(Guest Lecture): The History of Myeloma with Dr. Craig Cole

My name is Craig Cole and this is the kind of myeloma 101 and it's informal so it's conversational. So I was just going to kind of go through what myeloma is. I was going to touch on a bit of where we were and where we are now and then I'll take any questions. Does that sound reasonable? So myeloma I think, in fact we were talking earlier about where the name myeloma comes from and multiple myeloma and that name was coined back in the 1850s. So myeloma, I'll do the history right now, myeloma was I would say it was discovered by Dr. William McIntyre in 1847 and he had a patient by the name of Thomas McBean in Great Britain who was a grocer and he was in his 40s and he was vacationing in Scotland and he was kind of feeling poorly but went on vacation and he was, and this is in Dr. McIntyre's paper, he was vaulting out of a cave which I don't know what that means but it sounds like it could cause some harm and he had a snap in his chest and so he went to Dr. McIntyre which is really just an average family doctor in Great Britain and Dr. McIntyre thought that was unusual. He taped up his, he said well he was doing something strenuous, he taped up his ribs and then kind of sent them on his way. He comes back with more broken ribs and more pain so Dr. McIntyre really examined him and I mean he really, really examined him meaning that he, in his examination he looked at Mr. McBean's underwear and saw that where the urinate hit his underwear that it was starched and he was like what's going on? This guy is young and he's breaking bones but something in his urine is hardening so something in his bones is being put out in his urine and he couldn't quite figure what was going on. So he put a bunch, this is exactly what he did, put a bunch of leeches on Mr. McBean which was the standard of the care, did some phlebotomy to balance his humors, sent them on his way but he kept the urine and he had him urinate in a cup and Dr. McIntyre, and he did not need to do this at all. He could have just put the leeches on and let them go on his way but he said I'm trying to figure out why is this guy breaking bones so he boiled his urine then cooled it and it formed this precipitate at the bottom and he's like he's putting out something in his urine that's weakening his bones. So he sent the urine sample off to this doctor, Henry Bench Jones and you may have heard the Bench Jones urine and is named after Henry Bench Jones who was a, he was very different from all the other doctors in the 1800s because he felt that science was really driving medicine while other people thought it was balancing of the humors and were really, really, really connected to Galen and Hippocrates about medicine. He says I think science, chemistry is what drives medicine. So he examined urine and he, everyone sent all the urine samples to Henry Bench Jones for him to examine. So to get us urine sample from Dr. McIntyre was no big deal. He's like okay, he got the urine sample, found that this was a protein in the urine, quantified it and said that there are 4.1 grams of protein in the urine. I think this is related to this molythes asium softening of the bone and from now on if you see people with softening of the bone you should do this urine sample and that was the first test he did. The urine sample and that was the first test ever for to, a screening test for cancer and Henry Bench Jones, he never published on it, he was just like he went about his way and Dr. McIntyre then went back to Mr. McBean and then said I think this is some type of cancer that you have that's consuming you. This isn't just osteoporosis, this is something malignant and then Mr. McBean then had more falls, broke more bones and then got admitted to the hospital and then died and Mr. and I think Dr. McIntyre deserves a lot of credit because then he said we should probably figure out what happened to him and when they went to look at his bones it was, had all of these multiple lesions and it wasn't that the bones were just hollowed out, there were cells in there and it looked like marrow and so although Dr. McIntyre didn't coin the term multiple myeloma that was 10 years later it looked like there were multiple areas of bone marrow throughout the body and myeloma means marrow, multiple means the multiple bone lesions. Does that make sense? And then I think we had mentioned Dr. Kohler was a German physician said I don't like that name, I'm going to name it after myself so he named it Dr. Kohler and still if you look up the ICD 10 code for myeloma which is C90.0 it will occasionally pull up Kohler's disease which drives me bananas because doctors should never name stuff after themselves but that's my opinion. And then Dr. J. H. Wright in 1900 then wrote a really, and he's a surgeon at Mass General and he got his surgery residents to write a meta analysis so he wrote, they collected all of the I think it was like 40 patients, all the data from 40 patients on myeloma and wrote a paper on it which was including photographs of the bone marrows and the weird thing that was interesting is that there were so many blood vessels inside the bone marrow of myeloma patients which is different from any other cancer that all these blood vessels were inside and then again that was in 1900. You then fast forward to 1999 and we started to understand why there was so many blood vessels in the myeloma area and it's because myeloma biology is that those plasma cells, those malignant cells are very dependent upon the bone marrow stromal cells so the latest work, the architecture of the bone marrow is made up of these bone marrow stromal cells. We used to think we're innocent bystanders but myeloma cells are intimately dependent upon those cells in order to survive. If you take a myeloma cell out of the bone marrow and put it in a petri dish, which I've done before, and you feed it all the bovine growth factor, you have a nice incubator, you sing to it and you play nice music, you put a little pitcher up in the incubator, they'll die in two days because they need bone marrow stromal cells in order to feed the disease. The bone marrow stromal cells are not going to die in two days because bone marrow stromal cells feeds it the interleukin 6 which helps the myeloma cell survive. It makes them resistant to chemotherapy, which is why chemotherapy didn't work for myeloma for such a long time. It makes it resistant to dexamethasone eventually and so those bone marrow, those myeloma cells need those bone marrow stromal cells in order to survive and they produce something called the vascular nithelial growth factor which makes new blood vessels in the area which also helps keep myeloma cells alive and why they proliferate and grow. They make new blood vessels in order to feed the cells. Myeloma cells are kind of mean because if you put, the reason people have anemia with myeloma is that if you put a myeloma cell next to a normal blood making cell, the myeloma cell will punch it in the face and then reproduce and take over its spot and it will kill other cells because it needs those bone marrow stromal cells in order to survive and there's only a certain finite amount of area inside the bone marrow to live so it kills other cells in order to take over parts of the bone marrow which is why you have the anemia, why you have the low immune system with myeloma and of course that protein that comes out, the monoclonal protein or the light chain protein, the myeloma cells, normal plasma cells make a bit of antibodies then they stop. Myeloma cells because they get all these nutrients from the bone marrow stromal cells produce that protein and keep producing it and producing it and producing it and those proteins get stuck in the urine, I mean in the kidneys which filter the blood as Dr. Ben Jones taught us in 1844 which can cause kidney damage. So that's the other defying disease defining event and those myeloma cells eventually inside the bone because again they're dependent upon that bone marrow stromal cells, eventually they will run out of room in the bone marrow, they need to go somewhere so where they'll go is they'll go to the next best thing to a bone marrow stromal cell which is a osteoclast. So osteoclasts are the cells in our bones that dissolve a little bit of bone to keep our calcium nice and normal. The osteoblasts make bone and we have this balance between the osteoclasts that dissolve bone and the osteoblasts that make bone. Myeloma cells love those osteoclasts because they'll feed them, it's one of the only other cells that will feed those myeloma cells. So they'll float out of the bone marrow, find a nice osteoclast, sit on it and get nutrients from the osteoclast and those osteoclasts can activate it and dissolve little bits of the bone and then more myeloma cells grow in, activate more osteoclasts which then causes the lytic lesions that we see in myeloma. If you look at those lytic lesions you'll see lots of those bone dissolving cells and myeloma cells sitting on top of them getting those nutrients and because of that dependence on bone marrow stromal cells and osteoclasts that myeloma cells won't go, you rarely ever go to the brain, rarely ever go to the lung because they need those cells in order to survive. Does that make sense? I hope. And of course when it dissolves the bone it raises the calcium level which is the other myeloma defining event. We have CRAB as those defining events. The high calcium which is a C, renal insufficiency or kidney damage which is the R, A the anemia and B bone disease. So that's CRAB. I've got a little bit more time. And so we struggled and this is where my, when I had hair, I had a high top fade back then. I was very proud of it. And the early 2000s we were struggling in myeloma because the chemotherapy just wasn't working. I mean it was just like these trials had response rates of 20%, 20%, 30% struggling. And we knew a lot of myeloma science. All that stuff I mentioned about bone marrow stromal cells, IL-6, VEGF, all that was known but they, you know other cancer doctors would say gosh those myeloma doctors they have such big brains and they think about this stuff but they have no way to use all that information. And then I would say I think it's a miracle that Dr. Bart Bartologi who's at the universe, the University of Arkansas, he really is, I would say he's one of the, he's one of the champions of myeloma. He was giving total therapy, lots of chemotherapy and he had a patient that had two transplants and was progressing and was getting worse. And his, and the patient's wife talked to Dr. Bartologi and said, you know my husband's really doing poorly with this disease, all this chemotherapy. And everyone talks about blood vessels and cancer. And of course Dr. J. H. Wright showed us that in 1900. There were lots of papers showing all these blood vessels and there's like is there a way to inhibit those blood vessels to maybe starve the myeloma? Instead of thinking about chemotherapy maybe use something that's unique. And so Dr. and Dr. Bartologi did something I think remarkable. Is he could have dismissed that. He could have said, you know lady your husband's not doing well, why don't you just deal with the chemotherapy, do what I say and leave it alone. But he listened to her and said let me see if I can solve this problem that you're talking about. Maybe there is a drug that will help your husband and reduce blood vessels in the marrow in order to do something different than what we're doing now. So he called Dr. Judah Folkman who's at Boston Children's Hospital who is working on anti-angiogenesis agents, medications to reduce blood vessel growth for diabetic retinopathy. Because the reason that kids have diabetic retinopathy or diabetic eye disease is because when their blood sugars are high too many blood vessels grow in the back of the eye of kids. And his idea was if he can decrease blood vessel formation he could save the sight of kids. So when Dr. Bartologi from Arkansas talking about myeloma calls Nobel Prize laureate at Boston Children's Hospital and when I was in Boston I would go to the best cafeteria was at the Children's Hospital. And when Judah Folkman would walk in it was like this entourage. And he had a, this is weird I get chills, it's strange. I get chills just talking about him. And he would walk in and there would be this entourage and everybody knew this was the guy. So this Arkansas doctor calls Judah Folkman and says I want an anti-angiogenesis drug because my patient's wife says that I think this is a good idea. So what is the last drug that a pediatric person is going to give a child is thalidomide. Because thalidomide had, which is an anti-angiogenesis agent and he would never give it to a child. So he gave it to Bart. Bart gave it to his patient. His patient then was, did the same thing my patients do. I'm on the newest thing and talks to other patients in the waiting room. I'm on the newest thing. I'm on thalidomide. What are you on? Are you on chemotherapy? I'm on thalidomide. So then his patients were like I want to be on thalidomide too. I want to be on thalidomide too. And so Dr. Broglie says fine. I will open up a trial for thalidomide but then I'm done. And that trial for 168 patients with myeloma had a 30, I think 38% response rate. A pill outperformed all the chemotherapy. And the reason is that yes it did a little bit of anti-angiogenesis but what it really did is it did all that stuff that I just said that is the crux of myeloma. It detached those myeloma cells from the bone marrow stromal cells. And again like I said you can sing, you can have a nice incubator with myeloma cells in it but if it's not attached to it it's nurse cells they die. So it detaches the myeloma cells from the bone marrow stromal cells so they die. It starves them of IL-6 which they need to grow and proliferate. It starves them of VEGF which needs to make those new blood vessels. And then the drug, the cousin to thalidomide because it was too toxic, Revlimid and Pomelist which you may have heard of. Those drugs were 2000 times more potent than thalidomide but it did something that it took about 10 years or maybe 7 years to figure out was it activated the T cells in patients to go after myeloma. Because right now, before that the T cells which usually survey for cancer, they would walk by the myeloma cells and say, you know, what's up? Myeloma cells would say I'm not bad, move on. And you give thalidomide, I mean Revlimid and Pomelist, those T cells would walk by the myeloma cells and then say wait a minute, you're not that good guy. And they go in and kill them. And the T cells would say, wait a minute, it activated T cells in myeloma patients. Which I remember reading that and I was just like no way because we couldn't figure out why it worked as well as it did. And one of the defining events in my career was that on December, November 30th or December 1st, I was working in the lab at Dana-Farber and when I woke up that morning, the standard of care for newly diagnosed myeloma was either Malflain or Pregnazon, 30% response rate, basically no deep responses or Vincristin, Aegemis and Dexamethasone, Chemotherapy Regimen. And that had about a 60% response rate, again no deep responses and very difficult to tolerate. I woke up that morning, those are the statistics of myeloma that I was living with. I did my thing in the lab and I was growing myeloma cells and we were going to do some experiments. I stayed late and I was leaving at 10 o'clock and Dr. Anderson, Ken Anderson, who was my boss, got in the elevator with me and I was all nervous because my experiments weren't going that well. And he said, Craig, I need to tell you something. And I was like what? He said, you know, we did this trial of newly diagnosed myeloma with Ravimid and Dexamethasone and it has a 91% response rate. And I was like, you're kidding, 91% response rate? We were at 60%, the best that we could do. The vast majority of people in the United States with a Mulflinor Pregnazone, 30% response rate and it jumped to 91% response rate. And he said, I think things are going to change. And then he said, have a good night. And he walked his way and I walked home. I didn't sleep. I was, and I'll tell you, that was when I said, I got to get out of the lab. I got to get in on this and see patients and do these clinical trials because that's amazing. And now you fast forward to 2022, 2023, where we use Deritumumab, which is an antibody against myeloma. So it gets your immune system to attack myeloma. Velcade, Velcade is a proteasome inhibitor. Myeloma cells, what do they do? They do all that stuff, but they produce that protein, produce that M protein, those light chains and proteasome inhibitors stop up the mechanism of protein degradation, which puts a huge stress on myeloma cells. So I could put, my scalp is not making any protein, obviously. So I could put Velcade on my head and it would do nothing. But you put Velcade on a myeloma cell where the only thing it does is produce protein. You stop up that, you select out the myeloma cell more than any other cell. You add the Velcade, Revlimid onto that, disturbs the microenvironment and the dexamethasone, 99% response rate, 99% response rate. In 23 years, we went from a 30% response rate to a 99% response rate because of clinical trials. I mean it is, and then beyond that, harvesting those T cells to destroy myeloma cells. With the bi-specific antibodies where you get those T cells and you force them into battle with the myeloma cells and hand to hand combat, super high response rates and CAR T heavens. When I was in undergrad, I did my research product on genetic engineering, inserting genes into cells and turning them into producing other things. And that was in what, I don't even want to tell you what year that was. That was a long time ago. And now we insert T cell CAR genes into T cells and reprogram them to destroy cancer cells. That is so Star Trek Next Generation, it just blows my mind still. And response rates are off the charts. So the world, you know, from Henry Bench Jones and Dr. McIntyre, who we owe everything, I would say, I think he's the unsung hero of myeloma, I think he really discovered it. Looking at a patient's underwear, I never do that. But he did, he did, and he thought, he thought he wanted to make it better for his patient. I mean, he wanted to make it better because he did not need to do that. And Dr. Bartologi, you know, who should have, could have dismissed his patient's wife from saying, this is what I want for my husband. But he listened and did it. And Dr. Anderson, who figured out all of the science behind the myeloma cells, and Dr. Bob Kyle, who made all the definitions and who's one of the nicest people on this planet, all of those folks got together to make myeloma where it is today, where there's so much hope. And that's myeloma 101. Any questions? So I would say honestly, what the two things what I think is what's next. I think the big thing is what's next is to redefine multiple myeloma. And so, and as we were speaking this morning now, multiple myeloma means that inside myeloma there are multiple diseases inside myeloma. There are people that have extremely quiet multiple myeloma on one end, and there are people that have extremely aggressive myeloma at the other. And the fact that we have the same, you know, name for diseases that are incredibly quiet and incredibly aggressive is wrong. And it's not because of lack of trying. We've spent decades trying to define the different types of myeloma so we can individualize therapy. Because, you know, if someone has myeloma, my Hemanq fellows, if someone walks in with myeloma, they know DERA, DERA RVD. They don't ask any questions. They don't need, they ask about side genetics. They ask about type. But they just give one type of therapy. And that's not right. Because there's some people who are over treating and some people that were under treating. So we need to define the different types of myeloma so we can make it more individualized. I mean, DERA RVD is doing a terrific job, but I think that we could do a bit better. The second thing is really curative therapy. And that's really what, you know, when I first started doing this, when my hairline was really going back, no one would ever say the word cure. No one would ever say that was not our goal. Our goal, we were still treading water, you know, in the early 2000s. And now every myeloma doctor I know these days, the goal is curative therapy. And I think there's some people, some of those more indolent types, who've totally cured. I have patients that I have not done any, they've gotten one line of therapy and they've gotten a lot of treatment. They've gotten one line of therapy and they've been perfectly fine as long as I've been doing this for about 10 years. Never relapsed. And I have people that have relapsed and relapsed and relapsed in incredibly quick order. And so we need to find out and better define these different types of myeloma. But that's what's next. But it's cure. It's cure. And then I'll be out of a job. But that's okay. I can, I think I'll open up a tropical fish store. In the tropics. And my wife is like, she's listening like, what? She has a sense. That fool is talking about open up a fish store? So, any other questions at all? Yes, please. Are you seeing a lot of patients being treated with their myeloma being treated as a chronic disease similar to diabetes rather than progressive? Yes. So that's a very interesting question because thanks to Dr. Barlogi, we learned that when I first started doing this, we treat patients for a finite period of time. So they get six cycles, seven cycles of therapy, a year's worth therapy, then stop. And then we just wait and they would relapse. And that was built on a construct of lymphomas and other blood cancers where you treat for six months and you stop. And we didn't know any better. Dr. Barlogi kept people on therapy. He kept people on total therapy and did a maintenance therapy. He was the only one doing that. And people were like, that's crazy. But it was the absolute right thing to do because when we did trials of using Revlimid as maintenance therapy, people stayed in their emissions longer. So it's being treated like a chronic disease. Now, in the past, really in the past, I would say year, we've really examined, do we really need to have people on maintenance therapy, especially knowing about MRD, which is being able to detect myeloma cells well below the threshold of our labs. Because, you know, what two tests do you measure myeloma with? The S-PEP test, the serum protein electrophoresis and the light chain test. I guess, you know, Henry Bench-Jones urine, 24 hour urine jugs, which no one likes to do. The S-PEP test is from the 1950s, back when we were using urethane and using antibiotics to treat myeloma. And the light chain test, thank goodness, was, you know, from the 19, from the early 2000s, I think 2007. So that's an old test. And that 24 hour urine test, you know, from 1847. And so MRD is going to help drive us, you know, being able to detect one myeloma cell in a million cells is going to help really drive, do we really need to do maintenance therapy.