(Guest Lecture): November 2023 - Understanding Your Protein Markers and MRD

Nice meeting you. Some of you I know I see a lot of familiar faces. Good seeing you as well too. We have a day prepared for you where we will be discussing many aspects of myeloma, you know, including some of the diagnostics, some updates on therapy, and as you've heard from from Jenny, we want to make the most out of the day so you can at the end of it have additional information that makes you a more informed and a more empowered patient. So thank you also for being here. Like Jenny did, I want to thank the rest of the Health Tree team as well too for all what you've done to put this together. My colleagues Dr. Patel, Dr. Yadav, Dr. Costello as well too for, you know, putting your time forward for this event as well too and traveling to be here with us. And last but not least, two other heroes that I want to call out are sitting here on the right side. So and many of you know them. So Shereen Best, who is a nurse practitioner in our team and you know we all work together myeloma related activities and also Jayden, Jayden Pulino. You know Jayden as well too. So thank you for coming as well too. During this first session I'm gonna talk to you about a couple of things. I'm gonna talk about the myeloma markers, I'm gonna talk about MRD and what it means. And again just you know write down your questions so we can address as many of those as possible. Okay so first of all we have seen a huge improvement in outcomes and better outcomes and longer survival for myeloma patients. We won't be satisfied until we get to a point in the future where the treatment for myeloma is one pill one day that costs zero dollars and has no side effects right. But until we get there we're making a lot of approximation so we keep improving. On the left side you see what I call the old survival. When I was in training with my colleagues at Mayo Clinic in Rochester after the time of diagnosis the median survival was two years. So you take a hundred patients after two years half of them would unfortunately have passed on because of their disease. On the right side I cite to you three studies that have been recently published or presented that look at current survival statistics for myeloma patients. There's one that came out of Emory University where they said for patients who have no high-risk features about 13 years, patients with high-risk features about eight years. And I will point to you that in these three studies I'm telling you they're not even getting the best that's available. So these are good treatments, very good treatments, we can still up the ante with what you're seeing there. A study from the organization of Dr. Patel from Andy Anderson, stem cell transplant and maintenance with Reblimid, linalytomide, a hundred and eleven months they reported. And lastly there's a Canadian study which looked at patients who were treated in that case with was CyBorD. Some of you may have received CyBorD, it was a great regimen, it's still good, but now it's like a B- as we compare it to other things and they reported 159 months. So things are much better. I am convinced and I would tell this to any of you if we were meeting for the first time that we have the opportunity to actually cure some patients with newly diagnosed myeloma right now. It's gonna take many years before we can look back and say that was the case, but our clinics are becoming enriched with people that are out 15, 20 years plus and you know the myeloma still remains under good control or not detectable. So very very pleased with that, but again our goal is to get to that one day treatment right. So we'll work towards that. Now I already covered a little bit of this, but you know this is a slide I often use just to say that the treatment process usually is just putting together different blocks and this would be like a block that I would use for what we're seeing with the treatment for someone who would go through a stem cell transplant. So you know induction is a term of course we use for the very first treatment we have. Then you can call it consolidation or we have transplant, you know that's something we offer to patients frequently. There may be a future where we don't do transplant, but right now for patients usually under the age of you know 70, 75 we will consider transplant as one of their options. Most patients get maintenance now, even if you don't get a transplant most patients still get maintenance. And then I put an estimate of what I would say if you were only given one treatment at the time of myeloma relapse, if that were to happen with very conservative numbers one should be looking at at least another you know three years. So not perfect, the best scenario would be you're not here today, but again we're moving forward and there's significant progress with where we're going. Now this is another way to look at this and this is the study shows you a little bit of what's happening over time. We published a study back in 2017 so that's six years ago now. I think many of you are familiar with this curve, if you're not let me just explain it for a second. This curves we call them Kaplan-Meier and a perfect curve where nothing ever happens it's a flat curve. So the flatter it is the better. So as curves go up that means there's improvement. In the bottom part and what the x-axis you see the survival in years and then in the y-axis in the vertical line you see of course the probability. So again the best curves are would be completely flat. What I wanted to highlight with the studies you see the three blue curves are patients with myeloma in databases that come out of the insurance companies. So we can actually cross-reference these databases with the outcomes for this patients and we separated those three blue curves by the year of the diagnosis for the person. So as you can see it's much better if you're diagnosed more recently than if you were diagnosed way back in 2006 and 2007. And the reason is there's better treatments that always come and are available for patients. Now keep in mind we closed the study at 2012 that was the last year we allowed for the diagnosis just so we had some follow-up and we could report on what was happening on this patients. So most of this patients have not seen carfil semiped or atumumab. Certainly none of them had seen you know like the car keys and things like that. So if we're to repeat the study again in 10 years I bet you that blue curve will be even significantly higher than what you're seeing here. The second concept that this is very very important I know that the economists do something that's called the value of options and that's partly what this slide reflects and what I mean by that is you're diagnosed at the time point and and hopefully are you know part of the goal and the mission of us and Health Tree is that you're gonna get the best treatment when you're diagnosed. You should be getting the best treatment but if in the future there's another treatment that comes along and you did well because of that first treatment you get the benefit of that first treatment however much control that provided but also there's a benefit that it opens up a new option because now you have a new treatment. A good example would be CAR-T's. So if you go through therapy and the therapy lasts but then it turns out that at some point additional treatment is needed but a hack is what now we have CAR-T's then you start linking those things. A great example of that is I'll use this is when we started dealing with the epidemic of AIDS and HIV I was in fact in training when that was happening about a third of all of our admissions to the hospital were AIDS related complications and there were no very not very good treatments and there are some patients who were getting you know some of those pills or you know just okay then what happened is some of them lived just enough so that they got to the next generation of pills and some of them are still around here today so someone who's diagnosed now with HIV and AIDS often can be close to normal life expectancy and that's just because of this process of innovation so that's what we you know we like to see as the research keeps going on. Okay so let's go to my topic so I'm going to talk to you about two things one is explaining the protein markers and the other one is going to be the MRD and by the way if anyone wants this slide I'm happy to share them as well too so you can you can have those for reference. Myeloma it turns out is B cancer that has the best biomarkers as we call them I'll explain this in a second of any cancer so that means we indirectly can measure what's happening with this cancer cells better than for any other cancer and and the reason for that is primarily because the myeloma cells when they were normal before they became myeloma cells they were plasma cells produce the antibodies that protect our bodies. I think you'll know we you know and with COVID now everyone knows this we have antibodies that are part of our immunity that help us fight off infection. Now through the course of our lives you know our body produces thousands and thousands of different antibodies in fact if we look at the bone marrow it can be somewhere between hundreds of thousands sometimes millions of different antibodies each one of them is custom made to the bacteria or to the virus that it's you know threatening us. One of the ways that the body sort of has learned is that okay I already fought that virus so I better keep a copy of that cell I have a blueprint so if in the future again that cell comes back I already know what to do I know how to produce that antibody. Now those antibodies chemically are proteins and that's why you hear the word proteins a lot the antibodies chemically are proteins and those antibodies are predominantly IgG and IgA we have a little bit of IgM and you know some other antibodies that are less common but most of our our blood the antibodies that we have is IgG. Now if I was to take out all the IgGs from your blood and line them up against the wall they would all be slightly different from the next because again each one of them has been designed specifically for one given threat. So in the case of myeloma one of this plasma cells instead of just being quiet there in the bone marrow and kind of remaining waiting there for the for the turn to be cold again just has a mind of its own and starts making many copies kind of many selfies I say for that cell right so that cell grows so now it turns out that we have all these thousands of antibodies but then there's a lot of one that's what we call a monoclonal protein so that's what you see on the right there so we can you know through blood testing measure for protein abnormalities. Now maybe some of you were first diagnosed if you went to your primary doctor and they said oh the protein is high there's something abnormal first thing that should come into the mind of a doctor if the protein is high could this be myeloma. Now then you do other tests and I'll explain that in a second. An analogy I use for this and I'm sorry for some of you who are probably going to hear this for the second time is we use proteins in a way such as you could use the smoke to see if there's a fire so just bear with me you're walking down the street you're walking past the building and see smoke coming out of a building so first thing you do is you make a diagnosis there's a fire inside the building and that's how we use this abnormal proteins but then as the firefighters come along and you start seeing that you know they use the water in their trucks and the the smoke goes down then you know you're putting the fire under control so the same happens with your monoclonal proteins we want them to go down and ultimately we want everything to be normal so no smoke. So you and for some of you perhaps with smoldering you know that there's a little bit of smoke but it seems to be not too bad and that's how we use the proteins and that's why they're so critical in how we measure for myeloma activity. On the right side so I show that the end protein base for many many years we have used this in the clinical test we you know we get results pretty quick now more recently there's some improvements that we can go very deep there's a word you might hear which is called the mass spec and the mass spec allows us to go to very very minute amounts of abnormal protein in your blood which we now actually do quite routinely here at Mayo for patients who have very very deep responses. Now the other way we monitor for myeloma is what you see there on the left side which is monitoring for what's going on in the bone marrow directly so this is going into that building okay we know there's smoke on the right side but now we're going to go into the building and there we do everything like you know we stain the cells we count those cells so the percent plasma cells you have heard we do the genetic markers for risk and we'll talk a little bit more about that and we also find the DNA fingerprint for those myeloma cells so we can use that for tracking and that's what we call the MRD testing. Now I told you you have the cells right you have hundreds of thousands of different cells in the bone marrow from exposure you know during early life that made you have that protection. How does the body make different antibodies? How can it make so many different types of antibodies? And the answer this is a little bit strange it's through mutation so when our body faces an infection the cells that will produce antibodies they belong to a family we call B cells they're just changing their DNA they're cutting and pasting and nicking and this and that they're changing so you can imagine that's a pretty dangerous thing to do in an organism. Perfectly healthy beautiful babies have B cells that are mutating all the time just so they can produce different antibodies our body is very very unforgiving if you make a mistake when you're mutating that cell it's no good but if you do this millions and millions of times every now and then one of the cells gets through the process it's like a little typo that changes the whole history and that's what gives rise to to the process that we call multiple myeloma it's just sort of an accident in nature well it turns out with this mutations actually you leave you leave tracks you leave like a DNA fingerprint and that's what we use to track when when we do the test for MRD through the colonel seek we're looking for that so I'll tell you a few more words about that too as well now with regards to the and we're going to talk more about this there's many many genetic abnormalities I know this can be a little bit overwhelming and it's changing all the time you know even within hematologists we we know we're always changing classifications but just know that one of our interest is to see which type of genetic markers you might have and as we will talk later there's some that are high risk meaning we're a little bit more concerned about them they might be associated with with more aggressive disease we'll talk more about what that means and some that are a little bit perhaps more sort of a more quiet or stubborn but not very aggressive myeloma some of them that we are targeting now like some of you might know there's an abnormal fusion that happens in this mutational process between chromosomes 11 and 14 that gives us a great target to use one of the medications for netto class so so that's part of part of what we do so let's just say a word of two about the proteins this is a plasma cell so if this plasma cell becomes abnormal then this becomes a myeloma cell and I put the word plump there just to show you how they look it's like a fried egg if you may the white of the egg we call it the cytoplasm and this is a microscopic image we call it electron microscopy so you can see actually looks like there's all the streets right in that white of the egg the cytoplasm all of those are folds that the cell has that are 100% dedicated to produce antibodies proteins so this is the classic myeloma proteins and what they do is they they produce them there they fold them and then they're pushed out so they go into our bloodstream that's the function of that cell of course the myeloma cell is confused because now it's just producing proteins without the need for that production but we can use that protein to track what's going on in in in the bone marrow for the blood now one of the one of the things that we do is we actually do a test that's called the protein electrophoresis the test looks like the little strip you see at the top that little blue is kind of a little bit of a smear but what they do is they put a drop of the blood and then they run it in a gel that has you know it's under electricity we call it electrophoresis that's what is the protein electrophoresis then you can actually spread out the proteins and you'll see a pattern like what you see there in pink that is actually a normal pattern that looks like a normal protein you know composition in your in your blood so if someone doesn't have myeloma it looks like this it turns out that's a protein electrophoresis from my dad who recently got it done i thought the image was pretty beautiful so i seem for permission to show that i said dad i know a little bit about this so let me show that image now unfortunately what you see on the right is what happens when someone has one of these abnormal proteins it's called m spike m stands for monoclonal or myeloma now you see there's a there's like a steep upwards curve that goes there on the right side right so now we know this person has an m spike an abnormal protein and then that should alert also to the possibility of something like myeloma now when you see that little spike you just know it's abnormal but you don't know what it is so then our pathology friends will do things such as adding extra dyes now in the bottom part you see a g and an l those are dyes that are very specific the g is anti-igg and that's positive you see underneath the a is negative and the m is negative so we know this is an igg protein now and then at the bottom you see a k and an l and i know many of you will recognize this kappa lambda and it's positive for the l so now the pathologists would say this is an igg lambda protein and then they can measure you know how much is there in that protein so that's how we use these proteins to to to track the disease now i mentioned before we do this thing with that's called the mass spec so the mass spec is a very very sensitive way of looking at at your blood our pathologists in rochester have done a lot of work in this dr mary in particular um a way i explain it to to my patients is imagine the aspect is like doing a chest x-ray the mass spec is like doing a cat scan on your blood it's that precise so now we can go to really minute concentrations of proteins and and we're learning how to use it but we're very fortunate we think this is a good tool to screen with greater sensitivity for activity of myeloma there's many other things we can actually do from from this test now this is one i i want to spend a couple of minutes explaining it's a very important one this is a free light chain this creates a lot of a lot of confusion that igg molecule looks like what you see on the left side there so you see there's two long strips those are called the heavy chains then there's two shorter ones the ones that have the little red there those are called the light chains and when when plasma cells work and work normally they produce about just the right amount so there's a foursome that is you know kind of well organized and you know organized like like a good you know golf shop right it gets the foursomes right at the right amount it's they're all going out and and doing well together now under normal circumstances our body produces just a tiny amount of extra light chains very very little so if i were to draw blood on someone who doesn't have myeloma i'm going to find a tiny amount of light chains but sometimes patients who have myeloma their cells will produce much more of that and sometimes only that sometimes there's patients that may produce only light chains now there's a test that was developed that is called the free light chain that measures in the laboratory only the light chains that are free and if there's so so if you look at your test results it must say free sometimes people measure things that are called light chains but it doesn't say free so we'll measure the ones that are free but the ones that are attached to the igg as well too so it's very important to keep in mind now the way i used to explain it what is a hot dog bun doing there right so the test was developed imagine the igg is like that hot bun and when it's closed you don't see the white but people develop the test that would measure the white so it only measures what's unbound to the igg and that's why that test is so important this is a test we used to monitor of course that you know where the myeloma is it's critically important to understand whether someone is at risk for kidney damage these are the things that can create most commonly kidney damage in myeloma patients and and and one that really should be monitored in every patient so it's very very important that that you know this is done this is part of our routine testing so this is a free light chain now a couple of other sort of quick comments on the light chain number one is i tell my patients that i would tell you as well to ignore the ratio the ratio is more confusing than is helpful i know some of my colleagues are going to start throwing tomatoes at me saying that but ignore the ratio the reason is if you're kappa and then you know you look at the ratio your your ratio can change dramatically by what happens to the lambda the lambda has nothing to do with the myeloma so if the lambda goes up by 50 then the ratio is going to go up it's going to go twofold and then everyone's going to be alarmed so once you make a diagnosis i would say just focus on the absolute number the absolute kappa or the absolute lambda i know this is hard because a lot of publications talk about this ratio but i tell i tell the patients let me look at the ratio and you look at the absolute because there's so many things that are abnormal i promise if something comes back we will let you know but the ratio can be very very confusing the second one this doesn't happen often but it's important for some reason different institutions report this in different ways sometimes they report it per deciliter and sometimes it's reported by liter so you have to look at the units because once you know in a while we get someone who's really scared who tells me oh my kappa went from six to sixty is exploding it turns out is the same concentration is just different units so so keep that in mind as you look at the units most commonly is reported in liters we reported at may unit deciliter so you just have to keep that in mind so i hope this gives you an overview of of what the protein markers are and why they're so important and again we measure them in the blood and we can measure them in the urine for the most part i don't tend to do a lot of urines i do one at the beginning just to know exactly if the kidneys are doing okay if we're putting a lot of protein but given the light chains we can actually for the most part skip having to collect urines every time in the old days that was the only way we could test for light chains was by looking at the urine but now with the blood test is a lot simpler okay in the few minutes i have left i'm just going to talk to you about mrd and minimal residual disease and if you were in the parking lot my my car has a plate that says mrd neg because that's the aspiration we have unfortunately everyone in the street says what is mr deneg is like oh it's mrd neg but i'm the fellow there on the far left when i was in training back then getting into a plateau was enough meaning when we use mouthful and prednisone if we have the concentration of the monoclonal protein we thought that's good nowadays we know that we want to do much better so the modern version of that is getting to mrd and and i'll talk to all of you and some of you may be mrd negative some of you not and then just what this means i'll tell you that from my perspective at the start line the very first time we meet with someone my goal is to put a plan of treatment so that we're in the best possibility of achieving this mrd negativity now this is another way that we can look at progress i show you those survival curves now this this is a bar graph so the higher the better here that shows outcomes with the various treatments that are now being tested for for multiple myeloma looking at the possibility of creating mrd so way in the in the past with very few patients would get mrd in fact we didn't even have a test it was pointless to do that test but then as you see as you progress towards the right that's kind of the series of all these new regimens we went from an old time where maybe five percent less than five percent of patients could get mrd then along came transplant and you know we say 20 maybe 30 percent of patients when we're optimistic now with the most recent clinical trials and this is particularly clinical trials that now have added the monoclonal antibodies like our tumor map or is a toxin map we can get mrd negativity in up to 80 percent of patients now this is at the threshold of 10 to the minus five we have a way to go even higher with when we do the clonocic we do 10 to the minus six so that's even deeper but even with it with a study on the very last one with the measure of 10 to the minus six it was 66 percent of patients are mrd negative so again when we when we start the game we want to do everything we can to make someone a mrd negative you can't always do that and it's not necessarily bad but at the beginning that's what we try to do we go through this one now this is what we call a meta analysis so this is a way by which you know doctors get together information from many other studies and get it all together and do some studies like i guess you know similar to what you can do also with with with health tree as well that more information is gathered so you get more accurate answers and this looks at outcomes by mrd and and what they they show and this is the reason why you know we push for that is that if someone can become mrd negative in general outcomes are better i'll say and this this is very important it doesn't mean that if one does not become mrd negative for sure things will be bad no it just means that there's a a better chance of better outcomes if you're able to become mrd negative now what i don't show you here and but other studies have shown i think there's at least five studies now that show this is that it does not matter when you get to be mrd negative it could be before transplant if you're going through transplant it would be after transplant or it could even be later after maintenance or consolidation but as long as things are moving in the right direction that's what matters and that's why we track it so closely i tell you know my colleagues that one of my favorite things to do in my clinical practice is that if i get the mrd results i usually will get an email and if it's saturday night i will call you home just with those results now uh you know there's we open that email and there's you know obviously trepidation we want to i know this means a lot more of course always to the patient to you and to your family but we also get excited we see that results yes yes that's good that's a great result so i want to make sure you know uh about that when when when that happens because you know obviously that's that's a very significant implication for how how are you going to think about where you are with your your treatment now one of the things that is often misunderstood with mrd is um and you'll hear about this in seminars or in conversations amongst those you know in the myeloma world is like oh is mrd ready for prime time and can we make clinical decisions and this and that i say on it from my perspective mrd is clearly ready for prime time it's just one more test just like i told you about the free light chains that's how we should use mrd um there's some people would say well we need to get clinical trials and i tell them we never had clinical trials for the free light chain it's just a more informed clinical practice so why do i put a dashboard there in the supreme court you know justices some some years ago i tell everyone managing myeloma is like you're flying a plane you have to look at all of your dials and it's you know getting all that information together that lets you what you need lets you know what you need to do mrd should not be used like the supreme court like the ultimate decision maker of everything that happens after you do an mrd test so i have patients for instance who get treatment and let's say they're two years in maintenance with revlumid and they become mrd negative i'm not going to walk into the room and tell you it's sober forget about revlumid we're going to stop it right it's always a conversation and some of them have told me you know i would feel an easy stopping therapy can we go for longer and my answer would usually be yes we can do that someone might say you know i'm really having a hard time i can't concentrate i'm having all this diarrhea and so forth knowing that i'm mrd negative can we stop and i would say obviously this is very good this is good to know you're there and we can stop therapy every single clinical recommendation has to be personalized has to be adapted to you know your preferences are what we know about the disease what we know about this testing so it's critically important that we don't think of mrd as the ultimate decision maker for everything but it's just one more part just like mass spec just like free light chain that informs our practice better now this is how i think about mrd right now so this this this square i'll explain what it means first of all we're using it to measure the depth of response and in my mind as we develop new treatments and you're hearing about these atoxam and daratumum we want to choose those treatments that produce the greatest rates of mrd so that's the depth of the response but what we're seeing too as well is mrd may be used to stop therapy our colleague dr krishnan from the city of hope has said one of the unmet needs in myeloma is the ability to stop therapy and i think once you have patients that start becoming mrd negative i think we'll be able to stop therapy altogether and i say that you know historically our treatment of myeloma was like paxformino you got to come in with overwhelming force and you stay there for a while and we want to do that for those myeloma cells but you'll see this image i put the boundary an orange boundary there that means that there are patients that can actually do very well without being mrd negative i have patients that were transplanted more than 15 years ago who may have a small m spike and are still doing great the only problem is that we don't know that from the get-go we know that as we look back but looking forward it makes sense but once you go through treatment and and i know there's some amongst you here that are still mrd positive but you might be doing very well one of my my my favorite patients that you know has shown me this was transplanted about 16 years ago keeps an m spike of 0.2 so that's a lot more than just being mrd positive no maintenance and continues to do well so i hope this gives you just an overview i think that's my last slide i'll try to stick on time thank you again for for coming and i always say in arizona everything is possible so thank you