. And you can see that with looking at the different image, telidomide and lanolidomide based with a high risk signature should get lanolidomide when they have a high risk. So in the future we hope to have more clear view on what the plasma cell characteristics of the different myeloma patients are. So if you come to the outpatient clinic already in a newly diagnosed setting but also in a relapse setting we have the bone marrow. We look at the genetic upmake of the patients and we treat based on the genetic signature of the patient and really target the genetic upmake of the myeloma plasma cells achieving the best response but also, you know, therefore hopefully getting also a better quality of life of this patient not to give treatment that are actually not working but only giving collateral damage. So that ends actually this talk by actually mentioning that in the future we hope to identify the right treatment for the right patients and one of the most important thing is that we really characterize the myeloma but we also characterize the patients and find the best treatment for the best patients. Thank you for your attention. So if there are any questions, please, sorry. Sorry, can you hear me? I think I was mute. I can hear you. Thank you very much for your wonderful explanation about personalized medicine and now I will open the floor for questions and just quickly remind you that you have two ways to ask questions. One of them is using the microphone in your computer by clicking in the right hand button and the other way is just send the question in the Q&A window in writing so I will read the question to the doctor. So if you have any questions, just use one of both ways to ask your question. Well, some of you already asked some things so I will start with the first question. The first question said, is personalized medicine the same as a stratified medicine? If not, what is the difference between them? Well, stratified medicine. We use stratification more when we want to divide the patient into clinical trials to be sure that they are equally divided and that we can really evaluate the risk of the patients and the treatment that they get. That is first of all, targeted therapy or personalized medicine. There are actually multiple ways to say it but it actually says that you also have tailored therapy, targeted therapy. All it says is that you want to know actually the plasma cell characteristics of the myeloma and to know also the characteristics of the patients to really give the right treatment for the right patients and that can be in different ways. So at least genetic make sense. Hedquan musoma abrasions, they make sense to find the right treatment or to use the right treatment and on the other hand personalized medicine also means that you look at the patient yourself to take their wishes into account but also take the form if they already had treatment before to take the comorbidities and toxicity that they had before into account. So that is really tailored to the patients. Thank you very much, doctor. The next question. Where could patients get their myeloma genetic test done if the test is not available in their country? Only if the test is available but that is also by the company that developed the SKY92 they have already with number of centers contact and for example in England but also in Italy. I think that there are already centers that have the SKY92 available but not all centers as yet. But it is something that we want to roll out further and that could also indeed be implemented in hopefully in the future clinical practice especially because we now see more and more the utility of the comorbidities but also of the SKY92 risk signature. So but not yet in all centers and if the centers have no connection with SKY and Skyline has not talked to the centers yet then the SKY92 signature is not available yet for those patients but hopefully in the future more centers also will use the SKY92 signature or the new developed signatures that we are all working on. Thank you very much. The next person would like to ask the question with the microphone so Jürgen I'm amused you so you can ask your question directly to the doctor. Hello this is Jürgen. I'd like to know if SKY92 replaces the fish test. That's a really good question. Well I have showed in one of the... I hope you can still see the slides. I will go back to one of the slides to show something here in this analysis. We looked at all the available risk factors. So as you can see on the left side you can see that there's deletion 13Q, deletion 70P, translocation 440 in ISS stage on its own. And we actually saw that comparing or using all the different prognostic factors that when you combine the SKY92 signature with ISS that gives the strongest separation of high risk patients versus standard risk patients. But in the end it will not replace the translocations or deletion 17P as yet. Not at all. That is really there's more research necessary to see the difference between that and we have with some of the clinical data we have already shown that for example I think it was the last study that I showed. I think this study showed that this was a study done in elderly patients with my malform prednisone telenium mice and with lenon telenium mice that it was the best way of defining the patients into high risk was based on the SKY92 signature. So I think that both the SKY92 signature and the fish data both are necessary for the future. And really most of the studies and trials that are developed now used both. So the Mug9 trial that I showed used the SKY92 and fish data but some trials only used the fish data still. So I think in the future it will be both used until we have more and more evidence that we could use one or the other but I think it will go even further. So we have this now but in the future I hope we also have like more predictive signatures. Signatures that predict if you use a certain treatment for example potassium or carfilzomib that you have the signature of the patient that says okay I will respond to the carfilzomib or I will respond better to the lenon telenium mice. So that goes more towards the predictive signatures and they are being developed in the coming future. Okay, thank you. So the SKY92 is not part of normal diagnostic? Yes, in our center it is. But in most centers it is not yet. So we still use the translocation for 14 and deletion 17p because guidelines as we have now tell us then to do for example a tandem high dose malvalent transplantation. But that will already also change probably in the future getting more and more data handed but it's not standard in a workup of the myeloma patient as yet in the most centers. Okay, thank you. Well next question, should you do a genetic profiling every time when you have a relapse to see if there is a higher risk than you know before? Yeah, I think so. To be honest in practice we do not do that yet. And it is because we cannot, we don't know as yet that when a patient has a relapse we do the bone marrow but not all the time we do the wrist signature and we do not know exactly what the genetic makeup is of the myeloma at relapse. If we have in the future the sort of more predictive signatures then it would be more utility than you know when a patient has a relapse what is the genetic makeup, what should I give the patient now? For now we base ourselves mostly on what has the patient already had. So we had the patient's protezomib and was he not responsible on protezomib we give another proteosome inhibitor but we give an image like linoleumites and we base our choice on did the patient have neurotoxicity in the beginning then we give another agent that does not give neurotoxicity. So but in the future, in the future would be interesting to do this but and then it would be really necessary to do a bone marrow each time to tailor the treatments. Thank you doctor. Next question. You only showed higher risk along genetic profiles. Are there also other signals of higher risk because there are a lot of, there are also a lot of differences in the way patients react to therapies? Yeah exactly but that is exactly why we want to look at more predictive signatures in the future to find out if the genetic makeup shows that for example let's take the translocation 1114. If a patient has translocation 1114 we will have a high chance that the patient will respond to treatment. So that might help us to choose treatment in the future. Thank you very much. The next question. Are there any difference in the results using the Sky 92 between M component or line chains disease? No, not between light chain or M protein disease. No differences. Thank you very much. The next questions. Apart from genetics or biological characteristics to test the efficacy that a drug can have, is the quality of life something explored in this kind of medicine? I mean are there drugs with less side effects for a specific group of patients compared with other group of patients? That's a good question and that is difficult because for example if you, suppose we take again the example of the translocation 1114 because that is the best example that we have for now and then you want to actually give for NATO clocks because that is the most effective. Then one thing you can say that at least you give treatment on which you know the patients will respond. You don't have to give like other medication for example linoleumite to which the patient will less likely respond which also has some side effects. So you can tailor the treatment in that way that you will balance effectivity versus quality of life. But the quality of life is of course still, there is a major importance. But that is why I said before indeed you want to prevent collateral damage because of giving agents that do not actually target the myeloma that will give side effects. So the quality of life plays an important role and the major role. So for example if we see that a patient will respond very likely to potassium but has neurotoxicity already great two or three then of course that will overrule the choice of giving potassium to the patient. Then you will search for another car sales map or whatever. So of course the quality of life and toxicity play an important role. Thank you very much. Next question. What are the barriers to apply personalized medicine in healthcare systems? I think we heard something about access but not sure if there are other barriers. Do you mean for the high-risk signature or do you mean for the agents? I think this person is referring in general. I mean for example if you don't have a availability of diagnosis text or if you don't have access to the medicine, not sure if there are any other barriers. Yeah, well those are the two most important barriers, especially the letter one. So not having the agents available that you would actually want to give to a patient based on their risk status, that is the major problem. So and that is something very difficult to attack. The other thing is not having the SKY 92 risk signature. That is also something most of the countries do have fish available. That is almost in all countries. And there's also a very important prognostic marker to which we now adjust our therapy. The SKY 92 is one of the markers that we have developed and that we see works good. But we will also in the future look further to all kinds of methods in which we can look at the plasma cell genetic upmake and to use for treatment choice. And in the future we'll also come across barriers in which the genetic signature has to be of the diagnostic have to be approved by regulations and be available in the different countries. But that is something that I cannot foresee in the future how that will go. But for now the SKY 92 will hopefully be available in more countries and more centers. Thank you doctor. That was the last question. So thank you for this interesting webinar. Just remind you all that this webinar has been recorded and will be available in the MP website which is www.mpu.org and it will be available also in our YouTube channel. Thank you doctor and thank you very much for your attention. Have a nice evening. Thank you. Have a nice evening. Thank you very much.