Speaker: Mohamad Mohty
hi everybody it is uh 1 p.m. in Paris uh 12:00 p.m. in London uh 7 am. in New York and 7 P.M in Beijing a very warm welcome to all of you uh this is the I the international academy for clinical hematology around the globe and across the hematology field I’m Mohammad miti from the Sone University and San Hospital in Paris in France and it is my great pleasure today uh to deliver uh this webinar uh dedicated to multiple maloma a summary of the highlights uh from the latest ASCO and eha 2024 and ual meetings as you may guess multiple maloma is always on the podium this is like a very fascinating disease where almost every month every week we would see a lot of advances and the outcome of multiple maloma patient is significantly improved proving thanks to this uh amazing Global cooperation and collaboration between all stakeholders trying uh to bring uh the best treatments uh to Patient so these are my uh disclosures I will structure this webinar into the usual sections the newly diagnosed multiple maloma traditional uh chapters transplant eligible and Transplant ineligible then we’ll move on to the relapse refractory setting and I’ll distinguish The small molecules antibody drug conjugates B specific antibodies and immune therapy in general when it comes to the uh transplant eligible patient we keep on uh talking I think and highlighting uh the results of the so-called perious phase three randomized trial that was published earlier six months ago in the Newland Journal of Medicine on behalf of the European maloma Network you can see here the design of this trial very nice uh uh relatively straightforward design classical vrd bomide dexametasone compared to a quadruplet dirab VD followed by hyos mlan consolidation and maintenance the traditional maintenance with lenalidomide alone in the vrdr and doublet maintenance with dun and lumite in the quadruplet arm there’s also uh guidance of uh uh the maintenance uh with Dara and Len based on mrd but we don’t have these results yet and you may remember uh the uh original presentation and publication about the primary endpoint absolutely terrific results highlighting an 84% progression free survival at 4 years versus 68% so a clear benefit in favor of this full treatment package consisting of a quadruplet followed by transplant followed by consolidation but also doublet maintenance what we have seen at the uh latest uh eha meeting is shown here and this is about the evaluation of MD negativity and comparing uh between these two arms you can appreciate that first of all in the quadruplet arm we have a doubling of the rate of Deep mrd negativity including the most sensitive threshold namely 10 minus 6 and what is really important is that the mrd negativity keeps on increasing during time and actually during the doublet maintenance we had approximately 30% of the patient who were able to improve their mrd negativity and this is an important piece of information highlighting the importance of continuous therapy but probably also the importance of this doublet maintenance which is something transformative this is something new because usually we would rely on single agent lomite and mrd negativity deepen over time patient becoming M negative are increasing over time but it’s also about sustained MD negativity and we have significantly more sustained MD negativity in the quadruplet arm and on uh the bottom right hand of the slide you can see the mrd conversion rate for patient who remained MD positive at the end of consolidation so all of this will translate into a significant advantage in terms of progression free survival according to the mrd status again the most important threshold 10 minus 6 and you can see these beautiful uh curves for those patient who are achieving 10 minus 6 sustained MD negativity and these patients are really enjoying a long uh progression free uh survival so clearly an important message from this trial quadruplet induction Dera VOD is the standard of care and uh there is definitely a tendency and a CLE clear suggestion that dublet maintenance would be the right thing to do and this is reflected here in the conclusions from the uh investigators at time of presentation of uh these data another important highlight uh of uh eha was the long-term follow-up update of uh the Copa trial which was a collaboration was a collaboration between the ifm group and the Hoven group it was initially published by Dr Morrow and colleagues and here we have seen uh a long-term follow-up update of this trial which actually was also published simultaneously in the Lancet oncology uh a couple of weeks ago you can see the design of the trial this is the trial which has actually established the proof of concept about quadruplet induction and in this case it was Dera tum plus vtd boras idite dexa metazone but this trial had also a second randomization looking into maintenance with datun map single agent and I think it was a first trial to test the proof of concept of using an anti cd38 monocon antibody or maintenance the long-term followup is showing again a very significant progression fre survival in favor of the quadruplet uh arm as shown here on the red curve when you look to the uh PFS from the second randomization again there is a clear benefit and the median followup is very long and decent in favor of the datab maintenance obviously uh this wasn’t randomized against the standard of care lenalidomide because when the trial started lenalidomide wasn’t the standard of care it has become uh was approved later on but still I think it’s a very elegant demonstration about the value of dataton Maintenance it’s Al also an interesting uh demonstration about the value of using datat both before transplant but also after transplant because there was an initial debate uh questioning whether we still need Duma post transplant if patient have received it before transplant here it is clear that there is a benefit for using datuma before and after transplant when it comes to pfs2 and uh this could be a sort of a surrogate marker of the overall survival uh again you can see a significant Improvement uh of the second so-called pfs2 from second randomization so you can appreciate now that taking into consideration the Copa trial the persus trial but also the Griffin trial published earlier the phase two randomized uh riffin trial from the US all of these trials are highlighting the value and importance of quadruplet induction but also likely maintenance based on D plus lat we do have also roughly similar data although it is not approved in this setting with the other uh anti cd38 monoclonal antibody this is uh the uh German hd7 phase three randomized trial looking into isim vrd compared to vrd followed by Auto then randomization between atic linomide versus lenalidomide and uh we have a similar non-randomized design with the CTIC map krd in the high-risk patient uh in the concept trial that was published in the jco earlier this year during uh the eha meeting we had an uh update about uh uh the uh results of uh this hd7 uh trial and uh the uh key message is there is a clear advantage in terms of response rates in favor of the quadruplet arm but again it highlights now the high rate of amod negativity also deep am negativity that we are able to achieve with this kind of quadruplet induction prior to transplant but also the double it maintenance again highlighting the importance of an ant cd38 plus lenalidomide maintenance last but not least regarding the transplant eligible population I thought to highlight this Phase One open label single arm study from China uh using a dual targeting against bcma and cd19 a so-called fast car you can manufacture this car in a few days it’s a phase one so only 22 patient all of them are high risk either based on cytogenetics based on extra medary disease but also other features and the investigators were brave enough to test Frontline after vrd induction a couple of cycles of vrd then FES to deliver this dual targeting bcma and cd19 car T Cell because we know very well that uh these high-risk patient are truly an unmet need despite the great advances we have seen it’s a proof of concept about using I think car T cells in the Frontline setting and uh it is quite reassuring to observe that the majority of the patient almost 100% actually will become mrd negative and obviously uh this is important given the fact that we have now in Europe and the US an ongoing important trial namely cartitude six trial randomizing AO against silta cell an excellent cartis cell construct and this trial is ongoing it’s not focused on the high-risk patient it’s all comers I would say eligible to transplant but definitely uh the car T cells are likely to make it into the front line at some point and uh here you can see the conclusion of our Chinese colleagues highlighting the benefit but also excellent safety of using this dual C cell construct that was a story of the transplant eligible patient we have also seen a very convincing beautiful data in the transplant ineligible patient and for the sake of introduction I would like to highlight to all of you that in the last four or five years or so the standard of care and the best results in the elderly nontransplant eligible population were achieved with their atum and de metazone thanks to this phase three randomized uh Maya trial already published and communicated several times by Dr Fon and colleagues and you can appreciate that with a long-term followup the seven-year overall survival rate was significantly higher and in favor of uh the Dara lindex arm and these are uh I would say very robust results long-term followup but also because one third of these patient were above age 75 so clearly derl index is the basis for what we currently do and the foundation uh to transform the prognosis of elderly maloma in parallel few years ago and still in some countries today we know that vrd is another standard of care and that was IR rationale behind actually this uh phase three randomized trial so-called imose trial that was presented at ASCO presented at eha at the presidential Symposium published simultaneously in the New England Journal of Medicine by Dr fakon and colleague and the design of this trial is very straightforward the control arm used the classical vrd b dex metazone and you can see the design of uh uh the schedle of the administration of these drugs and dosage and it was compared to an anti cd38 namely isab plus VD VD was followed by lendex maintenance and the quadruplet Isa VOD was followed by Isa Rd uh maintenance and what we can see obviously it’s a phase three randomized international trial the characteristics of the patient were balanced in both arms I would draw your attention the median age of 72 so truly uh an old population but on the other hand all of these patient are considered as fit and the upper age limit in this trial was age 80 the other characteristics are similar to what you would expect from this population in the real life and here is the primary end point uh with more actually with five years of median followup which is very important I think when it comes to a population with a median age of 72 there is a clear advantage of the quadruplet Isa vrd uh PFS test rate at 60 months at 5 years 63% median not reached versus an excellent actually control arm achieving a median PFS of 54 months at 5 years and we are able to achieve such long PFS because the response rates were higher with the quadruplet so you can see it’s a similar story to the transplant eligible population but here there’s no transplant and also you have deep mrd negativity but also sustained mrd negativity for instance at 12 months and one thing you may wish to discuss we had to wait here five years to get the results of this trial and if we were able uh to evaluate uh the endpoint the primary based on on mrd we would have actually reached this Con conclusion the same conclusion of the superiority of the quadruplet at one year so having mrd as an end point and just opening a parenthesis here is important for Rapid for bringing rapidly new regimens new drugs into the field looking into the different subgroups with all the pro and cons uh regarding the power or the number of patient actually all patient are likely to benefit from the quadruplet Isa vrd and these are the conclusions of the uh authors uh clearly uh showing that the imeros trial uh has established a quadruplet based on esab VOD as a new standard of care uh in the uh elderly but fit population and I think it’s very important to insist on the fit population with an excellent safety issue and obviously that was compared to vrd so the question is how does Isa toim vrd look like compared to lendex plus an ancd 38 something equivalent to darl index and this was the spirit of the ifm benefit TR presented by Dr l published simultaneously in nature medicine and it has compared a control arm with EA tuab Rd something similar to darl index at least we can speculate that is a similar an ant cd38 plus index like in the Maya trial and then in the experimental R adding basm Isa VD there are slight differences in the dosage and schedle of the drugs between benefit and imrose I will not go into the details for the sake of time but phase three randomiz trial the characteristic of the patient are comparable beat in age 73 so really an old population and the primary Endo here was mrd at 18 months and there is a clear benefit for the quadruplet uh actually uh arm and actually uh the results were already there at 12 months so again it looks like uh assessing mrd negativity at one one and a half year in this population can give you a clear uh picture a clear Direction on where to go and uh this is true in the different subgroup uh analysis and here is the conclusion of the osers in line with imose this benefit a trial is uh demonstrating that a quadruplet with Isa vrd when compared to a triplet like vrd or to a triplet like is and RD is proving to be superior and should be recommended for those patient who are non- transmit eligible or not willing to proceed to transplant but who are fit obviously there is an overlap because you know in persus trial in the transit eligible the upper age limit was 70 and here so you have a sort of a between age 65 and 70 where uh actually we have a proof of concept whether in the transplant eligible and nontransplant eligible about the value of quadruplet therapy and maybe the question is not anymore about transplant versus no transplant but quadruplet for everybody and then you can sneak in the transplant whenever possible and in the elderly population tripl it for everybody at least as a foundation for all patient including the frail patient because we can give darl index with an excellent safety profile and efficacy and then looking into those fit patient where you would like to upgrade with uh a quadruplet what about now the relapsed refractory uh setting and again uh the congresses brought a lot of Novel information a lot of Novel information not only about B specific andar T cells but also about the other small molecules but also some very new exciting data uh regarding uh actually the uh antibody drug conjugate because you may have noticed that we had the presentation and release of the dream 7 and dream 8 trial which uh have rejuvenated actually uh the uh use of bent the anti-bcma but first let me show you uh some uh data about selinexor an xpo1 inhibitor this is a copy of the poster I know it’s uh very busy uh to read so I’m not asking you guys to read it it’s just to emphasize that for those patient who are not able or eligible to receive an immune therapy with ctis cells or B specific we should not forget that we have a drug like selinexor an xpo1 inhibitor which can be combined with imids or protm Inhibitors and it’s already approved with protm inhibitor selinexor plus basm dexa metazone and actually it is now more and more used in many places where it is available and when we look to uh some updates of uh the the results you can appreciate that there are likely Regional differences but I wanted to emphasize that it can be a good option even if you’d like to use caras it could be a bridging options so please keep it in mind because some patient may need this kind of options dream seven so you probably uh remember the story of balent which was approved uh at some point based on single arm Phase 2 single agent dream stre trial I think and then it was discontinued uh because of a negative trial against pomex and the big novelty from the last meetings is about the dream seven trial which was published in the New England Journal of Medicine simultaneously and this is a very important in my opinion a trial randomized P three trial comparing head-to-head actually Dara Vex D B Deone the regimen that was validated and approved thanks to the Castor trial you may remember this from few years ago published by Dr Palumbo and colleagues and the head comparison was against balab combined to bzm deam metazone BVD uh a quick reminder belantamab is an antibody drug conjugate targeting bcma so it’s the usual I would say Target but in an anti-body drug conjugate so mechanism of action completely different compared to what we know uh about the immune therapies like BP specific targeting bcma or caras targeting bcma you can see the design of the trial in the davel deex they received daram mono therapy continuously and in the belantamab uh arm they receive belantamab mono theapy after cycle n and one figure can summarize it all and this is exactly what you can see here in the intention to treat population the combination of bant bzm dexasone led to a significant increase in PFS compared to Dara Vex obviously you may question whether Dar Vex is the ideal regiment for relapse but it is uh a valid control arm and you can appreciate uh at three years we have a median of more than 36 months of PFS which is uh definitely a significant and uh very important uh result in the relapse setting 60% Improvement compared to the control arm of course immediately people will rais a question about the toxicity of balent because one key feature or key issue we face with this antibody drug conjugate is the incidence of keratitis and its impact on the eye which at some point can alter the quality of life so here we have some good news obviously the ocular adverse events occurred more frequently with bent Valex as expected but actually uh they were for most of the time reversible and with good management especially lengthening the Cycles the duration of the Cycles actually you can overcome this complication and that provide you with a very practical useful effective regimen where you would give three or four cycles per year for these patient so clearly you can see here the conclusion of the authors about dream 7 uh where uh you can we have a PFS benefit an overall survival benefit deep prances and it is likely that now we are able uh to overcome this issue of ocular toxicity uh which is reversible but also manageable with those modification and then at the end of the day you had very few treatment discontinuations only 9% and there are no difference in terms of global quality of life as measured by the famous ERC ql tc30 scale so please watch out to the Advent of bant Vex especially that we have another trial presented at eha by Dr demopulos first author Dr trudel from Canada this is a dream 8 and this trial has looked into a different partner actually for balab namely pomex so uh BPD balent pomex experimental arm compared to a very good standard of care well established the PVD standard of care bzm mide dexasone and this was established and approved thanks to this so-called optimism trial again very beautiful data in favor of the balenta or so it looks like guys that targeting bcma is more effective than actually uh targeting cd38 or using a combination like P PD so these are really important information and we know the importance of bcma for the proliferation and the survival of the malignant plasma cells and this is reflected here in these uh uh results showing again a 48% Improvement in favor of the balant map homide dexametasone arm we don’t have yet final overall survival data but you can look into this in an indirect manner thanks to the pfs2 and this is looking into the treatments uh that were delivered to these patient who are progressing uh during the course of this trial you can see the list here I will not go through the details for the sake of time but again pfs2 is in favor of the balent PEX arm so in another word using a targeting BCM early uh in the relap setting is not inducing more resistance and you are also able to salvage uh these patient later so based on dream 7 and now dream 8 actually uh I believe and this is what I mentioned in my introduction that belantamab has been rejuvenated in the uh relapse refractory setting and I think this is important because this is an important family of drugs the antibody drug conjugates the mechanism of action is different from our other bcma targeting agents and obviously it will find its uh place in the uh overall landscape and will fulfill some unmet needs let me move now into the different BP specifics and uh theotherapy based on bispecific antibodies is really fascinating it’s a fantastic invivo immune therapy and this is about targeting a tumor antigen and the cd3d cells bringing them together establishing a sort of an immune syapse and then allowing the tea cells to proliferate to become cytotoxic and that will lead to the cytotoxicity rapid effect and we are very fortunate already having two B specific antibodies directed against bcma being approved namely the clista map the first to be approved aatam map targeting also bcma we have also a bispecific antibody targeting gprc5d namely Talam and during the last eha and ASCO meetings we’ve seen some very nice novel data with Costa map which is a bispecific antibody targeting CD3 but also bcma so a totally different Target and I have chosen this communication by Dr Kumar shaji Kumar and colleagues because they have focused on those patient who received prior antibody drug conjugates against bcma or prior car T cells against bcma because obviously these days at time of free labs when they are available almost all patient are receiving if they are not receiving caras but they are receiving clearly anti-bcma by specific antibodies but if these patient progress if they have received Bantam if they have received Carisa how can we servage them and this is the importance of thisa uh analysis where you can see uh the features of these patient the median lines of therapy is six uh median time since last anti-bcma therapy was uh five and I would consider these results are really very robust very powerful if you have received a prior kit car Tel against bcma you can still expect 73% of overall respons including more than 55% of vgpr if you have received an antibody drug conjugate you still have 60% of uh uh overall response rate and more than 20% of BG PR looking into adverse event it looks like that targeting fc5 is not really inducing severe or unexpected side effects CRS were uh mild and manageable neurotoxicity frequency low only one case of severe neurotoxicity when it comes to infections there are some opportunistic infections viral reactivations bacterial but maybe it’s not a compar randomized trial but maybe it is less than what you would expect with a bcma targeting agent so this is an important uh I would say option for those patient who are failing and anti bcma uh therapy the other data with have seen uh during eha uh I had the pleasure to update the long-term survival of the manism mm3 trial we published this uh last year in the nature medicine and with long-term followup uh you can appreciate that at two years we’re looking now around 88% of uh uh probability of durational fr resp was those patient who are in more than CR and this is uh 67% in those patient who with an overall response and if you look to the progression free survival again the median PFS is 72 17.2 months with a rmab and those patients achieving CR we almost at 91% at 2 years and that gives you an overall survival a median overall survival of more than 2 years 24.6 months so reassuring results about the use of a retab as a bcma targeting by specific antibody we have also updated the uh data from the French compassionate use program and again the results are in line with what we see in the uh mm3 registration phase two trial uh although the population was harder was more harder to treat more advanced but uh the important piece of information is about the safety and it looks like that with implementation of prophylaxis and uh preventive measures but also uh imunoglobulin supplementation you can significantly reduce the infectuous complications we have also some great news with the clist map which was the first anbc by specific to be approved and the clab works very well and we have here in this poster presented at eha uh a specific subgroup analysis on those patient treated in the Majestic one study this is the phase two registration trial and looking into those patient with highrisk features and by high-risk features the ERS uh defined pentad drug refractoriness High RIS cytogenetics very old patient above age 75 High tumor burden extr disease and ISS stage three the good news using the glap in pentad drug refractory in highrisk cytogenetics but also very old patient above age 75 is leading to a response rate similar to what you would see in the overall population and I think it’s very important to emphasize uh the capacity our ability to deliver by specific antibodies into old but also frail patient and this is important then you have this group of high tumor burden extr disease ISS stage three uh you may view the results as the glass is half empty or half full and we have exactly a similar pattern with a ratam map so there’s no difference among the different B specific antibodies targeting bcma those patient with extr disease highrisk stage three ISS or high tumor burden actually are going to respond less they are going to respond but this is lower to the rest of the population so in another word we really need to uh design new approaches for these patient and we are more and more discussing for instance the use of conventional chemotherapy to bulk the disease before starting by specific antibodies the other uh good news we had during eha and ASCO were from the Monumental one tmab uh study so I kindly remind you tmab is the first bispecific antibody approved directed against gprc 5D and uh this is another important tumor antigen uh highly expressed on the plasma cells I will not go into the details of the trial but with long-term followup actually we do have a confirmation about the efficacy but also the safety of using theam map but also another important piece of information because there were some were still some concerns about uh the toxicity of Talam especially when it comes to discosia mucositis toxicity on skin in nails and obviously with discosia mucositis patient are losing weight and now there is a learning uh curve and you can see that the side effect and the weight loss actually is mainly seen observed in the beginning maybe first two cycles but then things are improving uh with longer treatment and I think there will be a learning curve and actually lengthening the cycles of telam is likely to help solving this problem similar story to bentam AB youo and the eye toxicity the other uh I think good news is that it is likely and it has to do with the function of the Target and you cannot compare bcma and gprc5d bcma when you target bcma you are eradicating the normal plasma cells so you’re reducing significantly the secretion of immunoglobulins it is likely that with stab especially with a twice monthly dosage we are reducing the incidence of severe infections so really very good news and the Advent of Talam map targeting gprc5d is most welcome in the field because obviously we need to work on these targets if we would like to give uh different lines of treatment obviously the1 billion dollar question is about what is the right sequence should we Target first bcma then gprc 5D then fc5 or ABC BCA CBA I don’t know today the common belief that maybe targeting bcma should be started first and then uh we will look into gprc 5D or fc5 but this is not we don’t have evidence-based data to support this it’s just expert opinion in general and common belief based on the role of these molecules and their mechanism of action and speaking about B specific actually B specifics are really a fascinating platform so it’s a true immunotherapy and you can modulate play with this platform almost in a indefinite number of manner you know uh constructs and one important aspect is to play on the Affinity of The Binding domain you can play on the Affinity of the CD3 binding domain for the T cell but you can also play on the Affinity to the tumor antigen domain and if you play on on this you may end up with different constructs and we don’t know yet what’s the value of this or this this is why I think uh we like and we appreciate that many companies are developing uh different constructs and during uh the uh EA meeting we had the results of this uh ABV 383 bcma CD3 B specific uh antibody and you can appreciate that one specific uh feature of this B specific it’s an IGG like B specific design plus a balent bcma Fab so it’s different compared to the uh other uh uh BP specifics and uh this abbv 383 is uniquely designed uh with two bcma binding domains and it has a low affinity for CD3 and another important feature which is I think crucial for the patient for the organization of care the dosing frequency which is every three or four weeks the other BP specifics the clist map retab were originally approved on a weekly basis then we would uh give uh twice monthly later uh but here from the beginning you have uh longer uh cycle uh dozing frequency and it is likely decreasing the incidence of side effects especially severe infections but also the CRS and Ians and despite this actually you can still uh achieve uh the uh an excellent uh safety uh profile uh and it has to do clearly with this uh monthly uh Administration here you can see the overall response rate 65% so similar to what we have seen uh with the other bcma by specific median PFS 11.8 months also for instance similar to Tech Lista map of course I’m not trying to compare across trials but these numbers uh look like quite similar which is quite reassuring the other player in this field is this other BP specific called LMO camap and uh this is a human uh bcma uh CD3 uh targeting uh B specific it has a different design it was presented by Dr Susan Lynch during ehab but it was just published I think uh couple of weeks ago in jco a decent number of patient 117 patient median age 70 up to age 91 so highlighting as I mentioned that we can give byp specific uh really to old and even frail patient median par Lin of therapies five similar what we have seen when magnetism mm3 and in Majestic uh one but also so the abbv 383 trial and 80% were at least triple refractory and 26% at least pent refractory and 84% were refractory to the last line of therapy and here is the objective response rate 71% so including more than 46% more than CR and that would give view a very elegant PFS curve whereas the median PFS is not yet reached and the probability of maintaining respons at one year was 78% for all responders and 92% for all those patient with more than CR and if you look to the high-risk subgroups the respon rates are lower for extr milary disease for instance 58% High Cogen genetic 67% probably uh similar and so you can see there is some similarities among all of these by specific but maybe there are subtle differences when it comes to the uh profile of safety but also to the EIC obviously uh we cannot draw any final conclusions because we don’t have head-to-head comparison and also these are single arm trials uh but I think uh it is important to have access uh to these uh different B specifics and it is uh crucial that we uh would be able to use all of them again the message in terms of infections because of the t- cell exhaustion when using by specific because of the imun compromis status of these MoMA patient because of the inhibition of the secretion of immunoglobulins it’s important to use all the preventive measures with cotrimoxazol uh antibacterial antibiotics amoxicilin for instance antiviral fic cyclop and imunoglobulin supplementation but it is likely that we will not use these byp specific alone as single agent forever and we can improve their efficacy especially we can reduce t- cell exhaustion and we do have already some proof of concept at least in vitro about this feasibility especially if we rely on the easy to use imits like lenite lomite but maybe also the uh upcoming cell modes like alomide or mdom and this is exactly uh what has been done actually in this nice Monumental two trial where Talam map the gprc5d targeting by specific was combined actually uh with pomalidomide and here the idea by using pomalidomide is not about in my opinion to use the antim maloma activity of emids but rather the imuno stimulatory imun modulatory activity and it looks like it works again it’s not randomized but definitely you can see a higher uh percentage of an overall objective response rate so a very nice proof of concept about the possibility uh to combine by specifics with other agent especially for instance agent that allow to improve t- cell function and uh this is leading you can see here the response rate which are deepening over time and they are likely uh improving uh the uh PFS of uh these patient so really very fascinating proof of concept So based on all this I believe that we are really in a scenario that where we see that long-term followup of the trials using bispecific is showing some longlasting deep prances no additional toxicities and I can even say that based on the real world our own practice the toxicity profile is improving over time there is a learning curve I think we need to pay attention to these new constructs new formats of B specific the high Affinity binding to bcma low Affinity binding to CD3 Half-Life extension all of these tweaking I would say might improve the efficacy and safety but you don’t need high technology actually to improve the efficacy and safety for instance looking into fixed duration or treatment with extended treatment free interval would probably allow uh the uh recovery of the te- cell Fitness and reducing the risk of t- Cel exhaustion but also a tumor Target a tumor antigen uh loss and last but not least combinations are likely to come and you may be aware that we have now trials testing B specifics into earlier uh lines of therapies with this I’d like to thank you all for your attention uh I know that there are many new data but I had to make a selection I hope you have enjoyed it and I can see already an incredible number of question uh that I’ll try to do my best to handle so we have a question about uh in a resource limited setting is there a value in adding the map uh during consolidation and maintenance when you have used uh vodd induction well it’s very difficult to answer I do appreciate that we need to find solutions for uh all situations all I can say that the map and targeting ntcd 38 is Cru crucial uh in the natural history of multiple maloma and at some point the patient need to receive an anti cd38 malol antibod like der as soon as possible uh we do have a question from Dr hammad uh what about basm as maintenance therapy well historically especially in the highrisk cytogenetics there were studies is looking into combination of bzm linomide Maintenance however I don’t believe that is the most optimal way of doing maintenance and I believe today that if we have to do doublet maintenance it’s likely D and that in my opinion are the best options we have another question about evaluation of mrd because we speak a lot of mrd and it’s a relevant question how how do we evaluate MD well either NGS Next Generation sequencing or next Generation flow but of course Imaging is important uh I will not go into the details but obviously these two techniques are valid uh if you want to achieve a 10 minus 6 stretchh hold obviously NGS the clono technology is likely easier Dr Francisco Dondo is asking me uh that in dream 7 uh there is also ocular toxicity even the control arm is it because the study is dealing with elderly patient or there is an ocular toxicity of durum I don’t believe uh there is a concern about ocular toxicity of derat I believe it’s simply when you do randomized control trial you are able to detect signals that you usually Miss sometimes in the real life and this is why uh we pay attention and it is mandatory if you want to bring a drug into routine years to do these prospective and monitored trial that is my explanation and obviously the older are the patient the more uh uh issues and toxicities you will see here we have a question um about whether we should use by specifics at time of relapse or at time of mrd positivity this is a brilliant and timely question uh well today the clab retab talaab are approved for those patient who are triple class exposed or triple class refractory they are used at time of relapse today we’re not yet at the level when we can do preemptive uh relapse therapy and based on mrd probably this is what we do in other hematological diseases in lymphoma if you see a positive pet scan you would start a new therapy or you would modify your treatment approach we’re not yet there in Myoma but I think this is uh wise an important comment uh Dr Iram s is asking uh why adding pite to buy specific if patient have already been on it or progressed on it very important question this is why I insisted on the fact that we’re not using at least in the Monumental 2 trial assessing Talam plus pomalidomide we’re not using uh pomalidomide as an anti malom drug but rather uh to uh allow the recovery of the t- cell Fitness as immunos stimulatory Tru Dr James yamaga is asking about the combination of a RAB VOD for induction well the short answer that I don’t know these results and of course we cannot comment on this all I can say that by specifics whether Teta map whether banam map whether teista whether sasta all of them at some point will U move into the font line or earlier lines uh of therapy we have another question about using caras after BP specific uh well uh I must confess I don’t know the very few available data suggest that we should rather use caras whenever possible first and then buy specific but this story can be different if we are using different or different targets uh this claim is valid when using an anti-bcma C cell and an anti-bcma bu specific but I think it’s a very rapidly moving Target one question I didn’t discuss car T Cell only one abstract in the front line but there is this uh I have a question here about reports regarding secondary te cell lymphomas following car therapy um well it’s a controversy today I think based on the advanced age of maloma patient I’m not today worried we need of course longer followup but I’m not worried about this issue of T cell lymphoma and of course I refer you to the different publication in this field I can see that time is running guys I hope you have enjoyed this uh uh post Congress webinar uh regarding multiple maloma we do have many other activities so thank you for being loyal to uh these educational activities brought to you by the I around the globe and across the hematology field see you soon