(Guest Lecture): September 2022 - A History of Stem Cell Transplantation

Sorry for the delay. I have a large slide deck, which we'll figure out how to get over. I could take some more slides out. And then I'll start talking. OK, thank you. And I noticed a lot of you wearing masks. If you have I don't know if you read Journal of Clinical Oncology, but the Emory group just showed that patients with myeloma getting active therapy don't make great neutralizing antibodies to COVID-19 despite appropriate vaccinations. So it's very important that we still think about this, especially in patients who are still receiving therapy because it's still a possibility. You may not end up in the ICU, but you may end up still getting COVID and getting sick from it. My wife has chronic lymphocytic leukemia, so we're always thinking about this. So the other thing while we're at it is this drug called EvuSheld. I don't know if anybody heard of that. Good. I'm glad to hear. EvuSheld is a combination of two monoclonal antibodies, one against something that's more common in COVID-19. The other has a different finds a different antigen, as you heard about from Dr. Gertz. And so it helps protect you. So it's not a vaccine, but the antibodies, it's the end product of a vaccine. We good? Who knows? All right, I'll just keep that. And so. So the. Antibodies have been engineered so that they last in your body for six months, as opposed to a normal immunoglobulin, which lasts for about a month. So the nice thing about EvuSheld is that it allows you to have a good degree of protection. It's for any patient who has multiple myeloma, they're eligible for it. So I strongly recommend it as something in addition to vaccinations. You just have to figure out. There we go. You just have to figure out the appropriate timing, because theoretically it might block the vaccinations effort. So I'll start with high dose mouth. I'm going to go through a little of everything because mouth lens, not the final word. And as you heard from Dr. Gertz, mouth land was first used to gas people during World War One. And if you want to read a really interesting book by penitence or genitent, no, Jenna Conant, and she is the daughter of the former president of Harvard Harvard University, and she wrote a book about the bombing of Bari Harbor, where muster gas was released and it was all covered up by Winston Churchill. It was one of those things. The Germans had muster gas, the allies did, and it was kind of like, we won't use it unless the bad guys on the other side do. And so a Liberty ship full of gas, of muster gas was hit and blown up during World War Two and released a lot of muster gas. And again, led to the whole idea later pioneered by Goodman and Gilbin that muster nitrogen muster can treat certain human religious malignancies. And we still use alkylators to this day, although we'd like to get away from them. This is my disclosures as a variety of companies who are conducting consultancy and honorarias. I thought it's important I let you know that. And I'll be discussing non-EMA European medicines agency and non FDA approved indications. So I like this. This is a little vignette from a colleague from from the Middle East. Before the new drugs treating my alumnus like waiting for a taxi and then would come. Then all of a sudden five come at once. So I think that's exciting that we have all these options available for patients, but it can be very confusing. And I'll get into why a little bit later on. Where do you put all these drugs together? And I know you heard a little bit about that from Dr. Gertz. So this is sort of the history of where we all come from. On on the over on the left. And I adapted this from Ken Anderson from 10 years ago. And the slides got a lot bigger because I keep adding drugs. And it's really getting crowded on the right hand side. So I'm going to have to sort of push everything over. We started in the 50s with Melfland, and we still have Melfland. It was used at first orally with a steroid called prednisone. It worked OK. Not great. And Dr. Kyle's mentioned earlier has a really cool article on sort of the history of treatment for a low, which included orange peel and some other interesting things which didn't work. And then McElwain in the early 80s pioneered the use of high dose Melfland. He didn't give a rescue. So these patients were like neutropenic forever as he dose escalated. And then as mentioned earlier, Bart Barlogi had a lot to do with the field. He pioneered the use of high dose dexamethasone, which I know everybody loves getting. But the and the V here stands for being Christine and Adria Mycin, which we don't use that much anymore. And then and then he was the one who really sort of pushed high dose Melfland with a rescue because Melfland kills good cells and bad cells. It's fairly nonspecific. Oh, by the way, BCMA is not specific for myeloma cells. It's also a normal plasma cells, just to correct, Dr. Grint's and as well. CD 38 is not only expressed on malignant plasma cells, it's on natural killer cells and a variety of other things. It's very immunomodulatory. We can talk about that later. Anyways, the whole idea of stem cell support came about in the 80s. So this has been around forever. What I love that we stopped on the shore. I'd love to have less toxic things that we can do. So that's our goal for the future. And then, as you know, the image came out, the litamide being the first horrible reputation for Burke defects because it was used for morning sickness. And it was crazy. And there was a woman at the FDA who blocked the litamide for being used in the US. It was used in Europe and Canada. I forgot her name. Somebody. Thank you, Francis Kelsey and Wyeth, who had the litamide, was killering her because why is she not releasing our wonderful drug? And she should have gotten a large medal for that. I think she did. She was given awards because what she did was prevent a huge number of Burke defects in the US. However, it was repurposed later for leprosy and then later on for multiple for multiple myeloma. That's a whole nother story, which I won't get into now. Then there was one of the litamide derivative, pomalidomide. And now we have because for marketing purposes and for patent reasons, derivatives of these drugs are now called the cell mods. And I bear to my and mezzogendermide, which I haven't yet figured out a pronounce are going to be hopefully available in the near future. We have the proteasome inhibitors, as was discussed earlier. And then all monoclonals, Eliotuzumab, which is again CS1, also known as SLAMF5. It's OK, not great, but Dara is much better as well as as is ESA, both against CD38. But in addition to actually hitting the myeloma cells and killing them, they also do a lot in terms of modulating your immune system. And in fact, some of the CAR T cell programs incorporate potentially Dara Tumumab help deplete natural killer cells. That's another discussion. Some of you may have seen Belantumamaphodotum or Belamap, that's an anti CD38 antibody drug conjugate. Very cool. And then subcued Dara Tumumab. And then we'll have the specific antibodies against BCMA and then GPRC5D, which are Teclistumab will probably be approved by the end of the year or early next year and TalcotaMab sometime beyond that. And then we have Selenaxor and Ibnistat, which isn't used too often. And then the BCMA directed cellular therapies, Idacil and Siltacil. So we got all these things that potentially will replace transplant, which is fine with me. Just to give you an idea of just how hard it is to take care of cancer patients in general is that when you go into remission, the level of remission is about a billion cells, a billion cancer cells is about the size of a sugar cube. So I can take a sugar cubes worth of cancer cells, stick them in me. And I won't find them until I have 10 billion cancer cells. In other words, they have to grow. So it's sort of like the tip of the iceberg phenomena. So that once you go below that tip, you now are treating, but you don't know exactly what's going on because you have to wait and see. So a lot of what we do is based on, well, what do we have for prognostic signals that we get from the myeloma at the gecko, so cytogenetics, stage of disease, a variety of things go into helping us understand what is the prognosis for a particular patient and what's the likelihood that cancer will come back sooner rather than later. That's another discussion. But that's why you get all these tests done when you are first diagnosed to help us understand what the prognosis may be. So what's the best therapy? That's another discussion, which we'll talk about a little bit later. I think Dr. Hillinghouse will. And and so what's the role of myeloma and high dose stem cell high dose mouth line and stem cell transplant? It's really not a transplant. It's a rescue. You're getting your own cells back. Transplants when you get something from somebody else. And then what's a transplant eligible patient? It used in France. It used to be up until 65. You hit 65. No transplant for you. But now they're expanding it in the US. It's really not. Age, it's fitness, and then everything gets different fit and frail. So a lot of its organ function, heart, lungs, musculoskeletal, how how much can you walk around? But patients who are in organ failure with kidney failure, who are on dialysis, they can get a stem cell transplant with high dose mouth line. Barparologi pioneered that. Also, a lot of its attitudes. Some people don't want to do it. Some people do. And so, I mean, there's all these factors that go into whether or not we should do a transplant. OK, I'm just going to do some quick definitions. I'm happy to share this. I'll trim it down if you want to put into a PDF with anyone wants it. How much more time do I have? Ten minutes. I know we start a little late. Just let me. OK, so this is important when you are interpreting data. I know it's I don't want to get too scientific, but I think it's important because we make decisions on what to do. And the FDA makes decisions on what to do, improving or not approving a drug based on progression free survival and overall survival. Those are both very important elements when we look at whether or not you're going to approve a drug or not. In fact, you may know Mel Floufan, which was on the market for a very short period of time, seemed to look very promising. But unfortunately, it had a nice progression free survival, but it had an inferior overall survival. People actually did worse. And they're in the middle of trying to salvage drugs. Same thing with Venetoclax. Inferior overall survival, better progression free. So very important. Progression free is the length of time during which the treatment of disease, such as cancer, the patient lives with the disease, but doesn't get worse. Or they've gone into remission and then it comes back. That's progression free survival. Overall survival is obvious. You are you're treated for your cancer. And if you're alive, you are you have met an end point. But if you die, you've met another end point. So that's overall survival. We want to have obviously an improvement in overall survival. And then the median overall survival or median progression free survival is the time for which if you take 100 patients requiring therapy, 50 will either have died or 50 will have progressed. And that's the halfway point. So that's very important as well, because you may see all these things in papers or your doctor may describe this to you. So it's good to have a rudimentary understanding. I don't understand all of it either. I have to talk to our statisticians half the time. So a Kaplan-Meier analysis, I'll go through this very quickly, is to estimate progression or survival. And then you follow all patients, but everybody doesn't get treated on the same day. They're all treated on different days. And then some people may say, I don't want to do this anymore. So they go off study or they get they move out of town and nobody can find them. So there are all these things that happen while you're trying to do an analysis. These are all the things that make cancer treatment complicated when you're doing a study, because you've got to make sure that you're accounting for all of them and that also they don't have a toxicity that you are not expecting. And that has happened with several drugs. And so this is a I got this from it's a Vanderbilt thing from Wiki, WikiPub. And so these are people who have all gotten treatment, treatment and representation. This is just the the mall lined up and this is time. And so different things happen to them. Some of them may die. Some of them may go off study. Some of them progress and they're all starting at different time points. So what a Kaplan-Meier curve does, it lines everybody up as if they're all starting at the same time. So it's very important. Now, if you've heard this before, I'm sorry, I'll go through it quick. So this is a very simplified Kaplan-Meier curve just showing percent of people surviving. But what happens is things may happen. They are censored. They they leave town. So you can't follow them anymore. So the curve drops and then some may meet an end point. They've progressed or they've died. And so the curve keeps dropping. So this gives you an idea of how something is working relative to something else. And I'll show you that in a little bit. So this is from a fellow named David Robinson, he presented in blood a few years ago. And what it shows is actually this is an abstract he presented in a different journal. And what it shows is how we've gotten better over time in terms of patient survival. You can see here back in the 70s to 1980s, the median survival here was about it was pretty bad. It was about three plus years. So that was back in the day when we really only had oral melphalan. And then as you see over time, we got better so that the median survival keeps rising. So here the five year median survival for patients were treated five. The median survival for patients treated from 2001 to 2010 is about five years. And I'll tell you how that's even gotten better. And this is another one that was an abstract, which they published in another economics journal, I think. And this just shows how things have improved. The blue line here is for people less than 65. And then from 2006 to 2010, and this is for less than 65 from 2011 to 2012. And you can see on the Kaplan-Meier curve, things have gotten better. But what's really cool is for the over 65 crowd from 2006 to 10 here has now improved up here. And you can see it stops here because you have to have patients live long enough for you to be able to follow the curve. So that's another issue. But this is exciting. We've gotten better at what we do. And then lastly, here's autotransplant. It's very simplified. There's our patient in green. This patient has their stem cells collected. Many of you who've had a stem cell transplant know what it's about. We used to do bone marrow harvests, which are pretty crude. Now we do peripheral blood. And even then it'll change because maybe it'll always just be CAR T. Cells are put in the freezer and then very cold. And then patient receives high dose therapy. And people have tried to improve upon Melflain and really it's still Melflain. So that wipes out the hematopoietic system. Cells are infused back in and then patient is rescued. And for those who have had this, it's not a lot of fun. So I'm going to start to wrap up. This is the determination trial. Paul Richardson led this. It was just published a few months ago. And this was RVD, which at the time was the gold standard. Everybody got RVD and they not only did it in the US, they did it in France. And I can we can talk about it later. The difference between the French trial and the American trial, because there are differences on the maintenance arm. And the patients who got RVD only got it for two or three cycles, had their stem cells collected and then got RVD for up to eight cycles. And then the transplant arm got RVD induction two to three stem cell collection, high dose Melflain. Then the back end, they consolidated. And this is very popular in Europe and the US. We you know, you've just had high dose Melflain. It's day 60. Oh, we're going to give you more RVD again. More patients. Are you kidding me? So so that that's why we don't do that that much. And that's another study where we showed that it probably doesn't matter if you've gotten an RVD induction. And then they all got land maintenance. And the primary endpoint was progression free survival. And then there are other safety endpoints and overall survival. And this is that Kaplan-Meier curve for the patients who got a transplant. They had a superior progression free survival. In other words, it benefited them in terms of when the disease came back. It progressed or they were in remission and they had relapse. And the blue line of the patients who got RVD only. And so the median progression free survival. That's why I gave you all that stuff at the beginning. It's 46 months for RVD alone. And it's 67 months for those who got a stem cell transplant. You say, well, why doesn't everybody get stem cell transplant? Well, the overall survival is not that different. Why? Because we've got great salvage options for patients after progression from if they have a stem cell transplant. So right now, there's no difference. And we don't expect there will be over time. So I'm going to end here with a few other things. People have tried to improve on things after transplant. This one using Elo Tuzumab as part of consolidation maintenance is a German study. And you can see here all they had all these different permutations. Lendex alone, Lendex plus Elo, Lendex alone, Lendex plus Elo. And they had different approaches. You could either get a two transplants versus one. But anyways, the bottom line, no difference when you add the Elo Tuzumab. Now, the French study added this is VTD, which is Bortezumab. So I'm going to add my Dex transplant and then with or without Dera. And then Dera versus observation. This shows that Dera is a single agent compared to nothing. Benefits people with. Oops. Who received the Dera Tumab as opposed to nothing, as you know, now the gold standard is or at least the FDA approved gold standard is Linolinamide, we can talk about that if you wish. But this is where it gets really confusing. It turns out that the patients who got the VTD, the Lidamide, Bortezumab and Dex and then no maintenance, they are here in terms of their progression free survival inferior. Here, if you look at it, though, the patients who got BtD Dera and know for just alone, they did very well. But those who got BtD Dera and then got Dera on the back end for maintenance, they're about the same. And here are the ones who got Dera VTD and then observation also about the same. So Dera Tumab map is part of induction, seems to have a halo effect that goes well beyond the initials. Whoops. Is that me or are you trying to tell me to go to the next slide? So it's just it's an interesting phenomena. So Dera, in addition to killing plasma cells, modulates the immune system. We're just beginning to understand how that works. They can talk about that a little bit later on. So I'm going to end this part of my talk with what the Princess Bride teaches us about outcomes and multiple myeloma. And the sad part is, when I say this to students, they all go. What's the Princess Bride? And I'm like, oh, my God. So, kids, I guess it's like when you talk about the Rolling Stones and everybody looks at you, oh, those are a bunch of old men. So I always do recommend for those who have not seen the Princess Bride to go see it, because where Vizini and his well, as you know, he kept saying inconceivable when something he thought could never happen happens. So he his last word was close to inconceivable when he was having that with the with the Dread Pirate Roberts, when he's having the the game as to who's going to drink the poison. And so I know came poison. So he in your mind toy is played by Mandy Patinkin. And Vizini is played by Wally Sean. So he goes, it's inconceivable, says the Dini. And having heard this claim three times only to be confronted by alternate realities. Inigo Montoya says, I don't think you know what that word means. So how, you may ask, does this relate to myeloma? Twenty years ago, it was inconceivable that the median overall survival for myeloma patient would now be beyond 10 years. In the 1980s, it was three years. Now we're in excess of 10 years with or without transplant. And to consider alkylator free regimens or fit or fail, present patients is yet has become all but routine to use induction regimens that don't use alkylators inconceivable. And that post relapse outcomes could nearly be as long as the initial responses, if not longer in some cases, and the results of phase three trials could be founded by post transplant therapies. Great problem for the patients. Hard problem for the investigators, because it makes it hard when patients are getting great salvage therapies to say, well, we're going to use overall survival as an endpoint because now we're able to treat patients quite well. In fact, sometimes even better than the induction regimens they received. Some of the older studies, we used to use a doublet Lend X. That's like crazy. And so if you get a triplet, so you get Darro Lend X or Darro POMDX, you may even have a longer response than the original Lend X. So it makes it very difficult to figure out what's going on, even in the context of B cell maturation antigen directed therapy. So I'll stop there. I'll talk about I can talk about CAR T cells. I have some cute slides on that a little bit later. Thank you.