 Good afternoon, everyone, and welcome to the first webinar of this year. My name is Ana Vallejo. I'm the communications manager of Myeloma Patients Europe and I will moderate this webinar today. First of all, I would like to thank you all for attending this webinar. As you know, our main goal today is to review the most important updates on Myeloma and also in ELMeloidosis presented in the American Society of Pharmatology, annual congress, that was held last month in Orlando. And for your information, this webinar will be fully recorded and will be uploaded also to the Myeloma Patients Europe website, which is www.npu.org. And will be also available in the MP YouTube channel in case you would like to share it with someone or to watch it again. Before we start, I would like to make a small summary of the webinar agenda. As you know, the webinar is scheduled from 6 to 7, so the presentation will last about 40, 45 minutes. And then I will open the session for questions. Basically, there are two ways to ask questions to the doctor. One of them is using the microphone in your computer. So just press the right hand bottom that you can see in your screen. And then I will unmute you so you can ask the question directly to the doctor. And the other possibility is to there in writing in the question and answer window that you will see also in your screen. I will receive all the questions and I will read them so the doctor can answer them. The talk today will be given by Dr. Moshe Gatt, Hadasiri University Medical Center in Israel. And on behalf of Myeloma Patients Europe, Dr. Gatt, I would like to thank you for your collaboration and for your time to prepare and to give this webinar today. And I would like also take advantage of this webinar to thank you also for the two educational clips that we filmed in us with you that are also available in our YouTube channel. So thank you again and the floor is yours. Hi everybody and welcome to the webinar. I'm happy and thank you MP for selecting me to give you this webinar about the ASH 2019 updates. There are many updates of course I couldn't cover all of them but I'll be happy to share with you I think the most important ones that I see. I will start in general by let me see that it's working yeah okay. So before I start the webinar because I'll be talking about a lot about minimal residual disease I'd like to explain in two words what is minimal residual disease and its significance because this is very important in a way because Myeloma has become a chronic disease we know that patients will be without any evidence of disease for a very prolonged time. So if you give a new treatment and you want to prove that it's better than another treatment it will be very problematic to wait now for four or five six years in order to show the superiority of the treatment and therefore we're looking for other biomarkers that will tell us that these treatments are truly better than others and and they're worthwhile pursuing and even authorizing these treatments to patients even before we see long-term results. So the most advanced of these biomarkers would be the minimal residual disease and this means that the deeper the responses then the better it correlates with progression-free survival and overall survival of the patient. So we do know that most patients will eventually even if they're in complete remission as we can see here even if they go as deep as complete remission a long time at a certain point most of them will relapse and therefore we need something to show us that maybe even patients in complete remission are different from one another and this is what we mean when we talk about MRD. We say that when the patient has diagnosis he has a lot of myeloma but even when he's in complete remission and above the surface we cannot see any of the monoclonal protein whether it is by IgG or free light chain or whatever when we measure it with very sophisticated methods we can see even very low amount in disease and maybe these patients who have this low amount of disease are either cured or have a very prolonged progression-free and overall survival. So this is the basis of minimal residual disease and we have two ways of checking it one is by a method called flow cytometry where we can see and distinguish the myeloma plasma cells from the normal plasma cells by surface markers and we can actually by this method see one cell in a million one cell in 10 million and this gives us a very good way to distinguish the normal cells from the sick cells and another way is by what's called next generation sequencing this is done by a method that sees only the specific genetic changes within the cells and we can see again one cell in a million and therefore if we don't see the one cell in a million we know we say that the patient is MRD negative and this means that a long time he will remain without disease maybe for years and some of them of these patients will after a lot of years may relapse or not relapse at all so this is an important marker that we use now in clinical trials to assess the the way the drugs work and how deep is the response so we'll talk today about updates that I think are new and will influence treatment in the next year or the next two years actually and we'll talk about induction therapy for both transplant eligible and ineligible patients we'll talk about relapse disease new options for relapse disease and even for advanced relapses new and promising options so I'll start with induction therapy when we talk about induction therapy there are two very promising agents which have already proven themselves in second line and third line patients but now are becoming more and more popular to use in first line and the first of them is there are two which is a monoclonal antibody and I'll talk about four trials where it's been shown to be very effective in the first line the there are two more as most of you will know is a monoclonal antibody that is working either through the immune system or by itself it has a tumor anti-tumor effect by binding to the CD38 majority on the myeloma cells and cause their death it also modulates the immune system but in any way most of its effects are as a single agent and when combined with other agent and the most advanced I would say way of using it would be when it's combined with the most effective first time therapy that is now given in many countries over the world which is the combination of VRD, linalidomide, bortezomide and dexamethasone so this is a study called Griffin study and this is a long term or 22 months follow-up after the patients and the study shows two kinds of patients they was randomizing them newly diagnosed patients which were mostly transplant eligible patients randomizing them to get daratumab with VRD as the standard of care or just VRD without the daratumab all patients or most of patients will proceed to stem cell transplantation and will continue with this regimen and thereafter with maintenance therapy with daratumab and Revlimid or just Revlimid alone and the results are as expected the daratumab will give a very deep response so most patients at the end of consolidation and after that during the maintenance phase say 80% of the patients will be in complete remission which is far higher than VRD alone which gives very nice response and this is the reason that VRD is used as first line treatment in many patients nowadays but moreover you can see here that when we check the MRD negativity we get about 50% of patients as compared with 20% of patients will remain with minimal residual disease and this mostly means that if we now follow this trial for a very long time meaning for five six years we will probably also see advantages in both progression free survival of the patients and overall survival even though these patients got an excellent treatment so this is kind of a very good treatment even to date without the daratumab but see that we can make it better with the daratumab. Same goes with patients who are transplant ineligible and this is a trial that was published about a year ago called the Alcyon trial and it was again randomized the patients to get daratumab with venet with um uh Velcade, Melphalan and Prednisone these are elderly patients or patients were too frail to go uh for otologous transplantation and this was compared with um the Velcade, Melphalan, Prednisone only um and now we get a kind of a more advanced results after immediate follow-up now of 40 months so after 40 months we can see that even though most patients responded at the first analysis at the second analysis we still have most patients responding for a long time and much better than with Velcade based therapy alone and again we can see even though it's not as uh good as it was with the Griffin trial but still for uh many patients they become MRD negative even though um um they were treated with um um less intensive therapy and this MRD negativity is by far more than was achieved with the Velcade based therapy and it's also sustained a long time and this means again that these patients may remain in remission for a very prolonged time. Another trial that is showing very promising results and this is a uh a more prolonged follow-up period is the Maya trial again daratumab added to Revelemiden dexamethasone as compared with Revelemiden dexamethasone alone in transplant in eligible patients and so we can see once again that the overall response rate are higher and the MRD negativity is far higher than the one achieved with Revelemiden dexamethasone alone and this has also translated to uh a progression-free survival because we have now a median follow-up of 28 months a far better progression-free survival and what's interesting is also to note the fact that we get kind of a plateau here and this plateau is very promising because although we always say that do not look at these drawings do not look at the end of the drawing but look somewhere in the middle but this middle shows that many patients will probably remain without progression for a very long time and hopefully this plateau will continue to be along the next few years and these patients have benefited a lot from the combination therapy. So in many countries I suppose that during the year of 2020 and probably 2021 the combination of daratumab with Revelemiden or Medicaid-based therapy will become the standard of care if possible in most countries at least for transplant ineligible patients and probably a long time also to transplant eligible patients. Now this is a trial which was done in Europe and it's an interesting trial because it was done for patients not only they are transplant ineligible but these are also frail patients um with uh either they're unfit or very frail meaning that their performance that is is low and it was combining again daratumab with xazamine which is an oral proteasome inhibitor so it's a very convenient method to give patients even with their when they're at home the beginning is more intensive but afterwards a long time when you give the daratumab once a month it's very convenient and you can give the most of the treatment at home and the patients do not need to get into the hospital and this is a very early report because it's only 23 patients were frail and 23 patients were unfit and you can see here from the patient population that the patients in terms of myeloma were kind of the same myeloma patients but very elderly the frail patients are even 80 years old and and you can see that when we talk about the ability to do things this is the performance status most patients will be in an advanced uh not so good performance status and nevertheless the toxicity was low and the response rate are really excellent for a very low intensity a regimen which is combining just two or two and a half medications with the dexamethasone low dose so this is very promising in terms also of the frail patients going over to another intriguing way of seeing things this is a negative trial it's called the gem claridex but because it's a negative frail it's important to understand the limitation of what we believe in how important trials are to be done this is a trial which was comparing patients who are getting revlimid dexamethasone as an induction therapy patients who are transplant ineligible to a revlimid dexamethasone combined with clarithromycin clarithromycin is an antibiotic it by itself it has no effect whatsoever on myeloma and this has been proven in many trials in the 1990s but when it's combined to imid it has been by retrospective reports mostly or even small prospective reports reports it is shown to show very nice and deep responses a a added to revlimid dexamethasone so this trial is was extremely important because it's a randomized it's open label but it's randomized trial so half of the patient got the clarithromycin with the revlimid dexamethasone and half got just revlimid dexamethasone so you can see here that unfortunately the progression for survival was not different between the two arms although the responses was much better with the addition of the clarithromycin and deep responses of very good partial remission complete remission were far far higher than the ones achieved with revlimid dexamethasone but this did not translate to better progression for survival or better overall survival which stayed the same with both medication and the reason was actually because of excess toxicity of this antibiotic most toxicities was due to infections so patients who got the clarithromycin even though it's antibiotic actually suffered of more infections and therefore the results the bottom line results are that this addition of clarithromycin to revlimid dexamethasone did not make anything superior in the treatment of patients and what the investigator concluded is that this phase three trials has shown no significant improvement and actually even though the clarithromycin significantly increased response rate the this addition did not translate into better survival rates and actually in patients who are old and frail it was even detrimental and they suffered of severe infections which prevented them from getting treatment and even prevented them from benefiting from these better responses and possibly one reason would be that clarithromycin elevates steroid levels and so in the future if you want to deepen the patient's response you may want to add clarithromycin but do delete the dexamethasone which causes a lot of infections other severe problems a very promising drug which we know for a long time is the carfilzomid keep release which has been shown now in the two trials to be very beneficial to patients the first trial is forte trial it's kind of like the griffin trial in a way that these patients are transplant eligible patients a large trial which was done in Italy and in Europe was randomizing patients to get carfilzomid with revlimid dexamethasone and compare it mostly either to short-term carfilzomid revlimid dexamethasone or to carfilzomid cyclophosphamide dexamethasone kind of like the velcade cyclophosphamide dexamethasone vcd cyberd regimen and to see which regimen is better in a long time with maintenance and we get early results from this trial and this trial has been showing to be the forte trial very efficacious so you can see that most patients will respond these results are better than with the cyclophosphamide when you combine the carfilzomid with revlimid and not with cyclophosphamide and as you can see here the MRD negativity rates are very close to those seen with even the daratoma based therapy with the revlimid dexamethasone or with the velcade dexamethasone and or protein zone sorry so carfilzomid seems to be a very efficacious and very good medication to be used in the upfront setting as well and here is a small report but it's important to very high-risk patients and we're talking here about primary plasma cell leukemia which we know is a very detrimental disease and these rare patients with myeloma plasma cells in their blood will have a very poor prognosis so this is the first large trial prospective trial again done in Europe and this is a report of the first 15 patients in the trial were treated again with carfilzomid revlimid and dexamethasone with tandem autologous transplantation and thereafter consolidation and maintenance treatment and in a way this treatment was very well balanced in the patients and the patients endured it very well and it had stellar results meaning that patients with plasma cell leukemia which is a very difficult disease to treat and in the past we used to treat it mostly with high dose chemotherapy and a lot of chemotherapy here with little amount of induction chemotherapy the KRD regimen we still get very high responses and some very deep complete remission and very good partial remission responses so this is very encouraging for these very difficult patients what about relapsed myeloma therapy so there are old and there are new players in the block and I would like to talk about two main trials one is the combinaid the candor trial which combined our atoma with carfilzomid both medication which we talked about a few minutes ago and here in the second line the combination of both is showing very promising results and also I'll talk about a little bit about veneto clocks so the candor trial was a study design where the patients got carfilzomid dexamethasone and daratumumab is compared with carfilzomid dexamethasone alone which is the standard of care treatment for relapsing patients nowadays and the combination the idea is that the daratumumab will probably was thought to enhance the progression for survival and in the future the overall survival of the patients and indeed this has been a late-breaking abstract and very impressive results where we have higher response rate even for relapsing patients 84 percent of overall response rate is really good and a very good partial remission which is stellar for relapsing patients and also quite a lot of patients getting MRD negativity even the second third fourth line setting for some of the patients as compared with carfilzomid dexamethasone alone talking about veneto clocks this is a new medication which was put on hold for the last year and the reason is is because of its toxicity it's been used in CLL and nowadays in acute myeloid leukemia quite a lot with very good results and it's been tried in myeloma the idea of the medication is that it blocks a protein called BCL2 and BCL2 is a protein which is important for cell survival when it's high it prevents the the cell from dying it's called apoptosis the dying of the cell and BCL2 prevents this dying and when you add veneto clocks and you inhibit this BCL2 the organelles in the cell cause it to undergo apoptosis and to die so it's been thought that it will be efficacious because it's very efficacious in many diseases in myeloma as well and now it was combined with veneto clock the veneto clocks was combined with carfilzomid as we've spoken before and this very early phase trial 42 patients advanced disease one to three prior therapies and the veneto clocks was checked in relatively high levels that was needed to to treat the patients nevertheless the results are very good the median in a in a short median follow-up we can see that most patients actually responded very well the overall response rate were again very good for relapsing patients 80 percent of the patients with an overall response rate most of them or almost most of them are in complete remission and that is even though more than half of them are refractory to previous therapy interestingly veneto clocks works mostly on these patients the transplant the trans translocation 1114 positive patients these patients you can see here that almost all patients respond and these respond responses are very deep so veneto clocks seem like a very good medication for T1114 positive patients mostly the interesting part was coming from a trial which was actually a negative trial and put veneto clocks on hold for a long time this trial called the Bellini trial compared veneto clocks with portesumib to portesumib alone and it was expected to get better results with terms of response rate and progression free survival so indeed progression free survival was much better when veneto clocks would add to velcade but this did not translate translate to overall survival benefit quite similar to what happened with the gem claridex trial although the responses were much better these responses did not translate to overall survival benefit because of infections so it might be too toxic and in the trial it was mostly it was mostly important to understand who are the patients who actually even though the survival benefit was not evident a long time would benefit from the veneto clocks treatment and again we can see that these drawings show that everything left to the panel favors veneto clocks and everything right to the panel favors velcade alone and you can see here that not only the transplant the translocation 1114 patients benefited a lot from the addition of veneto clocks as expected it's also those who had high expression level of bcl2 gene so maybe in future when designing trials for veneto clocks treatment it would be very important to select patients who are t 1114 positive and or bcl2 gene expression high and these patients may benefit from this treatment much more than all of the patients so this has been shown also patients with both of them or either of them showing very high response rate very high deep response rate and this is actually translated to better progression free survival so this is a very important message to a drug that was almost withdrawn because of its toxicity but seems like some patients may benefit a lot from it so let's go over to therapies for advanced stage multiple myeloma and here i'm going to talk mostly about new agents and about anti bcma therapy and we're talking about either car t cells which are the highlights of the ash or newer antibodies and we don't know yet which will be better because there have not been compared and even these are very preliminary bcma itself is an epitope on the membrane of plasma cell and it's very specific to plasma cell so most cells in the body will not have bcma and it becomes therefore a very important target to try to find antibodies that will be able to attach to it or to use car t cells to kill these myeloma cells and when we talk about car t cells just a general because talk about car t cells just because it's so important and this is going to become the next generation of treatments for very advanced patients you know that tumor cells whatever tumor are in being evading the immune system which is trying to eliminate it but the tumor cells have found many ways to hide from these immune system cells that in normal immune system or in very small tumors are possible to overcome them but the tumor cells themselves when they interact either with some of the immune system cells or with the t cells themselves they become hidden from these t cells and the immune system of the body of the patients with myeloma are unable to to put the patients into deep remissions or to even to to eliminate most of the tumors and so this car t technology was designed where we take an actually an antibody which is against the bcma epitope on the membrane of the plasma cells and we attach it over the membrane to a stimulatory molecule and this will be the membrane of the immune system t cells which are cytotoxic to the tumor and when the t cells will attach the tumor they will eventually kill it so this is how it's done the antibody is inserted it's anti bcma it attaches to the bcma and then more t cells come there and eventually they release cytotoxic granules that will kill the plasma cells so that's the idea of the car t cells but it's a difficult procedure where you take the t cells you isolate them you input into them this receptor to the bcma you grow them you modify them and when they're ready you infuse them this takes roughly a month so from the moment we collect them if we may manage to collect them and manage to grow them and manage to do everything we give them back to the patients and it takes about a month so it's a very prolonged and and very vulnerable situation where the patient is now with active disease and has to wait a month till the cells come back and so this is a report from the new england journal of medicine it's a very important journal this is um has been shown uh the result of the first car t cell in myeloma before that we have very good results in lymphoma and also in acute lymphoblastic leukemia but now in myeloma here in about 40 patients where you take the patients you take their t cells you manufacture the car t cells you give them in the meanwhile some sort of a bridging therapy and lympho depleting therapy in order for these car t cells to expand and you infuse them and go a long time and see what happens to the patients and you can see here not a lot of patients but very nice responses so most patients will get to complete remission very good partial remission and even MRD negativity you see these asterisks in most patients and these results these lines show that these patients are with ongoing results for a long time and so the progression for survival to those patients receiving enough car t cells was pretty much it's not forever but pretty much uh for a long time with the median progression for survival of 12 months which is far better than any other medication for advanced stage patients either patients after five six sometimes even more lines of therapy and by now we have about four or five different car t cells in clinical trials and it for myeloma itself and maybe more are coming in the future so this is a very exciting times for myeloma treatment using just immune therapy and at this ash was reported the report the results of two large trials relatively large trials one is called legend two and the other is an extension trial which is called the car t tube the legend two is actually a chinese trial it was um car t is very explored and done in china and again the car t was uh uh manufactured after collecting from the stem cells giving some kind of a conditioning regimen and after that infused to the patients and this is a prolonged follow-up time after these patients because the results were already published um in 2018 ash but this is a long-term results and one of the main problem with car t is the toxicity of the treatment and two most important toxicities are crs which is cytokine release syndrome this is a severe side effect that happens from the car t it um uh causes kind of a cytokine storm it means that the patient will have high fever low blood pressure and they can even get to severe um pulmonary congestions and fluid overload and some of them are needed to be transferred to the uh intensive care units for prolonged periods of time and it can even kill some of the patients unfortunately so this is a very serious side effect that happens with car t and the other one is neurotoxicity that can range anything from being just a little bit disoriented to severe depression of consciousness and even loss of consciousness but you can see here and this is very important that in car t patients in myeloma unlike in lymphoma uh these uh side effects are not very severe grade one two three are not severe grade four and five are very severe but most patients did not have severe side effects only one or two patients had severe side effects from the car t so this is very encouraging that this uh therapy even if it's not entering for uh indefinite periods of time is safer in myeloma patients than in lymphoma patients and the long term here in 57 patients this car t showed very high 74 patients are in complete remission almost 68 percent of patients in MRD negativity so these are deep remissions and the patients who are in complete remission had a 29 months median duration of response so this is a long time for patients who are usually something like uh third fourth or even more lines of treatment so most people will say okay that's in china in china they do things different these are uh patients who did not get daratum these are not these patients were very resistant so same construct like the legend two was tested um in the united states it's a cartitude one study so these are less patients but same protocol same car t cells from these patients using the same contracts but the same results only 29 patients but side effects are pretty much the same no severe side effects most patients had not severe side effects and the results are again 100 percent overall response rate and most of the patients in complete remission and even most of the patients have very severe very low MRD or MRD negativity so this is very impressive and very encouraging in terms of what's going to happen in the myeloma field within the next couple of years and the duration of response is pretty much prolonged it's not very it's not a long time of you know just six months of follow-up but 27 of 29 patients are in our progression free of their diseases so this is very good for patients were in general after five six or more lines of therapy and you can see here that during the ash there were kind of um a lot of talks regarding a car t cells and about ways to prolong these progression free survival to expand periods to expand the number of car t cells very um sophisticated methods to to elevate their levels and so probably within the next few years we will have a very effective therapy so the summary of CAR T-cell therapy in multiple myeloma today is to say that um we can see that most of the patients will respond to it so far the responses are not permanent but they're very prolonged much more than with any other medication and ongoing studies are showing that there are other CAR T-cells moieties that might be used that maybe you can target dual CAR T with two types of CAR T one against the BCMA one against the CD-19 or CS-1-SLAMF7 there are many other ways to enhance this CAR T-cell toxicity and efficacy so the future is really bright in these terms but to patients who do not have this available or because probably it will also be extremely expensive and also because it's very preliminary there are antibodies and I'm going to talk about one antibody that was presented in during the ASH and it's very promising as well maybe you've heard before about an antibody which was presented last ASH in 2018 which is called Belantemab Mefadotin or it's a GSK antibody and it's also directed anti-BCMA showing in the preliminary trial very nice results about 60 percent overall response rate to very advanced patients who got again five six lines of therapy so with the median progression fee survival of roughly eight or nine months so it's a very promising agent and it's already being used now in phase two and phase three trials hopefully will be registered by the end of 2020 the FDA and probably after that in Europe as well. There is a new technology using antibody which is called Byte which one side binds the T-cell and the other side binds tumor cell the myeloma cell and engages the T-cell with the tumor cell just the way it was with the CAR T-cells but just without the CAR T just with an antibody but this is very preliminary and we still don't have results for these preliminary trials however during the ASH was presented a kind of a byte it's called an Engager and it's an antibody which one side of it binds the BCMA and there's another motif over here which binds the CD3 which brings actually the CD3 the T-cells to the myeloma cells and therefore allowing the cells to destroy the T-cells to destroy the myeloma cells and you can see here just 30 patients very advanced patients some of them having 13 lines of prior treatments median of five prior lines most of them completely non responsive to image and proteasome inhibitors and dark tumor mob also most of them got anti-CD38 antibodies so they're actually these patients are resistant to most therapies there are and they're high-risk patients and these are the results again actually treatment related side effects were not that severe there was cytokine release syndrome but mostly very easy cytokine release syndrome just like we get in CAR T low amounts of cytokine release syndrome some infections and you can see here very stellar and good results we're talking once again about 60 percent responsiveness and most of these responses even though short time of follow-up are prolonged and very good so this is another very promising target antibody which hopefully will come into clinic very soon at the end of my talk I'd like to talk about two more trials one is called Ikaria using a new anti-CD38 antibodies and the other using selenix or the anti-CD38 antibody which is called Isatuximab was combined to pomalidomide for advanced stage patients as compared with pomalidomide alone and it's already been published in the literature in the Lancet in about a month ago and showing very nice results and prolonging progression free survival actually even overall survival for patients when you combine the Isatuximab the dark tumor like antibody with pomalidomide and dexamethasone and this is a very impressive results in terms of very advanced patients. Another agent is called selenix or and it's actually a very interesting molecule which prevents the cells from moving things from their cytosol to the nucleus which is the brain of the cell and when you prevent that the cell will die and also some medications will remain within the nucleus and be more effective so when you combine selenix or two other agents like pomalidomide or Velcade or whatever it will make them more potent and these are the results from a big trial called the stomp trial combining the pomalidomide with the selenix or and you can see here that most patients even got of course the nanodomide and bortezomib but some of them even got pomalidomide in our refractory to pomalidomide even though they were after refractory to pomalidomide I'll go over the adverse event moment even though they got it even though they were exposed to pomalidomide and resistant about third of them regained their sensitivity and those who never got pomalidomide were actually with very nice results so it's a very promising agent problem with this agent is that it is toxic in a way that it causes mostly nausea and fatigue so most of the patients will suffer a loss of appetite and will feel very weak with this medication so we're still learning how to balance these side effects with the efficacy which is very impressive when you compare these very advanced patients when you give it with another agent so in summary we talked today about new first-tide options mostly with the artumab and with with a carfilzomib we talked about the potential of venetoclax we spoke about anti bcma therapy car t-cell is very very impressive and very promising and so are the new antibodies which are coming during the next two years I didn't have time to mention new data on mrd and fine methods for monitoring patients I didn't get to mention transplantation feasibility in elderly patients and xasomib for second-line amyloidosis patients melphlufen which is a new chemotherapy like melphalan but much more effective for advanced stage patients and much more but time is up and I'm ready to hear your question thank you very much for listening and I hope that you are coming out of this with much more optimism thank you very much very much doctor I got for your wonderful presentation now I will open the the for questions just quickly remind you that there are two ways to ask questions one of them is using the microphone in your computer by clicking in the right hand bottom and the other way is sending your questions in the q&a window that you will see on the screen and obviously I will read them to so the doctor can answer them I can see one of the hands in the in the screen so we will start with them with that questions in the microphone which is come from David so I'm going to unmute you so you can ask your question so David let's see if you are listening well it seems he has some some technical problems so if you have problem with your microphone maybe you can send me the question in writing and I will ask to the doctor so then this question is regarding condom condor trial it says thank you for explaining the result of condors the results were really good but what about side effects what were the main side effects for patients well the condor trial was was a trial combined just to remind you there are two mob and carfilzomib together for relapsing patients and it the side effects expected are both from the dart to mob and the carfilzomib so the most probably recurring side effect would be infections and we know that to both dexamethasone and carfilzomib and dart to mob infections are the main side effects that happens and each medication has its side effects dart to mob is actually very easy and only first infusion gets a lot of side effects but after that allergic side effects but after that it's very durable and not difficult to enter however carfilzomib has a little bit more side effects in terms of lowering the blood counts and also causing some chest discomfort sometimes shortness of breath but it's also not a very difficult medication in the long term so most patients will enter it very well and actually the side effects when you compare these to the carfilzomib dexamethasone alone therapy were not higher and we're not and these side effects were not higher than what was recorded with dart to mob with other agents or to dart to mob combined with with velcade and and and or revoluted and neither was it more side effects severe side effects maybe a little bit more infection than with the carfilzomib alone thank you doctor the next questions card T use the existing immune system to kill the tumor plasma cell so when you have a low hemoglobin and low leucocytes will car TV be lesser effective less effective no the only problem would be with collecting CAR T cells and we know that in order to expand them because we need the T cells we need about at least 300 to 500 T cells or usually requirement of more than 1000 lymphocytes in the peripheral blood in order to collect the CAR T cells the T cells to to make them into cars and to expend them so if the counts are very low not the hemoglobin but mostly the lymphocyte count that might be a problem but if they're okay then the cells are collected and afterwards whatever therapy and the CAR T we lower them the counts but that would be kind of like a small transplantation that will take two weeks and then everything will revive and get better again and and so counts are not the main caveat to to having CAR T cell therapy thank you doctor next question how do you see CAR T developing in the future do you think donor CAR T will become more preferable okay so donor CAR T are very promising in a way that you do not need counts you do not need the the immune system of the patient in order to make them and they're off the shelf because you have these donor CAR T and all you need to do is to take them off the shelf and give them to the patients and you don't need to wait a month till they expand if they expand and and the disease does not progress during this month and so it's much a better idea problem is that it's donor and it's still very early and very difficult to know if these cells will not attack the body if these cells will not the the body of the recipient by the donor cells and if it will be as efficacious as the CAR T coming from the patient himself so this is very preliminary but probably the future will be not only CAR T but also other immune system cells like natural killer cells nk cells and other cells that might be the real future for CAR T allogeneic coming from a donor thank you very much next question trial with with Veneto glass a carfilzomib and dexamethasone a lot of patients discontinued the trial what was the reason mostly toxicity as we said there are many infections due to the when patients get Veneto clocks and carfilzomibs might be sometimes not very easy as well to to ender but still the results are are pretty much very exciting because most patients responded and had deep responses so we still need to learn how to manage the toxicity mostly of Veneto clocks which seems to be much higher in myeloma patients than in CLL patients or even in acute myelod leukemia patients we're learning this medication thank you very much doctor the next question is about minimal residual disease what were the the main updates in minimal residual disease and is minimal residual disease already used as a regaining point in clinical trials okay the first part of the patient the of the question again main updates in the minimal residual disease and if minimal residual disease is used as a surrogate and point in clinical trials i'm not sure so the main the we do see of course that the the earlier we use high efficacious treatments we get better results in terms of minimal residual disease and this has been shown by now in many trials minimal residual disease is really and truly correlating with prolonged a progression free and overall survival one question that is not answered or two questions that are not answered yet is one the durability so we take a certain point say three months post transplantation and we measure MRD but does this mean that in if we recheck it in six months it will still be MRD negativity this may be much more important than checking it once and getting much better correlative results in a way and second question is whether this is really a good biomarker or is it just a coincidence meaning that the fact that we get the patient to MRD negativity so if you're the lucky 50% that gets MRD positive is this because we got better therapy or is this because this is the genetics of the disease which allows it to become more sensitive to the medications and MRD negative so we don't have an answer to this yet and the biggest question would be is it worthwhile to take patients where MRD positive and not negative and to add more a intensive therapy in order for them to become MRD negative will this change anything in the long term so we don't have an answer to this yes yet and this is why regulatory authorities are not yet really convinced that this is the only way to look at clinical trials and we still use progression free survival and overall survival both of course as the main endpoint of most trials but it seems like this MRD negativity I think within a year or two will become a very important biomarker that will be used even by regulatory agencies as well. Thank you very much and the next question is was there any important update regarding Yale amyloidosis is there any new treatment in this area? Okay so I was quite disappointed to see that there weren't too many trials reported on alamyloidosis many small things the largest trial reported was the one that I did not describe which was actually a very big trial and it was started eight or nine years ago and that's what makes it a bit disappointing because back then the therapies for alamyloidosis its second line were either melphalan or revlimid not much more than that pomeridumide was not authorized back then daratumumab for sure was not authorized back then and so it was comparing eczasumib and dexamethasone treatment to any standard of care second line or third line treatment which was these agents cyclophosphamide melphalan and revlimid and it was showing that eczasumib was actually as good as there were more deeper responses which is looks very good and very promising the thing is that by the time that this trial is is is published and it's very nice to know that eczasumib is a good medication and it's not very toxic and we can use it in al patients it's worthwhile to say that nowadays a patient who will relapse after a first line treatment will probably get a daratumab based therapy which has been shown to be extremely promising in both in terms of responses and especially responses in al amyloid patients where the myeloma proliferative part is not very deep so we get very deep responses with this agent whether combined or not combined with other agents like velcade or revlimid or even pomeridumide so in a way we didn't get a lot of things about al amyloid dosis in this ash meeting hopefully there is a amyloid b annual meeting in two months and we'll hear some new things in this respect thank you very much doctor and the next question is again about minimal residual disease will the use of minimal residual disease as a trial and point lead to a heavier treatment more to reach a minimal residual disease so that's the big question there are trials being designed now to answer this question meaning we take patients who are MRD positive and randomize them to get more intensive treatment as compared to standard of care maintenance treatment and and see if this will change anything in the long run we will have an answer unfortunately in a few years from now when probably MRD will become the standard of care point that we want to get to but this is how things work it takes a long time to get real definite answers but it took a very long time to establish for instance revlimid as a maintenance therapy because we weren't sure if it was really really benefiting the patients a long time and now we think that it is benefiting but there still is we don't have an answer for instance if revlimid maintenance is as good as giving dartumab and revlimid maintenance or or waiting with the maintenance therapy and giving dartumab and revlimid after the first relapse we really don't have any good answers to that and probably by the time we'll have answers to if we need to put the patients into MRD negativity using any aggressive treatment we have by the time we get the answers we will probably be somewhere else with all other treatments and that's good because this means that we are going to have in the next few years a lot of newer treatments thank you doctor we are running out of time but we have some times for the last question and is selenexor already a standard therapy for relapse patients so selenexor is authorized in the united states only right now in terms of the FDA authorization as a fourth fifth line treatment as a single agent um as i said it's not an easy agent but it's very promising seems like when combining it with other agents it will be very effective even in very advanced patients so um it remains a future to see where its place will be in especially in terms of these severe side effects which are very problematic when you will advance patients you like to have some sort of um of a quality of life when you get the treatment however um we will learn how to use it i guess in the next couple of years right now it's certainly not the standard of care but it's very promising so many patients will get it on a compassionate basis in europe and in israel and in the united states it's it's obtainable and physicians are starting to use it and to learn how to use it thank you very much uh doctor gatz well we we don't have time for more questions but thank you for this interesting webinar and just remind you all that this webinar has been recorded and will be available in the mp website which is www.mpu.org and will be also available in our youtube channel so thank you very much for your attention thank you doctor gatz and have a nice evening thank you very much all for listening