 Good morning everybody My name is Mohammed Motie from the Sorbonne University and Saint-Antoine Hospital in Paris And it is my great pleasure and honor to be with you today as part of this fantastic master class and I'm very grateful for the invitation and I'd like to Thank MPE for really their hard work for the benefit of Myeloma patient in Europe and across the globe so for this morning, I've been asked to give you a sort of a summary snapshot about the new development and controversies in the treatment of multiple myeloma and As you may guess, this is really a very broad title We can spend days and weeks actually looking into the new developments in multiple myeloma because every day you have something new Especially that as you probably a few weeks ago We had the ASCO and IHA meetings and there has been some fantastic novel information During these congresses so I do apologize that I will not be able to cover everything But I will give you a sort of a snapshot about what I feel are The most important things that would be practice changing my disclosures are shown here So what I wanted to highlight exactly is how these novel data are going to impact the management of Patient with myeloma from a daily clinical practice. So the idea is really to be focused on the practical aspects and By the way, I wanted to highlight that we have for for this purpose you can refer To the IHA ESMO clinical practice guidelines that were published Three or four months ago and they are very clear very nice and they should serve as a good reference As it is usually is a tradition. We divide Usually research in multiple myeloma about transplant eligible Elderly non-transplant eligible and relapse setting and I will follow this same Structure and highlight. What do we know and the transplant eligible patient? Well, first of all, I think Otologous stem cell transplantation in multiple myeloma is here to stay We have today the long-term a follow-up results from different randomized trials One of them is the IFM 2009 trial Showing that after seven or eight years of follow-up. There is a clear advantage in favor of auto transplant Compared to the best regimen you can use without transplant. For instance VRD or tazamiblaenilidomide dexamethasil So a very important message Transplant is standard of care. So this is for me Not a big issue So if you want to perform transplant you need to start with an induction regimen and Actually, the induction field has been moving very rapidly and while For almost 15 years We've been living with triplet inductions Vcd Vtd VRD Bortazimib cyclophosphonide dexamethasil Bortazimib thalidomide dexamethasil or even Bortazimib linilidomide dexamethasil Actually now we are moving to quadruplet induction regimens by adding an anti-cd38 monoclonal antibodies and for this now We have the approval of Dara Vtd Dara tumimab Bortazimib thalidomide dexamethasil and thanks to the Cassiope trial But also we have the randomized phase two trial Gryphon published in blood and updated recently Showing that Dara tumimab VRD Bortazimib linilidomide dexamethasil is also a very good induction regimen especially when it comes to inducing a very deep level of MRD Negativity so clearly major advanced practice changing moving to quadruplet induction regimens Induction hi-dose melphalan What is the role of post-transplant treatment any role for consolidation for instance, so should we deliver a couple of Cycles after transplant to further deepen their response And I think the advance we have and this is why it is a recommendation I think in Europe in general based on the European maloma network data that two cycles of consolidation can translate into long-term benefit I know this has been a bit controversial Especially in North America where consolidation is not always used But definitely from a European perspective based on our randomized trials consolidation is recommended Next is the issue of maintenance We all know that linilidomide maintenance is really the standard of care after transplantation in multiple maloma patient and the question is can we do better than Linilidomide alone and here we have emerging data Suggesting that a doublet maintenance using two drugs for maintenance can be useful And this is also based on some European data. This is the Italian 40 randomized trial Presented several times by dr. Francesca gay showing for instance that car physio me Plus linilidomide maintenance is clearly improving the outcome of these patients Of course, car physio me is IV. This is not very convenient But you have trials now testing X azomib plus linilidomide full oral combination or Daratumumab subcute plus linilidomide so in the transplant eligible population if you look to the overall recommendation from IHASMO all Young and fit patient should be able to receive an auto transplant for induction The recommendation is about VRD or quadruplet plus Daratumumab For post-transplant treatment for the time being linilidomide Maintenance is a standard of care. So it is becoming Very well structured and you can see the field is really moving and all of these changes Are translating into improved outcome of these patients Let me move now to the non transplant eligible population and You know very well that the majority of multiple myeloma patient are non-transplant eligible because of age but also frailty I think the biggest and really major advance in this population is about This combination tested in the so-called Maya trial Combining Daratumumab linilidomide dexamethasone and Compared to linilidomide dexamethasone This trial has been published and updated and there is a clear progression free survival advantage In favor of Daralan decks and the good news We have just heard a couple of weeks ago at IHAS This is the later breaking abstract is that There is an overall survival advantage and this is very unique I think to show an overall survival advantage. So and here we're talking probably about a median PFS of Five years, which is very unique Remember all our treatments in the elderly population were around 30 to 35 months Median PFS now we're almost doubling this Plus an overall survival advantage, which means by using the best combinations from the beginning You're not inducing more resistance. So clearly practice changing the use of Daratumumab linilidomide dexamethasone in the elderly population is becoming the standard of care and this is true and recommended because Actually these combinations based on the Daratumumab linilidomide dexamethasone but also other combinations are able to induce a high level of MRD negativity up to 30% of these patients and definitely MRD negativity is translating into improved outcome, especially when it comes to Sustained MRD negativity So if you have sustained MRD negativity, these patients are really going to enjoy a better outcome This is why you can see here the IHASMO guidelines clearly recommending Daratumumab linilidomide dexamethasone as a Combination in the elderly, but we have also other options for the sake of time I will not go into these details and as I mentioned in my introduction I'm really focusing on the most important highlights from my point of view Let's move now to the relapse refractory group of patients and actually these patients A majority of these patients are going to become linilidomide free. I have just Discussed this in the transplant eligible patient. We're using linilidomide maintenance continuously So at time of relapse they become linilidomide resistant But also in the elderly population as I have just highlighted if everybody is receiving Daralindex Well at some point you become resistant to linilidomide. So what are the treatment options we have in these patient Well, let me start first by the imid free options. Well, this is about combining actually a second-generation protism inhibitor Plus an antibody an anti-cd38 antibody like Daratumumab in the candor trial Daratumumab Carfism Abdexamethasone and this has been now published and updated There is a clear advantage in this population of linilidomide resistant patient in favor of the triplet combination with Daratumumab Carfism Abdexamethasone We have exactly a similar story in the Ikema trial With Isatuximab Carfism Abdexamethasone and you can appreciate here the very high level of MRD negativity so we have in hand very nice and effective options in Those patients who are linilidomide refractory But of course not every myeloma patient can receive for instance Carfism Ab Because of the cardio vascular risk, so you would like also to have options Avoiding Carfism and this is where you can introduce other imids like pomalidomide And pomalidomide is oral so very convenient for patient especially in a COVID-19 pandemic for instance and highly effective and safe and This is what we have seen in the Icaria Trial looking into Isatuximab another anti CD38 monoclonal antibody plus pomalidomide and dexamethasone and this triplet combination is highly Effective in the patient who are linilidomide refractory we have also the Apollo trial which actually used pomalidomide dexamethasone plus Daratumumab and this trial has been presented at the ash meeting But actually it was just published I think three or four weeks ago on the 2nd of June if I remember well in the Lancet oncology by Dr. DiMopoulos and colleagues and you can see that it is highly effective in the linilidomide refractory patient so very good option especially if you are using Daratumab subcute Both of the patient it is very convenient But I can tell you because the topic is about the innovations, you know the advances I believe this story will continue for the next two or three years because we are now having the new Generation of image we call them now cell mode as this is about iberdomide and iberdomide is Rapidly coming in the field and will have the opportunity. I'm sure to discuss it later at some point and These different options that I have summarized are already Incorporated included in the IHASMO guidelines and I will not go of course into these details Last part of my talk about all of these advances in the field of multiple myeloma is About the immune therapeutic options for many many years. We didn't have immune therapy in multiple myeloma Thanks to the introduction of antibodies on the CD38 we started having our first immune acting agent But now you will see we do have cellular immune therapy and Bispacific antibodies T cell engagers the Bispacific antibodies are really a clear breakthrough in hematology and in myeloma, I could see over the last 12 months that Seven or eight different bispacific antibodies are being Tested in different clinical trials one of them is this one the teclista map which has received few days or few weeks ago a breakthrough I would say Consideration by regulatory agencies Because of the very high and very deep level of responce that can be achieved in heavily Pre-treated patient with a good safety profile and the story of bispacific antibodies and T cell engager is very interesting because Instead of manipulating the cells as we will see in the CAR T cells Actually, you are giving an antibody that can on one hand I would say target the CD3D cells, but also then bring it to the tumor cells. So very attractive very refined mechanism of action But also we have now by specific antibodies targeting different antigens teclista map was against BCMA But now we know that it's always better to have different antigens And we have for instance talcata map, which also The data have been presented at the last ASCO and IHAM meetings one month ago targeting GPR C5D Again was a very very high level of responce and very Good improvement and heavily pre-treated patient If we're talking about immune therapy, of course, I can't skip the CAR T cells And the CAR T cells are moving really very nicely in the right direction and I believe now We have in hand to key CAR T cell construct one of them is this one SILTA cell and SILTA cell is quite Amazing in terms of results and we've seen this update Again one months ago at the IHAM and ASCO meeting Showing in heavily pre-treated patient more than 20 months PFS medium of six lines of prior therapies and you have of course 20 months, this is very unique and the safety profile is rather good So I think this CAR T cell the SILTA cell construct will make it rapidly Into the Routine practice. It is not yet approved the product that is approved for the time being is the ID cell And this has been published in the New England Journal of Medicine five or six months ago and you can appreciate Very good results and a very large single-arm study heavily pre-treated patient patient who failed Anti-CD38 antibodies the proteasome inhibitors Emmits, but the response rate more than 80% and We have a very nice decent progression for survival overall survival. These patients are supposed to be in You know supportive care because you have failed all the previous options so CAR T cells are providing a lot of hope and when you look to their safety in Contrast to the CAR T cells in lymphoma or acute lymphoblastic leukaemia Actually, the safety profile is rather good in CAR T cells in multiple myeloma Because they were not approved Already at time of publications of the EHS Mo Gaiden. They are not included here But you will see now we do have really a large Variety of regimens and products to tackle to treat these Relapse refractory multiple myeloma patient and this is really good news because we will be able more and more to Refine and to personalize The treatment choice the treatment combinations to fulfill to fit the needs of Every individual patient and I think this is really the greatest advance and very Grateful to all the myeloma community, but also to the patient and their families For their great involvement in the clinical trials in the research effort Thanks to you actually We are able to advance as this field So with this I'd like to thank you all for your attention and of course at some point I'll be more than happy to take questions or comments if needed. Thank you very much