(Guest Lecture): The Ever-Changing Landscape of Treatment | MCRT Webcast: Why Physicians Are Optimistic About Newly Diagnosed Myeloma

My name is Leif Bergsogel. I'm at the Mayo Clinic in Arizona, and it's a pleasure to speak with you this morning. And I hope that we have some fun this morning. I'm going to give you a history of myeloma. It's not just 50 years. I'm going to give you about 70 years of history of multiple myeloma in a few short minutes. And I think it's helpful because when you're familiar with the history, I think you'll see there's a lot of reason for hope. And the story really starts with my father, who's shown in this slide here, who got his first job at the MD Anderson in Houston, Texas in 1955. And in one of the first papers my father published was this one in 1962. And if you look at the title, what he's proposed here is a plan of study. And that's very unusual in the medical literature to write a paper about what you propose to do as opposed to you've done. But basically the premise was that a spontaneous regression of myeloma had basically never been reported. And most drugs that they were trying to treat patients with were really not effective in more than 20% of patients. And they expected most drugs that they tried would be ineffective. So he basically proposed to treat 11 patients with a drug. And if it didn't work, they would discard it and move on to the next drug. And this was a way of doing a very rapid clinical trial where they could test a number of agents and try and find some drug that would be active in patients with multiple myeloma. And the fourth paper in this series of papers that he's published, they use this drug, L-phenylalanine mustard. Many of you may know that drug. If you had a stem cell transplant for multiple myeloma, it almost certainly used melphalanine. And this is one of the first patients that was ever treated with that drug. And what this figure is showing you is what's called a serum protein electrophoresis. And the spike that you see on the left is the M spike. And with treatment, that M spike goes away. And so that M spike shouldn't be there. And so you may have seen this in your own records. And our goal is to get rid of it. So this was an amazing result at the time to completely get rid of that M spike. And what was even more remarkable was that a year later, the M spike was still gone. So here was a treatment that could get rid of the disease. And it turned out that the man in whom this was done was a truck driver in Texas. And shortly after that electrophoresis there in September of 1960, he lived in Texas. And so, not surprisingly, he got into a gunfight and he was killed. And my father approached his widow and asked her if he could perform an autopsy on this man because he couldn't find any myeloma in this man when he was alive. And he wanted to look as extensively as he could for any evidence of myeloma. And at autopsy that the widow agreed on that autopsy, he couldn't find any evidence of myeloma. So at the time, my father thought he was this close to curing the disease. And he reported this in one of the major medical journals, the Houston Chronicle. They wrote an article about this fantastic new drug that seemed to be curing patients. And he also reported in another article, which is more prestigious, Science, in 1965, about an observation that there are two kinds of patients with myeloma. There's patients that make kappa and there's patients that make lambda. And you may have seen this in your own records, the kappa light change or the lambda light change. Well, he reported that all the patients who had kappa responded and none of the patients that had lambda responded. And this was an amazing result. Unfortunately, it didn't turn out to be reproducible. And it didn't take long for the East Coast Medical Establishment to say that they had results that were complete variants to those of my father. And in fact, this one doctor, Dr. Osterman at Columbia, reported that he had a lambda patient who swam 100 to 150 yards a day while being treated with melphalan for several years. And really a sign that things have changed. This was written in May 1965. In August 1965, this letter from an anonymous person appeared in Science. And the person objected that he didn't swim 100 to 150 yards a day. But this was actually Dr. Osterman's patient who swam 500 to 550 yards a day. And I'm afraid that's the kind of correspondence that we don't see anymore in the medical literature. So to summarize, then, about 50 years of myeloma history, and this was really the span of my father's career. The very first drug that was found to be active is related to dexamethasone. It's called a glucocorticoid. And I'm sure many of you, probably all of you that are patients will have taken dexamethasone. And then shortly after that, in 1962, my father reported melphalan. And there's another drug that we often use called cyclophosphamide. And then pretty much for the rest of my father's career, there were no new active drugs identified. And if you look at that line and that curve and the improvement of the five-year survival, it was just inching up at about half a percent per year improvement. And if it continued on that trajectory, it would take 140 years before it would get up to 100%. And so my father, at that time, when I was finishing my fellowship and starting my career in myeloma research, said, you know, if you want to make a difference in the treatment of multiple myeloma, you need to have one, you need to have two things, really. You need to have a better understanding of the biology of the disease, and you need to have better drugs. And the story I'll tell you now is how some of those things came. Well, I won't tell you too much about the biology, but I'll tell you about how we came to have better drugs. And some of you may have seen these articles that appeared in the press about 10 years ago. Celgene to widow who discovered thalamid, go take a running jump. Lawmaker says drugmaker Celgene stole her ID. Celgene, of course, is the company that makes Revlimid. And did Celgene steal this woman's idea? And if you look at this, it talks about a patient named Jacobson, who contacted her doctor to suggest that he tried thalamid. And so it turns out one of my patients saw this, this press and actually looked at the lawsuit and contacted me. Here's the lawsuit from Beth Jacobson against Celgene. But the reason my patient contacted me and told me about it was that I featured in this lawsuit. And it turns out in November 1997, I received a call in my laboratory at the time I was in New York from a desperate woman who's the wife of a patient, asking me if I had any ideas of things that could be done for her husband. And I had just come back from a conference in Stockholm, where I'd heard Judah Folkman talking about inhibiting angiogenesis with a drug called thalidomide. And so I told her about this. I thought it sounded quite exciting. And I told her to call Dr. Folkman and to get on his clinical trial of thalidomide. And the story is really quite amazing is that Dr. Folkman didn't take her calls. And so eventually, she called him at home on a Saturday night. And he was forced to take her call. And he agreed that he thought it was reasonable to try thalidomide in her husband. But he was actually a pediatric thoracic surgeon. And he didn't treat people with multiple myeloma. So he told her, well, just have your doctor call me. And he can get compassionate use of thalidomide. So she went to her husband's doctor, who is Dr. Bart Barlogi in Little Rock, Arkansas. And he scoffed at the idea. He thought it was crazy. But he was convinced enough to speak to Dr. Folkman, who convinced him. And her husband turned out to be the very first patient to be treated with thalidomide for multiple myeloma in the modern era. And unfortunately, he didn't respond. But as they had some leftover drug from treating him, the patient in the room next to him said, well, why don't I give it a shot? And the second patient to be treated, the disease disappeared completely. And that is how thalidomide came to be used. And we don't use quite so much thalidomide anymore, but we use Revlimid and pomelist, which are related. And the other drug that really changed things is a drug called Velcade. And it inhibits something called the proteasome, which was identified by Dr. Marion Orlowski. And his son, Dr. Robert Orlowski, was the first physician to treat a myeloma patient with a proteasome inhibitor, Velcade, and also see dramatic responses. And so with those two discoveries, the shape of this curve changed dramatically. And what you can see is that instead of increasing at a rate of half a percent per year, the rate of increase has now gone to 2% per year. And if we continue on this trajectory, you see that we'll be at 100% for patients diagnosed in the year 2030. And the drugs that really changed it was thalidomide and the related drugs, Revlimid or lenalidomide and pomelidomide or pomelist, all called imides, and then the proteasome inhibitors, Velcade or bortezomib, carfilzomib or kipralis, and hexazomib or nilara. And then more recently, the use of the antibody daratumumab or Darzelex, elatuzumab or Ampliciti have also made a big difference. And the question is, can we repeat what we did here today if we quadruple the rate at which we're improving the five-year survival, which we did here, and with the new drugs like the Netaclax, the bispecific monoclonal antibodies, the CAR T cells, belantumab, which has just been improved. If we once again quadruple the rate at which the five-year survival improves, then patients diagnosed now will have 100% five-year survival. And I've just plotted out in a more precise form so that you can have a look. Whenever you're looking at survival curves, you have to look at people who were diagnosed back, you know, 2012 here or 2009 here. And so you have to say, if someone is diagnosed in 2021, and we've continued on this trajectory, we haven't improved it, we just stay on the same one we've been on for years, then the five-year survival rate for someone diagnosed today is about 74%. And same thing for 10-year survival, about 60%. So we're making tremendous progress. And the question is, why don't we cure more people than we do? And it's a very complicated subject. But I think one principle that I'll try and illustrate for you is something called clonal tides or clonal heterogeneity. And what this slide is supposed to show is that the tumor of a patient isn't basically one single thing. The tumor cells are actually different within that patient. So at the beginning here, the tumor cells are predominantly red, but there's a fraction of them that are orange and a fraction that are green. They have different genetic differences between them. And as we treat them with different drugs, the different subtypes or subgroups or subclones of the myeloma shift. And you can see this orange is small here, but gets bigger here, and the green is big here and gets smaller here. And eventually at the very end of this patient's course, there's this blue clone, which is very aggressive and takes over. So the reason basically our drugs stop working is that over time the myeloma changes and acquires resistance, and we're no longer able to control the disease. And that's led to the principle that in order to try and treat all these different colors, all these different subclones of myeloma, that it's helpful to put more than one drug together. And this slide illustrates the response rates in patients as we use one drug or two drugs or three drugs. And I'm not showing you here, but as we go to four drugs, it keeps going up. And so the principle has been that as much as possible, if we can combine more drugs, we can take care of these subclones, which maybe are not so much of a problem in patients with sort of low risk or standard risk disease, but are really quite a problem in patients who've got high risk disease. Now, obviously there's some problems with this approach. One sort of practical one is cost. The cost of a true drug regimen is about $100,000 a year, three drug regimens about $250,000, four drug regimens, perhaps $500,000 a year. And so that's one sort of thing that needs to be dealt with. The other concern is that we may get rid of the myeloma, but we may not be doing the patients any favor. If a little chemo is good, a lot must be better, has a limit to how far we can go with that. And so we're not going to be better, has a limit to how far we can go with that. And so I'd like to propose for you on the next slide, my regimen, oncologists are famous for making acronyms for how they want to treat patients. And I've come up with the one that I think that could be the winner. It's Psydilpobosidepsp, which includes every single drug that's active in the treatment of multiple myeloma, but obviously isn't a serious proposal. So how are patients treated? Well, most patients in this country are treated something like what you see here. And here I'm showing you patients who actually treated on a randomized controlled clinical trial. So they flipped the coin and half of patients received this upper treatment and the other half received this treatment. And so this is Revlimid, Belcade, Dexamethasone for eight cycles followed by maintenance with Revlimid. And here they added a transplant. And when these patients up here, when their disease progressed, then they got the transplant. So about three quarters of them got the transplant when the disease progressed. And you can see that the complete response rate or the very good partial response rate is higher when you've got a transplant. The minimal getting rid of, you know, and only having minimal levels of disease, detectable minimal residual disease, 10 to the minus four is higher with transplant and at 10 to the minus five. So that's one in a hundred thousand cells or less is higher with a transplant. And the time it takes before the disease progresses is longer if you have a transplant. And based on this data, many people feel that having a transplant right away is the best approach because the disease stays away the longest. However, it's a complicated subject that I won't get into. And at the ASH meeting, which is the annual hematology meeting, which is coming up in a couple of weeks, they are presenting an even longer term follow-up. I think it's seven years and there's no difference in overall survival. So if you get the transplant right away or if you wait and get the transplant when the disease comes back, it appears that the overall survival is the same. But this would be the way that most patients are treated in this country. And it may be that that changes in the future. It may be that we'll add in the fourth drug, daratumumab. And in older patients, we may choose to use just two drugs because it's much better tolerated. And this study shows the use of just Revlimid and dexamethasone also giving excellent results compared to what was used previously. And so you might wonder, well, how does with all these different choices, how does your doctor decide what he wants to do? And I'll let you in on a secret. It's not like this. We have a lot of data that we use to inform our decisions. And during the question and answer period, I'm sure we'll be happy to answer any questions that you have. Thank you. Great. Dr. Birxigel, what an amazing story and family history you have. I think it's so stunning that you've continued this important work. And I just want to let everybody know that Dr. Birxigel is one of the leading genomics experts in multiple myeloma in the world. So thank you for sharing your deep experience with us.