(Guest Lecture): Will the Smoldering Myeloma Diagnosis Phase Out?

and I'm looking forward to that part of the discussion as well. So today's topic is going to be will the smoldering myeloma diagnosis phase out? Now there's been some buzz in the myeloma community and even disagreements between different myeloma specialists concerning the smoldering myeloma diagnosis and we've seen the smoldering diagnosis evolve over the last even decade of determining what really is high risk smoldering myeloma and when is it treatable? Sometimes the question that arises is could it be possible that the smoldering diagnosis phases out just to leave MGUS and active myeloma? So Dr. Karellis is here today to provide his opinion on the subject and help us understand how we can use this information to better manage our care. It's now my pleasure to introduce him to you and he's going to introduce himself a little bit more as well. Dr. Karellis is a hematologist, internist, and oncologist working in the bone marrow transplant program in the hematology department at the Mayo Clinic in Minnesota. In 2015 he got his hematology oncology degree at the Mayo Clinic division. He got his oncology degree and later in 2016 he got his myeloma amyloid and dysproteinemia disorders advanced fellowship. So I'm going to turn the time over to you now Dr. Tax to be able to explain more about yourself and then launch us with the subject of does is smoldering phase out or not? So I'm looking forward to it. Yes thank you Audrey for the introduction and everybody for um gifting us your time and attention today. I hope we'll make the best of this. Let me share my screen and again this is I think meant to be an informal interactive you know presentation so feel free to ask questions whenever you feel like something is confusing okay. So I'll just give you a practical perspective I was discussing with Audrey. It's always nice to have you know two opinions like eventually I have to give you my opinion. I'll try to balance things as much as I can and give you both perspectives but again if anything is not clear these are my disclosure just some research dollars for from novartis looking at L1 intubation and smoldering myeloma. So the outline of this presentation will keep it practical and straightforward just a slide on who am I. Some definitions I think these are important I mean I understand many of you are dealing with these conditions and I want to call them diseases but conditions or have family members that you know deal with amgas or smoldering and then you know start with why do some patients why some some folks say that oops myeloma smolder myeloma won't exist why some others say that it will and I think it's important to discuss this in the context of how has prognostication of these precursors evolved right when the myeloma diagnostic criteria would change in 2014 it's because they were more refined and when we identified an extremely high risk subset of patients high enough to say you know these smolders just get treated because they're going to progress into myeloma very very quickly so I think this is where this whole I guess discussion is is arising from so we'll discuss the history of prognostication existing trends and also a little bit of you know lead time bias and actually what does it mean when you diagnose when you try to shift the diagnosis of active myeloma right which means therapy earlier in the disease course and then conclude and discuss any questions so well my myeloma and amyloid doctor at Mayo I'll always say amyloid because that's my sort of side passion I do some fun translational clinical research in both diseases and and I do see a lot of patients I'm still a very active clinician so I fully appreciate the you know the stress and anxiety that comes with the diagnosis of smoldering myeloma and even m gas sometimes and and I can see why I have some patients with smoldering myeloma and m gas being way more anxious than myeloma patients and and I can see why that is when you have a precursor that you don't know how it's going to do so definitions you know I'm going to use some acronyms I'm going to try to minimize acronym usage but just to save space on my slides you know m gas as you know monoclon gum up with your fundamental significance smm for smoldering myeloma mm for active myeloma you know plasma cells sorting them down to pc these are the cells that give us the you know the malignant clone free light chains I'm just going to abbreviate them to flcs and these are the proteins as you know that these myeloma cells most of the times make and you know bm for bone marrow so definitions right existing definitions place a big emphasis on is there organ damage or is there no organ damage okay I think that's the 30 000 foot you you have any organ damage that's myeloma irrespective of how much of it you have how many plasma cells how high your m spike is so on and so forth we don't have damage you know you consider most of these to be precursor diseases with a few exceptions and of course there is the bulk based concept I mean if you look at definitions of mwg or you know you google stuff you'll see cutoffs of like m spike less than three four m gas if it's more than three it's smoldering there's you know ranges for your plasma cells and don't have to go into details there's like ranges for your free light chain ratio if it's too high nowadays we just call it myeloma sometimes straight away so and generally speaking there is you know an increasing increasing m spike increasing plasma cells your bone marrow if you had a bone marrow as you go from m gas to smoldering to myeloma but this is not always the case and then the next slide there are just some clinical examples and I think this is important and as we discuss further down the road about early diagnosis and contemplating early therapy just to get a sense of how this disease develops and these are all patients that I've seen in the past I don't know two to three months all right patient number one had an m spike of five for light chains around 100 or so you know they had bone lesions or their ct scan they had some kidney damage so their creatinine was going up right clear cut dextrug myeloma this other patient had no bone marrow plasma cells nothing at all m spike tiny m spike 0.5 light change completely normal but then you do a ct scan or a PET scan and your widespread bone lesions you biopsidem you know their plasma cytomas so that's it's a myeloma so again the the bulk I guess is a relative thing more more myelomas have lots of bone marrow plasma cells and high m spikes but that's always the case third bullet point you had a patient who had a prior m gas and they started off with a normal hemoglobin and over the years let's say a decade or so their hemoglobin slowly dropped and you know it dropped into nine and nine is the the definition of the crab criteria right in the previous slide I didn't emphasize so the crab criteria is c for high calcium that's kind of leaking out of your bones if you have myeloma r is for renal failure so that's usually an elevation your creatinine is anemia and you know nine is is a cut off and these bone damage you can see it on a ct scan PET scan MRI so yeah this patient did develop myeloma because they had a crab feature right so they had anemia nothing else in their bones nothing in their kidneys patients feeling totally fine you do a bone marrow and they're like oh 60 percent plasma cells okay so this is myeloma but the patient was again they did fulfill diagnostic criteria but feeling perfectly fine because this happened very very slowly another patient that I saw several months ago m gas for 30 years like very slow progression and then we end up getting a marrow biopsy and now has 20 plasma cells yeah okay sure now they do fulfill smoldering myeloma criteria because they have more than 10 percent but is this patient the same as a patient who walks through the door they have an s-pep of two and they get a bone marrow the next day and it shows 20 percent and you have no idea what's going to happen you know not exactly so there's a bit more uncertainty in the second scenario versus this scenario you say okay yeah I mean you are got to keep a closer eye on this but you also had this for 30 years so you know more likely than not it's going to continue to be um indolent or you know final bullet point patient has an m spike of three bone monoplasm cells 20 percent and just one asymptomatic bone lesion everything else is fine kidney function anemia calcium none of that stuff so but again this patient has myeloma because they have a high enough bone marrow plasma cell percentage and a bone lesion so that just to give you an idea of the spectrum of how the disease develop it doesn't develop always in a especially in patients that are followed right in a devastating way it can present in a much more indolent way also so a bit again high level sort of definitions you know how does the how does myeloma evolve I guess we don't know exactly what the initiating event is there are studies suggesting there might be some clonal clonal meaning identical sort of brothers and sisters B cells and B cells are sort of the grandfathers of plasma cells you know you start as a B cell and then you end up being a plasma cell so you might see some clonality even in these cases and then on top of that you add some genetic changes epigenetic changes that they perhaps accumulate over time and then this turns into a more sort of aggressive malignant situation but whatever the the initiating event is all patients that have myeloma always started at an m gas phase now most of them don't most patients that have m gas and m gas is a very common condition right again all of these the median age of diagnosis is late 60s to 70s for m gas molding myeloma m gas is the more common precursor right we see it in about two percent some studies now say might even be higher two percent of the general population ages above 50 so that's you know hundreds of thousands if not millions of people and natural history studies or screening studies done at mayo where we just took a bunch of patients and screened their serum shown that showed that only 20 percent of people that had an m gas when we screened them actually knew that they had an m gas so 80 percent of people have m gas are just working on the street don't even know about it most of these folks will not progress at least in one's lifetime some of them you know do progress into smoldering myeloma and again some patients might have an m gas they know about it and then you know they progressed in smoldering myeloma but a different concept as to you know compared to somebody who just has no idea and then they get diagnosed with smoldering myeloma is a bit more uncertainty smoldering myeloma is a is a high risk precursor many of these patients many more I guess compared to myeloma to m gas will progress into myeloma and then of course myeloma is you know when you have end organ damage in terms of basic biology again I think many unanswered questions there's one group of thoughts saying that you have like a static model where people start with the same pool of genetic material in these abnormal plasma cells even in the m gas phase and just they grow into myeloma just because they have you know enough time passes and they divide they keep accumulating and then in the end they just something happens and you know you end up having myeloma and there's the evolving model where you actually do have evolution of some of the genetic material in these pre-malignant cells and they you know become some of them become more aggressive when they cause end organ damage but this is still you know I think an area of active research just the one brief slide of myeloma and how this is currently treated so unfortunately for most people and there's certainly you know exceptions but for most people myeloma is still considered an incurable disease you can certainly have very very lengthy remissions you can certainly have folks that get diagnosed old enough and you know they get a 10 20 30 years of remission while still requiring therapy and they their life expectancy is not limited but they still require therapy but true cures where you give therapy and then you stop therapy forever it never comes back in one person's lifetime are not that common hopefully this will get better with new therapies but I think the emphasis in this slide is once you start myeloma therapy there's it's not going back and get the clock starts you have myeloma it's only going to give a little bit of therapy and then sit back for a very extended period of time and do nothing so there's some induction therapy some people get transplants some people don't get transplants most people get maintenance after they're transplant generally for a long time not necessarily there's some cases where we can you know stop it now there's studies looking at what's a more informed way to say when we can stop maintenance and then when myeloma comes back try various different medications and then there is a point there's just a mix and match approach there's no great study to say okay this therapy is better than the other but again this is not very relevant to this conversation just wanted to emphasize that myeloma is generally incurable once you start therapy that's you know you can't go back there's no going back until like a smoldering or an m gas phase for the majority of people so take home points myeloma can develop quickly or slowly so it can have many phases right since some patients can develop you know with all the crime criteria a very dramatic way other people can have a more indolent progression okay now to the question of interest here right will smoldering myeloma be phased out as a diagnosis people that say yeah it will they say yes because we we will have evolved i guess in the near future such sophisticated ways to predict patients that are destined to progress into myeloma that we might as well start treatment early so we can help people live longer or better people that say no they actually do agree that you know what yeah i think fairly soon we will have very very sophisticated ways to progress who's going to progress into myeloma who is not and when but unless we actually have clinical studies randomized clinical studies that show that if you treat these high-risk folks sooner you're going to make a solid impact in their long-term outcomes meaning that you're going to make people live longer or better then we really can't say that smoldering myeloma is not going to be a relevant diagnosis and i'll explain that i'll try to explain that a little bit later later on and during the q a of course okay so i think to discuss prognostication which is i think what it all boils down to we'll go back in time a little bit okay so i think prognostication started with i think m gus which is the more way more common precursor many of the studies were done at neo i'm going to highlight these having said that there's great studies from you know the nfr group the slowing catering group dr landgren there's people there's studies from the you know the spanish group that have sort of added to the body of literature in prognosticating m gus and smoldering myeloma i'm just going to highlight some of the classics you know from dr kyle so dr kyle was the first one who published back in 78 he got a bunch of patients and said that m gus and said you know the risk of progression to myeloma is about you know one to two percent per year and he showed that this was more common in males compared to females and it becomes more common as we age all right these were seminal observations now we take them for granted but this was not always the case now more recent papers again dr kyle still publishes new england general medicine in his 90s all right and he still published updated data in a much larger cohort and says yeah the average risk of progression for m gus is about one percent per year but you know if you look at some risk factors like an abnormal light chain ratio of your m spectra is more than 1.5 you can you know stratify these patients a little bit better but you can see m gus even if you have you know high risk m gus right you have both of these risk factors positive it's still you know about one and a half percent per year so it's not terribly high so 10 years 15 percent 20 years 30 percent that's of course in the after the holder for a young person this is very significant but somebody has m gus in their 80s this might not be as you know anxiety provoking other groups again dr landgren has the concept here in the non-progressing versus progressing patterns is that look okay we can have a static prediction model where you say okay patient walks through the room we get their labs and this is their average length of progression but i think a smarter way to do this is to kind of follow these people a little bit and and see how they progress and you have m spikes that are not progressing so their m spike over over time stays relatively stable and it's very self-explanatory that you know these patients are going to do better and patients that are progressing are not going to do as well now this is a curve comparing m gus progression rates versus molding myeloma progression rates you can see that small during myeloma is a totally different beast it's a much higher risk of precursor much higher risk for progression to myeloma compared to m gus and and you can see that i think most of the action for smoldering myeloma meaning chances of progression is the first five years another key point is that this is cumulative so all of these both smoldering and m gus once you have them you can't say i'm going to follow this for five years 10 years 20 years if it doesn't progress i'm okay unfortunately the risk is always there or as long as we are alive with these disorders which also adds to the anxiety of having them right now for smoldering though what i want to point out is that the majority so it says that 50 percent of people will progress in the first five years and then you still progress over time but if you see the curve kind of shoots up in the first five years and then yeah it goes up but it goes up at a much slower pace and this is kind of important it what it tells us is that smoldering myeloma is probably you know a mixed bag of people some of them are going to have more of a myeloma like biology and they're just going to behave you know progress into myeloma fairly quickly others are going to have more like an m gus like physiology and yeah they will progress but at much lower rates and and one of the key questions is all right how do you you know predict the early progressions but this this is just to give you an idea of you know m gus and smoldering how they they compare and additional you know smoldering myeloma prognostic factors have been initiated by mayo and and again other centers i'm just mentioning mayo because this has been adopted by the international myeloma working group it's been well validated and and what dr rascumar here used is you know three free laboratory laboratory abnormalities an m spike more than two bone marrow plasma cells more than 20 and a free light chain ratio of more than 20 so the the two 2020 scores kind of easy and catchy also to to remember and and even within smoldering right you can have significant variability with five years of progression of you know about 20 percent the people have none of these risk factors about 50 percent for people that have some of these risk factors and people that have all of these risk factors so the high risk modeling myelomas is a risk of 80 percent of progression in the first five years again this was a static model though right and and and the easy criticism is you can't really predict very well just from one time point things change so you got to follow people a little bit better and again dr langren has done a study so the morris slant is long catering group now he's in miami mayo has done studies that the spanish group has done studies looking at this and they defined the problem with these studies is that they haven't identified a uniform definition of what's progressing versus not progressing or evolving smoldering but they they basically looked at the m spike and they they had some various cutoffs your m spike increases by this much and your hemoglobin decreases by this much and the first you know one to three years or so you call that evolving you know smoldering and you can see that these patients are you know did much worse first five years of progression like 90 percent this was the mayo study that identified a bunch of other risk factors and even the first you know one to two years you can have like a 90 percent risk of progression the problem with these studies is they haven't been validated as well as that's why these haven't made it out to like um they haven't been incorporated in international recommendations but it does show you that in addition to a static prognostic model where you sort of try to predict the future by just getting one time point and seeing what's going to happen in the future you can you know following things over time you know makes more sense and this is something that you know all of us do routinely in the clinic these studies have tried to quantify the quantified a little bit better but they haven't been validated as well that's why they haven't they're not used very frequently and you know the more recent and more cool stuff of course are looking at other more sophisticated pieces of information so not just what you see in the chart right and easy laboratory parameters but what is actually happening down at the genetic level so this is Dana Farber study from the the gobral group right which is I think making performing all if not most of the most if not all of the cool research in myeloma precursors currently and they identified various gene groups and if you had some of them you know you had a high risk of progression if you had others you had a lower risk of progression and this just gives you a flavor this again has not been this was actually validated but it hasn't you know come to the clinic yet because you know you need larger data groups more samples there are expensive tests to to uh to perform but it just gives you an idea of where this is going we're just not going to look at oh hemoglobin and light change and m spike and you know born matter plasma cells that some people might say you know might be quite crude but you can look at you know the genomic information who knows maybe the next step is looking at the genomic information and dynamic method you know every year or something um the uh again the spanish group or there has done and you know phenotyping uh where they look at surface proteins instead of the genetic material and how these change or how these uh correlate with progression single cell approaches where you basically instead of kind of getting all the myeloma cells together and analyzing their genetic materials you try to identify the genetic material in each and every cell and that's important because you might have some for instance patients that have you know high risk smoldering myeloma and that's because a tiny amount of their myeloma is is is expressing some very high risk genetic anomalies but if you get all of your myeloma cells and you look at them um a genetic standpoint you're like all right this doesn't look that bad but if you look at them at a single cell level standpoint you can really identify the bad players that are destined to sort of expand as time goes by um so prognostication take home points so far uh so progression risk can average is cumulative so again it's not one of these things like i'm going to follow it for five ten twenty years i'm going to stop worrying about it unfortunately uh m gus even high risk m gus usually does not progress and does much better than even low risk smoldering myeloma and again smoldering myeloma is a high risk precursor and some of them can you know have like an m gus like physiology some of them can have a myeloma like physiology and there's let's say there are various risk models that have been developed some of them are better validated and have been included in clinical studies others are now being sort of explored better and they're more refined so here's the bringing bringing us back to our initial question right why do some people say that it's going to be phased out the um the idea behind this is that our ability to prognosticate ultra high risk molding myeloma right that's safe and people say in the near future we're going to have a the perfect calculator you're going to plug in your laboratory values your bone marrow parameters your genomic stuff your you know immune profile or whatever else comes out and it's going to tell you you know you're going to develop myeloma active myeloma right with crab features and all the classic stuff in two years three months one day six hours guaranteed 99 accuracy and and these patients we should treat so definitely agree with the first part the second part is where it gets complicated now bear with me because this can get confusing all right so what what folks that are I guess betting that at least you know the small myeloma is going to phase out they're betting on this scenario here so you got two patients one of them has molding myeloma that's destined to become myeloma right this is destined to become myeloma here but you say nope I'm going to start therapy here so start therapy here and then unfortunately the patient you know dies there this patient says you know destined to become myeloma but I'm going to delay therapy until this actually becomes active myeloma so this is the active myeloma part right you start therapy there and this patient dies sooner so you do have some life gained by starting therapy earlier so folks that say small myeloma is going to phase out as a diagnosis are hedging their bets that they were a are going to be able to identify progressors very accurately early progressors very accurately and that by starting therapy going to make them live longer scenario number two however could be this start myeloma therapy there these are both aggressive myeloma small during myelomas right aggressive small during myelomas you know they're going to progress quickly you start therapy there and then you know patient unfortunately dies over there this patient says I'm going to delay therapy I'm going to start when actually I get the crab features and then I still die there so do we know if early therapy makes people live longer or better do we have any data not really so there's two big studies in my mind two big random my studies one of them I'm not going to mention although I haven't mentioned in the slides but I will discuss it because it's very important thing to discuss the study done eight years ago or so in Europe and they took some high risk small during myeloma patients and they treated them with treated them with lenalidomide and dexamethasone half of the patients were treated this way half the patients were just observed right they got no therapy and they found that actually yeah patients had the survival benefit they got so they they lived longer the cat the major caveat with this study that's why I think most people in the US wouldn't agree that this is really informative in this day and age problem number one is how they define high risk small during myeloma they use some of the you know some specific tests that are you know we don't routinely use and number two not everybody got state-of-the-art imaging um and also the new criteria were not included so the new criteria is a bone marrow plasma cell more than 60 percent free light chains ratio more than 100 and nowadays we almost always do you know at least the low dose whole body CT many patients have PET scans or MRIs to identify bone lesions that study just used x-rays so the theory is that you know there's a very very good chance we probably missed some through myeloma patients in this study and we know I mean if you give patients with myeloma revlimit yeah they will live longer so that's why I'm not going into details the most recent study is a study that was led actually by Dr. Asgumar here at the Mayo Clinic it was done through the eco cooperative group and they got patients with high risk small during myeloma based on the Mayo 2020 to 2020 criteria and they gave them revlimit no dexamethasone and they the end point of the study right what they were looking at basically is were we able to delay progression to active myeloma and organ damage from active myeloma were we able to create to do you know delay anemia development hypercalcemia bone lesions kidney failure and just end organ damage they didn't look at the other stuff to test it which is you know just clinically relevant and they were able to show that however they weren't able to show that there was any survival benefit so patients didn't live any longer and there was no quality of life improvement so patients didn't live any better why is that you know and again it's tough to kind of pinpoint specifically why but one theory is again going back to the examples that I showed you right why if you delay end organ damage is not my quality of life going to be improved how does that make sense again having a patient who's been closely followed because both of these groups were closely followed irrespective of whether they got therapy or no so if you have somebody closely followed who develops you know one asymptomatic bone lesion that causes them no problem that's the end organ damage based on this study but the patient feels nothing so I mean or you have a slight elevation your you know creatinine for instance which means that your kidney function declined a little bit and then get therapy that goes back to normal and the patient feels okay you know that doesn't really mean anything to the patient is the bottom line same thing for survival many maybe patients that were treated later with revlimid right they just waited and got no therapy they just caught up and that's in the end everybody lived the same length of time so I guess the other counter argument is what do I have to lose by starting early well long-term outcomes are not going to be worse it's not like oh you start therapy and you said oh the clock is ticking or maybe I'm starting to develop resistance sooner no none of that stuff there's no issue with you know your myeloma outcomes are may not guarantee to be better but they're definitely not going to be worse cons of course there's you know drug toxicity you know these medications have side effects financial toxicity revlimid can be expensive and especially you know if you're going to get these drugs probably for many many years so all these things add up so there are significant you know parameters here to be considered I'm just saying I'm going to start therapy early because I have high risk small than in myeloma and again patient preference is always important but in these cases where the data is a little bit iffy I think it's more important so consider a 90 year old patient right who has high risk myeloma and we have this futuristic calculator say you're going to get active myeloma for sure 100 in two years but I'm 90 years old I don't want to deal with revlimid who knows I might not have two years to live fair decision or a 40 year old patient with three kids you know it's like uh I'd rather you know do something keep the tabs on this and then see how things go or somebody who is kind of in the middle let's say of age these are random scenarios but they already have you know kidney dysfunction they already have osteoporosis or bone dysfunction and they're like uh if I get myeloma on top of this maybe I'd rather be on something to make this more predictable again fair decision or again 65 year old patient with bad insurance is not going to cover the revlimid so these are real life scenarios that we consider so and we're going to conclude and then we can chat further so I think many people have given the example right many experts are giving the example like oh if you had a high risk you know malignant polyp in your colonoscopy wouldn't you remove it or you had a malignant breast lump found in a mammogram wouldn't you remove it should be the same for high risk small during myeloma not exactly because if you remove a malignant breast lump if you remove a malignant polyp you're done you're done this is you don't have to worry about them this is not going to develop into anything we don't have a therapy yet that we say we're going to start therapy in a high risk precursor stage small during myeloma let's say that's destined to develop into myeloma if I start the therapy then I'm going to make a difference for sure in this patient's lifetime so it's like you know it's preparing to go on a road trip right and you start a timer and when you reach your destination you kind of click back that timer to kind of stop the time so if if starting early therapy and your myeloma journey is just starting the timer when you're still packing your bags right versus starting theater versus starting the timer when you're actually in the car it's not a good idea yeah I mean it seems that you've kind of prolonged the time right because you started the therapy the timer at a different time point but you know you're going to reach the destination at the exact same time but if actually early therapy is going to make you help your car go faster that's a different story that definitely makes sense but to do that you need well-designed randomized trials that have length of life so survival and quality of life as endpoints everything else in between is a little bit iffy so and also we have to consider that you know many of these medications and especially as future myeloma trials are combining more and more medications together they can cause some side effects we have to consider that so you know and again my lame sort of you know star wars meme here you have to keep an open mind follow the data I think when there there's some conflicting data or conflicting consensus or specialist opinions I think patient preference is the most important it's always the most important but here it's really important and then randomized trials with survival and quality of life end point are the best but my opinion sort of take home point bottom lines I don't think this modeling myeloma diagnosis is going anywhere anytime soon that's it awesome thank you so much that was such a great presentation and I did appreciate your little star wars meme at the end so thank you for sharing that I think you brought a great point to the pros and cons of starting treatment early and just to explain it a little better because I know that there were not a little better you did a great job but just a little bit more clear to some patients that are asking hypothetically if the smoldering myeloma diagnosis were to phase out the high risk smoldering myeloma and even maybe some of the standard risk would be absolved into a myeloma diagnosis and the rest would be considered a precursor condition so that's why we focus so much on on whether or not we should treat this high risk myeloma smoldering myeloma I just wanted to clear that up because there were a couple questions so thank you one of the questions that I appreciated where does neuropathy come to play when it's from the disease and not the treatment and why is nerve damage not considered organ damage or myeloma defining event yeah so that's a that's a great question the so neuropathy is a complicated phenomenon so problem number one is that you know what kind of neuropathy yes and I give an analogy I don't want to you know misinform people or give you know the wrong information but there are very specific syndromes in which there is a clear causal association between the the myeloma protein or myeloma itself and neuropathy and these are pretty rare amyloidosis there's IgM related neuropathy with a specific phenotype you know poem syndrome cryoglobulinemia there's some like weird things like that the reason why we don't consider the myeloma defining event is that people can have neuropathy from other autoimmune you know etiologies etiologies that are very very common so the fact that you say you have and that's assuming right that's assuming you have none of the other crap criteria I mean if you have hypercalcimidone failure there's no question I mean you get therapy and that's the end of story and irrespective of neuropathy but if you have none of the other criteria and you have m gastro smoldering you have neuropathy that doesn't really fit any of the classic syndromes that I mentioned which are pretty rare the reason that you don't treat is because the fact that two things exist together doesn't mean that one is causing the other so you have some sort of autoimmune neuropathy that's most likely you know immune mediated like CIDP or you know idiopathic or whatever and you have an m gas which is also very common but doesn't mean that one is causing the other like it's like having a fire and people are exiting the building it doesn't mean that people that are there just cause the fire they're just there because there's something going in this patient's immune system causing probably boston neuropathy and who knows maybe contributing to some extent to their m gas but you know you don't you don't consider that causal and that's a very important thing to to define because it means that many many people would get chemotherapy which is a big thing right um uh so it's it's very important sort of secure the the causal association not to mention that several men velcade in particular can you know worsen neuropathy or even cause that you know so you have to yes and even you know honestly and even in conditions where you know like IgM neuropathy or amyloid where you do treat patients with with chemotherapy although I shouldn't mention that like let's say IgM neuropathy we don't go beyond reduction at least at Mayo because we really haven't seen any clinical benefit I mean these these folks you sometimes you give them therapy and you decrease the amount of the monoclonal protein neuropathy is still there which tells you that either it's loosely correlated or not correlated or something else might be going on interesting interesting thank you for your thoughts on that um let's there's several great questions here let's target this one is there any correlation that you've seen between the type of immunoglobulin and the risk of progression with regards to smoldering myeloma so IG yeah yeah usually you know the non-IGGs tend to be considered high risk at least for m gas for smoldering myeloma not so much and it wasn't thought to be independent from the other classic you know risk factors so that's that's what I think what I'm going to say I think non-IGG tends to be considered but it doesn't really matter if you have the other you know classically established risk factors or if you don't have them mm-hmm it wouldn't be defined the defining risk factor in in progression at least is that what you're for smoldering yeah for uh for m gas I think it's still a you know a reasonable risk factor and all these things you know there's just a google search away if you want to get like more specific numbers and stuff yeah be careful though on google who knows yes yes all right you can email me and I can forward you know more specifics Ida is wondering did she understand correctly that if you are diagnosed with smoldering then you definitely had m gas first let's talk about that progression yes so this is dr langren has done this study and found that every patient that has um that has you know had any sort of dysproteinemia there's always an m gas face there's always a pre-existing m gas face uh there can be you know several years ahead I think dr khal had presented that data he mentioned something uh very lengthy actually like at least 20 years before sometimes maybe longer than that but I don't quote me on that okay um if you are standard risk smoldering should you still wait and watch until it progresses um I mean I think the the consensus the community consensus is yes the only setting where we consider some sort of treatment like rev limit for instance is only high risk smoldering yeah yeah so if there's any trials I have to say you know always encourage participation trials for whatever risk they allow and stuff but so far I think observation yeah yeah that's a great point yeah that's a great point I appreciate that Lisa brings up if you have smoldering myeloma does that mean that your immune system is already compromised she's worried about you know the risk of walking around with smoldering being more vulnerable to viruses like COVID and other bacterial infections that she might do better on multiple myeloma therapy that can get your m spike down and improve your immune ability to fight germs all right two questions there so number one I think I don't think we have very specific ways of predicting with a few exceptions predicting how you know compromise the smoldering myeloma patient is the the the risk for COVID is slightly higher for smoldering myeloma patients not for m gas patients that was ash data that was presented last December but but again even within the smoldering you know pool of patients there's huge variability I mean one very crude way is to look at this phenomenon called immunopariesis where your you know your antibody levels are low but this is very tricky and you know certainly have patients that you know have very low antibody levels and they get in they get infections other like other patients don't get any infections and keep in mind if you're getting frequent infections smoldering myeloma that is considered by some to be a you know potentially a reason to actually consider therapy however if you're not clinically having any problems from your myeloma from your smoldering myeloma I should say starting therapy might not necessarily be a good idea especially if infections is you know periodic every now and then infections I guess is the only thing you're dealing with because myeloma therapy itself is quite immunosuppressive at least in the short term yeah that's not a very specific answer but that's also because there's not a very sort of I think specific data or consensus to say who is more immunocompromised than the other when it comes to smoldering myeloma yeah I understand Lisa and I understand your concern I think it's a good question that you bring up but you know I was just talking talking to you about how I talk to hundreds of patients and the I just echo what you were saying that the treatment becomes immunosuppressive as well the treatment is hard on your body and it when you're on treatment you're more susceptible to infections in cases and so it's not a you're on therapy and therefore your m spike is guaranteed to go down and your immune system is guaranteed to go up I mean it's just not a plus b equals equals c in this case although I do understand your concern and it's hard not knowing I mean it's hard not knowing um all right somebody is wondering if you could summarize again your conclusion about the Mayo study of lemon lenin linovimide versus observation did you say that there was no pps or progression free survival shown in the study there was progression free survival benefit that was shown but what does that mean and how important is that for all patients okay so it didn't show so it's if you give a myeloma medication to a patient with smoldering myeloma well duh I mean it's right it's going to delay its progression into active myeloma it's a bit of a no-brainer this study to its credit was better because it looked at you know again actual end organ damage again you know just the crap criteria not the you know the secondary newer criteria and stuff but so um but it didn't show any length of life presentation I'm sorry um extension and it didn't show any improvement in quality of life so patients didn't live longer or better um that's why I think it comes down to what the patient feels like you know doing I'm not saying that there isn't but the study didn't show it um yeah can you um confusing end points sorry it's okay this is a this is a complicated topic um so it's hard to come up with absolutes like you were saying earlier David is wondering can you explain how low hemoglobin level can take you from smm to mm yeah so I think this is um uh this just goes to um all of all blood counts right when you have more of these myclonal plasma cells I don't want to call them malignant because m doesn't smother me they're myglynda malignant but it's only malignancy so the more of these you have the more they kind of start crowding out the normal cells you're in your uh in your bone marrow so your bone marrow is not able to keep up and you see you know multiple um types of blood counts going down and we have three types right red blood cells going down and we have three types right red blood cells so that's reflecting hemoglobin white blood cells platelets so I think that one of the first to go down is the hemoglobin that's why I kind of made it to the criteria for diagnosis um and then you know there's some clear-cut indications like oh your hemoglobin is seven you have 60 all right done but there's some cases where you have somebody who says the normal hemoglobin let's say you know 15 and then next year it's 14 and then the other year's 13 and then it's 12 and it's still you know it hasn't dropped down to like eight or nine which is the official criteria but it's no it's drifting down so that makes you you know wonder see all right this might be actually you know an evolving process into myeloma and we might need to kind of pull the trigger but it depends as we discussed and I think that shows the importance of seeing a specialist even in the precursor phase because if you have questions and if you have concerns you know those are important and seeing somebody who specializes in myeloma versus a local oncologist might be able to explain things better or appease those fears that you might be having and make informed decisions with you Charles is wondering given the long timelines for clinical trials and the long follow-ups that are required when would we be likely to actually have the answer to this question benefit to early treatment 20 years from now 30 years from now yeah that's that's a good question and I think there's another attendee who asks something similar these are very these are very slow trials and that's why you know that's why we sometimes say okay it's reasonable if people are worried or if there's other concerns or other people are very young and they they want to consider early therapy to do it even if it's you know not like by the book but it's probably going to be several years I mean the ongoing ECOG study looking at data every mid versus every mid like chugging along I still might be another like five six seven years before it reports anything out so I yeah I think these estimates are unfortunately quite accurate yeah yeah it's going to take some time but that just shows the importance of participating in myeloma research so that we can accelerate it there's a way to do that there's another question about for example people at MD Anderson and Donaena Farber have started to do standard risk smoldering myeloma trials with immunotherapies such as daratumumab, venetoclax, or even blend rep to control early and save the heavy duty chemo like you know what the like stem cell transplant for later what are your thoughts on these kind of trials yeah so I don't specifically you know know the exact design of many of these trials I think is smoldering myeloma is it's a rare disease so it's difficult to get people on trials and it takes forever to complete them I mean conceptually they sound certainly you know interesting but we really can't predict something that makes sense in the lab or in our minds might not necessarily translate into benefit for the patient number one and number two what I'll say is is I think it's really really important to have you know randomization in smoldering myeloma of course we were talking brand new drugs right like you know blend rep or venetoclax or things like that you need to have like a phase two trial phase two meaning you just you don't have a control arm that's not going to get therapy it's going to get some other form of you know therapy like every mid but so if you don't have any experience yeah you need you know to do a small trial with a few patients and see you know see what's up so you can inform the design but whenever you can I think randomized trials and have where people get one approach have other people get the other are the ones that give us answers awesome thank you so these are all interesting trials we'll have to wait and see yeah larry is wondering if you would recommend you know full body pet ct um for m gus patients instead of a bone marrow biopsy in order to assess the myeloma activity in the body oh um not I wouldn't consider one or the other I think you know you probably need to have both most of the times so the bone marrow biopsy gives you different kinds of information so first of all I mean it's needed for the definition like you have less than 10% your m gus more than 10% is smoldering now are there cases where you know you do you know you do a blood test and your m spike is like 0.2 and you're like okay what are the chances this is going to be smoldering right very low so it's okay we can skip the bone marrow certainly you know it's done all the time in clinical practice but I think I think most people end up getting a bone marrow because that's what shows you the molecular profile of the of these plasma cells you can see some of the highest features less highest features so different sorts of information the bone scan be it um you know a pet scan whole body pet whole body mri I think these kinds of ultra sensitive approaches are important for smoldering myeloma patients because they can catch very tiny issues again if you have a clear cut m gus m spike of one normal light change and stuff um you know total but whole body ct is okay we still do that though over whole body x-ray so the new standard is some sort of city based or mri again if you can have access to it a base assay it's more sensitive and yeah I would still recommend it even in the low lowest of the low risk scenarios and the reason the fact you do it in all patients at some point in time maybe not right away but early on after diagnosis it might save you headaches say you have m gus and then 10 years later for some reason you get a whole body ct and they say oh there's an indeterminate lesion there I don't know what this is you haven't had a baseline you know you're stressing out saying could this be myeloma I have to get rescanned or get a biopsy or whatnot but if you had a baseline you said no this was there 15 years ago nothing to worry about so I always do get a baseline yeah awesome thank you um we have is there any other questions that you see that you would like to answer before we finish up there's several so I just if any of them catch your eye I wanted to give you the chance to and we can let's see try and go through some of them uh correlation between degree of indolence and once treatment begins a slower time to relapse yes and no I think once disease starts you use different kinds of prognostic you know features so there's some standard or kind of non-high risk patients when they actually get diagnosed myeloma but some of these genetic abnormalities might be considered more high risk in the smoldering phase for instance so not necessarily miss store any anything in the horizon that would suggest a new type of treatment for smm versus feralign treatment again I think as one of the other attendees mentioned you know some immunotherapy based approach with teratoma are currently being studied there's of course you know other more kitchen sink light approaches like you know combination quadruple therapy and transplant stuff so who knows um essential essential from what I thought an m gas and I saw I think another question the patient had cml um no I don't think there's any indication I think we still use the same prognostic criteria that we use for m gas and smoldering and you frequently see various different hematologic abnormalities coexisting in many not frequently but not infrequently especially in referral centers uh recommendations the slow progression of smoldering I think not any general recommendations it's you know has to be individualized so kind of know your specific details the health tree is studying just sorry to interrupt but the question was are there any recommendations that you can give to slow progression with all the slow progression oh I see um outside of you know treatment approaches right not really there are tons of laboratory or you know epidemiologic data but not really I guess one thing is keep a healthy weight there I think pretty decent epidemiologic and basic science data saying that yeah you know you have more um more obese folks might have high risk of progression so that's the only thing that comes close to evidence-based recommendations but nothing else and just yeah that's all I can think of studying with a couple different doctors the the relationship between fitness and myeloma progression and then diet and myeloma progression so if those are studies that you viewers are interested in participating in as um smoldering multiple myeloma patients for that diet study and then we'll have more details about the fitness study to come but as long as you're a part of this chapter you'll be able to hear about those studies and when they're ready for people to enroll in we would love your help so that we can get that answer to the question is there anything that we could do we're nearing the top of the hour so I think we'll end there but thank you so much for your time yes bring all the questions and this was a complicated topic I think you handled it excellently and thank you so much for for sharing your time with us today no thank you for having me and thank you for your attention yeah thank you bye finished with the bye bye we're gonna finish um for my viewers here with a couple of outro announcements and then we can end this chapter meets every other month so please join us in may as we have a specialist come share their insight on why seeing a multiple myeloma specialist in the precursor stage whether you're m gus or smoldering myeloma is so important more details to come on that about time and we'll make sure that you have access to register for it when it's ready on the 22nd at 6 30 p.m eastern is our florida myeloma crowd community chapter launch we're looking forward to that and hope to see you there if you're in the florida area and would like to join that community on the 23rd is our nutrition and wellness for myeloma chapter we're going to be hearing from dr sarah lee about how inflammation relates to cancer and then on the 24th at 1 p.m eastern is our african-american myeloma community chapter we're going to be hearing from financial coach diana valentine how to recognize and overcome financial challenges the african-americans face when seeking treatment for cancer the link to sign up for any of those events and even more events i have not mentioned today is found at the bottom of this slide and will be sent out in the follow-up email within 48 hours of the events completion i will say if you haven't seen our new website yet we did a couple of updates we're always continuing to improve our website and our team was working really hard so if you haven't seen our new website yet make sure to take a look at that today and as always i would like to thank our sponsors with that one this would not be possible bristol myer squib amgen oncology genentech adapted biotechnology sanife jansen oncology cariofarm therapeutics ticada oncology and abby thank you to each of you for taking the time to be with us today we really appreciate you and hope that you have a great rest of your day thanks all