 High risk myeloma is a term or nowadays we use ultra high risk myeloma even to describe the patients that with current standard of care treatment do unfortunately encounter an early relapse and because in younger patients we use very standardized treatments with an upfront induction therapy transplant and a maintenance therapy. That's often the kind of treatment that we use to define who is relapsing early or not because there's about 20-25% of patients who relapse with a disease within two years after the transplant and we know that these patients unfortunately have a very unfortunate outcome afterwards. The problem is that the disease is really difficult with current treatments to bring into a good remission again and the remission again that is kept there. So we have done over a long time gone in many groups in terms of trying to find genetic markers that can help us identify these patients before they even start their very first treatments. That's a very, very diagnosis of myeloma and we have made big progress there so we can identify patients not on the means of genetics in terms of co-occurrence of two or more high risk markers or double hit or by means of gene expression profiling which shows us a gene expression high risk signature. So the OptinMark 9 trial is a trial that we designed about 7 years ago when we saw that these genetic markers can help us, that genetic markers and gene expression markers can help us identify patients with high risk disease so patients who have a high risk of their disease coming back within two years particularly with the current standard of care maintenance treatment with linolydomide. So we designed a trial whereby we screened everyone for these genetic markers at the time in the UK, these were not standard of care everywhere so not every patient could access them so we asked for a sample centrally where we did molecular profiling for two or more genetic high risk markers as well as for gene expression profiling and if any of the two was positive the patient was given the option to say I want to type part in this trial and our thinking was that the treatment has to particularly be improved both at the beginning but particularly the maintenance therapy has to be improved. So we actually used 18 months of a three drug combination maintenance therapy and then they move all on to diurel and maintenance therapy and this concept was actually highly successful we compared the outcomes against the patients that we enrolled in the previous trial with the same molecular features and the outcome was on multiple times better so the progression free survival instead of being below 40% in the new treatment regimen was 77%. The outcomes are so good that we're even now taking the results forward to a commissioning application to see whether we can potentially get reimbursement for this treatment in our healthcare system. So although we have made big progress with Optimum Mach 9 and really many patients are still in a remission now that would normally have relapsed due to their aggressive disease we did nevertheless see that 20% of patients even with this currently best treatment that we could think of relapsed with their disease. So we wanted to learn more about who are these patients and I think in this case it came as an absolute advantage that we had done so much effort on doing the genetic profiling and the gene expression profiling because we could now look at whether any of these genetic or gene expression markers were more likely to be linked to an early relapse. So we identified particularly patients that had three high risk markers co-occurring as well as a slight trend towards those that have a gene expression high risk signature or and or plasma cell leukemia to have an early relapse within these first 18 months of treatment despite the very good treatment so the as much as that's of course as such a sad finding I think it nevertheless gives us the hope that we can use these diagnostic tools in the future to identify these patients early to really try new treatment approaches such as by specific antibodies or CAR-T cells. So we have several ways of identifying patients with high risk myeloma either through genetic profiling this uses the DNA of the cell which is the inherited information normally that is present in every cell but in a tumor cell it has really gone through a lot of changes a lot of mutations and we have identified several mutations that are linked with a shorter survival now on their own they're not very powerful and with new treatments we actually can overcome some of them but when two or more of these markers co-occur unfortunately we do know that the disease is more aggressive seems to be more resilient against treatment and find ways around treatment more easily and that is actually true the more of these risk factors are present the more aggressive the tumor unfortunately becomes so for example we call those with two markers double hit and those with three triple hit they can even be four co-occurring markers in forms of quadruple hit. There is also another way of looking at the aggressiveness of the cell it has not to do with the DNA but with the RNA the RNA is kind of like the living library it's a status of how the cell is behaving at that very moment and we know that RNA and gene expression profiling which you use to identify the RNAs that are present in a cell can tell us something about how the cell is behaving and doing in this moment and there are signatures that have been identified so effectively a combination of genes when they're expressed that can tell us that the cell is more aggressive than another one and particularly we have found that many of these genes have to do with how quickly these cells can divide how quickly they can multiply and this is a different type of information than the genetics so you can not get the full picture with either the one or the other test is actually really combining the two tests where you get the most power of giving the patient a very precise diagnosis about the current disease. So I think the results from the optomark 9 trial for example and this has been unfortunately shown in similar trials like the concept trial or here the IFM 2018 trial were presented as well we know now that probably for three quarters of patients with otahyros disease we can offer really good treatment much better treatment than we could offer before through combined induction therapy for our five drugs with the CD38 antibody but particularly by improving the consolidation and maintenance therapy however we still see that there is a quarter of patients or 20% of patients that do even with such treatments have very aggressive disease and early relapse and I think this is a very strong signal both of these findings mean a we should really really work very hard and jointly together to offer better diagnostics for patients if you don't know about these markers you will never know how to identify these patients and of course this is often different access in different countries so it's very clear that there is also money involved so there has to be really a very clear strategy in the community moving forward that we really try to make it as equal as possible the access but I think what it also tells us that we still identify patients that need or could really be considered for yet new trials new approaches with new treatments coming on we always have the choice whether we recommend to a patient maybe a more risky but very novel treatment and I think with better diagnostics we can have a much better in communication and discussion with the patient about whether to take part in the trial for example so we have seen an improvement of the outcome of patients with high-risk and ultra-high-risk patients already by the current treatments that we have by mostly by combining several different agents together we realize that the joint effect on these aggressive cells is better when we attack it from different sides of course what we have with that also borders that the patient needs more treatment ideally of course we would want to have a treatment that really really goes to the source to the reason why these cells are more aggressive and these are tools that we're lacking at the moment there are very promising new developments about for example the new drugs that are targeting the product of the T414 translocation which is called NSD2 and if these inhibitors are successful they could potentially offer hope for patients with this type of high-risk disease another option is of course that we have more powerful drugs in itself in themselves such as for example we now see by specific antibodies as a single therapy already having higher response rates than even if we combine three drugs before and it's going to be a lot about finding out how these drugs work in ultra-high-risk disease and how we can use them best to benefit our patients