 I would like to introduce Dr. Garderay from the Hospital Saint-Antoine in Paris. Some of you know him already. He talked to us last AGM in October. So Dr. Garderay has to leave very, very in point. So here we have to stop in each way at 12.30. He's going to celebrate his birthday today and show he has to go back to his family. Thank you Dr. Garderay for coming here and you have the floor. Thank you very much. It's always a great pleasure to share with you the new drug developments to treat this disease. So actually the program is huge. It's both AL amyloidosis and myeloma, focusing on the new drugs and the clinical trials, the ongoing ones. Actually after I suggest that we start first with AL amyloidosis since Professor Mellini just made his talk. So I will move, sorry, to AL amyloidosis first and then come back to, yeah. So actually these are really two different diseases, AL amyloidosis and myeloma. Both come from you have abnormal plasmocytes, that's for sure. But the number of abnormal malignant plasmocytes are low in AL amyloidosis while there are much bigger number in myeloma. And while you have, as Professor Mellini already mentioned, bone lesions, kidney failure in myeloma, myeloma is a medullary disease. While you understand that AL amyloidosis is a systemic disease and you have heart involvement, kidney involvement, GI involvement, neuropathy. So really different diseases but actually the treatment is more or less the same. The major, how do we treat this disease? That was already mentioned. There are two targets. For many years the only target was to get rid of the abnormal plasmocytes and this is still the case of course because the light chain comes from these abnormal cells. But now this is the brand new development. It's the ability of monoclonal antibodies targeting these fibrils, either as oligomer or full type fibrils that are destroying the organs. So this is really the major breakthrough and we have three monoclonal antibodies. So this talk will be split in two parts. First, how do we get rid of these abnormal plasmocytes? And second, how do we target the fibrils? There's a lot of overlapping you will see, Professor Mellini already mentioned, but anyway it's good to repeat. So he mentioned this major study. It's a major study because for many years the gold standard of AL amyloidosis treatment was and it still is the combination of a chemotherapy, Melfallon plus high dose steroids. He mentioned that steroids are very efficient to get rid of these abnormal plasmocytes, those are so-called M-dex, Melfallon plus dexamethasone. And obviously you know that we have new drugs for myeloma, but this is also true for AL amyloidosis because we are targeting the same abnormal plasmocytes and we have new proteasome inhibitors such as the first in class was bortezomy, Velcade, and it was also mentioned the other one, exasomy. So what was done was to combine to add to M-dex bortezomy and that was a major phase three randomized international study comparing M-dex plus or minus bortezomy. And so this is the schema of the trial, but the results have already been shown. The overall, the adverse events where let's say acceptable, a little bit more cytopenia, maybe trombosatopenia because Velcade does induce trombosatopenia and neuropathy because as you know Velcade does induce some kind of neuropathy. But the response was, you see, highly superior in the M-dex Velcade arm. That's the details on the organ response and on the hematological response. And these are the, that was already shown. You have a better time to second line therapy with the M-dex Velcade and even though the overall survival was superior but not statistically superior, if you look specifically to the subset of patients with the cardiac involvement, stage two, you do have an overall survival benefit adding Velcade to M-dex. And that's also the hematological response and the cardiac response. So that's the conclusion and that's what he said actually that in Pavia, now the goals, the new goal standard is to treat AL amyloid disease with M-dex plus Velcade. So this is important because we are moving from M-dex to M-dex Velcade. Now another study that has recently been published by his same team tested the emits, you know that we have the proteasome inhibitors but we have also the class the emits and we have thalidomide, ledalidomide and pomalidomide and they published, Pavia study published that for patients who have already been treated with the proteasome inhibitors, alkylating agents, ledalidomide, well you could treat them successfully with pomalidomide. So pomalidomide and in combination with DEX was efficacious in this setting and that's important and that's what he mentioned also that is treating quite often is AL amyloid disease patients with pomalidomide not in first line but in the relapse setting. So that's another treatment option for these patients. So targeting the plasmocytes, the new developments, M-dex plus Velcade and pomdex, pomalidomide dex. Now switching to the monoclonal antibodies, a third class, the proteasome inhibitors, the emits and now the monoclonal antibodies. And this was mentioned but this is really a breakthrough and I'm mentioning it's a breakthrough even in AL amyloid disease, even more in AL amyloid disease because the plasmocytes are limited and therefore if you kill this small number of plasmocytes, get rid of this small number of plasmocytes you have a very strong impact on treating your patients and this is true in AL amyloid disease and you will see it's obviously very true also for myeloma. And I'm just mentioning the way the monoclonal antibodies are acting and this is the classical way. We will come back on that but that was mentioned also. I'm not sure if it does have a big impact in AL amyloid disease but it does also have an immune effect and it restores, it brings back the immune effect to get rid of abnormal plasmocytes. So the first cases were published in October 2016 in blood, testing for the first time and that's the myoclinic in the U.S. In two cases of advanced lie chain amyloidosis and you see that these patients was already had received carfilzomib, cyclophosphamide, dexamethazone, he had been transplanted so really very advanced patient and he relapsed, you can see the lie chain and he was then finally treated by Daratumimab and he could reach a very deep response. So this is a very impressive response for such a patient. And that was shown again in another patient and you can see that actually it was almost undetectable. So very encouraging, very early results. And that's now, that's a clinical trial that is ongoing in France for patients who have AL amyloidosis and who do not reach at least VGPR as it was defined earlier then we are testing Daratumimab and we will see how effective it is. So for AL amyloidosis, not for myeloma, it's called amydara, well it's AL amyloidosis. So this is the first part, getting rid of the abnormal plasmocytes, m-dex plus bortezomib, pomalidomidex and Daratumimab. Now, how to get rid, and this is really new, that's why we are so excited. How do we get rid of the fibrils? And we do have at least three different types of fibrils. The first one is developed by Susan Lynch in the US, the second one by Pepe's in London, Pepe's team, and the third one worldwide, I would say. So I will not mention this one because it's at a very early stage of development. I will first start with this one, the anti-ACP, and you will notice that ACP, if you remember, is the protein that links to the fibrils, to the amyloidosis fibril. So this antibody is not only effective for AL amyloidosis, but it's effective for all amyloidosis. You remember the first slide of Professor Melini, you have all different kinds of amyloidosis, but all these amyloidosis, they link to ACP. So if it is efficacious, it will work for all amyloidosis, while this one, and you will see, the first preliminary results are outstanding, but it focuses only on AL amyloidosis. So I will just remind you that was published two years ago in the New England Journal of Medicine, and that was the first time that we heard from the PEPIS team in London about this very active antibody, the antibody against ACP. So it's actually a two-faces treatment. First, they give the antibody to get rid of the circulating ACP, then they had another antibody and that will get rid of the fibrils and remove actually the amyloidosis. So that's what is described here, and it was especially efficacious for liver amyloidosis, and you could see before and after with these two cases, and that was, I'm just showing you the number of patients and the different organs and the different amyloidosis that have been treated. So again, not only AL, but all kinds of amyloidosis, and so far it's very efficacious for liver amyloidosis. We have not heard too much since then, since this publication, but I believe it's trials are, I guess, ongoing. Now we're moving to the NEOD, that was already mentioned, and I must say that was first published also, you see, a year ago, and it was updated at the last ASH meeting, and the results are absolutely, so a small number of patients, of course, but the results are absolutely outstanding. You see the cardiac response, and I would like to stress again that what Professor Mellini said, cardiac is really the major problem, and if there is, I would like to say it again, a take home message on AL amyloidosis, Professor Mellini said it many times, but in my clinic, the patients that I see, they do have cardiac involvement, and when there is cardiac involvement, it may improve with the monoclonal antibody and the treatments that I've just mentioned, it's very difficult to treat them successfully, very difficult. So the take home message is really the early diagnosis, and you may have a major impact in advertising, because indeed it's a rare disease, you know, from Professor Mellini it's not so rare, it's like Hodgkin disease, but you know, a GP, he will see one or two myeloma patients in his whole life, and never AL amyloidosis, I mean never, but he should see at least one, and that's the one that he should diagnose very early, because that will make a difference. Otherwise, once you reach the stage of heart involvement, it becomes very difficult, really. However, and that's why it was so outstanding in these results, you know, we could see that the anti-probian period, that reflects the heart functioning, such a decrease, you know, with this treatment, and quite quickly, you see, made in time to response is two months, so this is quick, quick response, and so biologically, at least, the anti-probian BNP decreased. I remember that we discussed that with Protena in terms of heart function, because this is really what we want, I'm not so sure, but we can ask our colleague from the company. So outstanding result for heart, outstanding result for kidney, you remember, kidney is very easy, proteinuria, you see, you remember proteinuria, 50 cents to monitor. You see the decrease of proteinuria, and also that was outstanding, and I think if I remember correctly, that was, you correct me if I'm wrong, the first time that we could show response on the neuropathy, if I'm correct. So you see, the neuropathy was also much improved with this treatment. And that was not related to the previous treatment, so really all the signals were showing that indeed it was the monoclonal antibody, the so-called NaOD that was active in this setting. And therefore, two studies were launched, and that was already mentioned, the so-called vital, and you understand why it is vital, it was specifically for patients with heart involvement, and the other one, the pronto, was for patients who did not reach the VGPR, the so-called VGPR stage, that is the initial goal that we want to treat AL amyloidosis. So actually, I don't know how many patients have been unrolled, but I understand that it's been very successful because the unrollment is closed, and then of course the trial is still ongoing, and we are eagerly waiting for the results. How many patients did you include in both studies? In less than a year, I know, something like that. Yeah, so very successful trial. In amyloidosis ever. Yeah, so we are really looking forward to the results. So that's the schema of the vital study, and so you see standard of care, or placebo or NaOD, and the pronto study, this is for patients with at least one line of therapy, not reaching a VGPR, and again it's NaOD or placebo. So we will see the results. That was mentioned by Professor Malini, and this is the way it goes in myeloma, and I suspect, but Professor Malini will tell, but he mentioned that we are combining. We are combining the new mm, you want mm. This is almost my last slide. So we are combining. Now the new standard is MDEX Velcade. But of course you want to add Daratumimab, MDEX Velcade, plus a monoclonal antibody. And actually there is such a study. I mean it's not MDEX Velcade, but it's CyBordy, which is another gold standard to treat amyloidosis. So we will combine with or without Daratumimab, and so that was my conclusion for the future treatment of alamyloidosis. Of course I don't have the expertise of Professor Malini, but looking at the way we are treating myeloma, I was wondering if maybe in the future it will not be MDEX Velcade or CyBordy, plus Daratumimab, and plus an entire fibril. So you will discuss with Professor Malini. Of course he mentioned already this as a cost, but that's another issue. So definitely, and I will end my talk also with this, I think these monoclonal antibodies have really changed completely the landscape, not only of alamyloidosis, but also on myeloma. So if you have one question on alamyloidosis, I will answer, and then I'm moving to myeloma. Any question? Yes, go ahead. You had a slide about the pronto endpoint definition. Do you have a slide for the vital? I was not, sorry. You showed it in the endpoint, whereas we said, I mean hospitalization and mortality for the vital. Vital? Time to composite or cause mortality or cardiac hospitalization. So, moving to myeloma, new trials. So, you know, I had to make choices, right? Because, so, I'll start with this one, you know. This one is about Ixazomim. If you go to clinicaltrials.gov, you know, you almost have 90 trials, including alamyloidosis with Ixazomim. I'm just showing you this slide to show you that Ixazomim is tested, is trial at every stage of myeloma. But this is only a real small number among the 90 studies that are ongoing. So, you know, it's called Tumalin. You're probably familiar with this. So, I decided that I will have to make a choice. I will not go through carfilzomim and even pomalidomide and all these exciting new drugs. So, I will focus only on immunotherapy. Why will I focus on immunotherapy? Because it's extremely exciting. We believe it's a completely changing field. I will tell you a small short story. 20 years ago, I did dendritic cells, and I loaded the dendritic cells with immunoglobulins, and I tried to induce T cells, T cells directing against the plasmocytes. So, I completely failed. I mean, not completely. I published the results, the negative results, and I stated all the reasons why it failed. But at that time, for example, we had never heard of checkpoints, you know, that we know are so important. But some years later, my wife told me that actually she had been very impressed by the way I was talking about dendritic cells and that's part of my success. So, I did not completely fail in trying immunotherapy in myeloma. But for many years, people never did not believe in immunotherapy. And actually now it's different. You see this slide is really nice. It explains the different, the major ways to target, you know, the plasmocytes, the abnormal plasmocytes, either by a monoclonal antibody or by core T cells. So, you take the T cells of the patient and with a brand new technology, you put at the surface very specific receptors that will target the cancer antigen on the plasmocytes. So, this is extremely exciting. And you have also the checkpoint inhibitors and I will come back on that. You know that the immune system is ready to get rid of the cancer but cannot properly act because there are inhibitors. So, we inhibit the inhibitors. This is the so-called checkpoint inhibitors and then we release the break and it works actually. As you know, it works very efficiently in many solid tumors and it does work to some extent also in immunology and specifically in myeloma. And I will not go too much on this other pathway. So, let's focus first on monoclonal antibodies again. So, we are, we have in myeloma especially the two targets, SLAM7 or CS1 and CD38 that we already mentioned. And looking at CD38, we have three antibodies, DARA that I've already mentioned. SAR, is a tuximab developed by Sanofi and a third one at a much earlier development. But you could see that we have many other targets in development, only monoclonal antibodies. And the very first one I should mention is elotuzumab. Elotuzumab was the first one to prove that a monoclonal antibody could be efficient in myeloma. We had tried many antibodies, anti-IL6, anti-CD20 and it did not work. Well, this one was the first one, but I must say it does work in combination. It does not work by itself and specifically it needs to be combined with an image. It works best with an image. So, we should recognize that this is the very first active monoclonal antibody in myeloma. But, just right after, arrived daratumumab. And daratumumab, you know, not only is it very effective also by itself because I mentioned to you that it does act like all monoclonal antibodies, but also it regulates the immune system of the patient and it boosts the immune system. Actually that's the way we understand why it does work as a monotherapy. So, I'm emphasizing actually daratumumab because it's difficult for haelotuzumab to develop while daratumumab is, I must say, more efficient. And you can see that it is, it has been trialed everywhere. Of course, you're very familiar, I'm sure. I'm not mentioning it in the relapse setting, extremely encouraging results, especially the Pollux trial, Revlimid-dex plus daratumumab with an expected PFS in the relapse expected. I mean, not rich yet, but expected of around maybe 40 months. I mean, that's what I heard not too long ago while so far the best relapse treatment was the combination of carfilzomib, Revlimid-dex with a medium PFS of 28 months. So, you see the jump, if I may say. So, extremely encouraging in the relapse setting. The Cassiopeia, I will mention that. And we have just finished enrollment, more than 1,000 patients, a joint study with the oven and the IFM. And I will come back on that, but also, so that's in the front light setting, in the transplant-eligible, transplant-inelegible Maya study. So, definitely daratumumab will make a paradigm shift in the treatment of myeloma. And I will mention also Isatuximab, so its development is not as developed as it is with daratumumab, but you can see, you have many different studies, mostly in the relapse setting, but also for smoldering myeloma. And in France, I mean, this trial will start and we will enroll patients in the so-called Icaria trial, so that's in the relapse setting. It's spondex plus or minus Isatuximab. So, this is just the beginning and the IFM will be part of this important study. So, first, the monoclonal antibodies. Second, the checkpoint inhibitors that I mentioned and I'm sure you're familiar with. This is the schema showing the tumor, the myeloma abnormal myeloma cells and expressing PDL1 and inhibiting actually the active immune system of the patient. So, the patient cannot get rid of the myeloma cells and we do have now checkpoint inhibitors. So, interacting between PDL1 and PDL1 and it is, as you know, currently in development, mostly these two studies, Lendex plus or minus, I mean, it's not plus or minus, it's a phase two study, plus pambrolizumab and pondex plus pambrolizumab. So, this is ongoing in terms of checkpoint inhibitors in myeloma. Now, I would like to turn to vaccines that I mentioned and then to CAR-T cells because CAR-T cells look very promising. So, first, vaccines. So, the idea is that you will... So, this treatment will only be tested in the maintenance because you don't expect to have a very strong immune response, so strong that you could treat an active myeloma. But in the maintenance phase, it could be successful. So, you see, that's what I tried to do 20 years ago, dendritic cells fused with myeloma cells and you hope that you will boost the immune system and get rid of the myeloma. So, either in the maintenance phase or in the early phase of myeloma, so-called smoldering myeloma. So, this is actually currently tested and I know that Davidan in the US with the big transplant, American transplant network is testing this vaccine strategy in the maintenance phase post-autologous stem cell transplantation. But here you can see other different vaccine strategies. Monoclonal antibodies, checkpoint inhibitors, vaccines and I will close this immune overview, immune therapy overview with the CAR T cells. So CAR T cells have been presented by the Americans and also by Chinese, they do a lot of CAR T cells in China and I was at the ASCO meeting in Chicago months ago or two months ago and there was a neural presentation by a Chinese team and extremely impressive. Really, with limited toxicity, no cytokine release syndrome, you know this is a major issue with that type of technology, no neuropathy of the central nervous system and highly efficient. So efficient that you wonder if it's really true but that was presented in a major congress and of course it's still very difficult, the technology is huge, a very limited number of centers can actually produce CAR T cells. In France we are testing in one center, I don't know about Italy, do you have anyone doing CAR T cells? I think we are exploring in Torino, in Milan also, Coradini and we are also trying it in Pavia because it's ideal in Amelidosi because you have such a small clone but we are concerned about the side effects. It's still at a very early stage but you remember the very first paper was published in one case with a CD19 target and that was shown you could see the monoclonal peak decreasing to zero and that was the very first reported case and you could see the disappearance of the plasmocytes after this treatment and now it's very important also to choose the target so now we are moving from CD19 this was probably not the best target to BCMA and BCMA are currently the best target in the field of CAR T cells in myeloma so that's what I was mentioning with the Chinese team, actually it was a CAR T cells directed to BCMA so these are different trials ongoing with cell therapy, immune cell therapy in myeloma and these are the results you see that's the American team but I must say that the Chinese it was even more impressive I would like also to mention that you have what we call the bi-specific antibodies and specifically the bytes so one side targets the tumor the tumor and