(Guest Lecture): Myeloma Sub-Population Genetic Characteristics | HealthTree Foundation Round Table on Genetics

[Music] thanks to both faith and bran for setting this up i really appreciate this opportunity to speak with all of you um and i was actually very interested looking at all the questions that are coming in so thanks a lot for asking all those questions already we really look forward to addressing them as soon as possible so as uh as both brian and faith have kind of set up uh this is a complicated lots of new terms kind of a an area but at the same time you'll realize how both of them have done such an excellent job trying to parse it out and explain it that it is so part and parcel of how we treat myeloma these genetics it becomes extremely important for every single patient to at least try and understand and if for some reason they cannot understand then reach out and ask and and and that's i congratulate all of you who are listening to this today that you're already taking that step and you're trying to take that step towards understanding your disease understanding the care of myeloma and kind of going from there so uh let's start with some of these things um as uh we've talked about already i'm not gonna repeat all of the things that have been mentioned already but um there's this discussion about high-risk genetics and standard risk genetics and as uh faith uh went over these criteria i think it's important for us to realize that these are two distinct categories whether it is these high-risk genetic abnormalities uh with the translocation for 14 14 16 14 20 deletion 17 gain of 1 q or a mutation in the p53 gene or for example as faith just pointed out these are not the only high-risk features there could be other markers also so we talked a little bit about gene expression profile uh mayo likes to do this plasma cell s phase but also the revised iso staging system and then there are a bunch of standard risk disease okay so we uh i wanted to kind of put this out there some of the questions that are coming in are already asking hey i've been told i have one cue or um i think someone asked well one queue is present in about 40 percent or 40 percent of the newly diagnosed patients does that mean there is something significant about it what am i supposed to know or what am i supposed to do about it so i think i what i wanted to point out was this is a very good uh article which talks about what is the incidence or frequency of these abnormalities in patients who are newly diagnosed with myeloma and to the best of our knowledge right now what is the clinical implication what is the adverse risk factor what is a favorable or what is a neutral so this is something that you can look at but now when we say for example in the middle of this screen where it is hyperdiploidy 50 favorable what this means is that as compared to the adverse risk factors as compared to the high risk factors patients who have hyperdiploidy are more likely to respond to treatment or um have a better outcome have a superior outcome so i was asked to talk about some specific uh populations and if there are any specific risk groups um actually i am noticing a lot of questions coming in i'm just going to make sure yeah so uh going back so i was asked to talk about some specific populations i focus a lot of my work in racial uh disparities and with respect to myeloma also myeloma genetics per se there are quite a few uh racial variability and differences noted so i'll touch upon that just briefly there are lots of factors that can be taken into account when we talk about healthcare access and healthcare delivery and we know that socioeconomic and cultural determinants of health are going to play a much bigger role than anything else but there are some factors which i've highlighted right in the center of this figure which is age gender and hereditary factors or certain genetics which are beyond our control so we can talk about the natural environment we can talk about the health economics we can talk about access to drugs but there are some factors which are non-modifiable for example age gender and genetics so when we look at this this was a study back from 2013 which in my mind was probably the first one kind of talking a little bit more in detail about racial differences with myeloma genetics and what this study showed was lots of numbers they looked at they cobbled together basically a lot of different data from a lot of different studies and said showed that african americans had a lower uh frequency of trans locations just like my previous colleagues mentioned trans locations where a part of the chromosome has cut off and gone and joined somewhere else and then sometimes the one the portion from the second chromosome has gone to the first chromosome so that kind of a balanced or unbalanced translocation but it was shown that americans have a lower incidence of these translocations lower frequency of these translocations suggesting that african americans may have a less aggressive version of myeloma so genetically speaking the myeloma of african-americans may actually be less aggressive so those of us who are for example focused a lot on racial disparities and differences we were like oh wow that means that african-americans should actually be having better survival superior survival at that time unfortunately this was not being seen but now as of last year there is one large study out of the va which is showing that if given the similar treatment opportunities african-americans actually do have superior outcomes or survival which kind of goes uh with this explanation that they have less aggressive disease this was another study which was a little bit more sophisticated had uh looking specifically at the tp53 gene which as uh was mentioned before the tp53 gene which is also considered or sometimes termed the guardian of the genome because this is such an important gene to repair any kind of a damage that happens in our dna naturally so if this gene is mutated the the dna is not able to repair itself and those cancers that have this gene because this gene can be mutated not only in myeloma it could be mutated in lung cancer it could be mutated in breast cancer so whatever whichever cancer has this particular mutation that cancer tends to be more aggressive than its counterparts where this mutation is not seen so what this particular study showed in a few years later so in 2017 was that the tp53 gene is a mutation is seen less frequently in african americans again suggesting that african-americans have a slightly more favorable genetic profile this was a study which was uh done by the mayo group and my colleagues up in rochester what they did was well we have cytogenetics and fish that come to the male lab from across the world so they just took samples that had already been studied and they tried to look at the ancestry or seeing if the patients had an african descent or european descent and what they found out was the one of the things that showed up significant was that this translocation 1114 and also some other translocations were actually seen more frequently in african descent now you can say you know what you previously mentioned that the 2013 paper said that 14 translocations were less frequent than african-americans what i can say is that that was putting together data from a lot of different databases a lot of different setups this is a little bit more refined and what we are focused more on i think in today's myeloma agent beyond is that we are finally entering this world that we may have a biomarker driven treatment so for example there are medications that are being developed which specifically seem to benefit the 11 14 group so i think in that sort of a setting this 11 14 information for example or newer information that may keep coming in this direction that will be significantly uh beneficial so one thing we can say is that deletion 17p is less frequent in african-americans and translocation 11 14 is more frequent in african-americans right now these are the ones that seem to be of most clinical significance but the work is ongoing okay so now one of the things i wanted to reach out and and kind of touch upon is we've talked about what these translocations and deletions and hyper deployed et cetera are but as i was looking at the questions some people were saying well i've been told i have three copies of this particular chromosome translocation does that mean it's significant or somebody has said i have a two percent of this particular fish abnormality what does that mean does that mean it's significant or not what am i supposed to do with it is it positive or not i need a simple straightforward answer so to to preface those sort of questions i want i want to take you through a study that we recently published actually just last month and what that study did was um the agenda for today's talk said variability in cytogenetics actually what i wanted to talk about was variability in cytogenetic testing because i think while it's important for each and every one of you and every single patient to know what these cytogenetics mean it's also very important for you to know that when you're handed that report in your hands with well this is your fish test how am i supposed to interpret that how am i supposed to say well these are the three things that came out significant and the rest is not at least looking at that report what can i say so what we did was for this particular study um actually before that just a little bit of this has been covered already about what is conventional karyotyping or or how to um when brian explained how is a cytogenetic abnormality um detected it could be done by conventional karyotyping where all the chromosomes are lined up and any and every abnormality is picked up versus a fish test where we're looking for specific abnormalities so if you take a fish a sample from the patient a bone marrow sample and then we start putting probes for specific abnormalities for specifically let's say 1114 or 1416 or 14 20 or 17p or 13k or whatever so whatever probes go in only they will come back as positive or negative so for example if we use a probe for 13q deletion that will not tell us anything about 17p it will only tell us whether 13q deletion is present or not so before doing fish for any disease we need to know what are the abnormalities that we want to look for it's also important to know the sensitivity of these tests is different a karyotype a conventional karyotype counts on average 20 cells fish on an average counts about 200 cells so much more sensitive test as i mentioned karyotyping talks about the global changes in the chromosomes while fish is much more specific karyotyping is much more widespread availability although we're saying we're seeing and we're we're thinking in terms of the fishes giving us more clinically actionable and important information but as a part of my work i do also a lot of review of stuff that is happening outside of the us so african countries south america india and a lot of places fish may not be available still karyotyping is cost and time uh duration of doing the testing uh makes a difference and also and i guess this goes to one of the questions which was uh asked i think my friend jack from california jack ayala he asked this question well how frequently should the testing be done so we know as as brian mentioned that there is clonal evolution so the disease can evolve and some of these high-risk features can be acquired as time goes on so what our practice is typically that while we may not run it on every single bone marrow biopsy because of cost and and just how what is the appropriate thing to do but at baseline everybody should get it especially if the disease is not behaving clinically the way you want it to behave so you were expecting it to respond to regimen xyz it did not i think it's reasonable to see oh did something change or if a disease has been quiet for years a person has had smoldering myeloma for 10 years and now they have active myeloma or the disease is progressing uh differently it is showing up with many many more plasmacytomas of course if somebody has plasmas or leukemia so if the clinical behavior is different than what we expect i think it's very reasonable to check again and then in between whenever there is possibility again it should at least be discussed well do we need to keep checking fish again and again or not so talk to your physician so as i mentioned this particular study which we just we just got published so basically we looked at more than 1200 patient data which including about a little more than 1100 conventional karyotype and close to a thousand fish results over a span of about 18 years tested across 58 different labs in the us and what we noticed was that these were the number of samples that were tested at any given lab so for example uh there was on the left in panel a it is showing the number of samples in lab number one by the way we did not use any lab's name because we didn't want those centers to kind of feel offended but at least we wanted to say that there is variability so for example on the left panel that is talking about the conventional karyotype the conventional cytogenetic testing and there is one lab which uh so so there were actually 28 labs that only had tested one sample over a span of 18 years on the other hand there was one lab that had tested eight samples so the number of samples was very variable then we also uh checked the same thing about fish there were labs which had only checked one or two samples and there were labs which had tested many more samples when they were adjusted to and kind of per year so very variable in the experience of the lab we also looked at this is looking at karyotyping so again conventional cytogenetics interlab and intra lab variability i mentioned that the average number of cells counted is 20. but there were labs that were counting on an average less than 20 cells and for some samples less than 20 cells some for some samples that same lab would count more than 20 cells so the question becomes okay if somebody says you've got one plasma cell that was picked up and that has this abnormality what is the significance versus if 20 cells have the same abnormality what is the significance so generally it is said that if there is a gain type abnormality like a hyper diploidy etc then you want to see that in three chromosomes to say that it is clonal meaning that it is a true finding and if you have a lost type abnormality you want to see that at least two chromosomes to say that that is true so this uh came up as a difference in the lab handling this was looking at uh fish testing and again rather than going through all the details and this this this data is available publicly that the number of probes used for fish because i said that in fish testing you need to know exactly what you're looking for if you check for three abnormalities you will only find out if those three are present or not so the number of abnormalities tested across different labs was very variable there were labs which were only testing for one abnormality and there were labs that were testing for a slew of them i can tell you i previously trained or worked at usc in los angeles usc used to send its cytogenetics and fish to city of hope city of hope just like mayo clinic had an extensive panel i mean they'll these these sites would pick out such things where you're like you're thinking okay what am i supposed to do with this information there's so much information but at the same time there were there are labs that will only check for two or three abnormalities now some of it may be cost savings so for example a lab may say well if there are five high-risk abnormalities i'm going to only look for those five because it's cost-effective if those five are tested and are all negative then genetically speaking the myeloma is going to be lumped into standard risk so that's important for you to know i think as a bare minimum those five high risk myeloma abnormalities must be tested then we also found out that the exact probe that was used for a particular abnormality could be very variable i've put in some examples here so for example 11 14 13 and 4 14. i'm just quoting three examples we looked at many many more there were so many different probes that could be used now one can say that okay if there are mutations or specific abnormalities is it possible that one of these probes could miss or is it possible that one of these probes could overcall i don't think we'll be able to sort all of this out in today's discussion but i think this is where having that fish result and discussing with your doctor becomes extremely important so that you realize what that means and how it applies to your care we also looked at this this is kind of trends over the years and we looked at comparing the earlier years to now up to 2016 that the average number of probes being used by labs for testing and fish has been going up so more and more probes are getting used like i said in my mind if that is a push comes to shove those five basic high-risk probes must be tested okay so um as my other colleagues have very nicely and conveniently said okay we're going to talk about treatment a little bit later so i was thinking to myself how would i fit treatment guidelines when we were talking about genetics and our one first goal at least the way i look at it is that everybody at least understands what genetics are i'm going to leave you with some thoughts about treatment guidelines this will not answer every single question you may have and it may not be exactly what your doctor is doing for you i don't want you to think that something wrong is being done in your case i think we uh we want as a community to spark that discussion so that you can take this information back to your doctor have a discussion be more informed about your disease so that we can as a myeloma community work or and move towards curing myeloma so this is like i said one of the examples and this is what the mayo clinic guidelines are now by the way this is this has nothing to do with clinical trials what the way we have it set up is that all of us at mayo which is about 40 or so of us at the three mayo sites who focus only on myeloma every time a new study comes out we look at our data and we say okay does that mean something should be changed so this is for example saying one of the possibilities one of the algorithms is that patients who have standard risk myeloma this is talking about newly diagnosed and it is talking about transplant ineligible and what it's saying is that if you have high risk myeloma a combination of a proteasome inhibitor like potassium an immunomodulatory drug like lenolidomide and dexamethasone we should give that sort of a regimen for maybe close to 9 to 12 months maybe closer to 12 months and then we should continue towards progression um uh continue on maintenance till progression if somebody has standard risk disease and we've for example talked about 11 14 trisomies etc then it's still appropriate to start on that similar sort of a regimen there's nothing wrong about it and it's also very reasonable to consider other regimens like we have dartumumab lendex that is also approved so again there is no reason to say that one is the absolute right choice for one category but i can tell you when we go through these discussions it's a lot of discussion that happens amongst all of us and saying well this is what this study showed this is what that study showed so this is just one possibility i'm bringing up similarly if it is newly diagnosed but now transparent eligible then things are a little bit more complicated because we have to bring in the possibility of for example a stem cell transplant again newly diagnosed transplant eligible this is one of the algorithms by the way m smart or the mayo stratification it's available online it's free anybody can go into msmart.org and and you can access it but standard risk with induction transplant and then maintenance similarly high risk in the middle with the induction treatment but it's very reasonable to consider even a four drug combination again this has to be individualized one size does not fit all you've heard that time and again and then if a person gets transplant and then go on to maintenance similarly there was this mention about double hit myeloma triple hit or very high risk malama where you have someone has multiple of the high risk mutations then it's probably reasonable to consider again the uh four drug regimen potentially in important to discuss three drug regimen may be better for someone because if they don't tolerate four drugs there's no point going down that road transplant and then maintenance i did not even bring in relapsed hair because i think in the relapsed setting more so than genetics a lot of other factors go into the mix for example how did the person respond to the frontline treatment so let's say if someone has deletion 17p but they've responded beautifully and now their disease is in control for the past three years yeah that genetics of myeloma is playing less of a role and maybe if that person has severe kidney function is on dialysis maybe that has a bigger role to play in the choice of next treatment on the other hand we've all of us who focus on myeloma we have patients who don't have any high risk features but they start on treatment and six months later they're already progressing they get a transplant and three months later they're progressing so genetics or not that myeloma is telling us that it's clinically a much more aggressive clone so i think especially in the relapse setting a lot other factors have to go into the mix so what i want to basically end by is saying that genetic testing in myeloma is considered a standard of care not everybody may need a myeloma genomic panel or next generation sequencing right at the outset but at least basic simple fish and or karyotype should be done every single time a new myeloma is diagnosed cytogenetic testing as i said with fish or karyotype is most widely used and is available and is of very important clinical significance there is variability in testing techniques but more attention is being paid to that now and hopefully we'll have more standardized guidelines but i want everybody to consider taking that report and talking to your doctors cytogenetic testing must be used to make the treatment decisions as i said high risk and standard risk it we already said one size does not fit all but especially for high and standard risk that absolutely does not fit the same bill and then novel techniques will hopefully improve our understanding of myeloma biology and also how treatment decisions are taken in the future so while like brian and faith mentioned that we may not be taking a sample and doing a gene expression profiling and channeling the patients to say hey you get bertasmi you get len you get vrd you get krd you get dara etc we're not doing that yet but the technology is present and those processes are getting validated right now so the the future is brighter and much more hopeful than what we have seen so far thanks a lot and i'm going to stop sharing my screen and bring everybody else on now