I will be more than happy to introduce Jens Hilling Gas from our multiple myeloma service who will talk about therapies, cello, the and multiple myeloma. I should point out I was born in Amsterdam. I'm Dutch. Jens is German. We still get along. But when the Dutch and the Germans play in soccer, things might get a little dicey. Yes. Thank you so much for the kind introduction despite, um, our different background, uh, nationality wise. Now I'm, I'm really honored to be here and, uh, talk after re who's really like, brought a lot of new innovative ideas to Ross, which is, I think the major reason why we, my wife and I decided to stay, um, because the second one is that we just love Buffalo. Buffalo is awesome and we had really options in other areas of this country where, where they said the weather is nicer where they said whatever is nicer. But Buffalo rules and I think Ross Park does too. And, and I'm really fortunate to, to have come here and be able to develop the multiple myeloma program and also cellular therapies and it's very timely that I'm allowed to give this talk because last week I was surrounding on the cellular therapy and transplant service, which really made me very humble. Again, I have transplanted a lot back in the day, but it was autologous stem cell transplant. It's much easier. Um But I remember this one patient, actually lymphoma patient, I think it was who had a huge lymphoma visible in the beginning of the week, got all the complications we know. And at the end of the week, this was visibly smaller, which is something we in oncology, we really rarely see. So there was really an impressive experience for me. Again, motivating me even more. Um to yeah, to continue on this path together with Marco Andrene. What I want to talk about is the approved car T cell products because I know we have colleagues here from private practice who send us patients which which makes us happy, it makes the patients happy and I hope our collaboration is good enough that it makes you happy as well. Briefly talk about the clinical trials, we have alternatives to cellular therapies because not every patient is a perfect patient. It's just the case. And also what happens when the patients relapse after cellular therapy, I represent multiple myeloma and myeloma is still considered not curable. I think we are closer to a cure than we have ever been. And I think in major part because of the car T cell therapies, but we are not there yet. And I also want to talk about future options that might come our way and also what we do around cellular therapy, to improve the cellular therapy, to improve the outcome for our patients. I have realized um started talking at far too many slides. So some of them might be short, but I will explain what I, what I wanted to say with it. So just bear with me. The proof car T cell products are fairly young and fresh in myeloma. So we don't have a lot of them. The first one was I cell. I don't even try to pronounce the full name of these because I never really succeed. So I try to not embarrass myself. And um I do something in this talk that I should not do. I compare different products, different clinical trials because that's what we do in our heads, right? We shouldn't do that because it's, and I want to really point that out in the beginning, it's different patient cohorts, it's different products, it's different stages of disease. So it's really not fair to compare those, but we need something to kind of make our decisions. Which product do we offer a patient? And another thing I wanted to mention, initially, we were really struggling with the fact that we did not have as many products as we wanted or needed for our patients. So we had many more patients than we had products. And after the first wave and a lot of support actually from, from industry as well to get this up and running. We have many more products and can offer almost every patient who is eligible and who is available and is willing a product. And this was the first one, the patients were a little bit younger in the trials as they usually are in clinical trials because they are highly selected and as they should be because those were also heavily pre treated patients. So they had a lot of lines of therapy before. As you know, myeloma is a chronic disease. Nowadays, we treat it with lines and lines and lines of therapy we treat until the relapse comes, then we treat with another level, another line of treatment. And this is something that is approved now for four prior lines of therapy. And you can see in the middle over a response rate, 81% in this clinical trial, which is something we have not seen like that before. Usually when we have a new product in myeloma, the response rates are somewhere between 20 and 30%. So this was just a game changer to see that it can happen in a heavily pretreated patient. They can have a great response, still the side effects. And I'm not the expert here in the room. There are others who can talk more about it. But neurop obviously, something we know about hematologic toxicity, but also the cytokine release syndrome. When these cells come into the body, they start doing their, their magic, fighting the cancer. And then the patients oftentimes develop fever, sometimes low blood pressure, sometimes need oxygen. So it's really, it needs a special service and special providers who are used to these side effects to be able to provide help to these patients. But once they have overcome this, they have these good outcomes. And on the bottom, I show the neurotoxicity, which is something that we don't really understand that. Well, yet we are still trying to figure out what's going on there. And it is not super common but still common enough to mention it where patients struggle to focus on tasks that we tell them. And that's something where we still have to work on and have to learn more. And I think having more patients with these treatments will make us better in learning how to help these patients and to prevent eventually these side effects. There was another trial with the same product with a little bit less overall overall response rate, but still very impressive. This was more a kind of a comparison to real world. And then again, the toxicity is very, very similar, just kind of giving you an overview of what we have available right now. And then another company came out with another product, it looked like it has a bit higher response rate, but also a bit higher toxicity rate. And that's basically what we do in our head when the patient sits in front of us, and we say, ok, you might be a cars of therapy candidate. And then we think, ok, which product is the best for this patient? Because again, we are fortunate enough to be able to almost provide every product to every patient if eligible. And as you see, this seems to be more a little bit more effective. Again, not fair to compare different products in different trials, but it seems to be also a bit more toxic. So we in our mind, we think which patient can tolerate this better, which patient maybe has a more aggressive disease. And all these factors come into play when we make these decisions, the survival still those are heavily pre treated patients. And there have been ongoing studies doing that in earlier lines of therapy. Obviously, when something is new, we have to try it in patients who have really no other choice. Now we do it earlier and the response rates and the outcomes are even better. But this is what basically was shown that the median survival was between one and 1.5 years in patients who had had almost everything available. And you know, there's a lot available for myeloma and they had had almost everything and they still had a year more that they would not have had without this treatment. So this is not a commercial for cars, but that's how excited I am that I can offer that to my patients finally. And then comparing those again, not fair. I put on the right hand side, what we have had before S V D is selling sex me, which is actually not so bad this combination, but to be fair, this trial enroll patients with 1 to 3 prior lines of therapy, the carts and you see it's not better than cart and the cart had four and more prior lines of therapy. So just to give you a perspective of what has happened and again, it's not fair to compare trials, but I do it anyway, we need to get better, right. Patients are still not cured, they still have their relapse. So we do clinical trials. These just to be mentioned, please send the patient so that we can screen them for these trials. One is using an N K cell, a natural killer cell car product, not car T but car N K. Basically, we have a product with a new target which was actually developed by Dr Branch and his group, the GPS C five. And it took me long to pronounce it like that. So it's G PC five and we even have a maintenance after that because we know patients relapse despite car t cell therapies. So they need to remain in this remission. And with this kind of reset in the immune system, we might have a good chance to use that. And then we also start a trial with an allogenic cart because we know unfortunately, until a patient with multiple myeloma come to the point where they are eligible for cart, oftentimes their T cells are so exhausted and we call them exhausted, they cannot function that well anymore. So maybe trying the T cells from a healthy donor and use them as car T cells. That might be another another avenue to go our alternatives. Obviously, not everyone is eligible. What we can use is what I mentioned, the Cellino, which is a drug that is approved for this line of therapy, the outcomes in combination. But again, it is 1 to 3 prior lines of therapy. So much earlier, much less heavily pre treated patients still has a fairly good outcome. And then just recently approved tali map is a bi specific specific antibody where we don't take the T cells out of the patient, but we leave them there and we give them basically, it's how I explain it to the patients. A double antibody that brings the T cell to the myeloma cell and then kills the myeloma cell and still pretty impressive outcomes. As I said, usually what we see in these lines of therapy is 20 to 30%. This product shows 60%. And we at the moment when the patient sits in front of us, our first choice is still car T cells because more effective if the patient in our view and we are not really great in doing that objectively, it's still a fairly subjective decision that we make. But we decide if the patient cart cell eligible, if they are not, then we offer them the bi specific antibody. If they are not eligible for that, we offer them conventional therapy. What do we do when the T C comes back? And there's very little data, there are more studies coming, but we don't have a lot of published data maybe at the upcoming two meetings as and a we will have more. But there's not much known what to do after patient relapses having had all these treatments, then cart cells and still relapse. And interestingly enough, the University of Ca in San Francisco, they have done an analysis of their patients and they found that cartel is the best treatment after cara, which is a little bit of a problem because cart cells are not cheap, right? So the insurance companies are not super happy to give us two car T cells, which brings me back to our clinical trials because if the patient got cart or N K T or if they had that in a clinical trial, the insurance might still be willing to, to reimburse a commercial commercial. And I think that's something that we should keep in mind and also the same with the by specific antibodies. They also seem to work fairly well afterwards, future options. There are new by specific antibodies on the horizon. We hope they come soon. The target again is cheaper C five D, which is a different target than most of our car T cells or at least as all our approved card T cells. Again, pretty impressive response rates. And some of these patients even had prior PC MA direct treatment, meaning car or bites. So that's very promising. And then, as I mentioned, Dr Branson's group from Sloan catering at that time showed that a cheap car can work in Mylo as well, which is a different target. So we will really have the benefit to offer more to our patients even if they relapse after car I beam is a completely different topic. It's kind of a further development out of the lenalidomide and the polyamide, it's called a cell mot. It's celo modulator and it is also pretty effective and also very well tolerated, which is interesting. So this is something that is also used in combination with car T cells because it's an immunomodulatory in the wider sense drug which can then use or engage these T cells longer and their trials ongoing using this as a maintenance after car T cells. We want to have a lot of patients that we can treat, that we can offer these car T cells and for the commercial products, obviously, that's not scientific. That's something that's already approved. But we do a lot of research around this area. We don't want to lose the information that we learn from patients who are getting these commercial cart products. And we want to make the patients better and we want to make the treatments better. And what we are doing is we try to learn more about the myeloma itself and the immune system. And we are currently doing a study where we do biopsies of different areas of the body because we know that the disease is heterogeneous, especially in later lines of therapy. And we have just submitted a paper where we look into the immune micro environment in the osteolytic lesions, which is the hallmark of myeloma. As you know, and we compare that with the random bone marrow that we usually use to do our analysis. So that's something that we are working on which I find very exciting. We engage our fellows and one of our fellows is working on a screening before treatment. So actually, at the moment we do it retrospectively, but the dream is to do it later on to see if certain genes are down regulated. Like for example, a gene that is close to PC MA. So that we can see if this patient may be better served with a G PC five D product, right? So that we can select and personalize the treatment better. And what we also want to do, as I said, we also want to make the patients better. As I mentioned, the T cells are oftentimes so exhausted that they either cannot work with a bite or they cannot be used as a really effective cart later on. So we try to make that better. And it's very ambitious, I have to admit and maybe we will really sink sadly with this, but it's worth a try, I think. So we want to make we call it to improve the host factors. And we know that physical exercise, for example, is very effective in improving our immune system. And we have a post at the upcoming esco meeting showing that in a very small group of patients, patients, we measured the immune function before and we measured the immune function after and six months intervention of physical activity. And we found that the patients had a better t cell repertoire after the exercise if that holds true in a larger trial, which is right now ongoing. We don't, we don't know, but this is the trial that we do. We use physical exercise and look into the immune system. We obviously look in other things as well since we torture our patients anyway. So we want to get the most for them out of it. And we also use intermittent fasting, which is another intervention that has shown to be effective to improve the immune system and the host. Basically the patient and we use paid up locus space and work from Betsi Roski, from our immunology department who has shown that this is also effective to improve the immune system. And this is what our patients do and they actually love it on the top. The last name is not by accident. This is my wife and she is a nurse and she became because she didn't get her license in the New York State, which is a completely different topic, but she became a personal trainer and she can now train these patients and we do it virtually because of COVID and the patients love it. She loves it. So it's a win, win and now we hopefully can show that we can improve the T cells. And there's some data already showing that this might be effective. In summary, we have approved car T cell products. Please send your patients at least to be screened and then we work together to find the best product for them. We have alternatives if it's necessary. We try still to find a treatment after cart and obviously car t seems to be the best post cart. So we, we count on doctors branch and Davila to develop new car T products that we can do in clinical trials afterwards. And we try to make both the treatment better and the patient better so that the outcomes overall will be better for our patients with this. I thank you for your attention. Um I think we have questions in the end.
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