(Guest Lecture): Risk Classification | HealthTree Foundation Round Table on Genetics

[Music] hi everybody thank you very much brian for um that great talk and for setting the scene um for um the next section what what i want to talk about is um risk classification i want to talk a little bit about what risk means and what when we talk about high risk and standard risk genetics what that that means for a patient i also want to talk a little bit about some of the challenges and i guess opportunities because we need to be positive about these different risk classifications and then in closing just a little bit of a i guess kind of um discussion about how this actually fits for the individual person because much of this data is from large groups of patients and it's always important to try and bring it back to the individual [Music] patient so how do we go about assessing risk and um as far as the genetic risk of myeloma the way we do that at the moment is that we look at the um myeloma cells um as dr van ness was saying and so we need to have a bone marrow where unfortunately we can't do it from peripheral blood at the moment so we need to have a bone marrow test where we can get the myeloma cells and look at the genetic abnormalities within those um and so that usually means that we can do it well at presentation and we can often do it at relapse the i guess good thing about is when a patient's in a good response it's actually very difficult or challenging to do um assess a patient's genetic abnormalities because when a patient's in a good response they probably don't have very many myeloma cells in the bone marrow and therefore it's more difficult to actually look at the genetics of them but the important thing for doing this is if we are able to assess risk can we tell how a patient's going to respond to treatment how long their remission is going to be for their first treatment and indeed you know how long is their response to overall treatment going to be and we call these prognostic factors and essentially what's happened is over the years we've studied lots of clinical um trials so lots of patients who've been treated in different ways and we've compared different groups of patients within those trials to try and figure out which patients did well with the treatment and which patients unfortunately probably didn't do so well and we've learnt that just as in fruit when we're comparing patients we have to compare like with like so we have to compare apples with apples or pears with pears we can't be comparing patients which are just not like each other at all otherwise we don't get very good results now as a general rule we've tended to classify patients into low risk standard risk and high risk more recently we've tended to move away from the low risk category when we're thinking about myeloma for the very simple reason unfortunately we know that myeloma um is not a good um disease to have it's not something anybody wishes for and so therefore it's a little silly to have a low risk category because we know myeloma can cause lots of issues and problems so we've now tended to move towards having a standard risk and what we call a high risk but one of the important things that both patients and physicians and relapses researchers are struggling with is that we don't always have the same number of patients in each group so it's not that let's say if we have 100 myeloma patients 20 of those would be considered high risk each of the different definitions we have will have a different number of patients who we might consider as being higher risk and so that's something important for the mathematicians within us to remember when we're thinking about this now we're obviously talking about genetic risk today and that's the genetics of the myeloma cell itself but i think we have to think about it within the context of a bigger risk and that's things about both the patient and the actual myeloma itself so i just want to talk about those for a few minutes so when we're thinking about the patient there's actually lots of things about the actual patient that determines how well they tolerate treatment how well they respond to treatment and what the overall outcome can be because i guess if you think about it it may be that for we need to give slightly different treatment to an older frailer patient than we do to a younger patient we can't treat an 80 year old for example the same as we would treat somebody who's 40. and the important thing is it's not necessarily about the chronological age it's more about the kind of general fitness of the of the patient that's important we all know that um you know some people are playing tennis and running marathons when they're 70 whereas other people are struggling when they're 50 and so we need to take that into account we also need to take into account patients other health conditions so some treatments for instance steroids are much more difficult for patients with diabetes to maybe um handle um some of the treatments we use may be more problematic if you have issues with your kidneys and so all of these factors add in together to determine how a patient's going to respond to treatment and that overall um kind of outcome but in addition to that there's lots of kind of actual myeloma related factors so um the actual amount of myeloma within a patient's body is important and kind of i guess we know that you know if there's a lot of myeloma around then patients may have high calciums or may have low blood counts but also where the actual myeloma is is important so some patients potentially might have plasma cell leukemia or might have lumps and bumps of myeloma and so that's important to know and can again alter the way that we maybe think about treating and the effect on the kidneys as i've mentioned before and then the bit we're talking about today is the actual biology about how those myeloma cells grow and the genetics of it and the reason i've said this is that often um and physicians like myself are just as um guilty of this often when we talk to a patient we'll say oh you know you've got poor risk myeloma because of these genetics but you have to put that little piece in with everything else so just because you have poor risk myeloma because of the genetic features doesn't necessarily mean that's a bad thing it needs to be put into the context of everything else how fit and healthy you are and what else is going on um with your myeloma okay so let's just go into that genetics in a little bit more detail so um dr van ness mentioned that um the myeloma abnormalities um can come in different types so we've got that change in chromosome number that he mentioned we've got the change in structure where you can get breaks between chromosomes and they re join um in a different position and then we've got a change in the actual code of the myeloma and so you might get a change in the way a gene is working the end result of all of this is that the myeloma grows differently and it has different sensitivities and resistances to our therapies so when we're looking at the bone marrow myeloma cells what um what are we actually looking at so initially if we're thinking about changes in chromosome number we'll often potentially get a gain which in the jargon we use is often called an amplification or an amp or we can get a loss which is sometimes called a deletion or a dell of either a whole chromosome so for instance instance chromosome number 13 may get completely lost so that would be called a deletion of chromosome 13 or we may gain a whole chromosome so for instance you might get an extra number three and that would be called a trisomy because we then have three chromosomes numbers three it doesn't necessarily need to be the whole chromosome it could just be part of a chromosome the chromosome actually comes in two parts and it has a short arm which is the p arm and a long arm which is the um pew arm and so it could be that you maybe lose a little bit of the p arm and the common one that we think of in myeloma for that is a 17p so we've lost a little bit of chromosome 17 or we could gain a little bit of a chromosome and again the common one in myeloma is a gain of chromosome 1q so rather than patient having two chromosomes one q they actually have three or sometimes even four chromosomes of one cube when we think about the chromosome structure so that's when chromosomes break apart and rejoin but don't rejoin um correctly then um that's a translocation and common translocations involve the chromosome number 14 and that can change and move to other chromosomes and we'll come back back to that in a minute and then as we as um dr van ness mentioned we can get changes in the actual chromosome code and the two common ones that we often look for is a change in the raz gene or a change in the p53 gene and the reason we look for those is that they not only have some significance for prognosis but also might help us a little bit with treatment so just hold that thought and i just want to take a couple of steps back for a minute i actually started doing myeloma research kind of back in 2000 and my initial work was actually looking at this new test called fish and you can see over the years we've got lots and lots of different tests that have been um produced and one of the important things of this is just as dr van ness was saying about it's cheaper to look at things when we were doing the old testing we were not very precise it wasn't very um kind of it was more of a an overview than a specific kind of very detailed view and we could only look at one thing at a time but as we've gone through the years and the technology has exploded we've been able to look at many different things at a time now what that does mean is what we knew about myeloma genetics 20 30 years ago is very different to what we know about it now and it's continuously changing and what's happened is some of the things that we thought were important back 20 years ago are actually not important now and i guess one of the things that i would like to stress is that it's really important to discuss your myeloma genetics with a myeloma physician for the very simple reason things are changing all the time and many of the things that we thought were bad news actually are no longer bad news okay so that's key and this slide will hopefully show it in a little bit more detail so as a kind of bird's-eye view these are the different kind of abnormalities that people think of as being either standard or high risk so hyperdiploid is when we have those three copies of the different um uh chromosomes we've then got the translocation where a bit of 11 ends up on a bit of 14 and a bit of 14 ends up on a bit of 11. and they're thought of as kind of neutral we then have these selection of adverse um abnormalities or often known as high-risk abnormalities now the important thing about this is that it's not that these things occur in isolation it is possible to actually have more than one of these abnormalities and it's also been shown as well that certain abnormalities hang around with other abnormalities and the really good example of this was back 20 years ago chromosome 13 and a loss or a deletion of chromosome 14 was thought to be bad news okay but what's happened is over time with these technologies and the fact that we've learned more we've actually learned that chromosome 13 often hangs around with this translocation of chromosome 14 so the 414 and so it's patients that have the 414 and the chromosome 13 which are the ones which are thought to have a poor prognosis it's so it's not really anything to do with the chromosome 13. it's we've learnt more and we've actually found out which is the bad player but having said that just as we've been learning more about genetics we've also learned more about clinical and the way we use our drugs better and so in many instances now patients that have a chromosome 414 are often not considered as having high risk because those patients seem to respond particularly well to bautism so the reason i say that is this is a continuously changing field and what we know 20 years ago is no longer right for today and probably what we know today may not be correct in a couple of years time as these new treatments come about and get introduced so what what kind of systems are out there what what things do um physicians use so as i say we use this fish test which is done on the bone marrow where we look to see what's happened with the the different um chromosomes and this is a very i was going to say simplistic view but patients can get divided into a standard risk group a high risk group or an ultra high risk group and the ultra high risk group is really just defined on whether you have more than one of these lesions there's other ways of doing it as well though in the fact that we can move forward and say right okay let's not just look at the fish test let's try and look at patients broader let's put in some blood tests as well and so um the revised international staging system or the r i s s looks at three blood tests which are quite commonly done which is the beta2m the albumin and the ldh and at some of these genetics and is able to group patients based on that there's then another system which not only looks at the fish but also looks at those mutations we were talking about and that system is able to pull out it's a much smaller group of patients but a group of patients that we think will potentially do particularly poorly with our current treatments and those are called the double hit patients and then as dr van ness was mentioning there's this bar coding like in a supermarket the gene expression profile which again can pull out another group of patients now one of the issues and one of the things that we're trying to do as a myeloma community is that each of these different kind of risk stratification systems pulls out different patients as being either standard risk or high risk and so you can actually be standard risk in one and high risk in another okay and so there's a myeloma community we're working together to try and figure out which are the most important things and maybe more importantly what we can do about that and so i guess my take-home messages to some extent are is that this is changing day by day and we're learning more as we study more big data sets but importantly just because you have one high risk factor does not mean that you have high risk disease and need to hit any panic buttons and that is a combination of factors both the genetics but all of the other factors related to myeloma that are important and that's why i think it's really important that you discuss the kind of more finer details with your myeloma doctor so that um they can actually give you a true um kind of reflection of your own personal risk okay which just brings me to this so and it's coming back to personal risk if if you look at the the graphs over um on the left if you for imagine that the green is a group of a thousand patients okay and theoretically those patients have what we call a poor survival they don't do so well as those patients in the red curve but that's very much looking at a large large group of patients it doesn't tell us what one patient within that group is going to do and that's clearly what we actually want from a patient's perspective and a doctor's perspective is it's all very well looking at these large groups but what does it mean for me individually and that's what we call a predictive test and we are getting a little bit closer maybe not for working out kind of long-term outcomes but we are getting a bit better at working out which patients may respond to which drugs um in better detail um and um my colleagues going to talk about that in a little bit more detail um in a minute so what my conclusions i'd say that the myeloma genetics is just one factor that influences how quickly myeloma cells grow that we need to think about patient and myeloma factors when we're thinking about how a patient's going to respond to treatment and their outcome the um just as dr van ness said myeloma is very heterogeneous and we need to study the biology of this so that we can learn much more about it and learn to dissect out those specific differences and we really do need to concentrate at the moment on those patients with what we think have high-risk disease so that we can try and help to tailor treatment for those in a little bit more detail we have learned a lot about the myeloma genetics of myeloma and we can actually group patients into different groups and to some extent configure a little bit about what patients may respond um better to certain treatments and as i could say my colleague is going to um continue with that theme now so i'm going to stop sharing my screen and hand it over to him and we'll take some questions in the longer run you