(Guest Lecture): January 2024 - Understanding FISH, Genomics, and Myeloma Genetics

So what are we speaking of today? You guys know because you actively chose to sign up for this webinar, but we're talking about understanding fish, genomics, and basically myeloma genetics. Now the reason why we chose this topic is because I do have these post-meeting surveys that you're able to take as you leave the session. And as I went over last year's surveys, the majority of you requested that we do a deeper dive into these genetics and genomics that your myeloma specialists might talk to you about or that your general oncologists don't really understand to the depth that they should. And so I think this is a very interesting topic. Over 200 of you have registered for today's presentation, so I know it's important to you as well. So let's get started so we can learn more together. Dr. Atiya Sivanasanca is a graduate of Chulalongkorn University in Thailand. She completed her residency at Albert Einstein Medical Center in Philadelphia and a fellowship at Roswell Park Comprehensive Cancer Center in Buffalo, New York. She joined the Indiana University School of Medicine in 2003 and currently serves as an associate professor at the IU School of Medicine and researcher at the IU Simon Comprehensive Cancer Center. Dr. Sivanasanca's research interests are in the molecular mechanism of drug resistance in hematologic malignancy and precision medicine. Her clinical expertise includes hematology, oncology and bone marrow transplant. Dr. Sivanasanca, we're really excited for your presentation today. Thank you for the preparation you've put into this and I look forward to hearing from you. Thank you very much Audrey for the opportunity to meet with everyone today. I was quite excited and also surprised to hear that there were 200 people who wanted to talk genetics because whenever I need to give a lecture that involved genetics, either my students show up with coffee or they try to sit as far back to the back of the room as possible. So similar to those students, I promise to not quiz anyone at the end and I'm going to try to make the talk on the short side because I would be interested to hear your take on where you are with your sort of understanding in the genetic background of myeloma, but also to see whether there's any questions that I could help answer. Just know too that the lecture or the talk today probably will become obsolete in the near future because myeloma just changed that fast. So if you give me a minute, I will pull up my slides. And I think we had it set up so beautifully as the shared, but one second. Audrey, I think I actually. That's OK. If you do remember where the display settings. All right. We did it just a second ago. We did. Yes, we did. If you want to go back to. No, you're OK. It happens. If you want to go back to presenting in the full view and then we can click the display settings and try to get that changed. Yeah, it's. This one, correct? Uh huh. And then at the top that was near the show taskbar. I think that's where the problem is, because I think the closed caption thing was actually blocking it. Oh, you can turn off the closed captions if you'd like. If you may need to stop sharing. Give me just a second. No problem. And there's another way we can do it if you want to try as well. I think this may actually be. I just did the duplicate slide. I think it's not that hard to do, but I think you can do it. It's not that hard. OK, I think we can do it. OK, so we're going to try it again. I think this may actually be. I just did the duplicate slideshow, but. I. Audrey. Yes, I don't think the zoom likes me very much. You know what? Just so that I don't end up taking time too much from everyone. Let's just try it one more time where before you click that button, do you see where it says display? You with me? Yeah. OK. Where you were about to click that button a couple of months to the left says display settings. Near the bottom of your screen again where you were going to click to presenter mode. If you go a couple left, this is display settings. Do you see that? That bar is not on with me. On my site at the moment. But if I actually, that's if I do it this way, hopefully it's actually big enough. Is it? Yeah, yeah, it looks great. All right, perfect. OK, so we're talking genetics in multiple myeloma. And I think we just wanted to talk about what they really are and also how do you even make sense of the report that comes back? Well, doing tests is easy interpreting what we get the report back and how to use it to guide the decision about myeloma treatment is what we hope to try to tackle a little bit more deeply today. So the kind of genetic information that I'm hopefully going to go over is something that's called somatic mutation or somatic information. We were all born with a set of DNA that's already available in every single cell in the body. That kind of genetic information is the germ line, which is sort of in every single cell. The germ line sort of means the very first starting point. Now, somatic mutation, though, occur later in life. After people were born, something happened in a certain set of cells, including mutations, gene changes, however you slice it, and that potentially give rise to cancer or in fact any other diseases. And that is the analysis that's typically used in myeloma care. It's specific to changes in the myeloma cells, not in any other cells and also not passable to the next generation, which also means that whatever report you get from the genetic testing from your born marrow is not something that we would be telling family members to go and get that screening. All right. So why do we even think of the genetic changes being important in myeloma? It really is because myeloma really become myeloma all because of the genetic changes. How each and every cell in the body behave eventually rely on the last terminal signal, which is protein. That's really sort of your workers. But the DNA, which is in the nucleus of every cell, is actually sort of the headquarter. And that's really where the command comes from. As the cancer cells grow and change, the first change actually happened within that headquarter. The first change happened a long time ago before patients even have multiple myeloma. If we think about myeloma sort of being a journey where the normal cells started to misbehave and have already acquired mutation. Patients then have small number of cells that do not die and they're not needed. And oftentimes, if one would be looking at blood tests, we would see that those cells can make protein that can be detected in the blood. That protein is called M-protein because they show up as a unique peak in the gel run. When your doctors order something called protein electrophoresis, well, that protein is a marker of the cells that are already misbehaving inside the bone marrow. That first change, though, were usually the signal in the genes that allow them to not die off. Usually, our plasma cells live in the bone marrow in very small number. When you come into contact with germs, get infection, the plasma cells are expanding and they make antibodies to go fight infection. When the infection resolves, they kind of recede back instead of wait for the next attack. Something happened that makes a certain set of plasma cells going from just the one wrong cell, not die off appropriately. So the first signal usually isn't the signal that makes cells divide fast. It just makes the cells not die. So if things don't die off as they should, they will accumulate over time. But also that first change, which is typically either a change in the number of certain chromosomes that gained, lost, or the cross of chromosomes that should have never seen each other, but they come together and they activate signal that allow the cells to live around and not die. That becomes the first gate. Then as the cells don't die and they divide, there are other changes that can happen. Those other changes enhance the behavior of the original cells that don't die off. Now, they're eventually going to acquire enough changes within themselves that would allow them to progress, to invade into the bones, to take advantage of the home where they live, and eventually that in causing patients to have symptomatic myeloma. So by the time patients come to us with multiple myeloma, they might have already had this period of time where gene changes occur in that clonal plasma cells for a number of years. As the disease continue to change and progress, mostly also through the journey with treatments, eventually the cells become more resistant to treatments because they're capable of activating other gene changes that allow them to outsmart the kind of treatment we have. So why do we think that this is an important information? It's really because it's not just a change that just happens when the cells grow, but it also tend to dictate how the cells behave, just like what I was talking about, the head quarter telling the workers what to do if you're working in a factory, really the message actually come from the headquarter itself. So we group the changes within the genes to different groups. The high risk changes were actually the changes that tend to occur in patients who don't do as well. And there are some changes that don't seem to be carrying that bad signal. There are many, many changes that can occur within the myeloma cells, and these relatively limited list are the changes that we have found to have some signal that relates to the behavior. There are many other that we just don't know. So this information about the genetic changes is now also incorporated into the staging of myeloma. So it's not just, do you have kidney failure? You have lots and lots of cancers that drive something called beta-2 myococlopelan in the blood or drop the level of good protein called albumin, but also the signature of those cancer cells themselves also help us in trying to understand broadly how they just might behave. It's just like if I say that my own lawn has weeds and the next door neighbor also has weeds. So we both have weed problem, but they might not be the same. And actually ability to understand what kind of weeds I'm dealing with and they're dealing with may also really separate the kind of prognosis and actually even the management of the weeds in different cases. All right. So how did we even come about calling these things intermediate risk, standard risk, or risk? It's because after a number of years of patients getting treated with multiple myeloma treatment, this is actually what we call a look back or a retrospective analysis. At the start, before we knew what these changes really mean, we sort of really treat everyone more or less in the same way. And years later, when we look back, certain group of people did really well and certain group just not so well. And this is really an ability and a detective work to try to see, well, was there any changes in the genes that tend to happen in patients who do better or any changes that occur in people who've done worse? So it's looking at those group as a whole. It's not a one person at a time. So the caveat is that not only it is looking at a group of people, but also it was related to a specific kind of treatment. So you'll actually see that as treatments improve. Some of the things that were thought to not be a good risk actually become less critical and patients with a better treatment, those patients could do really well. That still leaves us with certain groups that even though we have improvement in treatment, whatever improvement we have still doesn't seem to help that unique group of people very well. So that group then is the group that is now, there are just a lot of clinical trials now that are trying to help that subgroup of patients. All right, so you will see this kind of like different colors of graph kind of stack on top of each other a lot when you read up anything that relates to myeloma treatment. This is actually a plot that talks about follow up over a number of years and the percent of people who progress. You'll see that people who are low risk with, they were people who did better. They actually didn't progress as fast as the people who were actually high risk who at the start no one progressed, but then the high risk group actually progressed pretty quickly. So they progressed sooner and at the end with a longer follow up time, there are just less of them around unfortunately. And that's why it's important to be able to separate people apart based on the signature of their cancer cells. All right, so how do we go about using that information then? Not only to say that someone is more or less likely to do very well, it is also, well, can we use that information to guide the treatment? And the answer is yes. And this is still evolving. But just for example, this is that kind of graph again, the progression free survival, meaning patients staying in remission. And this one is talking about overall survival, meaning patients living. So say if we were to look at this four different lines, you'll see that the people who had the worst time with myeloma, the probability of staying in remission being short, probability of living with myeloma being less than everyone else, were actually people with high risk disease who did not get maintenance therapy after transplant. And it turned out that you actually help those people quite a bit by giving them longer treatment, by giving them continuing treatment even after they have already achieved decent remission. It would just appear that in those patients, if you just walk away from the terrible weed situation in the garden after you think that you've had it under control, the remaining weeds, because they were already having ability to survive the treatment, they actually come back pretty quickly. And if we would just deliver longer treatment, even after the transplant, patients actually did a lot better. Now it is true that patients who don't have those high risk features also have benefit, but they were already supposed to do kind of pretty decent. They have some benefit, but not as hugely comparing to patients who actually high risk, who had high risk disease. And in fact, these two lines were almost kind of like laying on top of each other, almost suggesting that patients with high risk disease who receive post-transplant therapy can do extremely well, almost as good as patients who don't have that kind of signature. So it is important to have that information because it does affect the discussion that you will have with your doctor about treatment. Not only that, some of these changes were so unique in that there is now treatment for it. This is a particular change, it's called translocation of chromosome 11 and 14. What translocation is, is a cross of two different pieces of genes on two different chromosomes. And rather than in the whole lifetime, they should never come in contact with each other or see each other, there's a break on both genes. And then there's a fuse between the partners. So out of sudden, there's a fuse signal. If you think of the chromosome 11 and 14, in this case, in this analysis, which we will talk about it in a little bit, we designed a probe that labeled one chromosome red and the other one green. So the red and the green should never really see each other. They should be two reds, two greens. But in this case, there's a yellow signal, which is a fuse between the two different pieces of genes. And that fuse is called translocation. And you can actually see this on your report, 11 and 14 happens in about one out of five patients with myelomas. It's actually one of the more common abnormalities. Well, the unique thing about it, though, is, no matter where you go, it was actually thought to be not a good thing to have. Patients with 11 and 14 actually didn't do quite as well. It turned out, though, that with better treatment and also now with specific treatment, they actually do extraordinarily well. There is a particular medicine that's called Venetoclax that block a protein called Bcl2. Now, Bcl2 is a protein that prevents cell death. It is routinely elevated in patients who have this translocation. So if you have this translocation, you're going to have more of this Bcl2 protein. And the Bcl2 in the green is actually overpowering the other group of protein that kills the cells. They usually should just kind of be in balance when the green is more than the purple or the cells actually live. So if you can design the medicine that actually block this Bcl2, it will free up that killer protein to go and kill the cells. So that medicine comes in pill form and it works specifically in the group of patients who have this translocation. It doesn't work so well in patients who don't have this. So that is also important information. And this is what the clinical trial looked like. It was a large clinical trial where half of the patients got that medicine I referred to, that Venetoclax. The other group of people, well, they got that Venetoclax together with no one my LMA medicine, Bortizumab and also dexamethasone. The other group of people only got these two medicines without the Venetoclax. In the group of people who have this translocation 1114, if they didn't have the Venetoclax, their chance of staying in remission was about nine months. But if they have the Venetoclax, it really was much higher at 36 months. Now on the other hand, though, you'll see down here that people who didn't have that 1114, really they didn't have that same benefit comparing to people who do. So it goes to say that that piece of information is critical for your doctor to help deciding whether this medicine is actually the right choice for you. And based on this kind of information, there are other pills now that are being developed that actually block that protein Bcl2. And one will see whether it's even more efficacious comparing to this Venetoclax, which has already been approved. Not specifically for the myeloma, but it's been approved for lymphoma and some other forms of leukemia and is usable in patients with this particular subgroup of myeloma as well. So we talk about why it's important, but what kind of testing you do in the bone marrow to derive this information you need. We have come a long way and this little rainbow thing is not just specific to myeloma, but the kind of technology that we have that we use in myeloma is sort of also used in other blood cancers. And I would first talk about something that have already been around in the 70s, 80s, and also just ever since how much better we have become. So this is the kind of test that continues to require a bone marrow test. Whenever I tell a patient said we need to do a bone marrow biopsy, they always ask, could we not find any other ways because it's not always comfortable. And most of the tests that has been standardized continue to require the bone marrow testing because we're trying to analyze only multiple myeloma cells. Since the cells live inside the bone marrow, they don't always come out in the bloodstream for us to be able to analyze them genetically. So when your doctor did the bone marrow, they pull out that liquid part of the bone marrow that has the myeloma cells mixing together with a whole bunch of other blood cells. They will then isolate out just the myeloma cells and the remaining of the tests that I'm going to refer to sort of look just at that myeloma cells. The oldest in the first test is something called karyotype or conventional sort of genetics. The name isn't as important as what it does is it actually required culturing the myeloma cells after they come out from the patient on a petri dish. And when those cells are dividing, the chromosome actually come together and form very tight band. So you can actually see, you can actually stay in those bands. And this is what those chromosome bands look like. And it goes from chromosome one all the way to the X and Y chromosomes. In this case, this is of course, a gentleman. So chromosome one is the biggest and then chromosome 22 is the smallest. So there should be a pair of each chromosome. Well, it turned out that in this case, there's a gain. There is extra piece of chromosome seven and chromosome eight. And there is actually a breakpoint in chromosome 11. Right. Where did it go? Well, it actually fused with this chromosome 14. And that was actually the 1114 translocation I was referring to. So it gives a big picture look for all of the chromosomes that we could get. Well, the problem then is it does require culturing myeloma cells in the petri dish to do this assay. And myeloma likes to be inside the bone marrow. They do not like to grow on the petri dish. So this test doesn't have great sensitivity because a lot of myeloma cells might die off. It also takes some time to get the results back, oftentimes two weeks, three weeks. And for a lot of our patients who we need to make decisions relatively quickly with what regimen we're going to use on the turnaround time, that is a slower time for this technique just makes it less appealing. And I must say that today I do not use this conventional set of genetics at all. And I'll tell you about the more sensitive test in a minute. So this is a test that you probably hear about a lot. It is called FISH or fluorescent in situ hybridization. So what does this lava long name thing means? It is an attempt to not grow the cancer cells in the petri dish, but after they're isolated, if we were to design a little color, a little probe that stay in different places on the chromosome, then you'd be able to, as it was mentioned, well design different colors for different genes and see whether they're crossing with different genes, such as in this case, it was at 1114. So 11 screen 14 is red, but the few signal were actually yellow. So normal cells shouldn't have it. Now you're going to see in the report that this the doctor's gonna, your report is going to have 1114 stratification being present. Now on this panel, the B panel, so I was telling you that the chromosome stage should come in pair. Well, if there is one extra dot of this blue dye, which in this case was standing chromosome five, you should only have two dots. Well, you have a third dot. So that's the gain of chromosome five. So this has more or less replaced that karyotype I was talking about, because it's much more sensitive. You don't have to grow the cancer cells. It usually require counting, doing this kind of staining up to 200 cells to improve the sensitivity. The turnaround time is fast because we don't have to grow anything. It's a whole lot more sensitive. The only problem is, well, we need to design the probe for the specific places in the chromosome that that probe is going to bind on. So it doesn't, if I don't have a probe for say in this case, chromosome eight, for example, and this patient had a gain of chromosome eight, I wouldn't know it because I didn't have the probe designed for it. So you do miss some of that information. But otherwise, this is the most commonly used test today. All right. Now, could we imagine combining those two techniques together? Because the first test looked at everything, every chromosome. The second test used the probe to label the chromosomes. So this is technique that I'm trying to combine both. So you'll see that all of these candy colors are actually different probes that were staining the whole chromosomes in different kind of colors. And then when you do the staining, comparing to the control, you'll be able to eventually see this is the patient and line them up altogether. You'll see, okay, so now there is a piece of chromosome one going to chromosome four. There's actually maybe also another piece that goes to chromosome 16. That seven has a piece of something that shouldn't be there. And this little chromosome 14 is a mess because it actually has maybe a piece of 16, but also on the other side of the 14, it also got a little green dot from something else, from somewhere else. So this improves sensitivity. The technique is not as widely popular because it usually requires quite a bit of setup. I mean, if you were going to do some fancy staining like this, usually each pathology lab just won't have capacity to run them. So this is a test that your doctor, if they want to order, they usually send it to sort of like a third party lab. And because it's a little bit more involved, the cause may also be an issue. So you'll see that some of the clinical trial reports will refer to this testing, but just know that while it's available and it's actually quite sensitive combining two first techniques, they're just not used as much. All right, so there is something else called gene expression profile. I was telling you about the DNA being the headquarter. Well, the worker, the workers or the protein, there is actually a transition between the headquarter sending signal to the protein. You have middleman and that middleman is actually an RNA. The RNA actually can be up regulated, down regulated, it can increase, it can decrease. Some of the cross, the translocation I was talking about, enhance expression of some genes. But also there's some change in myeloma, such as loss of pieces of genes. If those pieces of genes happen to suppress tumor growth and you happen to lose it, then those cells are going to grow. So how do we incorporate the headquarter information that we have talked about so far to also include the middleman to look at what signal is being sent to the protein? So that's called gene expression profile. Well, it incorporates so many genes into this like little chip. Well, but you don't want to have a report being 10 pages and the doctor's not knowing how to use them. So there is this algorithm where those changes were calculated into sort of scores. So just like if you think about your kiddos getting a grade from a teacher, so the grades are grouped based on the certain range of scores. A lot may go into what each grade is. Some people might forget to deliver homework, but they did really well in tests. Some may actually did not as great in the test, but they did really well with homeworks. So all of those things get combined and then you get a score. That eventual score then get in a lot into the graph and you'd have people who are actually having better risk, intermediate risk and high risk. So this gene expression score, a profile, one that's commercially available is something that's called GEP70. You may hear about it on clinical trial. Again, not widely used because one needs to send it out to a third-party lab, while that FISH testing is sort of readily available. Most big enough hospitals can run them and you get the results back pretty fast. All right. So now we're getting into the nitty-gritty more cutting-edge stuff because, well, all of the tests I was telling you so far, we're sort of having relative limitation in that the changes have to occur in enough number of cells for us to be able to see them. Well, could we potentially evaluate the genes at a deeper level to also acquire information that we may not know what they mean today, but we could potentially know about the value of these informations in the future. So there is then this technique of next-generation sequencing where once the cancer cells are isolated, the DNA from those cancer cells are extracted and then you chop, chop, chop that DNA into teeny tiny pieces, so many of them, and then analyze all of them. So now what you're going to get back is sort of like library of what is all in the mix. Then there needs to be an algorithm to derive that information for, well, how are we going to, you know, you think about all of those little information, there are like books in the library, you need to be able to categorize them some ways in some forms. So certain changes will line up with that translocation because you end up with the fused DNA, right? Or if you have gain or you've lost, you're going to see that, oh, certain books in the library you were missing, that is the loss, if there is an extra copy, it's a gain, but also you get so much more information about small changes that we might not have been able to see otherwise. So this is the test that's sort of up and coming and are now, it's now getting incorporated into all kinds of clinical trials because of course we wanted to be able to dive more deeply into understanding each person's myeloma rather than just those gross gain, loss or translocation only. Now the thing to look forward to is eventually, hopefully we will not need to do one more test, that we'll be able to look using that kind of next generation sequencing, but rather than looking at the myeloma cells, the DNA can actually be isolated from the blood. Granted that the cancer cells do not come out to the bloodstream, but even if they're inside the bone marrow, when they die, when they break off, the DNA product will actually be detected in the bloodstream and this hopefully will replace a whole lot of bone marrow tests that we need to do, particularly as the technology improves, hopefully it's more sensitive and this is really sort of technology development, if you may, that's actually looking at people who have converted, who are in remission and their blood doesn't have any signal of the tumor DNA, so if they don't have the tumor DNA in the blood, it hopefully means that they also don't have a whole lot left inside the bone marrow and that's why they're doing better comparing to the other group of people who actually have detectable cancer DNA in the blood, so they're actually just not having as good of a remission, so hopefully this is really something to look forward to, because we can do them pretty frequently, but then with these kind of information, when is it good to analyze them, we can't analyze them all the time, when does it matter, so usually I think the most critical time to get that genetic information would be when things are changing, so when patients are first diagnosed, it turned out that even though I was talking about myeloma in each person as if they're actually all similar type of cells, they're actually quite a bit of a mix, myeloma in each person have multiple tribes at any given time and those tribes, some will go away with the treatment, but some will come back, so if you're thinking about the changes of all of these tribes, there are many different patterns, like for example, this is an example from like different patients, you'll see that this patient, patient B, had this like blue group of cells that were gone after they were treated, when they're remissioned, but then when the cancer cells come back, the blue didn't come back, it was the green that came back, but also there's a new clone, there's a new group altogether, the red one, now this patient though, on the other hand, has mostly the return of the same thing that they had before, so because we can't always predict what will happen at the time of relapse when certain treatments no longer work, it's just important to have a chance to evaluate to see what tribes are dominant, some patients who, for example, may not have certain tribe, say that 1114 that I was talking about wasn't the dominant group at the start, they may become the dominant group when the cancer come back, the cancer cells don't live alone, they live with other cells inside their homes, inside the bone marrow microenvironment, so newer technologies hopefully also allow us to analyze not just the cancer cells but also other cells, these days and age, what we're really excited about is to look at the T cells, because a lot of our new treatments are activating the T cells and then the T cells go after the cancer cells, we are also all different people, so when you're getting medications, the side effects that each and every person experience were also different, and that also does affect the response, and the treatment is really the third party in this triangle, so I think it's just important to know that it's not an at all when you're looking just at the myeloma cells alone, and this is where we are with what we know about genetics in myeloma, it gives a general sense about the expected behavior of the cancer cell, but because it's a look back, patients need to have been followed long enough, new treatments come about, the things that we think was bad risk may no longer be relevant if we have the specific medicine that can overcome it, it also is difficult to predict each person within the group, what I mean is that there are some people who have so-called poor diseases that would do really really well, and there also are some patients who don't really have those bad features, but they actually have relapse that we have difficulty explaining, and that's why hopefully the next generation sequencing and ability to dig deeper into the genes, not just to look at a few different things that we know, may also help us understand the behavior of the cancer cells more. Some of the changes are actually targetable, meaning that they can be blocked and that will improve the treatment response, some may actually tell your doctor whether to be more aggressive with their approach, but many though we don't know the meaning, so that information hopefully is something that will guide us in the future, so that next generation sequencing type data, if you see a report that's a page long and your doctor said there was nothing that was immediately usable, it doesn't really mean that that will continue to still be the case in the future, and I think more than anything that changes over time within the same person is critical, so and lastly it really we need to take that information and also incorporate it into how our patients do, patients with so-called bad risk disease who respond and stay in remission can do really well, and on the other hand patients who don't have those bad risk, if they have poor tolerability to treatment and the cancer cells keep trying to come back, requiring treatments to be changed frequently, that may be the group that we need to have the high level of worries about as well, so that was what I was hoping to cover, and I would be curious to see how everyone thinks about the genetic information and whether there's any questions. Thank you Dr. Sivanasankar, that was a great presentation and the answer is yes, they have questions and they're great questions. First I just want to share with you what Terry said, she said thank you so much, you've taken such a complex subject and made it really understandable, so great job with your presentation, it was very well done and I loved the the slides and the colors and everything, it was just very well done and easy to, well easier to understand, this is a complex subject right, so I'm going to start with some questions, I've kind of organized them to create a hopefully good flow, talking about genetics can get a little confusing and I know you mentioned this in the beginning, the difference between the genetics we're born with and the genetics that we're talking about today, but in your professional opinion were people born with their myeloma or maybe a better way of asking is were they born with the potential to get myeloma under certain circumstances? And Audrey that is ever so true, we know that certain ethnicity, African ancestry for example, actually have higher incidence of myeloma, so there must be something about our own genetic makeup that relate to the risk, we also know that family members, any families that have more than two people with lymphoma or myeloma clustering may also have increased risk of myeloma, so there is something there, the issue has more to do with it's more difficult to know what drive it because it wasn't like say, if you think about what we really know, breast cancer certain subgroup right, so it's sort of this genetic change, if it's in the genes and someone in the family has breast cancer at young age, you're actually going to look in the next generation with whether they have that change and you actually act to try to prevent it. With myeloma it is a little bit harder, there is of course theory in that things that we were born with might have actually dictated how well we will repair the DNA, how well we will deal with insults that come our way and certain ability or lag off to repair the damage in the DNA may actually increase the risk of myeloma down the road. Now I think that is an area of very active investigation, we like to be able to tell folks in whom we would want to screen, their group of patients though whose myeloma occur at very young age and happened in multiple family members, we would actually recommend to do what we call a whole genome sequencing, which is pretty much to analyze your DNA to see whether there is some weird signal there and we would also analyze other family members, so that is really an attempt to try to get to people who we really have to prevent their cancer because they're so likely to have it. Otherwise this isn't considered hereditary, you'll see people, you'll like read up people talking about this being sporadic and patients would say well how could it be sporadic, I mean it happens in people that I know. You'd also see that sometimes it cluster because I'd be telling people that genome is supposed to be rare and they'll say no it's not rare in my shirt someone else have it and so and so have it and just you know I think there may also be part of the story that relates to exposure to the disease. So you know it's not one disease for sure and the story continues to be complex but I think we're learning quick with these modern technologies that allow us to analyze so many people fast and also at lower cost than before. Yeah very well said and like you said so much research being done in this field it can be its own webinar topic probably later on this year. A second question, so people are looking at their results and they're seeing something called plasma cell immunophenotype. Is this the same as myeloma genetics slash genomics or is this different? It is different could you imagine that all these techniques I throw at you and there is yet another name right? So immunophenotype you may know if you think about it's like immune system. So when we call immunophenotype it usually refer to a different test that we do in the bone marrow that's called flow cytometry. What it is is this cancer cells have protein on the surface that look a little bit different comparing to normal plasma cells not only genetically they're different but also they look different and if you were to stain them to look for things that are on the surface of the cells by this flow cytometry it'll get reported as this like immunophenotype certain proteins are activated and are present on the cancer cells when they're not on the normal cells and guess what that led to a discovery of new of immunotherapy because if there's a way to design antibody in the lab to bind on to the protein on the surface of the cancer cells that are not present on the normal cells then all of a sudden you can give those medicine in and they swim in the blood and they see the target on the cancer bind on to the target and activate the immune system to come and help clearing those cells medicine like that are going to be are already here today they are your daratumumab, isotoxumab, elatuzumab and in fact these immunophenotypes are also the the in the report you will see something that's called bcma which is not always done but it's now getting incorporated into into some of these immunophenotype testing as well and that protein is a target for the CAR-T and also for the newly minted by specific antibodies your taclistumab, your alrinatumab, tauquetumab, I know that I'm keeping throwing names at you don't have to remember these but the technology that allow us to understand why the cancer cells are different than the normal cells have already led to the development of treatment and while we're talking genetics I was telling you that that's the headquarter the your eventual work course would be the protein and immunophenotype look at protein but just not in the cell on the surface of the cells though. Oh that's fascinating I learned something there thank you so much how can fish results change during the course of your disease and a separate question we you did talk about this but how often do you recommend that your myeloma patients repeat fish tests to detect any new abnormalities or changes? Perfect so they change in time for various reasons first their myeloma in any given time has like different tribes right so your fish when they do a report they only count 200 cells or so so the problem is going to be if certain group of the cancer cells are sensitive to treatment and they die off but the there's a small number of cells with certain abnormality that were kind of rough and tumble and they were the cells that make a comeback when you look at what comes back it might look a little different it's um think about like if you kill weeds in your garden if you have different mixtures of the weeds and you throw in the weed killers well what's left behind and what you had in the beginning don't look the same and if you just wait for two months and look at your garden again it very well may be that the weeds that come back look quite different comparing to what we started out with so that's sort of we think about that process that's called clonal selection now there's a different problem that can happen because the weed killers themselves may also sometimes hurt the weeds but they don't kill the weeds so the weeds sort of like on their own gain ways to actually make a comeback right that is a treatment pressure so there also could be totally new mutations and changes that occur not because of the clonal selection but because our treatment actually caused the damage and unfortunately sometimes that kind of damage doesn't just occur in the cancer cells but also sometimes it occur in the normal cells and that could potentially lead to second cancer that's not even related to myeloma so and and i know that it's a little bit off topic but i wanted to also remind everyone that myeloma patients do still need to do cancer screening they live longer now and anything that we can do to prevent cancer that's preventable so that we only need to deal with the myeloma is is important so don't lose sight of that general health so when we do when do we do the the test so usually i like to do them first when you have enough number of cancer cells to analyze it's very difficult to do any of this testing when someone's in remission right so you're going to want to do it when someone's diagnosed and probably when someone's relapsing or progressing on current treatment because new treatment is going to have to happen and we like to understand the kind of bad guys or the weeds that we're dealing with so that we can really choose the right approach for those weeds wonderful thank you lots of good questions here so i'm trying to make sure we get as many as possible one of the questions um that i thought was interesting here oh hold on of course this happens when i'm trying to say that i'm trying to do it quickly um the font we we hear the term functional high risk how does that differ from being actually high risk and then one more follow-up question because i like squishing them together a couple people here are high risk and they're just wondering how concerned they should be in today's myeloma i was hoping for the second question i'm hoping that you actually heard what i was saying for the second question i'm hoping that you actually heard what i was saying that of course this this is only true when we look at the whole group um all right so so maybe and i love how you group them together um audit but let me actually kind of go at it by tackling the second one first and then i'll tell you about the first one so the the people who are in the high risk group right or the people who sort of like the headquarter has the wrong kind of signal that we're kind of worried about because when this happened in patients with myeloma after treatment if we look back at people who didn't do as well they seem to be having this signature but it's a group thing so it means that if i pick each person out of that group and you were asking me how long that person's going to stay in remission i'd say i do have worries about them but i actually do not know they can do really well as well and i think that that original information sort of give a framework for if someone is having high risk disease and you sort of know that you know what if you have um maybe a more aggressive weeds that you think you're dealing with you're going to actually have to be on the watch you're going to just maybe have to be on your toes a little bit more make sure that you really do them right get them into remission don't play around and really keep that remission going like don't walk away you know don't don't um we know that longer treatment oftentimes help those patients so you should use that information to hopefully improve your odd right but at the same time that doesn't mean that everyone who have poor risk disease won't do well on the other hand though how about the people who sort of they really don't have any bad signals that we know about right because but remember we only know about the tip of the icebergs there's just hundreds of things that are wrong in the cancer cell that we just don't know what they mean so they're going to be the people who made us look like they would be average risk we're all game for this is going to be you know a more smooth ride but what if i give them treatment and it doesn't seem to get them into a really nice remission then out of sudden i'm on my toes a little bit more i'm thinking that you know even if the genetic information isn't telling me what i'm you know it doesn't give me the signature there's something else about those cancer cells that are actually not behaving the way that they should whether that is because there are some other aspects of the micro environment that's contributing to the behavior of those cells or it's the person's own ability to handle medications the side effects for example how people clear medications there are other aspects right that we actually did not analyze in the fish testing or genetic testing of the myeloma so if i see people who don't respond well to regimen that should give really good response if the treatment should work and give reasonable remission and they don't sustain long enough remission i worry about those patients honestly as much as i worry about people who have high residual genetics or even more because it leaves us with less tool to chase after right i mean some of the people with high residual genetics i knew right off the bat that i was going to actually need to be kind of at my game in people who sort of i thought we would be okay we're not okay you got a pivot from there um you know so you'll um you'll see that some of the clinical trials are now looking at patients who may be not achieving complete remission after stem cell transplant we like to think that we they have gone through so much to get there to be in a really deep remission if they're not then maybe that's the time that we could do something so clinical trials are trying to get to those functional high risk or if they relapse say within a year after transplant that is under that means transplant as aggressive as that really underperform for that patient now we got to do something better right because the thing is if they're already misbehaving they're probably going to this may be a repeated behavior it's sometimes it just makes me think about you know you just like look at kiddos in class right there um and there is nothing that no previous bad behavior or anything that would make the teachers think that they need to be like watching anyone more closely but they'll know as as the journey continue but there are also some kids that wow for the past three years they have actually come in with the report that said this one we need to work on there you go so you're sort of like going to actually you're not gonna come loose you're gonna actually try to get the best out of them and that's really the sort of the story of what we start with but also how the story evolves yes i love your analogies and connecting it to the real world i really appreciate it um a couple questions here just on i know we're we're almost out of time fact i think we are out of time if you have just time for a couple more questions um there's a couple questions here about one q gain so there's conflicting information regarding the risk of one q gain so if you could briefly go into that and maybe explain one q gain versus one q gain amplification and then um is there attaching my questions together as i do is there any specific treatment for one q gain or any other trans locations like we're seeing with benedict clacks in 1114 so the one q i think if you put myeloma doctors in a room together and actually have them like battle it out right so maybe no one come out because they all bleed in there um it it has more to do with because this change so first is relatively common and chromosome one is the biggest chromosome so there's so many genes on that chromosome so when we say there's a game it's not just a little piece it's actually a chunk and you actually have so many things that you're having extra signal off for example um some of those signals happen to also be the thing that can propel the tumor cell growth so it's sort of stick out on this kind of look back type um clinical trials that people who have extra one q in some of these studies actually don't do as well and it turned out that because the piece that's gained has a lot of this like growth signal so if you have not just a one extra but several extra it's sort of the more the worse kind of deal so the strongest signal for that one q abnormality is actually the amplification which in this case means it's more than three um but you'd have people who have way more than like way more than three um so so those people are definitely in the high risk group and if you're having three without any other abnormalities um there is sort of a belief that maybe with all of these fantastic treatments that we have today we might have been okay there however if you look at people who are in relapse disease comparing to people who present with just newly diagnosed myeloma look at the whole big group you'll see that they're more one q presence in the relapse population so even if it doesn't stand out quite that you know just three copies or or i mean even if it doesn't sound so bad um at the start i think we need to be careful um because when we go to the relapse population we see more of those now there isn't anything that makes the cancer cells lose that extra chromosome that they've already gained they have gone bad right so there isn't quite a way to like switch them back you got to kill them off um but it turned out that um that piece of chromosome may actually upregulate something that's quite newly discovered called fcrh5 on the surface of the cancer cell and now there are all kinds of immunotherapy by specific antibody the car t that are trying to go after that fcrh5 because it's on the surface of the cell so it goes back to the immunophenotype that we were talking about if there's something on the surface of the cell that we can target and there are more of them because certain gain of chromosome just give you an extra extra set for example then maybe that's the group that one could really design some specific treatment for them we might overcome the chromosome one so for today it is a poor risk disease um yet this chromosome one particularly the amplification people but stay tuned wonderful thank you my last question for today what is the percentage in the flow or fish mean so when they're getting their tests back this is a very common question what does this percentage mean scary thing yes isn't it something because you like to think that all of the cancer cells whatever gain or loss they have they'll be the same but this i think highlight what we talked about myeloma being really mixture of different cells within the group um so because i was saying that fish was counting up to 200 cells when it's reported it's going to report um mostly as yes no do you have it or you don't have it but then when you go deeper into the report they'll say well 20 positive for that 13 positive for those so um if it's actually an abnormality that's present in large number of the tumor cells then that usually means that it's really a driver of that clone for the most part um and this was why i was saying that you know if it's actually a relatively rare event we could miss it and then it becomes increasing later so you'll see that some of these some of these clones actually have dynamic if you look at your report over time um so that's exactly what it means it's just sort of like out of 200 cells how many have these changes that we have looked for um on the flow it's more interesting it's sort of a little bit trickier because we actually don't stay in for everything that we can target um and flow tend to actually underreport the number of cancer cells you'll see that if you look at your own close automatology report at the report the percent plasma cells and if you look at your bone marrow biopsy it will report percent plasma cell percent myeloma cells as well and those numbers may not match um so i usually take that close automatometry um percentage less seriously comparing to the actual percent inside the bone marrow because some of them die off during processing and so on when you should expect to see cd38 being positive in the bulk of the cells you should see most commonly 56 would be positive and in any of your labs that incorporate this bcma you like to see them in nearly all of the cells um because they are really the target of our of our antibody anything that's more than 10 percent usually by flow will be reported as positive so oftentimes your doctor may say well it's positive because it's there in high enough number of cells it doesn't have to be every cell which is also why sometimes when we treat people with some with with antibodies like say for example daratumumab targets something called cd38 on the surface of the cancer cells when the cancer cells grow bad they may not have the cd38 as we see in some cases so um you know if if the cancer cells learn to shut down the target and the antibody it's like an an arrow without a target can't can't hit right so um that's why there's still a need to keep looking for new targets that we can really design something specific with and uh there are also um now studies that are trying to combine them right so rather than shooting one target at a time if there are two targets that we can hit why not just shoot both so that if the cancer cells are trying to shut down one there's still another one right away um so a lot is happening in myeloma and i think while we're talking genetics just know that that's really it's important but it's part of a bigger picture yeah definitely as you said in the beginning you know a year from now let's talk again because myeloma is constantly changing a lot of questions here about blood-based mrd testing like you were talking about earlier a lot of this stuff is still in the works still in these um still you know testing sensitivity and in clinical trials and things like that so just stay tuned as a myeloma patient it's so important to stay empowered to be seen by a myeloma specialist at an academic center who is aware of all of the new research and you know revealing things being done in myeloma dr savannasanka that was amazing thank you so much i do want to say to our audience i know there's several questions we didn't answer today as i was going through the questions several of you are asking specifically what things meant or terms meant that are in your fish or other genetic testing results and we have a medical navigation team or a myeloma navigation team i should say that is willing and able to help you out health tree to identify what these terms are and explain what these terms mean and can help interpret your labs a little bit they won't give any medical advice but they will try to help you understand the beast that is myeloma in all of its different terms so i will make sure to um i'll put it in the chat now for anybody that's interested our phone number that you can text or call and then you can also email support at healthtree.org you can say that audrey sent you and you're looking to have a help interpreting your fish results or something like that so before we leave today dr savannasanka any closing statements that you would like to make i mean of course i think you know knowledge is truly power and and i appreciate you all for joining today and also for health tree to really be a resource um no one should be on the myeloma journey alone and a shout out to folks who today have the report coming back to you saying that you're in the high risk group there's a lot that's being done to improve the ability to take care of patients in your situation and i think if there is clinical trial opportunity available near you these are really an effort to not treat everyone in the same way but try to find unique ways for the unique set of people that we are more worried about so think about maybe consider participating in those i just think that not only you might find that it offers an opportunity to choose the treatment that's more specific for you but it will help us learn so much for just why the high risk group why the why the cancer cells were actually misbehaving in with this particular type of signature completely agree completely agree thank you so much i'll let you go thank you so much i'll keep my audience on for just a little bit longer for some outro announcements but thank you dr savanasankar i'll be in touch thank you and i i apologize for my techno justico t at the beginning hopefully that worked out okay you're fine thank you it worked out great thank you to my audience i'll just finish up by saying we'll meet again as the newly diagnosed group in may however we're going to be having several uh sessions between now and then we are actually going to be deep diving into high risk myeloma next time that we meet other upcoming events on the 23rd is our non-secretory myeloma community i know we had a couple non-secretors here tonight we're going to do a deep dive into the bone marrow biopsy and how bone marrow biopsy specifically can help the non-secretory myeloma community on the 25th is our black myeloma health community we're going to be talking about staying afloat and balancing financial toxicity especially in the area of prescription drugs and how you can get financial resources to help pay for those prescriptions the link to sign up for any of those events is included at the bottom of the slide and will be included in our resource email that we send out to you with the recording and the slides and other resources that we mentioned today another special thank you to adaptive amgen jansen oncology abby gsk bristol myers squibb and regeneron for sponsoring this program and thank you to each of you for participating for sharing and again i will include our number and our email in the con in the resource email with like the slides and everything because i want to make sure that you get your questions answered it's important to me just like it's important to you so stay tuned for that email and contact our team to be able to help you understand the different terms that are out there thanks everyone have a great rest of your day bye