 Good afternoon, everyone. My name is Sanna Vallejo. I'm the communications manager of myeloma patients Europe. Welcome to this webinar included in the AGM 2020 webinar CES. As you know, our annual general meeting was cancelled due to the COVID outbreak and we are delivering this educational program in a virtual way. Today's webinar on personalized medicine in myeloma and ielamiluidosis will be given by Dr. Francesca Bonnello from the University of Turin in Italy. And just for your information, this webinar will be fully recorded and will be uploaded to the myeloma patients Europe website, which is www.mpu.org and it will be also available in our YouTube channel. Before we start, I would like to explain briefly the webinar agenda, especially for those who joined this webinar for the first time. As you know, the webinar is scheduled from six to seven, so the presentation will last about 40, 45 minutes, and then I will open the session for questions. You will have two ways to ask questions to the doctor. One of them is using the microphone in your computer, as I'm doing right now. Just press the right hand button that you will see in your screen. I will unmute you so you can ask the question directly to the doctor. And if you don't want to use the microphone, 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. Dr. Bonnello, on behalf of myeloma patients Europe, I would like to thank you for your time and your collaboration given this webinar today. Thank you. Thank you very much for being here with us today. So thank you and good afternoon to everybody. I'm Francesca Bonnello. I'm a doctor working in the hematology department of the Hospital of Turin in Italy. And I mainly work with patients with multiple myeloma and amyloidosis. Today I will give you a presentation about personalized medicine in the field of multiple myeloma and amyloidosis. So I will go briefly through definition and main characteristics of these two very different diseases. And I will rapidly delve into the core of the presentation, which is about the personalized approach to treat these diseases. So what do we mean by personalized approach and what are we doing now with this approach and what we will do likely in the future. So multiple myeloma is an hematological cancer originating from plasma cells. Plasma cells are a kind of highly developed B cells that in the healthy individual have the duty to produce immunoglobulins. Immunoglobulins are antibodies that are the weapons that our body use against infections. Of course, in multiple myeloma, plasma cells aren't working properly and immunoglobulins produced aren't working and they just induce organ damage. Multiple myeloma represent approximately 2% of all cancers, approximately 15, 10, 15% of all hematological cancer, and as an incidence of 5, 7, every 1000 people every year. It's considered mainly a disease of the elderly population since median age of diagnosis is 69 years old and more than 50% of patients is aged between 65 and 85 years of diagnosis. So it is a disease that's quite rare in the 30 people in their 20s or 30s. I'm sure you are aware that clinical presentation of multiple myeloma can be summarized with the chronybob crop, hypercalcemia, renal failure, anemia, and bond lesions. Why that? Because plasma cells proliferate in the bone marrow and proliferating in the bone marrow means that they steal the space in the bone marrow that is generally used from healthy cells, healthy red blood cells, healthy progenitors of platelets, so that plasma cells steal this place, and anemia occurs. Also proliferating in the bone marrow, which is inside the bones, means that the bones are damaged and the patients have bone lesions and consequently hypercalcemia. Because in the bones are made of calcium and when the bones are harmed, calcium is released in the blood flow and high calcium level are registered. And hypercalcemia can be very dangerous for the patients, so life-threatening consequences that can induce heart arrhythmia and also coma. And of course we have renal failure because a part of the immunoglobulins that the malignant plasma cells produce are filtered through the urine and accumulating the kidney-induced kidney damage. What do we do to diagnose multiple myeloma? Well, we do several tests on the blood and in the urine, so we do the electrophoresis that we use to quantify the monoclonal aberrant immunoglobulins present in the blood flow or in the urine. We do immunofixations that help us to understand which kind of immunoglobulins our plasma cells are producing. Of course, we do the bone marrow biopsy and aspiration, which is a very useful tool that help us to quantify how many plasma cells are in the bone marrow because plasma cells, we don't find plasma cells in the blood flow, we just find their products immunoglobulins, the cells stay in the bone marrow. So we need to do the biopsy to find them and to quantify them and to see their characteristics. And of course with bone marrow examination comes a very important tool, which is the genetic analysis. We perform the cytogenetic analysis through a technique called FISH, which is the acronym of Fluorescent in C2 hybridizations that help us to see the chromosomes of the plasma cells to see which mistakes, which error is occurred in the chromosomes. So we detect deletions in the chromosomes, translocation in the chromosomes, amplifications in the chromosomes, and of course, to diagnose and to investigate multiple meloma, we do the branch of radiological imaging. So we perform computed tomography or magnetic resonance imaging or PET computer tomography that helps clinicians to find all the lesions, the bone lesions located into the body. What is, on the contrary, amyloidosis, amyloidosis, AL, well, firstly, there are many kinds of different amyloidosis, we will focus today only on AL amyloidosis, which is a very different disease from multiple meloma. We can say they are like cousins and it's a disease in which there is a plasma cells, usually much fewer than in multiple meloma, less than 10%. So to do a diagnosis of multiple meloma in the bone marrow, we have to find more than 10% of plasma cells out of the total cells in the bone marrow. In amyloidosis, usually we have much less plasma cells in the bone marrow, less than 10%, because otherwise we are talking about myeloma, but these plasma cells produce a part of the immunoglobulin, the light chain, which is misfolded, is structured wrongly. And assumes a conformation called beta sheet. So the beta sheet conformation is very dangerous because our body cannot recognize this light chain and destroy it, so this light chain misfolded accumulates in the different organs and induce damages. As you can read, amyloidosis is a much rarer disease than multiple meloma. The incidence is 5 to 10 every million people per year. And this we'll see is going to be one of the problems to apply personalized treatment approach to amyloidosis, because since it's much a rarer disease, it's much more difficult to study, to investigate. And so we have less tools to apply the personalized approach to amyloidosis. So this beta sheet misfolded protein accumulates most frequently in the kidney, the heart, liver, nervous system, intestine, and subcutaneous tissues, inducing damages. To diagnosis the amyloidosis, the workup is very similar to that of multiple myeloma, but the diagnosis is histological, so we have to do a biopsy. And we usually biopsy or the abdominal fat, which is a peculiar place where the misfolded protein tends to accumulate, or we biopsy the involved organs. So if we suspect amyloidosis of the kidney, we have to biopsy the kidney if the abdominal fat is negative. And when we obtain the red Congo staining, which is a kind of staining positive, it means that we have a diagnosis of amyloidosis. Of course, we have to type to understand which type of amyloid deposits I am facing, because as I was saying, we have many different types of amyloidosis. And now we are focusing on AL amyloidosis. Other amyloidosis have different treatments, so it's very important to understand which kind of amyloidosis I am facing. As I'm sure you are aware, we have many, many treatment options, many agents to treat both multiple myeloma and AL amyloidosis. These drugs are divided in family, so we have the family of immunomodulatory drugs, which thalidomide, and its derivative, lenalidomide and pomalidomide. We have proteasome inhibitors with worktasomib, and there is second and third generation agents, carfizomib and exasomib, with the big family of monoclonal antibodies. We have chemotherapeutic agents, and of course, steroids, which are cornerstones of every treatment of multiple myeloma, especially. And then we have the wide range of drugs, still in experimental therapy. It doesn't mean that we don't have access to them in the clinical practice, but we have access to them only in clinical trials. So we can combine these treatment, these different agents together to treat amyloidosis and multiple myeloma. Because these diseases cannot be treated with only one agent. We have to combine them because, as you will see, in the same patients, there are very different, especially in multiple myeloma, very different cells in the same patients. And maybe one drug is very effective against one type of cells, and another drug is very effective against another type of cell. So we have to combine them together to achieve the most effective treatment. And all these drugs, especially novel agents, have been developed in the last 20-25 years. In 2003, Borthezomib arrived, and now is in every treatment for multiple myeloma, and also many treatments of amyloidosis. And arriving from the regent years with exazomib, Zaratumumab, Carphizomib, and much more drugs. So how do we treat patients with multiple myeloma and amyloidosis? So let's start with multiple myeloma. The first line therapy, so the first therapy we give to patients when we diagnose them, varies if the patient is considered eligible for autologous transplantation or ineligible. Eligible patients are usually younger, usually under 70 years old, 71, 72 in some cases, and they have good performance status and not too many comorbidities. So to these patients, we deliver a phase called induction, which is a combination of novel agents like Borthezomib, Lenalidomide, and steroids for a few cycles, four to six cycles, to reduce the burden of the disease. And after that, we collect their stem cells. So the progenitors of healthy cells, we collect them in procedures called stamina fear-resist. And then we proceed with autologous transplantation. So we deliver a high-dose chemotherapy, generally with melphalan, a high dose, 200 milligrams per square meter, 100 milligrams in some case. Followed by the reinfusion of the stem cells I have collected before. And after transplantation, we start what we call maintenance. So a long-term therapy with, usually with Lenalidomide, which is the agent, which is currently approved by FDA and EMA, so in Europe and the US for maintenance. And we administer Lenalidomide forever until the disease is your remission. In transplanting eligible patients, we deliver a combination therapy with novel agents. Now we will see, we will use much more. There are some of them also in first line for transplanting eligible patients, which is a monoclonal antibody, combined either with bortezomib and melphalan, or with Lenalidomide and steroids. And of course, we don't deliver transplantation, because the entrustment ineligible patients are generally more frail. But as you know, unfortunately, we don't yet have a cure for multiple myeloma. So we are able to send multiple myeloma in remission for many, many years, but the disease eventually tends to relapse. But even after relapse, we have many, many drugs combination that we can use to treat the disease and to send into remission. Of course, I'm not going through every, every drugs and every combination regimens, because it's not the focus of our presentation today. But if you have any questions at the end, feel free to ask. For amyloidosis, the situation is a little bit different. We have first line treatments, mainly with bortezomib and steroids and melphalan. Autologous transplantation in amyloidosis is much rarer, because patients with amyloidosis generally have a poorer performance stages, because their heart, their kidneys, is much more involved by the disease. So they're not fit enough to proceed to transplantation that can cause too much harm to them. So only 25%, 20 to 25% of patients undergo autologous transplantation at diagnosis when they have amyloidosis. After relapse, we have also agents used also for multiple melamosol, lenalidomide, pomalidomide, very interesting results with daratumumab, and maybe also with xasmi. But let's come to the core of our presentation. So personalized treatment. What do we mean by personalized treatment? Personalized treatment is an emerging approach to patient care, which is particularly appealing in cancer medicine that exploit individual and disease characteristics, including genetic characteristics, to guide clinical decisions and choose the right treatment for the right patients at the right time. So I have a patient in front of me, and I'm able to choose the best therapy, the right therapy for him, studying the characteristics of the diseases. So I will give you now an example to help you understand what do we mean by personalized treatment, an example that comes from a different kind of cancer, breast cancer. So in breast cancer, 20 to 25% of patients over express a gene called HCR2 in their breast cancer cells. This over expression is related to an inferior prognosis, a higher tendency to relapse. But what was seen is that patients that over express HCR2 had a better response to a monoclonal antibody called trastuzumab. So trastuzumab was started to be administered to HCR2 positive patients. And even if HCR2 positive patients have a poorer prognosis, they respond very well to trastuzumab. And trastuzumab is able to increase their survival and to reduce their relapses. So coming back to multiple myeloma, why do we need a personalized treatment? Well, because we are facing a very heterogeneous diseases. So not all patients with multiple myeloma have the same diseases characteristics. They have different risk factors. Some multiple myeloma are higher risk of relapse and of death. Other multiple myeloma are standard risk. So I have a lower risk of relapse and respond better to treatment. Not all patients respond the same way to the same treatment. So different depth of response is observed in different patients. And of course, different patients have genetic characteristic very different from each other. So their plasma cells express different genes from each other. And of course, even in the same patients, there are different subgroups of plasma cells with different genetic features. So that's what I was saying that we need to combine treatments because we have to combine different agents to try to treat a very heterogeneous disease. And also we don't have to forget that we are treating very heterogeneous patients. So not all myeloma patients are similar. They have different age. There are younger patients 55, 50 years old, older patient 80, 85 years old with different performance stages with different comorbidities. So we have to remember that we have to calibrate treatment intensity on the patients we have in front of us. So now I will give you some examples of what we are doing about personalized treatment in the clinical fields nowadays or in the research. And I will give you some examples first of all about an approach that is called risk-adaptive approach. So as I was saying, not all myeloma patients have the same diseases characteristics. Some multiple myeloma are more aggressive and more dangerous than other. So how can clinicians can locate, differentiate this kind of multiple myeloma? Different tools have been developed in the years. One of them is called the revised international staging system, RESS, that combines different factors, genetic profile, cytogenetic profile, what I was saying before, with blood values of an enzyme called LDHA, with another staging system called IIS international staging system. And combining these three different tools together, three classes of RESS were identified, stage one, two and three with different survival and response probability. So patients with revised ESS-3 have inferior outcome and response to therapy compared to revised ESS-1 patients. And of course, one of the corners of these classification is cytogenetics. So cytogenetics detected were by fish analysis in the bone marrow, find some lesions in the chromosomes of multiple myeloma cells that confer a higher risk of relapse and a poorer prognosis. Some of them are like deletion of chromosome 17, the translocation between chromosome 4 and 14, the translocation between the chromosome 14 and 16. And these features confer an inferior prognosis. So what can we do with this information? So we know this, but what can we do with it? Well, one of the hypotheses is to deliver different treatment strategies in high risk patients compared to standard risk. One of the examples in some areas is to deliver maintenance after autologous transplantation, instead of with linolegicumid, that is the proven drug with bortezomib, because it was seen that bortezomib might help to overcome the poor prognosis of cytogenetic a little bit. So this is one of the examples, but of course, most response will come from clinical trials. For instance, there is an English trial called MUK9 optimum trial that enroll only patients considered at high risk according to their genetic characteristics. And in this trial, these high risk patients are delivered a more intense chemotherapy approach. So induction therapy with four drugs, regimens, transplantation, and consolidation and maintenance with many agents. And we will see with these and other trials if high risk patients should undergo more intense regimens. Another personalized treatment approach is the response driven approach. So we know that not all patients respond in the same way to the same treatment. So I may have a patient with obtain a partial response to treatment. I'm okay. It means it's responding, but we classify it as a partial response. I can have another patient that responds with a very good partial response. Very good, better response, deeper response. And then I have patients that to the same treatment respond with a complete response, a CR. And that's a very deep response. It means that the disease is in very deep permission. But there is one category of response, which is superior to CR, and that is called the MRD, minimal residual disease negativity status. It means that even with highly precise methods, no plasma cells are detected in the bone marrow. So achieving MRD negativity is the goal is the dream of every treatment because MRD negativity has been related to increase overall survival and increased duration of remission during therapy. So we can see from this picture that patients treated with the same therapy progress in different ways, depending on the MRD negative status after treatment. So MRD negative status patients remain on study longer and have longer remissions. Whereas MRD positive patients do very well because maybe they are in CR and achieve a very good response, but tend to relapse earlier. So how can we use this information? One possibility is to use the MRD driven approach. This is not standardized in the clinical practice yet, but many trials are investigating it because if I have a patient which is MRD negative after the first part of treatment, my question is, shall I continue with the same dose, the same treatment intensity, or can I reduce the intensity of the therapy, maybe reduce maintenance, maybe stop maintenance after transplantation because sparing in toxicity, improving the patient's quality of life because of course it doesn't experience toxicity, he attends the hospital less. So can I use the MRD negativity status to choose less intense treatments and spare patients from toxicity? Well, we don't have an answer to that question, of course, but clinical trial are moving into this direction. For instance, we have a trial called the EMN 17 trial, which is a trial on transplant eligible patients. I will not describe the trial now because it's not the focus of this presentation, but focusing on maintenance after transplantation. Well, after transplantation in the experimental arm, patients undergo maintenance for two years with Daratumumab and Lenalidomida. At the end of these two years, bone marrow aspiration is performed. Patients who are MRD negative will discontinue Daratumumab and continue only Lenalidomida's maintenance, whereas patients that MRD positive after two years of maintenance will continue with maintenance at the same dose. And this will give these and other trials will help us to answer these questions because of course we want to spare the patient's toxicity as much as we can. But how much can we spare toxicity and reduce treatment intensity in patients? Can we do it according to MRD negativity status? Well, we hope to find answer to these questions from ongoing clinical trials. And another approach with, to my opinion, is one of the most interesting is the targeted therapy. That's one of the finest example of personalized treatment. Targeted therapy is what was the same with Trostuzumab. It means that I have a patient, patients A, with genetic characteristic A, and I am sure or I'm very confident that the treatment A is the perfect one for these patients. Differentially from patient B, patient C, and so. In multiple myeloma, one of the examples comes from Venetoclax. Venetoclax is an oral inhibitor of BCL2 protein that showed activity in multiple myeloma patients in clinical trials. Venetoclax is not approved now in clinical practice, nor in the US, nor in Europe. We have just data from clinical trials. What we saw it was that in patients with the cytogenetic abnormality, Translocation 1114, Venetoclax induced much more response compared to patients without T1114 Translocation. So as you can see from the first study, 40% of response versus 6% of response. It's quite impressive. 40% of response is very good because this trial eroded patients heavily portrayed that had already received four, five line of therapy. So achieving 45% of response, it's very good. And the same thing was observed when Venetoclax was administered with Bortezomib and the response in patients with this Translocation 1114 was much higher. So of course trial on Venetoclax in patients with Translocation 1114 are ongoing because these agents is very, very prominent, especially in this group of patients. And coming back to amyloidosis, also T1114, Translocation 1114 is important also in amyloidosis. It's a cytogenetic lesion very frequent in this disease, almost half of the patients have it. And what was seen was that patients with T1114 that were treated with Bortezomib and dexamethasone responded to therapy less or worse compared to patients without this Translocation. On the contrary, these patients T1114 treated with Transplantation or Melfalan responded at the same way of patients without T1114. So how do we use T1114 in amyloidosis? Well, it can help us in treatment decision. If I have an amyloid patients with amyloidosis and T1114, maybe it doesn't mean that I don't have to give him Bortezomib, but I think yes, Bortezomib, but maybe with Bortezomib also Melfalan or if I can Transplantation because just Bortezomib might be not enough for this patient. So another very important approach that to my opinion is one of the most important in clinical practice and clinicians can't forget about it is the patient driven approach because we have to remember that we are treating patients and not just diseases. So for example, I have patients A with genetic mutation A and I know that drug A is very effective on this mutation, but drug A is also very toxic. So maybe my patient A is a 85 years old man confined to a wheelchair with severe cardiac and pulmonary comorbidities. So should I give him treatment A, which is very effective on the disease, but it's also highly toxic? Well, to my opinion, spare toxicity and it's very, very important and we cannot treat just the disease, but we have to have in mind the global picture. So also patients characteristic should help us, should help doctors to choose the treatment. This is particularly true for elderly patients because young patients, most young patients are fit, they don't have comorbidities, they can tolerate most treatments. Elderly patients wear that the situation is very different because I can have a patient of 75 years old, which is in perfect clinical condition, no comorbidities, fully active. And another patients the same age, which is maybe confined to the wheelchair with lots of heart, kidney, liver problems. So these patients are very different. I cannot choose treatment confiding only on age. So different assessments, different tools have been developed in the years to classify elderly patients according to their fitness status. One of that is the EMWG phrase discord developed in 2015, but there are many, many others and the two that I'm showing you in this slide have been validated and they are used frequently in the clinical practice. And they are just examples to remind you that independently from age, I can have elderly patients very fit with very good performance stages and I can give them intense treatment quadruplets. In some cases also transplantation up to 70, 71 years old. Why not? But I can have other patients with much more impaired performance stages and severe comorbidities. And of course, those patients I have to deliver reduced intensity drugs. So these are some of the example of the personalized treatment. Now I would like to talk to you about some projects that are ongoing about precision medicine multiple myeloma. And of course, these projects are focusing mainly on gene expression profiles. So the genes are expressed in different levels at different levels, different genes expressed at different levels into more cells. And the genes are what tells the cell what to do. So we have some methods called gene expression profile methods that allow to identify the different pattern of expression of several genes in multiple myeloma cells. One of the the signature that has been developed is called SKY92 signature that a study is the expression of 92 genes in the myeloma cells. And patients that have a certain pattern of gene expression are considered a high risk. So they have a high risk SKY92 signature. And what was seen is that these patients and that was seen in many clinical trials. Here I'm showing only three clinical trial, but there are more than eight, eight, nine clinical trials are confirming this is that the patients with high risk SKY92 signature have a worse overall survival. So a worse survival and a higher risk of progression compared to patients without this high risk signature. And when combining these gene expression signature, the SKY92 with the staging system I was mentioning you before, it was seen that this combination was the stronger predictor of survival in multiple myeloma patients. A project that is going on is called the multiple myeloma predict project. And the aim of this project is according to the gene expression of myeloma cells is to develop a tool that is able to predict the response to the most effective treatment for every multiple myeloma patients. So it's a very fine model of precision medicine. It's a project funded in that started in 2016 that collected the 800 samples for multiple clinical centers and multiple myeloma patients that use the genetic expression profile methods. So the expression of different genes in the myeloma cell using the SKY92 signature and explore correlation between genetic characteristics of multiple myeloma patients, the response to treatment and also the toxicity. So one of the work that was conducted within this project is to analyze the genetic expression, the signature in 155 real life patients because most data about gene expression profiling come from of course clinical trials. But our question is, can we apply data from clinical trial into real life patients so patients we see every day in the clinics that are not enrolled in clinical trials because of course most patients aren't enrolled in clinical trials. They are real life patients that we see every day in clinics. So these projects collect 155 samples of 155 patients from three centers, Singapore, Turin in Italy and Germany and what was seen was that the high risk signature SKY92 that I was talking to you before was presenting 22% of patients and was prognostic. So as I was saying, it was seen that patients with high risk SKY92 signature have a two point risk of progression greater 2.7 times greater compared to standard risk patients and same patients had a 3.2 increased risk of death compared to standard risk patients. And also when combining the SKY92 gene expression profiling signature with ESS we saw with the staging system the prediction for overall survival was even greater. So there was seen that patients with high risk SKY92 signature went the worst. Patients with standard risk SKY92 signature went better than high risk patients and differently if they were ISS1 or 2 versus 3. The project, the MM predict project, the main aim is also to find predictive markers. So not prognostic marker, prognostic marker help us to see how the patient will go on treatment. Predictive markers on the contrary will help us to understand how these patients will respond to death treatment. So one of the thing that was seen it was that patient expressing a cluster of genes called PRL3 responded better when treated with lenalidomide. So in the ideal scenario in clinical practice in the future the ideal scenario is that I have a patient in front of me I can analyze his genetic profile and eye of his plasma cells malignant plasma cells and I can say okay with this genetic profile you will respond very very well to this drug and most important and also very importantly you will not have toxicity with this drug. So if I am able to do that in the future I think that this could be a very big step forward in treating cancer in general and multiple melanoma as well. Not to enter too much in detail but there are other ongoing projects using the gene expression profile signature different signatures so the sky 92 is one of the signatures but there are also others one is my PRS that uses 70 genes different genes instead of 92 and also this signature was found to predict outcome. So I will not go into much into detail because our time is almost finished. I just want to give you a few conclusions remarks. So what are the expected benefits of personalized medicine multiple melanoma? Well we said that through all the presentations so to find the right therapy for the very right patients at the right time but also to understand the mechanism of toxicity of drugs and of drug resistance. So why this patient doesn't respond to treatment? Well with these methods maybe luckily I will be able to answer and of course to introduce the targeted therapy in the real life scenario. Of course this approach not all that glitters is gold of course and there are some limitations to this personalized approach. Of course it needs very well trained laboratory and personnel is not available worldwide and so far it's mainly limited to clinical trials and to research field not in the common clinical practice and of course this methods needs standardization. So in conclusion multiple melanoma and also amyloidosis are very heterogeneous disease which varies a lot between patients and also in the same patients. Personalized medicine is already used in the clinical practice to some extent but the main progress will come in the future with gene expression profiling methods and delving into the genetic ocean of cancer will allow us to develop new tools for precision methods. So what I hope for the future is that I will be able, I and of course the clinician will be able to find the perfect treatment for every patient. So I hope that I was clear and that you heard me correctly. If you have any questions I would be very happy to answer. I thank you myeloma patient Europe for the invitation and for giving me the opportunity to give this presentation. Thank you very much Dr. Ronello. Thank you for this wonderful presentation. Just quickly remind you that there are two ways to ask questions. One of them is using the microphone in your computer and ask directly to the doctor and the other way is as we mentioned before sending your question in the chat window and I will read it so that the doctor can answer them. We have some questions that arrived during the presentation and I can see one hand in the attendees. So Jan Lalit I'm going to unmute you so you can ask the question directly to the doctor. Yeah thank you very much and again my yeah it was a very excellent presentation and very valuable information presented by you Dr. Ronello. I have more or less two questions. When do you expect that this personalized medication will become common practice in let's say in Europe? And second question which is a bit maybe a bit related. Do you expect or do you foresee that there will be any tools for you as the doctor to support you in the decision making because if we go forward maybe even more information will become available and more points in the decision tree to be taken and maybe it's very difficult for every doctor to be up to speed with with all the available information. So thank you thank you for the questions these are actually very very good questions. To answer the first question well honestly I don't have an answer because what I can say that this precision medicine approach will especially with gene expression profile methods will not enter in the clinical practice very very soon. Maybe in five to six years we can have some of them but not in the very near future. Instead with personalized treatment like targeted therapy with the example of Veneto class and the other exam so I gave maybe a little bit earlier. And for the second questions I fully agree that many many information are developed and are given every month in in the clinic in the research field. So it will be a very interesting challenge to give clinical practice clinicians or clinicians that are not into the research field and they are just in the clinical practice to give them tools that have to be simple and reproducible to apply these approaches to clinical practice. And this will be very difficult because we have also to understand how much these different methods of gene expression profile these all these signatures can be concordant. So can we find a point one or more points in common between all these strategies? Well this is a very interesting question there is not an answer yet and I think that the transfer must be given in the future because clinicians of everyday clinical practice need precise simple and easy to use tools and not too complicated for treating the patients. Thank you. Do you think that that let's say an area of informatics like artificial intelligence might play a role here? Yes of course of course I think that it could be it could be used of course and also maybe if some some exams can be centralized to big laboratories maybe we can standardize better the methods and they can be used more in clinical practice. Okay excellent thank you Dr. Bonelo. Thank you very much for the question. Thank you Dr. Bonelo. We had another question. I have I have heard a BRAF mutation can be important in myeloma too. Ben Muran Fenif has been clinical trial previously for myeloma patients who have BRAF v600E mutation. Do you have any information if that that practice is being researched? What is the importance of BRAF mutations in multiple myeloma? Yes that is that is true. Some clinical clinical models showed actually some some good potential target of this mutation in treating multiple myeloma to my knowledge. Clinical there aren't many clinical trial with this targeted approach. So I know that some responses were observed but to my knowledge there aren't the scientific interest in not so focused on this particular mutation. Thank you very much for very much Dr. The next question as many mutations happened in the subclonal plasma cell population how can we target the founder clone population in personalized medicine? Oh that's well that's one of the most difficult questions that we are asking ourselves also. Well there are different hypotheses on how the clones in multiple myeloma arise. So one of the hypotheses is that there is the founder clone and subsequently different clones that developed in different phases of the disease. Another hypothesis is that the disease arise from diagnosis with different clones. So the main objective well the aim is to use combined treatment even with precision medicines. I don't think that we will arrive to a point in which we will administer only one drug to a patient because in multiple myeloma since it's so heterogeneous we need combinations of different agents. So I can be sure that or almost sure very confident that my patients will respond to treatment A if he has mutation A but of course I'm not analyzing all these clones and so I don't think that treatment A that drug A could be the only one delivered. Also I think that this method these expression profiling methods cannot be done only as diagnosis but should be repeated even when the diseases relapse because maybe the expression genes varies within different phases of the disease. So I think that genetic medicine and gene expression profiling is a very dynamic process that cannot be done only once. Thank you very much. The next question we have is how can myeloma and ielomidosis patients find out about whether they fit into a specific subgroup or super specific type of myeloma and the ability of such testing currently in European countries? So I just didn't hear the second part of the question just the first. Can you repeat it please? Yeah the second one is this kind of option are available in the currently this kind of testing is available in the European countries. Okay so well the type of multiple myeloma the stage with the available tools such as the revised international staging system is well the fish analysis is available I think in most clinical practice so I think that you can have information about your cytogenetic characteristics in every in most clinical practice now. Regarding genetic expression profiling I think that this is still in well I'm sure this is still in an experimental level and it's done only in the research field. Some kits some tools can be both can be used by different centers but I don't think I think only to a research level especially the gene expression profile methods and I think this is still good because these methods are not fully standardized so the fish analysis is standardized everywhere and it's performed almost everywhere I think whereas the gene expression profile is less standardized and so it's not fully used in clinical practice so yeah fish analysis I think you can have it everywhere everywhere in most centers. Thank you very much and our next question what are in your opinion the barriers to personalized medicine healthcare systems? Well the barriers of course is well the main barrier is the as I was saying the lack of standardization and also that I at the moment this tool is not available in all clinical practice it's limited to big centers for the research so at the moment it's a technique that is not accessible to every center and that's the main of course barrier and the other one is the lack of standardization so far so I think these are the main two problems with the personalized approach using the genetic expression profiling. Regarding the same topic someone asked if the price or the cost of this kind of test can be another barrier to apply this personalized medicine in the healthcare system? Well I'm not fully aware of the cost of the different kits and the different tools but I think that yes especially for smaller centers it could be a significant problem. Thank you very much doctor that was our last question I would like to thank you for this interesting webinar and then all the the information that you gave us around personalized medicine in myeloma and also in the lamellidosis and just remind you all that the webinar has been recorded and will be available in the MPE website which is www.mpu.org and it will be available also in our YouTube channel so thank you very much all for attending this webinar today and especially thanks Dr. Bonnello for your time. Thank you very much to you and have a good evening. Have a nice evening.