hi good evening good morning good afternoon everybody a very warm welcome to this new broadcast by the international academy for clinical hematology uh I'm Mohammad moti from the sobone University and Central Hospital in Paris in France and it is my great pleasure to moderate this special webinar today dedicated to a small molecules in multiple myeloma and actually the idea behind the webinar came after the different post-asco and Iha broadcast we organized and that were mainly and almost exclusively dedicated to immune therapy of multiple malama because obviously this is really the hottest topic and most I would say debated topic however we received a few remarks and comments and suggestions saying hey guys not everybody has access to cartesa not everybody is able to use by specific antibodies for several reasons so maybe there are other options you can discuss and for the sake of fairness and in order to be balanced then we decided the steering committee decided to organize this webinar and I feel very privileged being joined today by three excellent panelists all experts in maloma namely Dr Lisa lipot hopefully I'm pronouncing correctly Dr Elias May and Dr Maximilian MERS all of them from Germany but this is pure chance guys and we exclusively relying here on their expertise so the way we will structure this activity I thought that uh Dr may may set the stage for us on how to define how you know a global overview about this so-called triple refractory or quedra or Penta refractory population and after his whatever 15 20 minutes or 25 minutes I don't know Elias how long it will take you then we go through a round table discussion and as you all know this is a live broadcast so you can join us at any time you can share your questions your suggestions your comments and I'll be more than happy to discuss them and distribute them among the panelists so that was my introduction and without any further Ado I'd like to invite Dr Elias May from Heidelberg to share his slides to give his introduction for the Roundtable discussion and then we will reconvene in a few minutes to uh Engage The Debate so eliasa floor is yours well thank you Muhammad I hope you all can hear me and of course I want to thank you and the panel for inviting me again uh last year I had the opportunity to discuss with you and Bruno some data from our recent hd7 trial and today I'm happy to give you an idea how we can identify the right treatment after modal clonal antibody exposure which is uh for most patients in many countries a reality even after the first line of treatment so here are my conflicts of interest and if you want to start the talk I think it will be important to have a look at the current treatment landscape which you're all pretty familiar with and especially for the fact that we subdivide patients into patients that are eligible for an autologous stem cell transplantation or that are not eligible and if we looked at the the majority of the patients is 70 years or older when they are first diagnosed with a multiple myeloma that requires treatment you can clearly see that for most of you that are here in the in the panel today and for the audience the option to treat the patients that do not receive transplant um that you have to make a choice between there are two more marble analytomide and dexamethasone and other options that either contain error in combination with VMP or vrd I think for most of you if you have to access directum up and then a little Mite plus xmasone is the standard of care and the data for that have just been updated coming from the Maya trial and on the left hand side you can see the progression free survival in the intention to treat population and you can see as compared to direct to land and dexamethasone the addition of thyroid to move up to learn alidomide and dexamethasone resulted in a media and progression-free survival of 69.1 months and the overall survival you can see the same Trend so just by introducing the anti-c38 monoclonal antibody you can see that the median overall survival in the Dara landex group has not been reached but 60 months overall survival is 66.7 percent as compared to um 53.7 percent in the um then a little my dexamethasone group and here the median overall survival has also been reached it's a 64.1 months but as you can see with the hazard ratios here on the left hand side for the progression-free survival and um on the um right hand side for overall survival significantly favors the addition of thyroid to move up so what is also in reality for many patients that receive their automide that there comes a point when the patients have a deep and durable response where you stop that dexamethasone or you you dramatically reduced it but in addition there are patients where you also stop the lenolidomide and I think it's important to mention here that this is at least in our clinical practice or in our routine practice in Germany that happens very very commonly because lenolidomide has a lot of side effects and if the patient sign is stable and deep response you can really ask yourself why should you continue to learn a little might while the patient is experiencing fatigue diarrhea or cramps of the muscles and here is a subgroup analysis of the Maya trial again that investigated what happens to patients if lenolidomide has been discontinued and as you can see and I've already pointed out that the majority of the patients discontinued analytomide because of side effects it's almost 92 percent of the patients and you can see diarrhea neuropathy neutropenia and constipations were among the most common causes but then interestingly you only received our Tumo map once per month and you can see that the estimated 60 months progression-free survival and overall survival rates were quite well and after a median duration of treatment with of almost 60 months with thyroid to move up so in clinical practice it appears reasonable for patients that are in a deep response that you discontinue some of the agents especially if there are Adverse Events that impair the quality of life of these patients so what happens then so this is the focus that we will have on The Talk today and on our discussion um will be the question what happens to patients that are already refractory to Dara to move up and then alidomide and dexamethasone in the second line so and you can subdivide these patients based on the data that I showed you in the Maya trial into patients that either discontinued lenolipumide or stopped lunalidomide for any reason and then you still have learned a little mind as an option in the second or later lines but the patients that are refractory to their tumor map which you normally continue in the majority of the patients that receive duraland accent are not eligible for transplantation and then become analutomite and there are two in my prefectory you already see that despite the plethora of agents that we have today in multiple myeloma the options that we have in the second line uh reduced down to only uh to only four combinations that are approved or available and it is recommended by the European Society of medical oncology that you of course try to keep up with some standard ideas and one of these ideas is that of course A Triplet is better than a doublet if that is uh feasible for the patient and that of course if you switch the Target that may be beneficial so another question some of you might ask and I think it's an important question that is very very hard to address from a scientific or clinical stand point of view is what happens if you just continue Dora to move up or if you re-expose patients of thyroid to move up and you can see here on the left hand side some results from the from the French myeloma group from the any cohort and here 137 patients had to receive two prior lines of therapy with an anti-theory 38 based combination regimen and you can see of those um where antitheater 37 patients were anti-cg 38 refractory and what you can see here is that if you re-expose these patients and they have already been refractory to an anti-city third antibody no matter if it's either talks about tumor map the media and PFS of these patients is only 4.6 months and this is confirmed in another single Center analysis from Greece that has been presented um last year at Ash and you can see here that patients that are being re-exposed to with an anti-c38-based treatments have media and progression-free survival of only four months so it is clear for now that you cannot reuse an entities 38 antibody immediately after the patient has become refractory the question has not been answered if you can reuse the antibody after some type for example if the patient is of treatment from an Intercity 38 antibody for six months for 12 months for two years we we don't know that but at least immediately it's not an option that you have so I want to speak today about the Boston trial it is a phase three trial that incorporated the linuxor into a regimen of velcade and dexamethasone and the mode of action of Celine EXO is unique in the myeloma landscape it's a small molecule that uh um is an xp01 inhibitor and what xpo1 does is that it inactivates tumor suppressor genes genes and it enhances proto-oncogene translation so by blocking that you can block the growth of the myeloma tumor cells and this concept was efficient in phase one and two trials and was thus translated into a phase 3 trial design which I want to show you in a second so um again if we go back to the two ideas that I mentioned initially so that you want to do a class which on the one hand and that you want to maintain with a triplet combination on the other hand if you go back to that slide from the e High asthma kite lines there are not much options left so if you look at the lenolidomide sensitive patients and if you want to switch the class comv is not the perfect option so because with pomalidomide you remain the image so you could use capitals in the dexamethasone that's an option then you can use the Linux of lkatex or you can use the need to collects velcade decks which is not approved at least in the European countries and also in the United States the same holds true foreign patients where you cannot use form VD because then you would stay on an immunomodulatory agent of course something we can discuss and that is not shown here on the slide and I want to mention it now is that you could use in these patients that are treated with teratoma taxometer so no matter if the alien and other might refractory learn a little might sensitive you can use either portazo map locate or car filter map in combination within classical cytotic toxic agent like cyclophosphamide for example vcd or kcd that's also an option that is available and not shown here on the slide however you can see that even after the first relapse the patients are already refractory to an entity 38 and an immuno modulatory drug and the options for these patients are limited if you consider this you can say that the combination of cellinex or valky decks is the only approved triplet combination at least in Europe allowing a double plus which because you can switch to NPI and you switch to an XPO one inhibitor in patients that are exposed to direct warm up and then alidomide so having to study in mind and I just thought out that we we don't show here again the the slide of the study design so I just want to elaborate a little bit on the Boston study design so it was a phase three trial and relapse refractory multiple myeloma patients and patients were either included into the standard arm that included twice weekly bortazonab combined with dexamethasone as compared to the experimental arm in the experimental arm patients received once weekly salinexor 100 milligram and bortezum whip once weekly and dexamethasone so you can see that in the Boston trial the dose of portasomib in the experimental arm was reduced as compared to the dose of um or tazumib in the standard arm so the result was that the media and PFS of this combination in patients with one to three prior lines was a PFS benefit a roughly 13 months as compared to nine months in the standard arm so four months in patients with relapse refractory multiple myeloma and one to three prior lines of therapy so now since we talk about the daratumo mobile andolidomide exposed or even refractory patients we want to look at some subgroup analysis of these trials and these include patients that have been exposed to an anti-tv38 antibody in the Boston trial analidomide refractory patients in the Boston trial and Pi or autosome inhibitor naive patients in the Boston trial so at the time when the Boston trial was started and conducted we had only little patients that were previously treated with thyroid to move up and you can see here that out of the um 400 patients that were available in the intention to treat population only 11 patients in the SED arm and six patients in the ve arm were previously treated with dhara and you can see that among these patients the benefit appears to be maintained it's a 12.2 months versus 5.6 months but of course um it's difficult to conduct the statistical test here because the sample size is simply too small so if you go on now and look at the patient's um that were Lena lutomite refractory of course have some more patients and you can see here in both arms we have 53 patients in the SVD as well as in the vdr and you can see here no matter in which line of treatment these patients were and you can see that the majority of patients received one or two prior lines of therapy oh excuse me that that sets the wrong row so the majority of the patients receive two or three prior lines of therapy here um you can see that there was still a PFS benefit um with the addition of salinexor to bortezolips and dexamethasone resulting in a PFS of 10.2 months as compared to 7.1 months so here are the couple of myoflots for PFS and Os of this subgroup analysis so but for these patients that we talked about I go back one slide you cannot say if these patients already received um proteasome inhibitor portazomib or any other drug or even any entity 38 antibody though this was a very small number so it's more important to look at the patients that are Pi naive so they did not receive a drug like what has them or have fill the nib and if you look now at the middle here um of this slide you can see 47 and 48 patients in the SVD and vdr and here you can see that this combination works really effectively in patients that are naive to and proteosome and ebitor or naive on the right hand side to board Hazelnut and you can see that here the addition of study nexo really yields a benefit regarding the progression-free survival with a hazard rate ratio of um 0.229 [Music] um and resulting in 29.5 months of progression free medium progression free survival if compared to 9.7 months if you only give CD so though these patients are naive the response to bortezuma and dexamethrow Zone even twice weekly was not a very sustained the same was true if you look at the couple of my uploads I'm sorry I go back one slide because I forgot to talk about the patients that have one prior line of therapy so um here we look at in subgroup analysis that includes almost half of the patients from the from from both arms in the ITT analysis and what you can see here that the patients that receive one prior line of therapy no matter what was the first line though we have to admit that the first line at that time did not include daratum up or any anti-c38 antibody you can see that the addition of cellular decks almost doubled the progression free survival resulting in a hazard ratio of 0.62 in uh favor of the SVD arm so this is the PFS I want to show you for the in this slide here and you can see that the curves diverge even at later stages for in favor of SVD as compared to easy but here are the slides that I talked about the subgroup analysis of the proteasome inhibitor naive patients and you can see here that the addition of study nexo really yields a benefit for for those patients although the overall response rates do not diverge so dramatically it appears that that in Excel Val K decks really adds some sustained response to these patients and the same holds true for the patients that are broadcast it's almost the same subgroup as the patients that are declared proteasome inhibitor naive in this analysis and you can see that a couple of Maya plots and the response rates look pretty much on the same so we also have to talk about the safety profile for the overall trial as well as about the safety profile um in the subgroup analysis and the first thing you can say is that with the weekly administration of Port Elizabeth the rates of clinically relevant and severe and peripheral neuropathy have been reduced dramatically in the patients and that is very important also for your clinical practice no matter if you use sport hazelmap in combination with the Linux or any other drug if you don't have a very very strong pressure to get the patient into any remission I think the weekly administration of potassium is really really helpful especially on the long run if you think that the patient will receive two three four or more lines of therapy if and if the patient does not have a neuropathy that is a huge difference in the quality of life these patients moreover the side effects of cellinex are expected where as expected and where mainly nausea and weight loss mainly during the first two cycles and decreased appetite and this was consistent across the subgroup analysis that I've shown you with that I would like to summarize and I'm happy to to have now a discussion with with my dear colleagues from Germany and um warm out of course so SED is the only approved second line triplet therapy allowing a double class which in patients that uh Dara Len refractory and we have some solid data available from the Boston study that support the use of SVD in second line in this therapy and the safety profile of the drug is well manageable especially if you give anti-imagic drugs and um the convenient use in non-transparent eligible patients that is something that we didn't talk suddenly nexo you take it once a week and it's only one single oral substitution and potassium is can be given subcutaneously once per week and as I mentioned especially the weekly administration of Port Elizabeth reduces the rate of peripheral neuropathy and another thing that we can discuss and I'm happy to discuss that in the in the panel is that I think it's also an optimized treatment sequence if you use sport Hazelwood which is considered kind of a first generation um proteasome inhibitor first and then you save car filter MIP even for a later line for example for the third or fourth line so I'm happy to discuss that with the with the panel and thank you for your time and thank you for joining us today thank you very much Elias for a beautiful talk and for setting the stage for our discussion uh it looks like that indeed things are not as easy as they appear and this is about the art of personalized therapy I would guess and here I'd like to kindly remind all attendees that they can send their questions share their comments and and again if you didn't join early in the webinar uh you may think that this is a biased webinar actually no we're focusing on small molecules because we have addressed immune Therapies in the last couple of weeks but obviously we do acknowledge that of course carti cells ID sounds but also by specifics like a run at a tecluster map are really a huge advance in the field but if for whatever reason these agents are not available let's say there are other options and this is exactly the spirit of the presentation of NES but before going into the details of the drugs actually we have a question from our audience and I'd like to ask the opinion of the three patterns because I don't think there is a single answer to this is how to define or to decide that this patient or this patient is a refractory to this drug especially when we use these drugs in combination so who would like to start Lisa ladies first thank you Muhammad and also again thank you Elias for this um great talk and great overview um I think this is a very important question and probably there are um if you ask like three different myeloma experts you get like four different answers um but um generally it's considered when a patient develops um his relapses or her relapse under treatment that you consider him refractory to all the agents he has received at that point so if he's under let's say there are two more Len and Dex when he develops three Labs then you would consider him double refractory both to the cd38 antibodies into the image it's different though if for example with let's have a look at those transplant eligible patients where you for example have a quadruplet induction with derive UTD and then the patient only receives the cd38 antibody and the induction treatment and then the maintenance only with lenolidomide single maintenance and in this case because there has been a reasonably long time and usually the patient would not be considered a refractory to the CD's 38 antibody but only to the image okay thank you very much Maximilian in your practice how do you define refractiveness yes so I think you found two doctors who are on the same page there because I'm completely um agreeing with Lisa's definition of refectoriness but I think it's worth adding something because we also had a question about cd38 and you mentioned it Lisa before so of course we we can say also for enrolling into clinical trials what defines reflectoriness usually within 60 days after the last dosage of the truck but I think it's also very important to to look at the sequencing because for cd38 antibodies usually it's down regulation of c38 but for some other drugs it's um really an irreversible changing in the biology of the myeloma cells for example for the imits and for the pis we have some mutations that cause basically the drugs no longer to bind to that Target so it's really hard to overcome the resistance with the respective agent but if you look for example at cd38 or different different antigens like bcma dprc5d I think it might be worse you know it's re-exposing the patient to the same drug that has been used before before for example if you apply one further line of treatment that lasts for for example only like three to six months or so I think it's really worth trying a cd38 on the body again but it's not so true for example nowadays for linealidomide for example if you're really respiratory to learn a little mild I don't think it's worth re-exposing the patient after let's say two or three further lines of treatment again to lenolidomide because the the modes of resistance were most likely caused by some kind of sanctuary mutation that caused the little mind to fail in that kind of situation but other than that I don't have anything to add to the perfect definition of refectolinus so just to make sure uh I understood everything and because there are so many questions about this issue do the panel believe uh do you all believe that when it comes for instance to resistance to anti-cd 38 monoclonal antibodies it's only about the expression because obviously there are tools and there are even Publications I think there's paper and blood from meals from the dog showing that we can upregulate expression of cd38 and even the expression would come after a few months is it sufficient to reverse sensitivity Lisa so um well first of all I think this is again some question that probably everyone has asked his or herself um I do think that obviously overall if a patient does not have any expression of cd38 of although this is like almost non-existent um it would not be very sweet exposing the patient to cv38 antibody however um because these antibodies well they need cd38 to bind but as long as there should be just in theory one molecule of series 38 on a single myeloma cell in theory this should be enough for the antibody to mediate its effect so it's not just and the density and the um expression level of cd38 which is responsible for the drug to be effective but also other immune cells because we know that there are different mechanisms of action like also the cellular phagocytosis so the immune system um is obviously very important for a CD studied antibodies um to be efficient and so I guess to put it in a nutshell no cv38 expression alone is not sufficient you also need other immune effector itself to be there to mediate the action actually I'm glad you mentioned the role of the immune system because we have here a question from Mrs solenne cleverel who is from maloma patient Europe and they are doing a lot to inform and spread knowledge about myeloma and advocate for patients with myeloma and her question is whether after car t or by specific antibodies which we know are impacting the immune system or at least the immune microenvironment one would be tempted or whether you have experience using anti-cd38 monoclonal antibodies also usually activated lymphocyte do Express cd38 and maybe you don't want to kill immediately your car T cells for instance any thoughts on salvaging patients with anti-cities that they ate after cortisol or by specific Maximilian I mean yes I think that's an excellent question and and what we've done in the past is that we look for cd38 expression during bridging therapy um and if we apply there are two mobiles that talks about uh based bridging therapy we basically see a lot of cd38 that's the same as for retaximup back in the day um but actually for those few patients that relapsed within the first year after after Katie usually either sell because it was the only agent approved in Germany back in the day and we actually saw resurfacing off of cd38 and based on our lab results we exposed to re-exposed them to cd38 antibodies and had some let's say limited response some of them respond but actually due to the the highly expressive disease activity after card relapse usually external LED some plus muscle leukemias we only saw has a short passage of stabilizing Disease by re-exposing them to cd38 but but what we see is basically a resurfacing of cd38 on on this melanoma cell surface but as you mentioned it it's more than just the expression it needs to intake the immune system and usually after car T that's no longer the case wonderful uh we have a comment here and again I do apologize the goal is not to discuss a whole spectrum of immune therapies because we have a comment from a colleague saying oh please don't forget to mention anti-slam F7 monoclonal antibiotic of course we know that elitismab is approved and not always available but obviously of course we do acknowledge this uh one so here my question to uh Elias and you actually describe the results of these next door studies and I believe you mentioned this because sinexor is approved and increasingly available it's an oral drug easy to use once weekly and you have nicely shown that despite the initial I would say results about the tolerance actually now with those adjustment it's becoming a safe and effective drug easy to use widely available especially in elderly patient patients who don't want to travel so we have a question here from Dr Amir tour from the U.S about the value of the combination you described between cell and exorb or tesma dexamethasone in the adverse risk side genetic abnormalities Elias would you like to comment on this and of course the others so there is there is a there is a benefit also in the high risk patients for the addition of the linuxo I don't have the very exact numbers on my mind but I can look it up and the colleague can write an email so I'm happy to provide some some data if you don't have access to the publication so um but we can definitely say Elias I can confirm that there is a clear uh tendency or signal of the efficacy of selling X or in the high-risk cytogenetics obviously there is no specific study dedicated to this population in a controlled fashion but there is definitely a trend in this population so maybe here and here I'd like to ask the same question to all three of you assuming uh you have a patient who is or she is candidate for cartesa and we have to acknowledge that being a single shot treatment patients are very keen on getting cars these cells they are not always available they are only performed in academic highly specialized centers but we know that it can take up to six eight weeks to get this car keys up then you need some bridging so I would love to hear from all of you about your bridging strategy uh bearing in mind that you know you may have by specific antibodies you may have small molecules you may have silly next or what is your approach how do you handle uh this issue of bridging shall we start again with Lisa and then we go to Maximilian and then Elias um yes so first of all bridging is actually very important because we know that the risk of CRS and side effects of and carotene cell treatment is higher in patients with a high tumor burden because as you could Wonder well why do I need any bridging at all we could just sort of Let It Go until we give the car T treatment um but as I said and as it has been shown um it does make sense to reduce the tumor burden before giving the curtisels and you don't have to be afraid of the Keratin cells of not being effective after it so um yes please do um the bridging and then mostly it comes down to the patient because um at least currently carotids are only approved on the later lines so a lot of the cases you really just don't have that many options to choose from um as Elias has shown the um preferred options already diminished by like already starting at the second line and then if you only um have it RTS available at the fourth line of therapy and it sometimes gets hard to even find any treatment from which you hope for some substantial benefit so that's really on a patient-based manner I must admit that we have not very often used eye specifics as a bridging because also currently and their use is very limited at least in their name patient program and then you sort of also have to decide from an ethical perspective whether you could give this treatment as the long-term treatment to other patients or just as a sort of single shot to this one um I think this will also be interesting to address in some clinical trials where you'll then also get some biological samples to look at how the immune system develops under this um treatment with biospecifics and Then followed by the Curtis um but yeah so to this question at least I think it very much depends on what the patient may have some substantial benefits from excellent Maximilian yeah perfect I mean just a few comments to add I mean like you said it's highly highly personalized that kind of decision uh one thing that you have or we always have to keep in mind is that there's also some kind of pre-pridging therapy because usually it's all put together in into one bucket you know leading to apheresis and then actual bridging therapy but um if if you have an effort authorized your T cells you really have to Choose Wisely which which kind of bridging therapy you will apply in between because like you said we've used a couple of times by specific antibodies just because we hadn't had any other choices and actually you run into trouble troubles by applying by specifics during aphoresis so you you exhaust your T cells and we had a lot of out of spec manufacturing using by specifics at the efferesis but usually if you have some time frame between your last buy specific and your efferesis you will get manufacturing of Also let's say in vitroactive artista so it is possible but you should avoid it in my opinion but once you get your tea sets ready and Manufacturing seems to be successful um I actually um tend nowadays with patients with high tumor burden like you said they are prone to CRS to actually go back to um conventional chemotherapy so we did a lot of pace we did a lot of ascts actually for bridging therapies and quite successful even in patients with plasma cell leukemia time of aphoresis EMD Progressive disease at time of aphoresis we admitted them through the ward for example some patients receive beam conditioning and then ASAT went into a very nice vgpr with decreasing emds and then got cartes as consolidating measures and it was quite successful until now so if you get your T cells you can basically based on the fitness of the patient you can go all in and then hope for the best and then apply the car tease as as a consolidating treatment thank you and we have just to for the sake of clarity we have a comment from a colleague mentioning that when it comes to bridging we have to distinguish two goals whether we would like to slow down the progression or reduce the tumor Mass I believe there is some overlap with these two goals between these two goals but obviously we do agree on this Elias what is your approach I I think I can only add up to the to the to what my colleagues said but I want to draw or bring another concept to to the attention of the audience and that is the question um if we use a bridging therapy pre-apheresis or post aphoresis so um I would be very careful or I always try to avoid to use cytotoxic agents or high dose of cytotoxic Agents or buy specifics free to aphoresis if I use it post other reason I know that the cytopenia especially for the cytotoxic agents will be prolonged in very likely in these patients and um I would say just going back to back civilian State Maximilian statement of course if you have a disease that really requires treatment and you have really a disease that is going to kill the patient because it's extremely aggressive you can you can go for an all-in approach but in general I'm a bit more conservative perhaps than like the really added saying um using such an aggressive like high-dose beam and then going to cut T cells with a prior stem cell rescue um it's something I would say as Maximilian already mentioned it's a very very individual choice and the more common thing that we do actually is that we say okay if we want some response but we know that the T cells will be available within six to eight weeks then we say okay why not re-exposed to an anti-city third and anti anti-38 antibody if that is possible so meaning that if the patient got it for example in the second line or in the first line and that's one or two years ago I would say that's a that's a reasonable choice also in combination maybe with a with a low dose alkylating agent or even a proteasome inhibitor so for example one thing I I did um many times and it worked quite well to get responses was a combination of Dara or Isa kcd colorful website refers for my dexamethasone but only if the previous history of the patient allowed that so if the patient received kcd in the prior line it was refractory to that of course that was not an option but that just reflects what what Maximilian and Lisa said it's a highly heterogeneous decision what I really like is to use the small molecules as well because um at least with cell Lenexa we have three patients or had three patients that worked and um what I also like to use is the Veneto clock so it's not a problem we'll come to this but let me uh well uh we have two uh one command I don't know if it's a question from Dr Salinas highlighting that image and Cell mode can improve the immunostimulatory characteristics of NK and cd8 positive T cells and I guess this is something maybe useful especially after cars these cell infusion but I don't know whether before collecting the cells because in general we would assume the patients are already a refractory to these agents so we don't use them we have a question here again because you mentioned cylindexor uh the issue is that people receive patient receive bortezuma usually early in the course of their disease and they are rarely refractory to bortez because then they don't see it anymore so do you consider SVD cell next robotism dexamethasone as something that is easily feasible [Music] while waiting for other options or and then you can start it and if the patient are doing well then you can postpone or delay other approaches what are your thoughts about the specific combination that's the question yes please Maximilian yeah actually I I just raised my hand because you know last week I I talked to an MD student again who's like preparing our car T Cell database and then we went through the refectoliness of our patients again and we've done around 40s now since 2021 and actually only 10 percent were Panda refractory because of the reason that you just mentioned they are coffins but they're usually just autism exposed because you usually after first line or second line you do not remember your blood Testament you use the novel agents the the four different agents that come after Buddhism but they are not reflectory so I think it's a very very um important comment to go back to autism because usually they are not refectory there's not much data on board Testament after carphillzema but the reflect the the the type of of mutations that you acquire for example from it must be completely different because the mode of binding to the proteasome is completely different since it's not a covalent binding for for both hazelmip so I think it's it's an excellent choice actually to go back to bautism and using a different change of of action using the xpo1 inhibitor select so because also it has only mild effects on the T cell compartment so um actually we like yes that we used it a couple of times now of course the the rates of permissions are quite not comparable to to buy specific antibodies but in that kind of situation you must avoid them to to get your car T cells to the patients so I think it is an excellent choice because you're not usually not reflector like you said no I I I like this and this is an important comment because the common sinking was that if you have received coffeesome then automatically your refractory to or exasomet which apparently may not be the case according to what uh you're saying which is obviously very good news let me let me take now the questions about beneteclax and eliasu and looted on on this and we have here a couple of questions about this uh of course we know that venetoclax is not approved in maloma but still we can debate the scientific value of the drug and Lisa do you agree that for instance the translocation 1114 entity would be the ideal candidate and how do you use the network wax in this population are off label yes well first of all it is off labels for each patient you have to apply to the insurance and sort of ask for their approval of the treatment but yes in the population with the t114 um I very much like to use vanilla Clarks because we have seen very profound responses lasting for a long time in those patients and I mean there are um clinical trials going on um evaluating venetoclax we all know about the Bellini trial which was an all-common population but then more recently the Canova trial which investigated venetoclax and Dax versus Palm decks just in a purely t114 population um is actually I think supposed to show to release some data soon um and the mechanism I mean vanilla clocks and t114 patients is a targeted treatment because the 1114 patients to show the spcl2 overexpression and venetoclaxis the bcl2 inhibitor um so that's where we all want to get to sort of um yeah get individualized treatment in this very diverse disease I mean it's called multiple myeloma for a reason um and so I'm also very much looking forward to other combination options with venetoclax because again I think it may not be enough to just hit or just Target one mechanism of action that also you know and take the immune system into account and other modulating agents so I also think that combining venetoclax with other agents and there are trials going on also evaluating it with cd38 antibodies and um others will be um very beneficial and currently I think venetoclex and fortesma Dex is the combination um to go or to to ask the insurance for Thank you Lisa very clear any other thoughts on the use of veneteplex Elias before we move to a few other options one thing you can do is not just look at 11 14 you can also look at um bcl2 over expression but Lisa already mentioned that but just to keep in mind you can normally easily ask the pathologist to just go and look for an over expression and that can also be in rare cases independent on 11 14 but on other translocations so we have the same problem of course all over the world that it's not approved and what I would like to acknowledge very briefly is that I think the Canova trial is among the trials that the myeloma Community really needs because it's a true head-to-head comparison of a single drug cost combined with dexamethasone okay but uh um and in a specific subpopulation of this multiple myelomas that we have and that we try to treat so um I'm really looking forward to see some results of that trial and what I think is that we will learn a lot within the next years from from such trials and true head-to-head comparisons and everyone in the community I just can motivate you you have the opportunity to to either conduct head-to-head trials or um have the opportunity to participate in such hypothetiles trials I think that that's just important and we as a community also have to communicate that to our partners uh in the in a pharmaceutical industry that this is will really bring us forward and this is an example of such a trial excellent thank you very much we have a comment from the audience about the use of NGS and biological risk stratification making therapeutic choices thank you very much Dr Tor and that brings me to the idea that when it comes to those Advanced relational factoring patients it is probably needed that we revisit the tumor because sometimes we end up with some nice observation useful observation and we have a question here for instance about beer off mutations because and it's an old story but actually if you find this kind of mutation you can have and you can apply a targeted drug any experience any thought on these beer off mutations and whether you look for them systematically in your practice you can start as well if you like yes well yeah I mean it's a it's a short story uh we treated recently a teacher who developed multiple extramular diseases and actually we performed multiple biopsies and found the B ref mutation in every biopsy but also and rest mutations in some locations and then we got the healthcare insurance to pay for silver cell and put her on um on a b ref and Mech inhibitor and actually she went into complete remission on her pet scan um actually at that time Point she wasn't Progressive when we looked at serological markers so basically the light chains were all gone but only had the emds and and now she was discharged yesterday actually from from our Ward after silver cell and we discontinued the Braff and make inhibition of course but it was quite a interesting story so also there were no negative effects of of the Braff and make inhibition on the diesel Manufacturing and the emds disappeared so that's so that was a bridging too yeah yeah oh this is fantastic and then also the Pet Scan before sales looked uh incredibly so she she had a huge tumor under her left underarm it was the size of a fist it was the largest EMD and it completely disappeared during the brf and mechan Division and now she got consolidating self-assell treatment and she's she's really happy at the moment I saw today at the aspect outpatient Department this is fantastic Ilias you wanted to add something on this yeah I think it's just important for all of you out there that uh Mark Rob who is the head of of my department here in Heidelberg last year he just published a small trial treating 12 patients over many many years we tried to recruit these patients if we lived through Factory myeloma who were positive for the brav v600 emutation and then treated them in the so-called gmmg Burma trial with uh incora for nip and bini metinip and we saw excellent response rates with just a single agent treatment in this uh heavy pre-treated population and we still have a patient now ongoing on this uh combination for for more than three years and for us in Germany and I hope also in many other countries this trial can be a backbone to to apply to get funding for for this drug because especially in Germany It's always important that if you ask the insurance that you have a trial where you show that this drug was efficient and that really helped and in my view The small molecules can be very very helpful and we are only at the beginning of dissecting um dissecting or molecularly dissecting the myeloma disease and over time it gets even more difficult and over the body so if you look at the spatial distribution as Maximilian pointed out in some tumors you maybe you CP rough in all the all the EMD tumors and then the bone marrow and then you see a Ras mutation or other mutations so that makes it even more difficult the spatial heterogeneity of the the disease and I agree that we we really have to think about a lot of options and the pathologist is often very very helpful and yeah so I think it's a it's a it's a good concept that we try to split up the disease and and see what our driving driving mutations yeah Lisa who wanted to add something okay I agree with my colleagues excellent fantastic there's a one question maybe I'll handle a very uh quickly uh which is about the role of hypermethylating agent and uh for instance five as I cited them and I believe maybe 10 or 15 years ago there was a very clear demonstration about the role of hyperventilation in multiple myeloma but my best guess at the initial studies was hypermethylating agents were not a big success in maloma I may be wrong maybe we should revisit them any thought on this Maximilian I saw you were raising your hand yeah I mean uh you're completely right because they were quite disappointing but um one super interesting uh talk at this year's eha was from from the Canadian group that showed basically the epigenetic modification of the dprc5d locus as mode of resistant to to take her map so they had also two case reports one was quite straightforward was nonsense mutations on a DNA level on the GPR c5p uh Gene but the other case was the complete absence of RNA expression of gprc first D with an intact Gene of GPR c5d so what they did is atex sequencing and they basically found a different methylation pattern of gprc5d so basically as you said maybe we have to revisit it in in some rare cases to reactivate the gene expression of our integens so that was really great work from the Canadian group absolutely this is really fascinating and maybe we may end up giving a little bit of as a sighted in to decrease the pressure of hyperventilation while bridging to something else so I mean we we can debate and discuss for the next five or six hours but I know it's already late for you guys uh and uh I hope everybody has enjoyed it I personally learned a lot from you and the comments keep on coming uh into the uh chat I do apologize will not be able to take all of them one thing for sure is that today there is a lot of Hope to the patient uh car seat cells are leading to some incredible amazing results and now probably they are moving into earlier lines of therapy the bi-specific antibodies the one we routinely use namely teclastema by Renata map are really very good and again they do have a very important strong efficacy including complete remission in highly pre-treated patients but obviously and that was the spirit of the discussion today we should not neglect or ignore all the other available options because all of them all of these options would allow us to gain some PFS and at the end of the day if you put together all of this this is how you extend survival and we heard and we discussed a lot about the importance of silanexor and civil nexo based combinations because it is approved oral drug easy to use we didn't mention malfloofen but obviously metal proof and at some point will be available and could be used I think we also agreed that it is always good to revisit the history of the treatment especially if you have a patient who has been treated for 10 years you may end up finding a drug where the patient was exposed but not necessarily refractory and then you can recycle I would say this drug and this is obviously always a great option so thank you all again thank you for your positive comment thanks to our three super panelists I would call you now guys the Three Musketeer of the ich and thank you all and wherever you are please stay safe and keep well see you soon and I think our next activity is just tomorrow dedicated regular blasted Peppino see you soon take care bye