(Guest Lecture): September 2022 - Evolution of Myeloma Therapy

This compound CLCCSCCCL. Got it. So, this was developed about 1910, the sulfur containing compound. And when it was first used, it was used on the battlefield in World War One. And when it explodes, and you're exposed to it it causes amazing severe irritation of the respiratory tract, the nose, the throat. The inflammation is so profound that it causes battlefield asphyxia, and the recruits die on the battlefield. Now, this bis chloroethyl sulfa amine is technically difficult but when it explodes on the battlefield, it's bright yellow it's the same color as the top of this sheet here. And I refer to it because it's just easy to identify as mustard gas. And so, mustard gas was used to asphyxiate against the Geneva Convention troops on the battlefield. Everybody exposed to this died of it. And what happened is that there were some military recruits who would survive the initial damage to their lungs for two weeks and then at the end of two weeks, they would die of infection, bleeding. And although it was very limited you could see that these patients had very profound anemia. Military recruits who die in the battlefield you don't need permission for post mortem examination so they routinely underwent post mortem examinations, and was found that their bone marrows were completely empty. And their lymph tissue, the lymph nodes in their body in the neck, chest, abdomen were gone, they were just completely depleted from the exposure to the mustard gas. And it was thought that must have therapeutic value. And, of course, this is 1916 now bone marrow technique hadn't been developed until the mid 40s. And so they thought there must be some value and so the Department of War, which is what it was called in those days before the Department of Defense hired pharmacologists and hematologists, there weren't really hematologists those people interested in the blood to try and make something out of it and you couldn't handle mustard gas it was impossible to handle a gaseous element. But what they did is they changed the sulfur to a nitrogen. And then they referred to it as nitrogen mustard. And that chemical it turns out nitrogen mustard is capable if you take DNA, which is a double helix and unwind it and flatten it it looks like a ladder. And the nitrogen mustard actually would hook up the uprights of the ladder. See, see, and see see. So that it couldn't unzip and if you can't unzip DNA a cell can't divide. And so it would poison cells trying to divide. And so they said, okay, we've got something here that we can use to kill cancer cells. Well, they had the whole thing developed about 1943, and wanted to publish their results about the first anti cancer drug in 1943. But the Department of Defense labeled it as top secret and block publication of the article, so it didn't come out until September 1946 in the Journal of the American Medical Association. And there are pictures there of people with very, very large lymph glands 10 days later, all gone. So, they published this use of this nitrogen mustard compound for the medical professionals in the audience I don't have Genesis here but the two pharmacologists who developed it were Goodman and Gilman. The two hematologist who developed it were damage Jack, who was the first editor of the Journal of blood and Max Wintrobe who founded the center in Salt Lake City, his pictures going to be in there somewhere. When you go in. But nitrogen mustard was difficult just like the mustard gas could cause respiratory burns if you injected this intravenously and it leaked out of the vein it would burn a hole in your hand, it was extremely caustic and difficult to use so they wanted to try and find something that was a little bit easier to use so I'm going to draw the mustard here. Boom, boom, boom. And what they did is they wanted to make it easier so they wanted to attach it to something that would get into cancer cells quickly. And so they wanted to attach it to an amino acid amino acids the building block of protein. So amino acid. Let's see. That amino acid that I'm drawing here is the amino acid glycine. And that is the amino acid fennel, Alanine, and then they attached it to a chemical group called fennel. And that was fennel Alanine, and when they attached it like this. That became L fennel Alanine mustard. Oh, that's not good. As long as I don't fall on it. So L. Alanine muster and or L Pam was introduced about 1960. And what they did they renamed it generically as follows, and he l p h, a l a n or Melphalan. So that's been around 60 years and Melphalan is the drug that everybody gets in the context of a stem cell transplant that is Melphalan at a very high dose and that really is basically a derivative of mustard gas it's not too far off and poisons the DNA so that was the very very first available drug for the treatment of multiple myeloma was actually produced in Russia. And it was introduced at two sites in the United States or North America. Dr. Daniel Berg segel introduced it at the Princess Margaret Hospital. And it was introduced at the MD Anderson Hospital those two by pioneers in the field. So that's one drug number two. It's the mid 50s. It's Germany. And they're trying to deal with the terrible problem that pregnant women get with nausea and vomiting, the technical term is hyper emesis gravidarum. And so they tried to produce medicines that would be both sedating and anti nausea, and they did develop a compound a very simple compound called the litamide. So the litamide came out in 1955. And they tested it in mice and in rats, and found not to be toxic with mice and rats don't have the same protein content as humans do now for little might never got approved in the United States never because it caused peripheral neuropathy and the FDA said, you can't sell this drug in the United States it's too dangerous because of the peripheral neuropathy, but it was sold widely in Canada, Europe, Australia, and the litamide caused terrible birth defects and so it was basically banned worldwide and became only available only available for the treatment of a skin condition that's associated with leprosy so it wasn't a big seller. And in 1999, scientists looked at medicines that could stop tumor growth by blocking the growth of blood vessels that feed the cancer. And they found that the litamide had this property of being able to stop blood vessel growth that feeds malignancies. And so the wife of a cardiologist knew this and she brought this information to Dr. Barthel Barlegui at the University of Arkansas Medical Center 1998. And he said he'd try it. And in 1999 at the American Society of Hematology he presented his results. I'd say there were 4000 people in the audience and when he showed the results of giving the litamide to patients with multiple myeloma you could have heard a pin drop. Because it was really the first new medication for the treatment of multiple myeloma in 35 years. So litamide isn't used much in the United States but it's very very simple derivatives, lenalidomide, also known as Revlimid, and its derivative, pomalidomide also known as pomalist are widely widely used as oral drugs for the treatment of myeloma so that's 99. So we go to 2001 now. 2001 there's some poor MD PhD at the University of South Carolina, who's looking at drugs that might take care of cancer cells. And so he was looking at drugs that would inhibit what's called the proteasome. So the proteasome in a cell is basically the sink garbage disposal. And when proteins have to be recycled in the cell they head to the garbage disposal and they're taken away. And so he tested this compound. Yeah, this would be about 2003 now in a whole host of cancers. Breast, no activity, colon, no activity, lung, no activity, pancreas, no activity, treated three patients with multiple myeloma. And the responses were dramatic and deep and very very impressive and very sudden. So the drug contains boron in it, the chemical element boron. The problem with boron is it damages nerves, it can damage nerves in your feet and that's a problem with it but that was part of the activity. And it was a inhibitor of the proteasome. Proteasome. And so they ended up calling it Bortezomib, sorry. And that trade name for that's Velcade. The person who developed it is Robert Orlowski and Dr. Orlowski is on the board here of Health Tree. He's now running the myeloma show at MD Anderson Cancer Center now. Bortezomib was number three. So that's the third class, alkylating agents, then secondly with the immunomodulatory drugs, the with the lytomidine, revlimid, lenalidomide, and then Bortezomib or Velcade. And finally, I just want to talk briefly about scientifically targeted therapies because those three are basically found by accident. All cells in the body, all cells in the body, have proteins on them, unique to those cells. And so they called those proteins antigens, about 1890. And antigens are familiar to you in a way because you know there are unique antigens on your red blood cells. Dr. Lengsteiner in 1902 described the unique antigens on red blood cells. The first one he found, he called A. The second one he found, he called B. If you had both the antigens, he called it AB. And if you didn't have those antigens, he called it O. But he didn't refer to it as red blood cell antigens. He called them blood types. But basically that's the principle, unique proteins that identify cells. Well, there are unique proteins that identify myeloma cells. There are two I want to talk about. One of them, unique, is BCMA. BCMA stands for B cell maturation antigen, not important, is a protein found on myeloma cells. And what's nice about it is it's found only on multiple myeloma cells and no other cells. And so what scientists began to do, this would be just seven years ago, is they took white blood cells, your white blood cells, white blood cells, killer white blood cells as a matter of fact, the white blood cells that kill viruses and kill fungus that are really key to your immune system. And these killer white blood cells, oh that's bad but I just did, are called T cells. The T cells refers to embryologically where they come from. And what they did is they wanted to activate these T cells, so they would seek out and kill myeloma cells. So what they did is they engineered these T cells. And what they did is they put scaffolding on the T cells like this. That was hooked in to the cell membrane with a recognition site here for the BCMA antigen. And so once it's engineered, your white cells, they can actually find and attack any cell that has BCMA but the only cells that have BCMA are myeloma cells, and they'll kill these cells. Now, the engineered white cell, once you put that scaffolding on it to recognize myeloma cells, it's not a natural cell anymore, it's been constructed. And something that has pieces of nature in it, but isn't really natural is referred to as a chimera. Goes back to the Iliad Homer described it, it was an animal that had a lion's body and an eagle's head and a snake's tail. So they created this chimera and this recognized the BCMA antigen on the myeloma cell surface. So it was an antigen receptor T cell or CAR-T. And so CAR-T therapy was specifically designed and engineered to directly attack multiple myeloma cells. We have two CAR-T products approved in the United States after failing four treatments, but there are a lot of research CAR-T trials, I mean a lot, including a trial now called CAR-Titude, where patients actually start treatment for their multiple myeloma and instead of having a stem cell transplant, they actually are randomized, a coin toss, half get a transplant, half get CAR-T therapy, the goal to determine will CAR-T replace the use of stem cell transplant. The second iteration of this is once they developed this scaffolding that was hooked in to the killer T cell, your white blood cell, and then would recognize the myeloma cell, we say well why do we have to engineer the white cell? Why don't we just produce a molecule that on one end recognizes the killer T cell and on the other end recognizes the myeloma cell. So it will attach at both ends, but it doesn't have to be engineered into the white cell. And this is what's referred to as a bispecific one, two antibody that at one end recognizes the cell that kills and number two recognizes the cancer cell, brings them together and so bispecific antibodies. I'm going to finish. BCMA is not the only myeloma specific cell. There's another antigen on the surface of myeloma cells called CD38. CD38 again is a protein that's found only on myeloma cells. And so they specifically, this would be Janssen actually, specifically engineered an antibody to recognize CD38 on the myeloma cell surface and kill it. And when it was first introduced, maybe experimental trials 2014, 2015 and heavily pretreated myeloma patients, it was found to be highly active in killing the myeloma cell because the antibody recognized the antigen, the protein unique to myeloma cells called CD38. And they called this monoclonal antibody daratumumab, you know it as Darzalex as the fifth category of chemotherapy. So, five categories, alkylating agents, mustard gas, immunomodulatory drugs, the ones that cause birth defects, but in humans not in mice or rats, proteasome inhibitors, the proteins that break the garbage disposal so the garbage collects in the sink and kills the cell. CAR-T, the engineered white cells to recognize specific BCMA proteins on the surface, and five monoclonal antibodies against CD38 of which daratumumab is one. There's a second one, isotuxumab, I don't know what the trade name is for isotuxumab, I can't remember. Sarklissa, thank you. And so those are basically the five drugs. I just wanted to kick things off by giving a little bit of an overview of the development of the chemotherapy drugs for multiple myeloma and Greg you can take it away from there.