Multiple Myeloma, Bicycles, and Working Toward a Cure


Looking back to the healthcare triage podcast? This healthcare Trieste podcast is sponsored by Indiana University school of medicine whose mission is to advance health and the state of Indiana beyond by promoting innovation and excellence and education, research and patient care. I you school of medicine is leading Indiana university's first grand challenge. The precision health initiative with bold goals to cure, multiple myeloma, triple negative, breast cancer, and childhood sarcoma and prevent type two diabetes and Alzheimer's disease. And that's perfect because today we're going to be talking about multiple myeloma our guest this week is rough it up norm. Who's the director of the mile Oma program at Indiana University school of medicine, we're going to be talking today about multiple myeloma? And where the cutting edge research is what people are doing what people are thinking where we might be going. So welcome. Thank you for joining us. Thank you for having me. Could we start a little bit? I've we're always interested in hearing about the backgrounds of our guests. How did you get to this position? How did you get interested in your research? How did you get here? So I started one. To become a transplant surgeon. But then I ended up doing just hematology followership and boomer transplant and I did my research on plasma cells. These are the cells that cause multiple myeloma. And then I started doing, gene therapy. And gene therapy was an exciting and dangerous. I needed to focus on something. So I knew plasma cells and I loved myeloma patients. So I decided to focus on that. So let's say what are plasma cells. So plasma cells are the cells that make antibodies to help us fight infection. We need them. That's how we survive, you know, one hundred years seventy years, whatever so one what happened is at one of these plasma cells become malignant and start reproducing itself and causing harm to the patient. So so there type of white blood cell. Yes, sir. Okay. Where they made. Well, they actually start in the lymph nodes, and then they migrate to the bone marrow where they reside. You know? So you get your first encounter was for example is a Tatton us or, you know, Newman. Yeah. Bacteria in the blood, and then the these cells much sure become plasma cells produce memory antibodies to help us fight infections, as you know, when we get exposed into the new Monia, and they reside in the moment when we need them. You know, they got out they make more new antibodies to help us fight infection. So can you talk a little bit more about how they work when they're working, right? How exactly do they help us fight infection? Well, they produce a specific antibodies. So we have a repertoire of plasma cells that capable of recognizing different pathogens, you know, from the mums to the measles to influenza to the new Monja and. And so every time we get exposed to one of these pathogens these plasma cells proliferate and produce more antibodies to fight the infection. So what happens when they produce the antibodies? What happens next? Well, the antibodies bite to the pathogens, and you just neutralize it or, you know, help other cells gobble it up. Okay. So what happens when things go wrong? Well, when things goes wrong is that one of these plasma cells start accumulating in the bone marrow. So you initially have for example, maybe five percent of normal plasma cells in the boom marrow. They don't cause any harm. We call that condition. Magas monoclonal Gama thief, undetermined significance just have a monoclonal protein doesn't cause harm to the patient. But what happened next is that tons of these cells stock, you know, accumulating in the bone marrow. They have like ten twenty percent, but it's still not causing harm. So we call that condition smoldering myeloma. And then eventually what happened is that these. Plasma cells can affect the patients in different ways. One is that it can weaken the bund so about seventy percent of patient was myeloma will have either osteoporosis holes in the bones or the star breaking bones. So they have you know, they just tried to lift a bag, you know, and then they break a bone in their back or something like that. So myeloma can affect the bones can cause a Nimia can cause very high calcium level because you lesion calcium out of the bone. So the patient become enable to think and may go into a coma or they can actually get kidney damage, so we call these of the crab criteria for diagnosing myeloma, the c is for high calcium, the are renal or kidney failure AMA or bone disease. So you have a lot of these abnormal cells in the and you have one of these criteria. Then we you know that patient has. Multiple myeloma. What makes the plasma cells? Go bad what what goes wrong? So we actually a lot of research going on in term of environmental exposures and just this week got big settlement against roundout because they when patients develop multiple myeloma from using them. So we think there is a toxic exposures farming communities. There's increased risk of multiple myeloma near factories, and you're mining communities, for example, I have patients in your a mine in south west, Indiana, where multiple people who worked in that minds developed multiple myeloma, you know, and the questions of what did they dumped into the water? These people are drinking water. And so I think we think chemical exposure plays a role in making these plasma cells so are become malignant, and multiply, and and you know, 'cause. Harman cosies. Okay. So once somebody is once we have a concern, they've met their the crab criteria. What what happens next to help make the diagnosis? So we do several things number one. Obviously, we need to do blood tests this anemic, they have high calcium or they have kidney failure. The the second thing is that we look for this abnormal protein because myeloma start from one plasma cells the protein, they produce is unique we call it mono clone protein. So we do a specific blood test to check for the monoclonal protein and find it we have to find a monoclonal protein or we find an abnormal part of that protein. Raise recall, it the free light chain. So we check that the second thing that we have to look and see what they have in the bone marrow. So we do a bone marrow biopsy to see the number of these abnormal cells, and what type of cells we do genetic analysis on those cells to see. What they do. Because my my Aloma patients some of them do very well, some of them, do okay. And some of them do poorly and the genetic makeup of the mile Oma can help you distinguish these three groups. So that was actually going to be my next question is sort of all cases of multiple myeloma the same or they already different or do. They fall into a bunch of category. Yeah. I mean, I think that term multiple may not be really because of multiple lesions was in the patients things multiple presentation of the disease. Okay. So I have patients who do very, well, they get one kind of tweet -ment and go on and stay in remission forever. And then we have patients who was in a year or two they relapse and they actually don't do. Well. And then so that's about twenty percent for each group. And then the rest the sixty percent those patients, you know, have multiple relapses, but you can control the disease the can live long life. So what is the treatment for the most part? Yeah. So the treatment has evolved that used to be more chemo. Arab your traditional drugs that cause hair loss or blood counts. Abnormalities? But now, we have these recall them, so our novel drugs, they work on things that influence the proliferation of the cells or the interaction was the neighborhood where they live. So these cells can't, you know, not really find hospitable environment was in the boomer to grow. So these new drugs that in combination have produced amazing results, we still consider high dose chemotherapy and stem cell transplant as part of the tweet -ment to improve the outcome. And some patient may need Menton therapy after you do the stem cell transplant. So for the most part, though, it's it's drugs. Yes is drugs. And so what's the typical course if of treatment? So most patients will require what we call induction treatment, you know, which is trying to control the disease trying to improve the symptoms and. That will take three to four cycles the psychos about four weeks after that, you do the stem cell transplant, which is two components wants collecting this themselves that support the use of high dose chemotherapy, then you give this big dose chemotherapy, which tells everything in the bone marrow. But you have the patient stem cells that make blood cells stored. So the next day you give it to the patients, and these cells will grow and make healthy cells. This is when you're doing a stem cell transplant transplant in the patient cells back into their own body. Yes, how does that work? So what you do is you collect the patient own stem cells I and these cells live in the bone marrow. So what you do is you give specific hormone that stimulates these cells to grow every day for four days on the fifth day. They're blood is full of these stem cells. What you do is you take the blood out, and you do a process like Dallas as a process called a freezes. So you collect the only the stem cells, and you store them you give the blood back to the patients, and you do this in the outpatient and a bloodbath. Four hours five hours a day. Sometimes in one day, you get all the stem cells you need sometimes you need to three days. How do you be sure that you're not collecting bad cells or that those won't turn into bed? So yeah. So we have looked actually we did research on that. So what we looking for is specific marker on the surface of these cells makes them stem cells called CD thirty four, and we look to see if we collect any Milena cells, and we did very sensitive essay and two things. One is the myeloma cells don't mobilize, you know, that effectively and the second things that they don't freeze. Well, so basically the products we give back to the patients, very unlikely to contain any Milena cells knowing that the stem cells could then are you assured that the stem cells won't then develop into cells, which will turn back into my or is that just you just have to take this stem cells are the cells that make white cells red blood cells on platelet, right? And the process of developing multiple myeloma doesn't really start at the stems. Okay. Stems stock to probably around, you know, when they sort of mature to white cells, and before they divide into lymphocytes or neutrophils different part of the white cells. It's the lymphocytes level when you know, they become B cells of the B cells become plasma cells. So maybe it's between the B cells and the plasma cells. So I guess I'm reading this question. Maybe totally naive given that we know that whatever was in this person to that such that their cells could develop into myeloma cells would they be better off with someone else's stem cells that dose sales are less likely or is that just too hard to do. Well, it's very hard to do. So we have done what we call allogeneic transplant donor stem cell transplant. The problem is that most patients in was multiple myeloma are in their late sixties. So I'll genyk transplant is very risky. We actually lose large number of these patients and despite doing an allogeneic transplant some patients have relapsed. So it's not really a route. Eighteen Lee us approach maybe in the young patients, and you may concern allergenic transplant. The issue was allergenic transplant is the risk of a graph versus house disease that immune cells from donor. Do not like that where the living in the new in the patients, so you get damage to the skin liver and the intestine, but the other thing is that the advantage of allergenic transplant used to be the graft versus disease and fortunately, the myeloma cells tend to hide from the immune system. And we don't get very good graft versus myeloma affect when allogeneic transplant. Okay. So patients get around of drugs and then stem cell therapy. And how what what's the usual course after that? So after three months later, they recover from the stem cell transplant, then some patients are considered for Menton insz therapy. So two things one we give him medicine to keep their bone from breaking down. We do that as an infusion or injection once a month, and then sometimes. We give pills of these novel chemotherapy drugs that will help maintain the, you know, the response, I think that research should be focusing on what to do after transplant when the patient have minimal residual disease. How can we improve the patient immune response to radically the residual disease is that the chemo pill, or is it some other strategies that we try actually to explore here? How many different types of drugs are available. I mean is it did everybody gets sorta the same octave of drugs or is it individualized? So when I started working on multiple myeloma, we had only this traditional chemotherapy in two thousand and three the first in class drug was approved which is a protease inhibitor and protease inhibitor is just thinking about it like a, you know, you have a garbage disposal, and you just clogging then you just accumulation of toxic stuff, and you know. The cells start dying. So that's how it works. And these are amazing. I mean, these drugs have changed the course of the disease now there are three drugs in that class available and in two thousand six we got a class of drugs approved called the immunomodulators drugs. So and the first in class was the drug thalidomide drug that cause a birth defect. When it was used in the fifties for motion sickness and nauseous associated with pregnancy and this drug we didn't understand how it works for a long time. But so and that but the problem was using thalidomide for a long time it can cause nerve damage. Okay. So the company that makes drug start developing next generation of that drugs that caused less neuropathy. We actually have to drugs in that class now. So we have three immunomodulating drugs three inhibitor. And then more recently the FDA approved drugs. We call him monoclonal antibody. So these are drugs that recognize the surface of myeloma cells, and sort of, you know, help eradicate these myeloma Celso protein that bind to the myeloma and bring immune cells to try to radically them Saturday decide which of those to us. Well, that's a great things. That's why we do clinical trial and in clinical trials, we find the best combination. So first of all we now know that one drug is not enough you have to use a cocktail of drugs. And so we just you know, the good things for patient today is that you have different cocktails so based on their medical condition, you can find the right combination therapy. So when you say their condition, what specific example, if somebody has significant nerve damage, you went to avoid drugs that cause further nerve damage if somebody have advanced kidney failure you and avoid the drugs that can be too toxic. If you have kidney failure. So that's a good news for the patient is that we can tailor. The therapy to were there conditions, and they're actually desire. I mean, some people would like only oral regimen. They don't wanna go to envision the can really go twice, you know, week to the clinic to get chemotherapy, we have oral regimens for them. So when you say they're cocktails a multiple drugs in a class or you're picking drugs from each different class. Exactly we pick drugs from different class. So basically what we do is synergy was at overlapping. Toxicity. Okay. And so what does the usual course, you have your dream Indra maintenance how to most patients too. So most people as I told you, you know, they really do. Well, they stay in remission for a long time. You know, now the average, you know, time in remission, maybe five to seven years, but unfortunately, we have these about twenty percent of patients who relapse was in the first two years, we call these are high risk risk of what risk of shorter remission shorter survival. That's where really a lot of research going on to try to improve the. Outcome of these patients. Do treat them again. Yes. Which read them again, we tried to find novel combinations. We tried to find clinical trials for these patients. We trying to employ some newer strategy. For example, one of the nearest strategy will be what we call Carty cells, which is basically taking the patient own immune cells expand them, genetically modify them to make sure that they can recognize myeloma and kill it. So we put to Sheen's one to recognize my Loma and one killer jeans. So that's why we call it kind Merrick receptor Antillean T-cells Carty cells. So these cells are I mean, these kind of therapy is now used and clinical trial in relapsed patients, but we may be able now to use it in a clinical trials for the higher spacious affront before they get to you know, relapse and have a horrible disease that how to control how hard is it to do that. So first of all you have to collect the patient and. T cells lymphocytes that become the killer cells. So basically, it's like we collect the stem cells. We do a free says we take the blood out separate the white cells from the rest of the blood. And then when you take these to the lab, I mean to the processing manufacturing facility, you separate the specific cells, we call them T cells. And then you incubate them was a virus that get two genes inside the cells after you expand these cells, and then you bring them back into getting back to the patient. So it's very expensive process. And you know, the FDA as, you know, approved to Carty saws one for lymphoma in one for leukemia that are very expensive. But there's a lot of different companies are working on it. We at Indiana University school of medicine put together grants, and we have a center the Brown center for immunotherapy. We almost ready to recruit the director. Of that. And our goal is to try to improve on the safety of these products, the specificity of these products and improve the sort of sustainability. I mean, unfortunately, if you look at some of the clinical trials the cells lasted about a year that's not good enough. Because if they start relapsing a year and you give them very expensive therapy. So our goal is to try to make Carty sells more specific safe and maybe less expensive house pensive visit. Well, I mean for the commercial products is almost four hundred thousand dollars charge for that. If we produce it locally, and may cost us probably forty thousand dollars, you know. But that's why our goal is to see if we can start making your own cartoons. What what's the usual prognosis for for a patient of developmental model? Really has improved significantly. If you look at patients when they were diagnosed fifteen years ago twenty years ago, he uses say you can live on average to three years now. Think if you look at patients depends on their station, you know, so if you have stage one disease, you know, you would think the spacious should live at least fifteen twenty years, you tell us what stage one is. So sage one is the we look at certain things we look at the chromosomes and the side of the bone marrow. The are they good chromosome backrooms? And we look at something called L D H is of you know, enzymes in the blood. We look at albumin. So if these are normal and there's another protein, we look at the blood called beta to micro glob, and so these are normal and the signings. Good one that's a stage one and these patients, you know, if you look at their five year survival more than ninety three percent of a life at five year. So the statement, you know, influence chirp how long they live, but we are seeing more patients living was myeloma and starting to die from something else. Compared to what we did ten fifteen years ago. What did the other stages so sage two and three? So three is the high risk where you have high beta to micro gloveman, high L D H. Hi, low albumin and bad cytogenetics in the bone marrow. Okay. So it it's more about the state like the actual chromosomes, and what the cells look like then how quickly you caught it or how much I'm obviously metastasized surely different. Meaning. Well, yeah, I mean myeloma is always sorta detected, you know, at a advance or all over the body. You know, so, you know, unlike you know, other tumors assist, always systemic disease. But it's you know, if you detected early stage before you have a lot of Milo, my you have a lot of bone destruction. I think you're gonna do. Well, now the trick is what we're doing is that a lot of research going on is first of all as I told you my only go is preceded by two conditions mug us and smoldering myeloma. So why don't we treat all smoldering myeloma treatment can have? Side effect. And we don't know if you'll really can cure patients, if we have a curative regimen, then we can use it early on and take some risk. So only specific group of smoldering myeloma, which we call him high-risk for progressing in a half of them will rely progress to my Aloma was in two years. We doing clinical trials on them and are to kind of clinical trials one use the combination chemotherapy that we have the novel, Asians, you know, the monoclonal antibodies that proteome inhibitor we put them together. And what we trying to do was in two years to see how many patients are we putting in really solid remission with the hope to cure, these shrines the other approach to the higher swelled among multiple myeloma is that can we actually make this myeloma cells visible to that mean system can we make that new system recognized myeloma? And so what we're trying to do is actually generate vaccine from these myeloma cells, and then inoculate. The patients was this vaccine was the hope that they develop immunity that will eradicate the myeloma. So the vaccine battalion individually each patient or just kind of vaccine for everybody. Yeah. So we take the myeloma cells generate a vaccine from their Milo myself. So it was that the kind of thing that's just going to have to be you think will be commercially like Dobie a company that does that. Or is that we're just you need to go somewhere. That's doing it in a lab, I think we should be commercially available. That's the hope is that you can generate a vaccine that for each patient's unique just send the cells, and they process it, and they send new vaccine, what do you think the most exciting works being done right now. Or what what is the most? What area I'm not saying we're in the country. I mean what area? Do you think is the most exciting for me? For example. I am actually looking at trying to figure out can we prevent the development of multiple myeloma. So I'm doing clinical trial in patient was monoclonal Gamaa, a thief undetermined significance, and I'm trying to see if we can actually prove, you know, prevent him from developing multiple. Milo moment. So let me tell you the background of that. So in my practice. I see a lot of monitoring gum with even determine significance. And I have seen patients who lost the mock Logam up at the so how did it disappear? So in the six to eight patients I have seen the lost weight and by weight loss, they lost the monoclonal gum up. Really? So we think obesity is an inflammatory state can stimulate plasma cells. So what we doing? Actually, we putting a trial together we start accruing here. We're gonna look at patients who undergoing weight reduction surgery, and what we're gonna do is screen them for Magus. And then those are positive for the monoclonal mafi. We're gonna follow them after the surgery and look at the group that lose weight versus the group doesn't lose weight. Sure. Are they going to lose the mug us or not? So if we can prove that they hit LA. Lost this abnormal protein. That's a good things. And we're gonna try to explore and see why is it you know, because they lost certain inflammatory proteins when they lost the weight or not. And so that will be a crate advances. And so basically a known risk factor for myeloma. Yes, if patient who are appea-, let me tell you if somebody has monoclonal Gama Pathy, and if you know, and they are obese they have four and a half a chance of developing multiple myeloma compared to non Opie obese patients. Yeah. So this is a big study that was done at Saint Louis VA hospital because they have records on patients who developed myeloma, and they have, you know, they know their weight, and they know if they had manga so not so that will be four and a half time just type two diabetes tied up in that too. Or is it just the obesity? I think just the obesity. I haven't looked at. I'm not familiar with any day down diabetes. But so besides the prevention what else is so prevention, I think the other thing is that we really need to screen. I mean, we need to see in this area that we talk about the higher scary near farming community near mining community near factories that was dumping a lot of these chemicals. Can we understand how many? People do have these premium conditions will be interesting to understand that. I mean, because then we will source study the impact of you know, this environment on these preconditions. And then what we would like to see is predisposing factor. In addition to the chemicals, if you have certain gene, will you get myeloma when you're exposed to certain pathogens. So I think that's exciting to us. And then finally can we find a way to deal with high risk Milo. My thing that's really the most frustrating. You know condition we deal with and Michael is to really understand the immune makeup of these patients and try to understand how we can enhance it to help us radical the disease Howard. I mean, just because clearly we live locally how are patients doing here. Locally. And what are we doing? What kind of studies are we doing locally to to try to help? So that's a great questions as you know, Indiana University issued this gr- gr-. Grand challenge. Grant, trying to really cure three diseases and cancers in Indiana and multiple myeloma was selected as one of these diseases. And so one of the proposal that we have is that we want to understand how myeloma patients do in Indiana. We want to understand their diagnosis their treatment their outcome their side effect. In addition, we want to understand their genetic makeup and also understand the myeloma genetic makeup and environment. So we putting together what we call a cohort of patients. We want to analyze one thousand patient was myeloma and Premio on condition in Indiana. We started actually accruing patients in November. And we have more than one hundred seventy patients thus far enrolled. So what we do is we looking at their sort of baseline genetic in formations. You know, we take saliva. We take a blood, and when we do a Blencoe biopsy. We take the mile cells and the neighborhood where they live inside the mirror cells. And we tried to analyze them. And the goal is to try to understand do. They have a predisposition to certain things what is their immune profile? Was there ability to metabolize certain drugs or not, and then sort of correlate the natural history of the disease was their genetic makeup, the myeloma genetic makeup and the micro environment was in the Bom omega. Are you looking at their broader environment as well where they live might be exposed to exactly. So we are doing that in collaboration with group down in Bloomington because you know, by zip code, you can figure out what they live what they exposed to and things like that. And we have sort of a that we ask the patients to help us understand, you know, their occupation. Whether they grew up things like that. So how long do you think that'll have to take to to get all the patients you want? So as you see I mean since November, you know, that's about four four months. Five months. We have one hundred. Seventy patients. So I'm hopefully, we can accrue all these patients was in two two and a half years. There's all new diagnoses or picking up pay our patients, you know, fr newly diagnosed relapse stations how common is myeloma to begin with. So my is about one and a half percent of all cancers, and we trying to figure out the exact incidents in Indiana's probably about twelve hundred new patients diagnosed a year, clearly the NIH has to you know, give money to this. But how else do you put money together? Dacians how else does myeloma research kit done as an avid runners, you know, I of about fifteen years ago, we were sitting with patients and trying to figure out how we can you know, sort of support myeloma research at Indiana University. So one of my patients said why do we just do five K for myeloma? And I said, well, everybody has a five K for mile on how about we do something different. You guys come to me from all over Indiana for a second of. Opinion, why go to your community and spread sort of word about the disease? And they said, wow, that's exciting. So how you know? But I'm not going to be writing a car to go there. I'm just gonna run, you know. And I year, you know, I wanted to go run to Fort Wayne. Okay. That was a huge far away twenty. Not really, you know. So what do we did is we saw in the first four years? We split it. You know, one day of frightening and one day of cycling, tell me about fifty miles off reading in the rest of cycling. So that's how miles for myeloma started. And then because the distance are getting like two hundred two hundred and fifty miles is just two days or three days of cycling. Okay. So we have, you know, come from Saint Louis, Indianapolis from Columbus, Ohio to Indianapolis miles for my we've raised almost five million dollars. But the most exciting thing about the whole thing is that we have patients who ride with us. It's organized by family of patients that do that. And so the thing about it is that makes me really excited to see you. My Loma patience writing. And I still remember one day because you know, you get these guys who wants to write was you. And they very really amazing cyclists. And they just you know, this is not a race. This is a group of people trying to write together to support each other and spray. Adored about my lowest. So if you have somebody already in Indianapolis, and the the other person's still in Tara hold is not fun now, it's hard. So I remember one time it was like I want to tame the group down a little bit. So I stopped everybody. And I said, do you know why we're doing this because of my Aloma? What we going to do about it? You know, we're going to spread the word we're going to try to raise awareness. We wanted to make sure that everybody understand this disease need to be cured. So I said how many of you writing was myeloma today, and there were two people. And I said how many a few writing, you know, was myeloma and still on treatment for myeloma one guy. I said, okay. So this guy is going to lead us and everybody has to follow him. Right. Do not pass this. So I was kind of probably doing it because I was tired when it's slow the pace down a little bit. So this guy grab a bottle of water? Pour it over his head, and we actually stopped at the bottom of a hill. And this guy was climbing so fast. I was like working hard to stay was when they say, oh my gosh. Why did I say that? But it was amazing to see how excited he was how aggressive he was climbing that hill, and it just makes me know that, you know, today myeloma patient can live a normal life. They is not, you know, a disease that stop you from living your life, and that's what we need to tailor therapies, so they can live healthy quality life, and hopefully, we can find a combination that cure them. So they're gonna stay on treatment forever. This healthcare podcast is sponsored by Indiana University school of medicine whose mission is to advance health and the state of Indiana and beyond by promoting innovation and excellence in education, research and patient care. I you school of medicine is leading Indiana university's first grand challenged precision health initiative with bold goals to cure, multiple myeloma, triple negative, breast cancer, and childhood sarcoma and prevent type two diabetes and Alzheimer's disease. Thanks again to our guest raff avenue. Our for our discussion of multiple myeloma. What causes it doing about it where things might be going in the future? Listen to the healthcare trash podcast each and every month for information about health health policy health research, we'll see next month.

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