(Guest Lecture): March 2024 - A Nationwide Trial for Smoldering Myeloma Patients

So the topic for today is a nationwide trial for smoldering myeloma patients. And we've had quite the interest today with several hundreds of you signing up for this webinar. I know that it's really important to you that research is being done in precursor myeloma. Lots of MGUS and smoldering patients reach out to me weekly asking what they can do instead of watch and wait because that's something that's frustrating to them. Smoldering trials are an excellent way for people with usually high risk smoldering myeloma but sometimes intermediate risk smoldering myeloma to join so that they can start testing is it going to be possible to prevent myeloma progression through these trials and other quality of life questions that can be answered. And we need your participation because none of it can happen without you. And it also can't happen without amazing researchers like Dr. Callan and Dr. Callander who are working hard to make these trials possible. It's now my pleasure to introduce them to you. Dr. Callander joined to the section of hematology bone marrow transplant at the University of Wisconsin in October 2004 as an associate professor in the Department of Medicine. She graduated from Tufts University School of Medicine in Boston, Massachusetts and has completed residency at Bellevue Hospital in New York as well as a hematology oncology fellowship at the University of California San Diego. Her board certifications include hematology, internal medicine and medical oncology. Dr. Andrew Callan is a hematologist oncologist who specializes in treating patients with multiple myeloma and other blood disorders. He leads clinical trials of new treatments for these diseases including the use of engineered immune cells, combination strategies and genomics data. An expert in trial design, Dr. Callan evaluates research proposals as a member of the Fred Hutch Cancer Research Center's scientific review committee. With that being said, I'm going to turn the time over to them so that they can share this important information with us. Thank you both for being here. Thank you. Thanks very much Audrey and thanks to all of you for joining. I'm really pleased to see the good turnout and to see there's such a high level of interest in smoldering multiple myeloma, something that I, both myself and Dr. Callan are very passionate about. I'm going to start the talk today by kind of reviewing some basics of smoldering myeloma 101 if you will with some recent data from some of the National Congress meetings mainly focusing on what this is, what happens over time and kind of what we do outside of treatment. And then Dr. Callan is going to focus more on the treatment trials. Here are my disclosures. So, again, first of all, we're going to start by talking about what is smoldering multiple myeloma. Next, we have some new data to kind of give us more information about how common the condition is. And it does seem like it's probably more common than we had thought. What is the natural history of smoldering multiple myeloma? So what's going to happen if someone has smoldering multiple myeloma? What does that look like? That's a considerable source of anxiety, I think, and understandably so. There's a lot of unknowns. There's all these things that could happen. And I can see why that uncertainty really, really drives anxiety and feeling like there's not a path forward. Are there any red flag symptoms or findings for progression to myeloma? And then finally, how do we risk stratify patients with smoldering multiple myeloma? So how do we decide who's at the greatest risk of progression, who's at the lowest risk? And we can potentially use that information maybe to help filter folks into trials. A lot of trials are more focused on people who are the highest risk of progression to smoldering multiple myeloma. And so we'll talk a little bit about that. And then at the end, I'm going to kind of wrap up with a couple of cases to just illustrate what can happen with smoldering when we observe, which I think will hopefully set the stage nicely for Dr. Callender to talk about treatment and why we might consider treating folks who are mostly almost all asymptomatic or not. They don't have any symptoms of myeloma, but we're treating to prevent. So smoldering multiple myeloma, you know, in the sort of scheme of history is actually only a recently coined term by the famous Dr. Kyle and Dr. Greip from the Mayo Clinic. The first publication that I'm aware of that described this was published in 1980. You can see here the lead of this publication from the New England Journal of Medicine. Six cases fulfilled criteria for the diagnosis of multiple myeloma, but there was no anemia, lytic bone lesions, hypercalcemia, renal failure, or other manifestations of multiple myeloma that developed during an observation period of five or more years. And so basically, these are patients who would otherwise have met the criteria for multiple myeloma, but never developed clinical disease. And so I think what's notable about this is they had really incredible foresight in sort of figuring out that smoldering multiple myeloma was real, that not that the patient sometimes could go on for a very long time without needing treatment. But they also note here, and I think this is interesting, despite these cases, it has been our experience that in most patients, overt symptomatic disease develops within a several months or a few years. And I think that's been my experience as well. The other thing that they note, I think again shows incredible foresight, is the sort of risk benefit balance of treating patients who don't yet have active signs of disease. And they note here, although chemotherapy, because remember back then, this is 1980. So what did we have for treating multiple myeloma in 1980? We probably had melphalan, oral melphalan. Stem cell transplants really were not widespread. So really it was just oral melphalan. And so that's a toxic therapy. And I think while it may have been true then that although chemotherapy may lead to leukaemia, thrombocytopenia, refractory anemia, leukemia, all true statements for that treatment, things are different now. We have a lot more options. And so I think this will be a theme that comes up when we think about treating smoldering or precursor conditions is that we're not stuck with just melphalan. We're even just revelamid, frankly. There are other options that may warrant investigation that could address some concerns about treatment-related side effects being a big problem. So what is smoldering multiple myeloma? So here's the official definition. If you do a bone marrow biopsy, we see greater than or equal to 10% plasma cells by CD138 immunohistochemistry and a core biopsy and or a serum monoclonal protein greater than or equal to 3 grams per deciliter. And very important, there cannot be evidence for active MM, meaning no hypercalcemia, renal failure, anemia or bone lesions, but also serum-free light chain ratio involved to uninvolved has to be less than 100. There can't be more than one focal lesion on a bone marrow MRI and bone marrow plasma cells have to be less than 60%. So that's what smoldering multiple myeloma is. Any bone marrow plasma cells less than 10% and M-spike less than 3, that's MGUS. That's not the topic of this conversation, monoclonal gemopathy of undetermined significance. So how common is smoldering multiple myeloma? There's lots of data sets for this. The one I'm going to focus on for you all is, I think, one of the most recent impactful studies, the I-STOP-MM study funded by the Black Swan Initiative from the International Myeloma Foundation, also called the Icelandic study. It's called the Icelandic study because basically what they did, and this is an incredible effort, they took all Icelanders over 40 years of age, which was about 148,000 patients. If they were eligible, they were sent a consent. And so the goal of the study was to screen the entire population of Iceland over 40 for gemopathies. And so at screening, they did S-pepid-free light chain analysis. And then patients were randomized to having either no further workup, bone marrow sampling, or intensive workup. And then patients were diagnosed with either MGUS or smoldering. And this focus on this arm of the study is on the smoldering patients. And that arm, folks had follow-up every four months. Everyone had a whole-body low-dose CT and annual bone marrow sampling. And so that was how they were followed. And so what's really interesting here is they were able to determine the prevalence of smoldering myeloma in Iceland in folks over 40. The prevalence of smoldering myeloma in the total population over 40 was 0.53%. So that may not seem like much, but if you were to sort of assume that the numbers are fairly similar in other countries of folks with European background, I mean, that's a lot of people, many of whom probably have no idea they have smoldering myeloma. So they estimated that prevalence is 0.53%. And what you can see here on the right is the estimated prevalence of smoldering myeloma by age and the population over 40 years. And similar to what we see with myeloma, as folks age above 40, the prevalence of smoldering myeloma increases. We see this with other diseases too, like CHIP or clonal hematopoiesis of indeterminate potential. So a lot of blood disorders tend to follow this pattern. So it's not too surprising that we see that this happens. And we also know that multimyeloma is considered to be an age-related disease. So if you look out here, I mean, just looking, the prevalence of smm is higher in men than women, which is not too surprising given the age distribution of multimyeloma diagnoses. In men, we see that at 90, interestingly enough, the prevalence of smoldering mm is 2%. So very interesting. What also was interesting in this population, the mean M protein concentration was only 0.62 gram per deciliter. And 73% had between 11 and 20% bone marrow plasma cells. So again, very interesting trial. I think should help us better understand, at least in this population and a European population, how common this disorder is. What we need in the future is better studies of the prevalence in other parts of the world and in different ethnic populations to better understand whether there's differences in prevalence. What is the natural history of smoldering multimyeloma? And this was another seminal publication by Dr. Kyle and his colleagues at the Mayo Clinic following patients describing what happens over time. And so this is something that I think you'll see a lot in talks on smoldering multimyeloma. And what it shows here is the time since diagnosis and the probability of progression for both AMGUS and smoldering multimyeloma. What you'll note here is there's two distinct patterns. There's a group of folks with very rapid progression in the first two years. Those largely have probably been reclassified as multimyeloma nowadays. The people with free light chains over 100, bone marrow plasma cells over 60%, and more than one full collision of bone marrow. I'm right, because remember, this was in 2007. So the slim-crab criteria were only put out in 2014. But nevertheless, the general pattern is we have a group of patients with quick progression, and then over time, we see the curve kind of flatten out. And so in the first five years, the risk is 10% per year, then five to 10 years, 3% per year, then after that, 1% per year, which is really more like AMGUS. So this forms the basis for the risk stratification is trying to understand which patients are going to be these AMGUS-like patients. These patients probably should not get treated. And which patients are more high risk, which is really more like myeloma. And these patients should ideally, I think, be a clinical trial should be discussed in patients who kind of fit this phenotype. So what is also notable about this manuscript amongst many topics is they describe the relative risk of progression to active MM and ALM lidosis. And one notable thing about this slide is each of those clicks that goes up, that's a progression to MM or amyloidosis or Waldensstrump. So this is any progression to a plasma cell-related disease. And so for all patients with smoldering myeloma, the relative risk of progression compared to the population norm to myeloma is 522. Important not to forget, and I have a vignette on this later, there's also a risk of progression to light chain amyloidosis. And the relative risk is 50. And so it's important to remember that amyloidosis, there's also a risk of developing amyloidosis. This should not be forgotten. And I'll try to illustrate that later. The most commonly used system for risk stratification of smoldering myeloma is shown here, the so-called IMWG, or sometimes you'll hear folks call it the 2220 risk stratification model. And basically in this model, we look at the following factors to risk stratify bone marrow plasma cells greater than 20%, monoclonal protein over 2, and serum-free light chains involved to uninvolved ratio greater than 20. And so if you have none of these factors, you're low risk. And again, that's like the curve I showed earlier that that's more like MGUS. Intermediate risk has a risk of progression of two years at 70.9%. And then high risk, if you have two or more of these factors, that has a risk of progression at two years of 44%. So almost 50% of patients will have progressed by two years. And so really a lot of the focus, as you'll see in these trials, has been on studying treatment in the high risk population. Are there other risk stratification models? Yes, absolutely. Just to highlight another one that I think is really useful and one that you all can access, the Pangea model published by, this was an effort that came out of Dr. Ibrin Gobriolos' laboratory at Dana-Farber. Excellent work here. This was published last year in the Lancet Hematology. It was a retrospective cohort study that included patients over 18 with MGUS or SMM. And they basically created the Pangea model, which used data on biomarkers, including S-PEP, soon free light chains, ratio, age, creatinine, and bone marrow plasma cells, plus hemoglobin changes over time to estimate the risk of progression. And they validated this in cohorts from Greece, England, and the Czech Republic. Here's what the web page looks like. You can all access this here, pangeamodels.org. And again, you'll get these slides later. So if you want to go do this yourself. But here's just a hypothetical case of a patient who was diagnosed in February of 2024 with smoldering multimilomia. So you can kind of see how this looks. You input the bone marrow plasma cells, the free light chain ratio, involved to uninvolved, M-spike creatinine. And down here, I didn't have a place to show this, but you can show, you can put in serial hemoglobin levels, because remember that was part of the model as they incorporated changes in hemoglobin over time. And that's actually something that is a prognostic factor in smoldering MM. We don't have time really to talk about it today, but just be aware of that. Then you get a graph here that's basically personalized for your laboratory values. And I think this is really helpful in understanding the, hey, smoldering multimilomia, we have these models that can sort of generally predict risk. This model might be better at individually predicting risk. But again, the caveat with models is they're not perfect. They're just models. They're statistical programs that help us understand the risk a patient has, but they should not be regarded as your fate set in stone either. The other common question that I think comes up when I meet with patients, and this is why I'm including this slide here, is what typically happens when people progress to MM? And there's actually a quite recent publication by the group in the Mayo Clinic authored by Dr. Abdallah in the Blood Cancer Journal, looking at myeloma defining events in clinical presentations leading to MM amongst patients with SMM who are seen at the Mayo Clinic from 2013 to 2022. And so what we're seeing here is amongst a group of patients with smoldering MM, and then in the blue, orange, and gray, we see high-risk, intermediate-risk, and unknown risk. What happens? So it's the event that leads to a myeloma diagnosis. And you can see here bone lesions are pretty common. 35% of patients with high risk, 50% of patients with intermediate risk. Anemia is also common. Renal failure, reassuringly a little bit less common. And marrow lesions on MRI. And what I think is notable about this, remember, these are patients who are observed. They were told, you can be followed every three to four months, and don't worry, we're going to find it. As you can see, we sometimes find these things after they happen, not just sometimes, in a significant proportion of patients. This shows how these things were found. They were found on surveillance labs in a significant proportion of patients. Bone pain led to imaging, presumably, in about a fifth of patients. Some patients were hospitalized, and some patients we just don't know. I think what is sort of disconcerting here is relatively few patients we detected stuff on surveillance imaging, which I think this particular finding is something we ought to think about in terms of how often we're getting surveillance imaging. But what you can see here, though, is that it is possible to develop MM despite having surveillance labs and imaging. And I think to me as a provider, that's something that gives me a little bit of anxiety as well. Because I want to prevent this stuff. That's the whole knowledge is power. And if we are not able to detect this stuff, then there's something we're not doing right. And so the other, I also mentioned, I'm going to try to move quickly here in the interest of time, there are other red flags that could be a sign of early progression to MM besides the risk ratification. One of them is the presence of circulating plasma cells. This is not something I would routinely get on patients, but hopefully we'll start incorporating this into future models in the future. But basically, the long story short is if they do a blood test and check flow cytometry, there is a high risk that a patient who has those and they're above 150 will progress to myeloma with a median time to progression of nine months. So this is something that I think is worth noting. How is smoldering myeloma typically diagnosed? My experience has been it's mostly during routine exams with primary care physician and they either find some a little bit of protein in the urine or an elevated total protein. And then the other situation where this commonly gets found is with the serum free light chain testing with an aspect that's set for evaluation of neuropathy or an evaluation of mild anemia. Rarely is it seen on imaging. What tests do I get when I suspect smoldering MM? I typically got a complete blood count, a comprehensive metabolic panel, S-PEP with immunofixation, 24 hour urine total protein imaging. Not enough time today to talk about imaging. That could be a whole talk in and of itself on smoldering myeloma. But basically, the modalities I use most with smoldering MM is PET CT and whole body MRI with diffusion weighted imaging. I typically get both, but there's still not 100% consensus in the field as to which one is better. And so for that reason, I tend to get both because honestly, the myeloma criteria, a part of that is lesions seen on MRI. So for me, that's important to get the MRI. Consider peripheral blood flow cytometry and then always a bone marrow aspirin and biopsy with morphology flow of fish and conventional cytogenetics. How do I manage people when observing? And again, we'll talk about treatment in a little bit, but what do I do? For most patients, non-high risk, no red flags, I'm getting three to four month lab and clinic visits with CBC, CMP, calcium, S-PEP free light chains. Imaging I get a diagnosis and then I repeat periodically. High risk patients, I'm getting monthly labs. I consider twice yearly imaging. And if there is an evolving pattern or things look like they're going to end up in myeloma, we start treatment for active myeloma. Obviously, I'm not talking about clinical trials here. That would always be a part of a discussion, but I'm just saying if we're going to be observing patients, what would I do? And then finally, we'll wrap it out here with a couple of case presentations quickly. 65 year old with a history of mild neuropathy found to have high risk smoldering MM. As you can see here, the labs look fairly benign, no anemia, calcium's normal, creatinine's normal, S-PEP is really not that elevated. Free light chains were really pretty reassuring. 25% bone marrow plasma cells, though, NFSCT was negative. And so he was diagnosed with intermediate risk SMM. We actually screened this patient for the DETER SMM. Patient was not eligible for reasons I won't go into, but the plan was close observation with every three to four month lab visits. And this is what we saw for a year. This is a graph of the monoclonal protein. It was stable. And so, you know, we felt great about this. Then the patient showed up a little bit late for their three month visit and this happened. The free light chain went from like this to this. And the patient was developing renal failure and we had to start treatment in the hospital. So this is a patient that we were following appropriately and they still developed acute renal failure. We were able to turn it around quickly, but, you know, this has kind of imprinted on me as a situation that I would have loved to prevent. Also important to note that smoldering multimiloma can progress to AL amyloidosis, light chain amyloidosis. It's not a topic of this, but something to think about. 50 year old with intermediate risk SMM, IgG lambda, bone marrow biopsy showed 15% plasma cells, S-PEP was negative, free light chain showed a lambda of 30. Here is a graph right here of the lambda light chains over a several, like a two year period. They were pretty stable. But then the patient started developing nuance at cough, fatigue, and dizziness. BNP is a heart blood test that was elevated. An echo showed signs of early cardiac amyloidosis, heart biopsy, so lambda type amyloidosis. So just to illustrate that amyloidosis is another diagnosis that can happen in patients with smoldering MM, not to be forgot. So to summarize, smoldering multimiloma is more common than appreciated. It's often diagnosed incidentally. It's a heterogeneous condition. Some patients have a course like MGUS. Others have a more clinically aggressive course. Even with observation, we sometimes miss progression to multimiloma. And I've shown you this here. And we see this from the trials. We need better tools to help improve risk stratification and really identify and treat patients at the highest risk of progression. And so that's it for my slides. These will be sent out later. If you have questions, there's my email. And again, if we don't have enough time to write that down, it'll be in the slides later. So thank you all. Well, Andrew, that was excellent. And thanks very much for this presentation, which sets up my part extremely well. And let me, I think, are you seeing the presenter mode again? Uh huh. Yeah. The zoom might be in the way, so you might need to move the zoom taskbar and to see that display settings that was at the top. You remember. Yeah, I'm just not seeing the display option here. Boy, oh boy, Audrey, I don't know where this went. That's okay. We have time. It's never seen my email. If you want to stop sharing and try starting again, that might be. Sorry. No, you're fine. Let me try this again. Let me pull this up and. You want to try to pull it up again. I can try to request remote access and do it for you and then turn it back to you. That's another option. Do you want me to sign you slide control? Uh, yeah. Okay. Uh, get it into the presenter mode one more time and then we'll see if that works. Okay. And then I'll request and we'll see if that works. Sorry about that. No, you're fine. Oh, there's a display. Okay. Now I can see it. Okay. Perfect. Okay. All right. Okay. So do I have the control? Yeah, now you have the control. Okay. Sorry about that. Obviously I need a 12 year old in here to help me with this. But thanks to Andrew very much because you set this up greatly. So, um, uh, so you saw the slide from Andrew and, um, I have to agree with everything he said. The, the people with smoldering on the left here covered by the sex. I think there has been agreement with the redefinition of myeloma in 2014 to take those individuals out and treat them like myeloma. And I also agree with him on the right here, these individuals who have the 1% per year progression or low risk smoldering myeloma, we think that it's still appropriate to observe them. But it's really this, uh, this group of patients here in the blue bar, the ones that have, as Andrew said, with all of the risk assessments, somewhere around 40 to 50% progression in the first two years, uh, once they're diagnosed that we really want to see if we can change the natural history for all the reasons that he mentioned, because even though patients are getting followed, they're still developing complications, which we hope we could prevent. So one of the big, um, I think tensions in this whole discussion of smoldering myeloma is this kind of illustration here that basically is saying, okay, here are some patients here with the precursor stages, MGUS and smoldering myeloma, and they can go into this high risk, uh, state where they develop myeloma. There are mutations that are occurring. There are other cells now that are cooperating in this, uh, transition from smoldering to actual myeloma. And the question is, okay, how do you alter this history? Do you do something by putting gentle pressure or do you try to do something very dynamic and just halt this whole progression right at the, right, right at the source, if you will. And that leads to this kind of dynamic that is going on right now is would it be better to just do something rather, um, uh, uh, limited to do something to slow progression to active myeloma, but maybe just keep people in an MGUS like state, or would you be better off asking people to go through really aggressive myeloma style treatment to complete, completely halt the development of myeloma? Now there have been a number of studies that were done early on, and I think as Andrew alluded to this, melphalan and prednisone probably are two earliest drugs going back to the 1950s. They were tested in smoldering and had no improvement. And then there was a thought that perhaps if you use bisphosinates, which can moderate osteoclastic activity, these are very important in the development of myeloma. Maybe that would help moderate the development of smoldering myeloma to myeloma. That did not work. And then there've been a couple other agents, thalidomide and then siltuximab. The thalidomide is interesting. As probably all of you know, thalidomide was developed in the 1950s in Germany. And as you can see with this graph, at one point, the sales of thalidomide were rivaling that of aspirin in Germany, but it was, you know, distributed widely over the counter, actually, for the treatment of morning sickness and led to the development of these kinds of very serious limb defects called phycomelia. And it took actually a obstetrician from Australia to deliver a few of these children in succession to realize that there was really a problem. But the properties that caused thalidomide to be teratogenic is also the reason that it is a good cancer drug. So it was somewhat surprising then, this is one of a larger smoldering study done by Bart Barlogi, who was a very important investigator in myeloma back in the early 2000s, where they treated smoldering myeloma patients, not defined by the risks that Andrew showed you, but they got thalidomide and pomidrinate. And the really odd discovery in this particular study was patients who responded here in the blueto treatment, meaning that they had a reduction in their protein levels, actually seemed to have a faster time to progression to myeloma. And this was really sort of surprising and very weird. And I'm not sure whether this is just more of a numbers issue more than anything, but something that really doesn't necessarily make sense. So imids, these are these immunomodulator drugs, they're chemically very similar. If you look at the structure of thalidomide versus lenalidomide, even pomalidomide, very, very similar. And they all work through the same mechanism by binding to this protein called cereblon. But suffice it to say, let a little my has really been the first drug that's been shown to alter the history of smoldering myeloma. And this was a study that was first published in 2013, and then updated a few years after that. And this is again from Spain with Dr. Mateos, who's still doing lots of research now, but she took 119 smoldering myeloma patients and divided them into lenalidomide with some steroids, primarily dexamethasone for up to two years, or just observation. And this table here on the right is meant to show that these were relatively young patients, an average age of 60. And most of the there's actually been, as opposed to that Icelandic data that Andrew showed you in many other states, many other data sets, females outnumber males, these were relatively recently diagnosed. And what she ended up finding is that there was a big difference in both time to development of myeloma or progression free survival. So blue was observation here and red are people who received the lenalidomide for up to two years, but also survival. And so there was some, I think, delay, particularly in the United States to appreciate these results for a couple of reasons. One was once again, and I saw a chat, which will talk about, you know, the definition of smoldering myeloma was not the same as what was in the US. And then they didn't require advanced imaging, meaning they only required bone surveys. And the thought is, is that they were probably included in this group, quite a few individuals who actually had myeloma because of how fast this this line drops off here. But it was really the first one to show this. And then the other issue was whether steroids were really necessary or not. So this led to the next lenalidomide study that's out there, a much larger one led by the Eastern Cooperative Oncology Group and groups like ECOG, Southwestern Oncology Group. These are all cancer treatment, clinical trial groups funded through the National Cancer Institute. And ECOG happens to be the one that I work with. So Dr. Lonyl from Emory took 226 smoldering myeloma patients. Initially, this study was meant for what was determined to be high risk only and divided them into just lenalidomide forever until they progressed or just observation after they had what they called in a phase one lead-in group to make sure that this was safe. Now, as I mentioned, the original intent was to have only high risk patients, but because accrual was hard, because this is a hard group of patients to get on trial, they actually amended the study to allow any type of smoldering myeloma patient on. So what they ended up showing because of that amendment was about a third of the patients here, what we would call low risk smoldering myeloma, meaning those are the people on that far end of the right graph that both Andrew and I showed you. But some of them were only a minority here, about 15% really those high risk patients. But despite that, what they were able to show for the entire group, if you look again at progression to myeloma at the three year time point, there was a 78% reduction in this. So at three years, only 7.3% of people who got lenalidomide had progressed to myeloma versus almost 32% of those on observation. And so now there were side effects from the from the lenalidomide, primarily low white count and low platelets. And even though this was mental progression, the average time that people spent on treatment was about two years. First, one thing that became very clear in this analysis is that low risk smoldering myeloma didn't benefit, meaning they didn't do worse, but they didn't do any better than those on observation. And there were a small number of black patients on this study, only about 31. And they did not seem to benefit either. And we don't know if that is a statistical aberration just because of low numbers of participants. Now there's also been a study that was updated recently using the drug daratumumab. Daratumumab is widely used to treat both newly diagnosed and relapsed myeloma. It is an antibody against a protein called CD38. And this study was interesting. It took all comers of smoldering myeloma and basically assigned people to a month of daratumumab, a much longer course or up to two years of daratumumab. And maybe not surprisingly, this drug is active on its own in multiple myeloma. The people who got the longer amount of treatment had a higher response rate, meaning reduction in their myeloma protein and a higher incidence of going into remission. But when they updated them just this December, they did not show any difference either in terms of progression-free survival. And what's not shown here, there was no difference in survival for the entire group overall, which just brings up the question again, okay, does things that include every risk of smoldering myeloma probably is not the right way to go. So the other dynamic here, as I mentioned, is doing something very aggressive, like you are actually treating actual myeloma for these smoldering patients. And this is probably one of the most aggressive outlines. This is the GEMS-Caesar trial that, again, led by Dr. Mateus in Spain. This had 90 patients who got very, very intensive induction with carfilzomib, lenalidomide, and dexamethasone, then a stem cell transplant, then two more months of the same chemotherapy that they got here, followed by two years of lenalidomide and dexamethasone maintenance. These patients did get advanced imaging. Once again, it's not quite the same definition of smoldering myeloma as some of the other studies. And their endpoint here was becoming minimal residual disease negative. So what they showed, now one caveat again is this 2014 redefinition of what myeloma means, a third of these patients would meet that definition, as you can see here, of myeloma. So again, it is a mixed population, but they showed that they had very high response rates and very high rates of minimal residual disease negativity at the end of all this treatment. And when they did an evaluation for who progressed, it's about 7%, meaning 93% of people were still without needing new treatment. Now there's also been more recently the ASCENT trial, which is something coming out of the Mayo group and also funded through the International Myeloma Foundation. But this is a study using four drugs, carfilzomib, lenalidomide, deritumab, and dexamethasone, considered to be one of the most aggressive treatments you could offer somebody with actual myeloma. And these patients get a combination of this for a year followed by another year of lenalidomide and deritumab maintenance. This was a primary endpoint here, was looking at the response rate, again, very high. Response meaning reduction of protein here, and also the stringent complete response rate very high. But once again, if you look at three years out progression-free survival, it's 90%. So now you have three modern studies that are showing, essentially, get very different intensities of treatment, but at the end of three years, everybody's doing about the same, which is something I think that you do have to consider about intensity of treatment and whether it alters the natural history. There are some more interesting approaches that are being investigated out there. One coming from Dana Farber using the drug ticlistimab that I'm sure many of you've heard about. These are a group of drugs called bispecific engagers that link an immune cell, a T cell, with a myeloma cell, in this case binding through something called B cell maturation antigen. This drug is widely used for patients who've had four or more different types of chemotherapy. And they presented some information in December about a trial with 12, 19 are going to be enrolled, but 12 patients were treated. And these had smoldering myeloma, went on to receive this drug ticlistimab, and they reported 100% response rate, which is pretty high, and 100% MRD negativity rate. They only gave about six months of treatment. And so now the question is, is whether this really will be an innovation that means a very short amount of treatment could really change natural history, but you will obviously need a very long follow-up here years before you know if this is helpful. And then not surprisingly, and I'm sure this group is no stranger to the whole issue of CAR T transplants, where you engineer a T cell to recognize whatever protein you're interested in. In myeloma, this has been primarily B cell maturation antigen, or that's what's commercially available at this point. And the same group at Dana-Farber is also doing what they call the CAR PRISM study, where they are going to do a silt to captegen autolucil, or also known commercially as CAR-VICTE, CAR T transplant for patients with high-risk smoldering myeloma. And they have just started this trial. So I do want to talk a little bit about the national trial that is going on through Eastern Cooperative Oncology Group, and both Dr. Cohen and I are involved in putting patients on this. And what this study is trying to do is perhaps a little bit of the middle ground here, and take true high-risk smoldering myeloma patients and either offer them lenalidomide and dexamethasone for a total of two years, or bring in that antibody drug daratumumab with lenalidomide and dexamethasone for two years, to see if you can really alter the natural history again with a time-limited therapy that should be, we hope, not too toxic. Now, this study has, I think, the correct endpoint here. You can look at response rates, but in the long run, what you really want to see is, are you making people live longer who have high-risk smoldering myeloma by treating them? And besides that primary endpoint, we're looking at progression-free survival, which you saw before, and response rates, safety on toxicity, which is mandatory. And one other feature that we're looking at specifically is whether or not we can collect stem cells that could be used in a future autologous stem cell transplant. Now, Dr. Cowen mentioned imaging, which is very important. And it's been known for a while that people with high-risk smoldering myeloma can have an abnormal PET scan, but not a myeloma-defining PET scan. And that occurs, at least in this particular study, about 16% of the time. And it looks like people who have this finding have a higher risk of developing myeloma. So we are specifically asking patients who go on this trial to have a PET scan and an MRI, not only to look for those who might have actual myeloma, but also to make sure that if we see an abnormal PET scan, that we are repeating it to make sure it gets normal, or actually figure out what happens. And we're seeing a rate of abnormal PET scans about 20% in the time of the patients who are now enrolled. As I mentioned, this is going to be a long follow-up because we're looking at survival. And we're hoping to have somewhere around four to six patients per month, which has turned out to be a little bit difficult. We also are asking about quality of life. And these are names of different types of ways to do that. One, to really ask you subjectively what your symptoms are like, and one, to find out how you're doing in terms of compliance with medications, whether it's hard to take these things or not. Since all the medications are provided, we hope there's no financial burden in this particular situation. We're actually going to compare. We think this is another interesting aspect. You as a participant get to say how hard or how many side effects you think you're having from this treatment. And then we're going to compare those with what the providers say and see if it matches up. As you can imagine, oftentimes there's a lot of discrepancy between that. To be eligible for this, you have to have a true high-risk smoldering myeloma, meaning you have to be within a year of your diagnosis of this definition, which is two of the four things, an abnormal light chain ratio above 20, but less than 100. That would make it myeloma, bone marrow biopsy between 10 and 59% plasma cells, a monoclonal protein above two grams per deciliter, or if it's IgA above 2000, one of these abnormalities by either fish or cytogenetics, and more than 20% plasma cells in a bone marrow biopsy. I don't think that Dr. Cohen mentioned this specifically, but there is an entity called light chain smoldering myeloma that seems to have somewhat of a natural history that's different or maybe a little bit more favorable. Those people are not eligible. SubQ-Dera2-meb is what we're using. Everybody gets that provided as well as linolytomide. We're also trying to look at some other things that we think are very important in just health in general, things like marital status because being alone can affect your outcome, insurance status, zip codes, things like that. We're hoping that the National Cancer Institute will let us add those things, and we're a little bit more than halfway there. I want to also close with a vignette because I think this is illustrative. I think Dr. Cohen and I would be very enthusiastic to have anybody go on a clinical trial if they have it available, but this was an individual that I cared for in some ways very much like the first case Dr. Cohen showed because this woman had been diagnosed with smoldering myeloma back in 2008 and had a bone marrow biopsy with 15% plasma cells and M protein here. If we use that high-risk definition, really only had one criteria, and then she was coming in every six months for follow-up, and then all of a sudden, boom, one day her M protein goes to 4.9 grams, had a bone marrow biopsy done, now showed 46% plasma cells. In this case, the patient didn't have any focal lesions and was negative. Because this patient had had smoldering myeloma in 2015, our study wasn't open, and she had had it too long to be on the ECOG trial that I showed, so she was treated with two years of lenalidomide and dexamethasone off study like the Quiridex trial. This patient, this was completed by the beginning of 2017, and this person is not in remission technically, but the last time that they were in clinic here, M protein is 0.3 grams per deciliter. So as far as this goes, after watching this patient for nine years, no development yet of myeloma. So to conclude, as Dr. Cohen mentioned, this is a relatively rare entity. I think the problem about the definition, again, trying to respond to the chat messages, the more we learn, the more it's hard not to revise it with the additional information we have. I think, again, I understand the frustration that leads to, but it's hard to ignore additional factors that we recognize that are important. I think we would both agree that advanced imaging is really mandatory to make sure you don't have myeloma, and we would very much recommend people look out for a clinical trial in their area. There are lots. I didn't mention all the active ones that are underway. And personally, if I had a person like the case I showed of somebody who's not eligible for clinical trial, I think you can make a case to consider linoleumide off study, and I will stop. Wonderful. Thank you, Dr. Callender and Dr. Cohen for excellent presentations. Dr. Cohen has done a great job of answering a lot of questions that are in the chat. I have a couple of questions, too, that were previously or kind of relate. I'll just start with the clinical trial specific for the DETER SMM study. What is the goal number for this study, and how close are you to reaching this? So it's 288 patients, and we're 56% of the way there, so we have a long way to go, and definitely would like people to consider it if they think they're eligible. This study is available through what's called the clinical trial or the CTSU, and so it's available in lots of different cancer centers around the country. It's not just in academic centers, so I think it's relatively accessible. And like I said, one of the big things about this is that the treatment is actually provided, which is a great part of this. Yeah, definitely. That was going to be my follow-up question. It also is available outside both of your centers. That is correct. Yep. Wonderful. And we'll put a link into this study, how people can look for it and enroll within our resource email that we follow up with. One of the questions was, there are specific trials that if you participate in them will disqualify you from future clinical trials, especially in smoldering myeloma. Does this constitute as one of them? I don't know what Andrew was going to say, but I will tell you, in EPOG, we are very cognizant of this. So our treatment trials do not specifically exclude patients who had treatment for smoldering myeloma. So no, we try to make sure that that is not disqualifying people. Yeah, and I think just to piggyback off of that, we need to work with our industry partners to make sure they do that as well. Because a lot of the industry studies, I think to the point of this question, they do say, you can't have had smoldering treatment. We need to change the philosophy behind that. Because I would hate for that to be a reason that someone said, no, I don't want to do a smoldering trial because I don't want to not be eligible for a myeloma trial. That seems like something we should fix. I completely agree. Thank you. We'll continue to advocate as well on this side for that. Generally speaking, I mean, we touched on it several times today. Dr. Cowan, I'll direct this towards you. The toxicity versus the benefit is kind of the biggest question here as we enter into these smoldering myeloma clinical trials. There are some myeloma specialists that are highly against treating precursor myeloma because they don't believe that the benefits outweigh the risks. How are we balancing this with the newer immunotherapies as Dr. Kalender mentioned, or this DETER SMM study? What are your thoughts on the subject when it comes to toxicity versus benefit? Yeah, I think it's a great question. The way to think about this is to remember that there are patients who have myeloma who are asymptomatic. There are patients who have free light chains over 100. They might have a lot of Benz-Jones protein, and they might have bone marrow plasma cells over 60, but they have no CRAB criteria. These patients were smoldering myeloma 20 years ago. Now we've recognized that we shouldn't just sit on them, that we should treat early because it's going to happen quickly based on the data. That's why these were included as part of the slim CRAB criteria. I guess what I would say is the risk-benefit balance we already feel is favorable in those situations. I do think it is also important to note that no one should ever twist your arm to go on a smoldering trial. This is a choice that you get to make. It is a discussion with a physician. I think there are risks to these drugs. Every myeloma drug has some risk, some more than others. Even though we're fond of saying that daratumumab is, quote, the easy drug to give, I've had patients go get anaphylaxis and go to the ER, and that's with subcudera. It'd be nice if we had a blood pressure pill like Norvasc or amlodipine or something for myeloma. That'd be great, right? The discussion would be easy because the intervention has minimal risk, but we don't really have that yet. I think it's important to be clear-eyed that, yes, there are risks, but there are risks in doing nothing, too. I showed you the data on mode of progression. Even with Q3 to 4-month observation, there are patients that we miss. I showed you a couple of examples of that. I recognize that it's a hard choice, and I think that's why these, I mean, smoldering myeloma patient visits tend to be my longest visits for this reason. I don't know if Dr. Kalender has anything to add. No, I would agree with everything you said. I think myeloma is a devastating disease. I think for those of us who treat people every day who have it, and we are well aware that people are continuing to die from myeloma, so I think an opportunity to change that natural history. One of the things that I tell people who are participating in the DETER trial, and treating myeloma or treating this whole precursor to myeloma situation almost ends up being like a chess game. You have certain moves you can make. We want to make sure every time we make a move that we think it's more likely to be beneficial, that's that whole benefit risk ratio, but also doesn't preclude any ability to get treatment in the future if you need it. I think that's why for the DETER trial, we feel that we struck that balance, that nothing that's being done here is going to make it impossible for somebody to receive myeloma treatment if they needed it, but we're also encouraged even if we can stop the development of myeloma for say some period of time, we hope years, then I think we do believe that science may catch up here and come up with a better treatment than just starting whatever for your myeloma, pretending like it's actual myeloma at this point. I think that those are some of the reasons that we support a trial like this. Very well said and great point that look at the progress that we've seen even within the past two years. If we can even get a patient two years further down the road and all of these in the pipeline are becoming approved, it's just incredibly helpful. I like that strategy. Thank you. A couple more questions. I know we're running short on time. If these studies in high risk show success with slowing progression over time with moderate risk patients, do you see this eventually moving towards? We could talk an hour about this. There's obviously things that we don't understand about the immune system that people can control the clone. They obviously have some people are doing that successfully. Boy, oh boy, I would love to know how they do that. Whether it's a property of the myeloma cells or what we call this microenvironment, the other people that are there in the bone marrow, in the blood modulating things. I don't know whether we're going to say we have a different treatment or whether we'll have an immune therapy other than just blasting the myeloma cells, which is what our immune therapies do right now. If we can come up with something that somehow really does boost immunity, I think that would be amazing. Thank you. Stacy is wondering, is the randomization based on national participants, not based on the hospital where you received the treatment? That's right. Also, yes, stem cell mobilization, it's an endpoint. It's not mandatory. You don't have to do it, but we wanted to make sure that if people were nervous about, hey, I might need a transplant in the future, we're giving people the opportunity to do that if they want. Wonderful. Then last question here, I've seen a couple questions regarding IGA, IGG, IGK. That can be confusing, especially in the precursor myeloma stages. Can you just briefly speak to whether or not treatments are targeted towards these or whether your subtype affects your outcome? I could take that one. I think at this point, we don't really change treatment based on the immunoglobulin isotype, which is what you're referring to, that IGG, IGA, IG. There's five of them. Right now, I think the isotype is considered a risk factor in MGUS. It's not part of any of the SMM risk stratification criteria. Some practices in IGA SMM will follow the IGA level because it might be more accurate than the SPEP, although in large academic centers, that has kind of gone away because we're able to follow an SPEP, IGA pretty well. I'm not aware of any practices, that any targeted treatments for those. There's so many mysteries about myeloma, which is part of the reason why I'm so passionate about this disease and treatment is because there's so much more to understand. We've barely scratched the surface, I feel. I completely agree when I saw those questions. There's more research to be done in this field, just like there is in a thousand other subtype myeloma fields. Thank you two specifically for doing your research for your passion. You can tell that you really care about myeloma patients and their loved ones and improving their quality of life, as well as the efficacy of their treatments. When I say myeloma includes smoldering myeloma, MGUS, anybody who's here today, I'll give a moment for each of you to say any closing statements and then you're free to go while I finish up with my audience. Dr. Callender, if you want to go first. Yeah, thank you very much. No, this has been great to be able to share some of our research with you. And just as Audrey said, this has obviously been amazing to have so many more things to offer people. I think we just want to keep on working until we really can use the C word, as we all know what that is. And I think we have a lot of ways to go here. But it's one of the things that's been very gratifying not to use up too much time. When I got into this field a number of years ago, I won't say how many, there weren't as many people as there are now. And that's only been great. It's been so fantastic to have so many researchers around the world interested now in myeloma. And that just helps us all. I guess I would echo those sentiments and say thank you all for joining. I'm just so impressed to see the turnout here and for letting us share what we know and share about our trial. Clinical trials are so important for smoldering myeloma. So really, we just want to get the word out to think about trials. They're always optional. But we want people to be aware of them because we're not going to be able to move the field forward unless we have innovative trials. So that's how we have the drugs we have today. And that's how we'll have the drugs of tomorrow is with clinical trials. So thank you all. Thank you both. We really do appreciate you and have a great rest of your day. In my audience, I'll finish up with just a couple of outro announcements. As a reminder, whenever you leave the session today, please take the one to two minute survey that helps us know what you liked about today and what we can do better next time as well as future topic suggestions. Our next meeting will be next month. Dr. Diego Kazanjian from University of Miami is going to be joining us explaining deep dive into smoldering myeloma and then also bringing on some of his staff to discuss current clinical trials that are happening there. Other events you may be interested in, we have a financial education meeting tomorrow. We're going to be talking about preparing your 2023 tax filing. And there's lots of things that you can itemize if you have myeloma or even smoldering myeloma, frequent doctors visits, things like that, that you may not be aware of. On the sixth, that 1pm Eastern is our stem cell transplant chapter. We're having a panel come to talk about their experiences and then you have the chance to get to know more about their experiences and then you have the chance to ask them questions. And on the 14th, at 1pm Eastern is our kidney involvement chapter. We're going to be talking about can you get a kidney transplant with multiple myeloma. The link for any of those events and even more events I did not mention is found at the bottom of the slide and will be included in our follow up email. Thank you again to Regeneron, Sanofi, Johnson & Johnson, GSK, and Bristol Myron Squibb. And thank you to each of you for helping us build this strong community. I appreciate you taking the time out of your day and we will be sending the recording out so you can review this again. Take care everyone and thank you. Bye bye.