[Music] how can myeloma genetics predict the risk of myeloma progressing so i'll give you an example of how how we we're using this this is a study we published almost 15 years ago now where we actually looked at how we could you know create these different subtypes of myeloma this is always something that is evolving and we said okay if you have these markers what is the likelihood that you're going to have events sooner now if you look at this curve and you go back at the one we have here you see quite a difference in how how the the slope of those curves has has changed back then it was mostly the the male flan and the dexamethasone we had for those patients but none of the new drugs but at the time we realized what you see in the blue curve means that that's kind of the most risky and dangerous situation back then was the patients who have this this abnormalities what we call the translocations the 4 14 14 16 and the loss of a little segment of chromosome 17. and if you read the medical literature they still remain as one of the the key ways in which we myeloma doctors think about more aggressive forms of myeloma there's even better ways to determine this right now but this is how most of the medical literature you know still is reported i don't think it it is crucial to explain the technicalities of how translocations occur uh just know that a translocation is i call them a little bit like swinger chromosomes so you have a chromosome 14 here you have a chromosome 11 and 14 normally it's going through a lot of you know cut and paste cut and paste cotton paste and if it just happens to be very close to for instance 11 if someone has an 11 14 and 11 has a break foot they switched partners so now it's a 14 with a little segment of 11 and an 11 with a little switch a little fragment of 14. it's kind of like like pens exchanging their caps if you may that's what a translocation is and that is one of the key seminal events that gives rise to myeloma now and that we use that and that's we've used that over the years now this is very very important and i know i see some faces in the audience that i know you know this is not deterministic at a hundred percent it just tells us there's a high risk that things may not go the way we want in fact we have patients who have these markers who can do very very well in the long term it just changes how we think about things it's not like you got this and it is predetermined that you're going to have this outcome likewise we sometimes unfortunately see situations where someone doesn't have any of this high-risk markers and yet you know the the clinical course is that yeah it's more aggressive so so none of this is deterministic it just gives us a framework on how we start thinking about this myeloma cells how can you know your level of risk the easy way to know whether you're low risk or high risk that's not that sensitive but it's easy to get is when you're initially diagnosed before you've received any treatment two tests are performed beta-2 microglobulin and albumin the tests just roll off the tongue don't they and you can see that if your beta 2 microglobulin is low on the top row these patients have more sensitive disease and on the bottom beta 2 microglobulin higher these patients have more chemotherapy resistant disease this was published a really long time ago based on patients treated and even longer time ago so ignore the columns on the right this does not suggest the survivals that are accurate or indicative of what is expected today but the what this talks about and reflects the biology of the myeloma that is still accurate a high beta-2 microglobulin before the treatment is always a bad thing now you'll notice that that's just blood tests and that's only part of the game that is a very insensitive measure of risk of how aggressive or how hard to treat the patient's myeloma is really we want to add in the genetics a little bit more information about these myeloma cells to complement the blood test obtained prior to treatment so we developed a revised international staging system which is slightly more complicated and you can see the beta2 microglobulin is still there you can see it down there in stage three so the criteria is there but now we add in primarily some genetics and we use terminology that's very difficult for normal people to understand we'll think of most of you except those in the front row on the right hand side as normal people and this is hard for you to understand because no one speaks like this normally so on that you're going to write see these acronyms and since you're already here you've probably gone on the internet looked at the myeloma you'll these acronyms will come up a bunch so no dell 17p is code word for the short arm of the 17th chromosome in your myeloma cells but not your normal cells is missing and this suggests that you have higher risk myeloma those t414 1416 that's when part of the 14th 4th and 14th chromosome got together when they shouldn't be getting together and same with the 14th and 16th these create proteins in the myeloma cells giving them tools to fight chemotherapy more than patients with low risk disease and hence the presence of any one of these changes pushes a patient to more higher risk myeloma more chemotherapy resistance and thus a shorter survival so primarily these are obtained by doing either a karyotype which we honestly don't do at osu anymore you get newly diagnosed myeloma we don't do a karyotype because it's so often negative and so often useless that why do it and a karyotype is a lot because you're essentially putting myeloma cells in a dish and expecting them to reproduce and myeloma cells are just like my in-laws they're absolutely incapable of being in a foreign environment reproducing being fertile and going on and flourishing they need to have their separate special environment that they've created in order to survive and do well so myeloma cells are just like my in-laws they're not going to survive in a dish and in general what you do is put some myeloma cells immediately after a bone marrow biopsy and stain them for specific mutations which describe high-risk disease the ones that we look at we look at patients with a deletion of the short arm of chromosome 1 the short arm of chromosome 17 these translocations people who are getting together who should not get together and how many of us know people who have gotten together who should not be together and lastly a 414 translocation with a number of other things that increase this pay a patient's sensitivity to or decrease the patient sensitivity treatment we often like to say that if you have a fish or a karyotype that are both normal and you're newly diagnosed you didn't they didn't have any myeloma cells to test one or both of these tests are going to be abnormal in a newly diagnosed patient virtually every last time and if it's not if it's not abnormal they didn't have any myeloma cells to test can you talk about risk and gene expression profiling there's um other ways in which we can talk about risk and one of them is this gene expression profiling and you probably will hear a bit more from from dr morgan which can you know it's another way to look at prognosis and try to separate those patients that actually may have a more aggressive form of myeloma so that's one one of the ways there's a there's actually a commercial assay that's available too for doing this through this you know sky company that can test for for the high risk markers now one of one of the things to think about with these two things is that again number one prognosis is not determinant it's not a black and white you have this you're going to do well you have this you're going to do bad we're still going to work together through those things and and uh you know the the the other thing is that this are only approximations because there's many other things that come into play you know if you come to the clinic and a person has you know severe diabetes and heart failure it's gonna be a lot harder to get going through that through the completion of the treatment so all of that plays out on how we're able to propose different treatments for for patients it's important to know what type of myeloma each person has because we cannot treat everybody as if they're the same we know that some people are more sensitive to treatment and have much longer survival and other people have very aggressive and very resistant myeloma that despite of chemotherapy their disease is tends to come back very quickly or does not respond well to treatment so if somebody has a diagnosis of multiple myeloma that's not enough for us to be able to know what are the best ways of managing your treatment and to plan your treatment for the future even though the induction and the transplant portion of treatment tend to be the same regardless of the cytogenetics it is important to know that the type of cytogenetics of your high risk or low risk or standard risk so that you can establish a proper maintenance so high-rise cytogenetics at the beginning when somebody's diagnosed is important so that we can have an idea of not just the type of disease that you have but is this a disease that's going to be hard to fight is this a disease that's going to be wanting to come back quicker and us have to be more cautious and surveil more frequently to look for relapses or is this a disease that is going to be more easy going and hopefully easier to treat that by the time we put it in remission there's a better chance that that person is going to stay in remission for a longer time so even though at the beginning it might not seem like a necessary thing for a patient because they say well why would i need to know my mutations and my cancer if the induction therapy is going to be the same with three different agents and i'm still probably going to go to transplant after finishing induction there are now some debates as to whether certain medicines should be used in high-risk disease as part of the induction and there are clinical trials currently comparing the use of corphylsumib instead of portusa mib in high-risk disease patients and if there is an added benefit or better control of this disease by using this change in in the triplets that we use as part of the induction just to give a simple example or a comparison if your husband or your wife comes home and says i want a car can you buy me a car you're not going to say sure you can go and buy a car you're going to want to know more details of the car what brand and what model would make and model of that car so that you can have an idea of how expensive it's going to be how much maintenance you're going to need if it's going to be something that you can afford or not if it's going to be a luxurious thing if it's going to be something that adapts well to your family or not and the same thing happens with cancer when that somebody has multiple myeloma we want to know as many details as possible so we can have a better understanding of what we're dealing with so we can have a better way of handling it managing it and at the same time have better information that we can provide to the patients so that they can have a a better understanding of what to expect in the near future and how to plan their life accordingly