Dr. Aaron Carroll talks with Dr. Rafat Abonour and Dr. Fabiana Perna about multiple myeloma research and ongoing studies, such as the Indiana Myeloma Registry. We'll also hear about how losing weight may help lower your risk for getting cancer and why immunotherapy could be a promising treatment option for multiple myeloma patients.
Dr. Aaron Carroll: Hi and welcome back to the Healthcare Triage Podcast. This week we're going to be talking about multiple myeloma again. It's been some time since we have. We have a repeat guest to talk about that. Rafat Abonour, is the Harry and Edith Gladstine Professor of Cancer Research. But joining him is a new faculty member, Fabiana Perna who is an associate professor of medicine at Indiana University School of Medicine. Both of you welcome.
Dr. Fabiana Perna: Hi, good morning.
Dr. Rafat Abonour: Thank you for having us.
Dr. Aaron Carroll: This Healthcare Triage Podcast is sponsored by Indiana University School of Medicine whose mission is to advance health in the state of Indiana and beyond by promoting innovation and excellence and education, research and patient care. IU School of Medicine is leading Indiana university's first grand challenge, the Precision Health Initiative with bold goals to cure multiple myeloma which we'll be talking about today, triple negative breast cancer and childhood sarcoma and prevent type 2 diabetes and Alzheimer's disease. I want to start with just a brief review of what multiple myeloma is because it's one of those diseases which I think it perks people's ears up but not a lot of people have a great understanding so, could you briefly tell us to begin with what is multiple myeloma?
Dr. Rafat Abonour: What is myeloma? Is really blood cancer. We have cells in our body, their job is to make antibodies to fight infection. For example, when you get a COVID vaccine, you're going to make an antibody to get rid of the COVID virus. However, if one of these cells become malignant, they can accumulate in the bone marrow, they start destroying the bone so the patient can break bones easily. It may cause kidney failure, it may cause anemia so it can be a really nasty disease. Most patients nowadays are diagnosed before they have severe form of the disease, which is a good thing because I think it made people are aware of multiple myeloma. The second thing is that myeloma is proceeded by two conditions. Relatively one of them is benign called MGUS or Monoclonal Gammopathy of Undetermined Significance.
Basically, we have a few of these abnormal cells, not a lot of them. They're not causing harm to the patients. If we have too much of it, then it becomes smoldering myeloma. Basically, most patients are going from this pre-myeloma condition to myeloma and the reason I'm talking about that because I want to tell you about our research to actually try to prevent myeloma because wouldn't that be great if we can screen earlier and we can prevent patients from presenting with broken bone or kidney failure?
Dr. Aaron Carroll: How could you prevent myeloma and how would you even know whom to prevent myeloma in?
Dr. Rafat Abonour: First of all, if you look at the people who present with multiple myeloma, mostly they are in their 70s and there's slight more predominance in male compared to female. But if you look at Black in America, they have twice the incidence of multiple myeloma compare to non-black. The question is, why is that? And should we be screening like American for myeloma and pre-myeloma condition? What can we do? We can do a blood test. We can send it for what we call serum protein electrophoresis and light chain assessment. These two tests will help us see if there's a monoclonal protein or not and then we take it from there. We looked at people who for example, in term of prevention, I told you that every myeloma patient had a pre-myeloma condition. When they looked at large number of VA patients in St. Louis area, those who were obese and had the pre-myeloma condition had four to five time a chance of developing myeloma if they were not obese.
What that means is that maybe obesity is actually playing a factor in progressing from pre-myeloma condition to full blown myeloma. Part of our research through the Precision Health Initiative is to screen people who are going to have weight reduction surgery for their obesity for the pre-myeloma conditions and our goal is to see what happen after the surgery and the weight loss. Well, they lose the pre-myeloma condition and our hypothesis based on anecdotal experience from our clinic is that by losing the weight, the pre-myeloma condition will disappear.
Dr. Aaron Carroll: Just by losing weight, you can prevent cancer? I mean, clearly there's lots of other diseases that you can improve by weight loss.
Dr. Rafat Abonour: It's not just myeloma. Our colleagues in breast cancer are looking at that too. They trying to see if weight reduction will actually prevent patient from progressing from a pre-malignant breast cancer conditions to full malignant breast cancer condition so yes, obesity is not just causing coronary artery disease and hypertension and renal failure. It actually can promote cancer growth through the inflammatory state. These patients are producing a lot of these cytokines that can stimulate cancer cells growth.
Dr. Aaron Carroll: Is there anything we can do besides weight loss to try to prevent myeloma from developing in people who are at significantly higher risk?
Dr. Rafat Abonour: What are the other risk factor? Actually, we are trying to screen for that and that's actually part of our Precision Health Initiative. If you look at certain occupations, there's increased incidence of multiple myeloma. Farmers who use pesticide for years without precautions, people living near factories where they were dumping a lot of chemicals in the water and they live down the stream from the water, they have higher incidence of myeloma and similar condition like lymphoma. The question is, can we prove that and can we study that more in a perspective way? And our job is to try to screen people in these high risk area for myeloma and pre-myeloma condition and use information from our environmental study colleagues on contamination of the water, of the soil and see if we can find a link between a certain chemical exposure and the development of multiple myeloma. Another way that we eventually hopefully we can prevent the development of multiple myeloma is we reduce the risk of exposure to toxic agents.
Dr. Aaron Carroll: Fabiana, I know that you're interested in the use of immunotherapy to treat multiple myeloma. Could you talk to us a little bit about what immunotherapy really is?
Dr. Fabiana Perna: Immunotherapy is a promising cancer treatment that uses the immune system to attack cancer cells in much of the same way that it attacks bacteria or viruses. There are several FDA approved immunotherapies which exist for several cancers now and they mainly include checkpoint inhibitors, which release a natural break on the immune system so that the immune cells called the T-cell lymphocytes recognize and attack tumors. And then there's another approach which is called the CAR T-cell therapy which stands for Chimeric Antigen Receptor T-cell therapy which has been a very successful in treating refractory and relapsed the CD19 lymphoblastic leukemia patients. I was recruited to develop immunotherapies to multiple myeloma. Despite these successes, it is still challenging to understand how the immune system can be manipulated to finally control immune responses.
For example, how to reduce the regulatory T-cells, how to enhance the tumor immunity, how to expand the antigen specific T-cells. We as a lab study how the intrinsic mechanisms of myeloma cells are able to shape the immune landscape and by understanding these regulatory mechanisms, we can target some of them and some of the mediators of these key mechanisms to develop novel immunotherapies for patients with multiple myeloma.
Dr. Aaron Carroll: I want to take two steps back or half a step back because I want to discuss both those things you mentioned in more detail. First, could you talk to us a little bit about what exactly checkpoint inhibitors are?
Dr. Fabiana Perna: Checkpoint inhibitors are antibodies that basically are able to release a natural break on the immune system so that endogenous immune cells that are called the T-cell lymphocytes are able to recognize and attack cancers. In that way, we can actually unleash the immune system of the patients that is able by itself to recognize and attack cancers. However, while this approach is very successful in solid tumors like melanoma or lung cancer, it's a more challenging for hematological malignancies because they present a low mutational burden which means that the number of somatic mutations of a hemalignancies is relatively lower compared to solid tumors and therefore the likelihood of generating what we call new antigens or molecules which are different from self is lower and so the ability of the immune system to recognize cancer cells is diminished. And therefore these therapies do not work as effectively as for solid tumors. For hemalignancies instead, the CAR T-cell therapies have shown a great promise based on the studies on lymphoid leukemia and neurological lymphomas.
Dr. Aaron Carroll: What exactly are CAR T therapies? How do we use those?
Dr. Fabiana Perna: CAR T therapy would basically use engineer T-cells so we would take patient's lymphoid cells so lymphocytes, engineer them in order to express gene that code for Chimeric Antigen Receptor. And once this protein is expressed into the patient's lymphocytes, then these lymphocytes become able to recognize and attack the tumor cells against the target that we have utilized. And so basically we redirect the specificity of the lymphocytes against the target cells.
Dr. Aaron Carroll: When you use CAR T-cell therapy, is that something that has to be individualized to every single person? It's not something you can just get off the shelf I imagine.
Dr. Fabiana Perna: Yeah. There are multiple ways. As for now, most of the commercial therapies are based on a patient's immune cells which are engineered and they're re-infused into the same patients but there are multiple ways that the one may take to use an off of the shelf approach so that ideally, we don't need to wait for the engineering of the patient's cells and which is quite technically challenging and also timely demanding. But actually we can use one approach that works for most patients. Also because it is shown that patients undergoing multiple cycles of chemotherapy have a less efficient immune system and so this would actually solve that problem.
Dr. Aaron Carroll: Rafat last time we had you in, we were talking about that there had been significant advances in multiple myeloma but you were even still excited that more things were coming down the pike, that there might even be more. Could you talk to us a bit about what have been the more recent advances in treatment of multiple myeloma?
Dr. Rafat Abonour: The field of multiple myeloma has been evolving so fast and when I started 20 something years ago, we probably had one or two drugs and they were not approved for treating multiple myeloma. Right now we have about 15 drugs approved for multiple myeloma which is really great advances. Unfortunately, patients are not cured but they're living much longer and we can do better by really starting to study our patients in a way that we can use the right treatment, the right combination for the right patients. Yesterday was published in a New England Journal of Medicine and articles about CAR T-cells to treat patient who have failed multiple lines of therapy. It's a great paper because it just tells you that it is possible that we can genetically engineer patient cells to attack their myeloma, we're getting good responses. The problem is the duration of response is about nine months so it's going to be a very expensive treatment, probably will be approved by the FDA this month for a short duration of response.
That's why I think our team here at Indiana University School of Medicine is trying to make the treatment more specific, safer and sustained because if you're going to spend half a million dollars on the products, you want it to last three, four years and hopefully forever. That's really very important and I think we are going a little bolder here at the IU School of Medicine. We probably want to make our own CAR T-cells for clinical use because we'll be much cheaper than the products available from a pharmaceutical company. I think that's one of the advances is the engineered patient's immune cells. The other thing is that we have now a next generation of these, we call a monoclonal antibody. These are proteins that look at specific target on the myeloma cells and it's a similar target that the engineered lymphocytes are looking at, but this is an antibody, will look at this target. It's bind to a chemotherapy agent when this antibody bind to the target, it goes inside the cells and destroy the cells also. These conjugated antibodies they have been approved by the FDA.
Last week, the FDA approved the new alkylating agents different than the one we use for years. Progress is being made but sustained cure has not been established and that's why we are very interested in trying to find the right treatment for the right patient.
Dr. Aaron Carroll: I have a couple of questions that come down to the fact. One of them is just what you ended with there, given that there are more and more options available, how do you decide which treatment is best for each patient or is there an order? Is it different for each patient? How do you make those decisions?
Dr. Rafat Abonour: Yeah, that's really the hardest thing because if you look at how people practice oncology, basically they go to what we call the NCCN guidelines. What's the NCCN guideline? It's the National Comprehensive Cancer Center Networks. We are one of those comprehensive cancer centers. Basically all the experts from these centers will sit together and come up with guidelines. If you look at the guidelines, it's almost like, I didn't know, have you been to one of these restaurants where they have two pages of menus and you get confused at the end of the day? This is what the guidelines look like. It's so hard for us to figure out what to do because you have multiple options. Sometimes you can say, if you have nerve damage, you don't use a drug that will cause nerve damage but that's simple, that's easy, but that does not answer. The question is, what is the biology of each patient?
Our goal in Indiana through the Precision Health Initiative is to have what we called the Indiana Myeloma Registry where every patient with multiple myeloma is entered into that registry where we can look at couple of things. We can look at their treatments and their outcomes, look at the side effect and also look at their germline DNA to look at their makeup. How did they react to drugs, how they metabolize drugs but also look at their myeloma cells. See what makes their myeloma cells behave in that way, a good way or a bad way.
Find a target on their myeloma cells that can use for choosing the right treatment. And also look at their neighborhood where the myeloma cells inside the bone marrow. This neighborhood has immune cells and other cells that may control the growth of myeloma cells. We want to study that because if we can enhance the patient own immune system to eradicate residual disease, we can probably cure a large number of patients. It is work in progress, I think everybody's trying to do that. Sequence every myeloma cells, sequence every immune cells to try to figure out how we can eradicate the disease for good.
Dr. Aaron Carroll: Fabiana, why do of these therapies only lasts for nine months? Why don't they seem to work for longer periods of time?
Dr. Fabiana Perna: There are several challenges, several layers of complexity. One comes from the lack of a suitable targets. The problem is that what we are looking for is a molecule that is highly expressed on all tumor cells, should be ideally also expressed in stem cells or cancer stem cells if we want to have DRD, if you want to reach the eradication of the disease but at the same time, these molecules should not be highly expressed on normal tissues. Otherwise, we will have the concerns in terms of safety. In addition, there's the problem of the heterogeneity of the disease so not all the cells are the same. Not all myeloma patients have the same disease, but each disease is characterized by certain genetic or epigenetic aberrations. And even within one patient, there are multiple clones of the disease that bear different genetics and epigenetic aberrations. And these reflects also on the cell surface of these proteins and so the ability of identifying one target or few targets that might be able to kill most of the cells.
On top of that, there's the increasing recognition of immunosuppressive bone marrow factors. The disease is not only based on the myeloma cells themselves but actually shapes the bone marrow immune microenvironment. And somehow, there's an impact on creating an immunosuppressive environment that decreases the chance of the endogenous system to recognize and eventually kill the tumors. And this reflects also on a resistance to the therapies that we use because they are able to impair the activity of a cytotoxic T-lymphocytes. Altogether, these are main factors actually hinder the therapeutic success. And at least for the available therapies, what we know that causes relapse is what is called the antigen loss. What happens is that cancer cells are very smart in the sense that they are able over time to down regulate the expression of the molecule that we use to generate these CAR T-cell therapy and so they can hide themselves basically from these T-cells that have been engineered. That's why we are looking for multiple targets or targets that have the ability to be up-regulated over time during relapse.
Dr. Aaron Carroll: How do we create our own CAR T-cell therapies? I mean, I think Rafat was saying that before. How do you actually create CAR T-cells in a lab?
Dr. Fabiana Perna: There's a lot of work and time spent in identifying the targets. This is actually the most challenging part. The technology is very promising, has shown lots of success in other diseases or in subtypes but the problem lies in the heterogeneity of the disease so we have to analyze large data sets of RNAC protein data from mass spectrometry. We have to look at different clones so looking at the cancer stem cells and then see whether these targets are also expressed on normal tissues. There are different types of targets that one may use. Some that have been used so far are called the tumor associated antigens. Basically, these are proteins that exists already also in other tissues, but they are somehow up-regulated in the cancer. Then there are the tumor specific antigens. These are the most interesting because they are not expressed on normal tissues, but they are uniquely presented on the surface of cancer cells.
And they generally are driven by mutations or some kind of a unique intrinsic aberrations. And then there are some unconventional targets that have not being exploited so far therapeutically. We look at all of them, trying to see what is feasible. Also, sometimes some of these molecules might not be targetable because of the structure or they have a high homology with the normal proteins and once we have identified something that looks very promising, then we validate its expression in normal primary patient samples. And that's why I tell you, we are very fortunate in having a very large bio-bank where we can actually test the expression of these promising targets in larger numbers of patients. And from there, then we go with the cloning of the CAR and then the assessment of the efficacy and the safety before running a phase one trial.
Dr. Aaron Carroll: Rafat, I just want to change our angle a little bit here. I'm a health services researcher. One of the things we talk about in the show all the time is disparities in healthcare and I know that you have actually been focused on looking at racial disparities in both the incidents and the outcomes of multiple myeloma in Indiana. I was hoping you could talk to us a bit about that.
Dr. Rafat Abonour: If you look at patients with multiple myeloma, as I told you, the incidents among black are twice of that for non-black. But unfortunately, if you look nationally at the outcome of black patient with multiple myeloma is inferior to that of non-black. And I think the problem was mostly related to access because if you look at black patients who receive stem cell transplant compared to other ethnic group, they do the same. They get the same result, the same outcome. The reason I think the general population is not doing as good as others because lack of access. I think patients need to get to see the doctors in time to get the right treatment, the right sequences of treatment and the right follow-up. I think that's something we need to address. I think we are falling behind in this country providing the same access to every patient with multiple myeloma and we want to study that.
I mean, we want to study also why the incidence is higher and why are we having trouble with access? Part of our work and Dr. Abu Zaid who's one of our colleagues is focusing on with a recent grant from IU is to look at Black and Indiana and see how we can screen better, how we can get our patient to access the physician at the right time, educate both the primary care physician and the community about the disease, the importance of early diagnosis and appropriate treatment. This is really work in progress that we need to get it done as soon as possible because it's just from looking at the data, if you get treated correctly, you're going to do fine. It's just you're not getting the right treatment, I think that's very important. But we also need to figure out what cause higher incidence of myeloma and pre-myeloma condition among blacks and we working on that.
Dr. Aaron Carroll: Do you have any ideas what that could be?
Dr. Rafat Abonour: We are doing a couple of studies. One, we collaborating with our colleague, Dr. Gabriela Dana-Farber in Boston. She has a big study called the promise study where she is offering screening for patient age 40 to 75 of African-American descent to be screened for the pre-myeloma conditions and then if they have that, then we will do further germline DNA analysis to see if there's any predispositions. And we also building a collaboration with More University. Indiana University School of Medicine has a strong collaboration with this university. We have strong cancer program there. Our goal is to also screen Kenyans in that region for myeloma and pre-myeloma conditions and do similar genetic testing. And the goal is to really see, what is causing increased incidents of myeloma and pre-myeloma conditions among blacks? Is it really genetics or is it environmental factor? This will be an amazing study that we will learn a lot from.
Dr. Aaron Carroll: Well, what work is going on right now in your lab that you're most excited by it?
Dr. Fabiana Perna: We are a small team. We just started so we have three main projects. One of them of course includes multiple myeloma. And we are very close at identifying one, two lead targets to launch our own phase one clinical trial so for sure, that is a dream come true to move up from the bench side to the bedside based on our own investigations and accurate analysis of the cell surface proteome of myeloma cells. And then we have a second project where actually we go more in details about the genetics of these hemalignancies which some of them for instance, let's say p53 mutation does not belong exclusively to multiple myeloma but also affects other diseases for instance, acute myeloid leukemia or solid tumors. And so we are investigating how these intrinsic genetics actually might shape a targetable cell surface proteome and it's very exciting because we are a small group of young people, also very motivated so we hope to publish our results very soon.
Dr. Aaron Carroll: Fabiana, I know one of your passions is also about women in science and specifically some of the challenges and how we can address those. Could I get you to talk about that for a bit?
Dr. Fabiana Perna: There's a concrete challenge in being a woman who runs her own lab and also sees patients and perhaps has a family as well. And I have the pleasure of collaborating with lots of colleagues in my same situation and having some kind of supporting groups is very important but at the end, I think what will address these real challenge is to create dedicated opportunities in terms of grant fundings and leadership positions in the universities that are dedicated to women and somehow we only know our needs and unconsciously, there's a lack of understanding of the practical challenges that we do face as we step up along our careers.
Dr. Aaron Carroll: Again, this Healthcare Triage podcast was sponsored by Indiana University School of Medicine whose mission is to advance health in the state of Indiana and beyond by promoting innovation and excellence in education, research and patient care.