(Guest Lecture): July 2022 - Emerging Research in the Smoldering Myeloma Field with Dr. Kazandjian

Today's sessions, the topic is going to be emerging research in the smoldering myeloma field with Dr. Kazanjian. And the reason why we wanted to discuss this is because there's so much research that's being done in multiple myeloma in general. And sometimes we forget to focus on what's being done in the precursor field. Precursor multiple myeloma research is progressing and the results are exciting. And for that reason, I've invited Dr. Kazanjian, who's passionate about participating in and sharing about precursor myeloma research. And I'm really looking forward to hear from him today, hearing from him today. It's my pleasure to introduce Dr. K or Dr. Kazanjian to you. His clinical and translational research interests lie in treatment of precursor plasma cell disorders, including high risk smoldering multiple myeloma and the role of immunotherapy in plasma cell dyscrasias. In addition, he's reevaluating the role of a natologous stem cell transplant in the area of highly efficacious novel drugs, immunotherapy biologics and cell based therapies, with the hypothesis that certain subsets of patients with myeloma may not benefit by default upfront. ACA, C, A, S, C, T, stem cell transplant. We are excited to hear from him. And now the time is yours, Dr. Kazanjian. If you want to share your slides. So first off, thank you, Audrey. Thank you for the invitation to you and myeloma crowd for having me. It's a pleasure for me to be here and give this talk on precursor disease, kind of focusing on smoldering myeloma. So just to begin with, you know, smoldering myeloma is within the continuum of plasma cell disorders. And here is a picture where we can see sort of the spectrum of disease from the normal B cell or plasma cell that lies in the germinal center of lymph nodes, all the way to sort of the worst outcome, which is plasma cell leukemia. And as this progression happens in some and some doesn't happen, you basically get two important events that are really occurring. One is you're getting more and more tumor disease, meaning the amount of plasma cells that are monoclonal. And at the same time, you're incurring more and more genomic and genetic defects in the DNA of the malignant plasma cell. So how did you know, how did this all start? What are some important things? Early on, we knew that some patients had M.G.U.S. or M.Gus. Some people had smoldering myeloma, some people had multiple myeloma. But it actually wasn't really known if multiple myeloma just happens on its own and can happen without this progression, or is it always preceded by a precursor state called M.Gus. So this was actually a very important pivotal study done by Langer and et al. It actually looked at the NCI PLCO screening study where 77,000 patients who otherwise were healthy adults had their blood and bone marrow, excuse me, their blood checked about yearly. And out of that, after 10 years, about 60, 70 patients had developed multiple myeloma. Those samples were then retrospectively gone back and screened for M.Gus. And in all 71 cases, patients at some point in their history in the preceding five years had a picture in their blood that was consistent with M.Gus. So this kind of locked in the whole biological trajectory of plasma cell disorders and the development of multiple myeloma. But how did smoldering myeloma come about? Well, interestingly enough, it was in 1980 when this New England Journal paper came out by Robert Kyle and Philip Greit, where they, long story short, identified six patients that based on their numbers alone, seemed like they should have developed the CRAB criteria in multiple myeloma, but actually did not in that time span. And so here you can see in green that they quoted although no chemotherapy was given, their condition remained stable for five or more years. And they designated these cases as smoldering multiple myeloma. And they want to really call attention to these cases because these are cases that that did not necessarily need treatment. So interestingly enough, this diagnosis came back in 1980 and was really developed on a basis of six patients. So since then, the general consensus was to withhold treatment until symptomatic multiple myeloma developed because of the potential of significant toxicity with treatment. This is 23 years later, in 2003, that the first diagnostic consensus criteria was actually published for smoldering myeloma. And prior to that, the Swedes actually published in 1993 the concept of early treatment in some of these patients. And in their study, they looked at 51 smoldering myeloma patients that were randomly assigned to either receive melphalan and prednisone or not a diagnosis or progression. And there's really no difference in clinical outcomes in the treatment of these patients with these drugs. So, in fact, there were a number of other studies that also were published using some of these older regimens like melphalan and prednisone and thalidomide. And more or less, the outcomes were all the same, where the toxicity did not outweighed any really direct benefit to the patient. And therefore, the standard of care really remained for a while or for a long time, even until today, not to treat smoldering myeloma. But it was in 2013 where a pivotal principal study, the Quiridex study, was reported. So in this study, they took patients with high risk smoldering multiple myeloma and randomized them to either receive placebo or renalidomide with dexamethasone. As you can see, this was a fairly significant efficacy result, where patients who received the treatment, actually did live longer and had a longer time before the myeloma came back. And this really this proof of principle study opened the doors of really trying more novel therapies, even though we knew that the older chemotherapy didn't work. Perhaps the novel therapies do work because they work better, first of all, and in general have less toxicity. And then a few years later, the sister study in the United States, the ECoC study, more or less showed the same thing, where they found an objective response rate of 50 percent or zero in patients who received one a little myeloma compared to just being observed. None of the patients went into remission. The two year progression for survival was 93 percent. And although the overall survival, it wasn't basically mature, meaning that study wasn't old enough to actually be able to assess that accurately. At about three years, there was no difference in how long patients live, as you can see on the graphs on the right. One troubling thing with this study was there was a fairly high rate of discontinuation of the lenalidomide in 51 percent of patients. And that was really because patients received the high dose of lenalidomide indefinitely. And so as some may know, many patients can tolerate that for very long periods of time. So how about smoldering myeloma and risk prognostication? We kind of lock the major plasma cell disorders, meaning MGUS, smoldering myeloma, multiple myeloma. In each of these buckets, you can kind of make sub buckets or sub categorizations based on risk. And of course, the risk in MGUS and smoldering myeloma that we're talking about is the risk of developing full blown myeloma and the risk in multiple myeloma is, you know, how bad is your myeloma? What is your, what are patients survival based on risk? So we focus on smoldering myeloma. There are a number of different ways to come up with this risk. As you can see from this table, there's the Mayo and Pathema that are well known criteria, just a less well known criteria for Heidelberg, Arkansas and imaging. But if we go back to this, and we look at the smoldering multiple myeloma category, in fact, the high risk that we have bucketed there was actually not all high risk, the same risk, meaning it was higher, higher risk and then standard risk. And at the time, previous to 2015, we would call this like the ultra high risk category, which in some ways really kind of sounded silly. And that's why really the IMWG came up to redefine and definition diagnosis of multiple myeloma and smoldering multiple myeloma. So the IMWG really recognized that there were certain disease characteristics so indicative of evolving into symptomatic multiple myeloma or full blown myeloma. That these quote unquote ultra high risk patients should really be shifted to be called maybe low risk multiple myeloma. And so some may think this is just, you know, a game on the words and it sort of is, but really, it was in order to initiate treatment. So when patients were bucketed into smoldering myeloma, for the most part, you wouldn't treat if they had the diagnosis of multiple myeloma, then that would necessitate treatment for the most part. And so the IMWG reached a consensus that there's reliable biomarkers associated with rough approximately 80% probability of developing full blown myeloma in a two year span. And those patients, like I said, should be recategorized as multiple myeloma. And so when they looked at the literature, there are three biomarkers that were identified. And of course, we all know that the crab is what differentiates smoldering myeloma from multiple myeloma. For those who may not know crab, crab is an acronym. It stands for the C stands for hypercalcemia, the R stands for renal or kidney injury. A stands for anemia and the B stands for bone or bone destruction. And traditionally multiple myeloma was diagnosed when you had one of those end organ damages. But as I mentioned in 2015 with these newer criteria, these biomarkers, quote unquote, were worked into the definition to in addition to crab to sort of gear a patient's towards the diagnosis of multiple myeloma, which would lead to treatment. So these biomarkers, there are three major ones. The first is the bone marrow. If you had bone marrow involvement of myeloma plasma cells of 60% or more, or if your serum free light chain ratio was 100 or more, or if on MRI you had one or more bulk lesions. They also made some other minor revisions, which are not so important for this talk today. So how do we put this all together, the diagnosis and the risk? Here's another picture where we see you have MGUS and those are the numbers that we use to categorize MGUS or divide MGUS from smoldering myeloma, mainly the serum M protein and the percentage of bone marrow monoclonal plasma cells. Then we have the high risk smoldering myeloma category, as you can see, using the various criteria, the most popular being the Mayo and the Pithema criteria, and then multiple myeloma that, as I just mentioned, is diagnosed when you have the crab criteria or you have 10% or more plasma cells in your bone marrow and one of three of those biomarkers. So early intervention. So as I mentioned, the Pithema report with the core index was really the proof of principle that started us thinking into how we can actually treat smoldering myeloma with better therapies that are more safe to use and efficacious. So it was back 2012 that carfilzomib, the second generation proteasome inhibitor, gained FDA approval in monotherapy for relapsed ufractum and myeloma. There's also being studied in combination with lenalidomide and dexamethasone in the ASPIRE trial and eventually led to its approval, the regimen KRD in 2015. At the time I was at the NCI, this led us to develop a pilot study of KRD followed by lenalidomide maintenance and high risk smoldering myeloma. And so why, what is sort of the rationale, the scientific rationale of trying to treat high risk smoldering myeloma? Here again is the pictorial where you really have three kind of options. One is not to treat smoldering myeloma where this in some subset of patients that myeloma will develop into progressive disease and overt multiple myeloma. Or you can initiate early treatment. What's important is that early treatment can come really in two flavors. One is with the goal of just trying to use something sort of on the milder side, not really full myeloma regimens to kind of slow the disease progression. Or maybe the other flavor is that we should, now that we identified the multiple myeloma even earlier, then we should really use the best therapy we have at the moment in order for an attempt to eradicate the disease completely towards a functional cure. These are just different rationales that different studies employ. So this is our KRD study. That we did at the NCI in high risk smoldering myeloma where patients were treated with KRD. It was recently published in September. So high risk smoldering myeloma with that treatment is characterized as having a five year risk of progression to symptomatic myeloma of about 75%. So early treatment with novel therapies we think may decrease the risk of progression. And death as evidenced by the QRDX and the ECoG studies. Early disease may also have more treatment sensitive biology, meaning if you hit the disease sooner, there may be less mutations and other molecular aberrations that may make it more susceptible to treatment. And then we know that randomized studies have demonstrated that novel triplet therapies have a higher risk of progression. And then we know that randomized studies have demonstrated that novel triplet therapies are better than doublet regimens in both the newly diagnosed myeloma setting and relapsed refractory. As I mentioned, carfilizomib is a second generation proteosome inhibitor and it really sticks out compared to bortezomib because it's not associated with any peripheral neuropathy. So we hypothesized that this novel triplet KRD would show a favorable benefit to risk in high risk smoldering myeloma. This was the trial design. Patients received eight cycles of KRD followed by lenolidomide maintenance for two years and then have been being followed definitely. Here you can see the dosing regimen at the time, once weekly was not available for carfilizomib so patients got bi-weekly carfilizomib at that time. And we did a lot of corollary work of course on these studies on these samples. So these were the outcomes, the major primary endpoint was MRD or minimal residual disease negativity. What that means is we use technique that has a sensitivity of one times 10 to the minus five. So we looked in the microscope and beyond the microscope using techniques like flow cytometry to be able to look at at least at 100,000 normal cells to be able to say that there wasn't one abnormal myeloma cell. And using that technology our MRD negative complete response rate was fairly high at 70%. And importantly, a lot in many of these patients, this MRD negativity was sustained not only in two years, but even up to seven years where half the patients were still MRD negative. How about really an even more important clinical outcome perhaps for patients is really what happened to these patients end up developing multiple myeloma or did this regimen able was able to delay or stop. And so we did see a significant, of course, this is not a randomized study meaning all patients received the treatment. So we can't compare patients within the trial, but if we if we sort of kind of Look at the numbers and try to compare it to what we know historically, we can kind of do that to not to make conclusions, but they maybe we can call it approximations. So at eight years actually 91% of patients did not develop multiple myeloma. And if you remember a couple of slides ago, I said the natural history of these patients are they will 75% of them will develop multiple myeloma in five years. So on this study at eight years only 9% developed multiple myeloma. Here you can see the overall response rates were fairly high. And so in this phase two single arm trial of patients with high risk small drug myeloma rates of minimal residual disease negative remissions were high at 70% and they were sustained. So the meaning duration of this MRD was sustained. So the meaning duration of this MRD negativity was five and a half years progression the multiple myeloma was low was 9% in eight years. It was the regimen itself was fairly well tolerated and feasible for the asymptomatic myeloma population. The one the one note is, of course, this was done at a highly trained center at the NIH. One thing using a regimen like KRD it really does require experience and strict adherence to things like judicial to avoidance of using too much IV fluids also thrombo prophylaxis meaning giving medicines to prevent blood clots was really important and how we did that, along with other factors. So how about other trials that that were our trials that again use that approach, not necessarily to slow the smoldering but to try to see if we can get rid of it all together. The other important trial is the GEM CSER trial. This was a European or is a European study. And these are the most recent updated results from ASH American Society of Hematology annual meeting in 2021. They enrolled 90 patients, you can see the complete response rates after induction after transplant after consolidation after maintenance. So what's the difference between this and our NIH study? The main difference was KRD was used just like the same but these these investigators incorporated high dose melphalanine and transplant into the therapeutic design. You can see what the complete response rates are and MRD negative rates on this table here. You can't you're not supposed to at least compare it to the NIH study because they weren't the same study and there's a lot of statistical things you have to be careful when you when you compare studies, but you can see that sort of on averages or in the ballpark they don't seem so different than the NIH study except that transplant was used in the study. Here you can see the toxicity. It's not too significant, it was in line with what we would expect. And then lastly, there's a CET trial. This is a US trial and for those who don't know what trial this is, this is similar again to the NIH study. Except instead of using transplant, the diuretumumab was added to the three drug regimen. So this was a quadruplet regimen where patients received diuretumumab plus KRD for a year, which was followed by diuretumumab and lenalidomide maintenance for another year. So far 54 patients have been enrolled as of 2020 update on the study. And the authors did present, as you can see on this slide, the different toxicities. Nothing really stands out as what we would expect from this regimen. However, there was no data yet published on the efficacy outcomes of this regimen. So risk models used for smolder myeloma, I think we really need to move forward. The current models that we use that I've been talking about predict the risk of progression of myeloma based on mostly clinical parameters, which are markers of tumor burden, meaning how much myeloma you have, which doesn't necessarily correlate with actually how aggressive or how bad or how genetically altered the individual's myeloma is. And that's really important to understand because there's a lot of folks maybe on this phone call know that in a lot of patients, smolder myeloma is just identified incidentally. So that patient could have been identified two years earlier or two years later and just may have had more plasma cells, but But again, may just have indolent disease. So the amount of plasma cells does not necessarily correlate with the underlying biology and molecular genomics of any individual patient's smolder myeloma. Here on the right, you can see some of the earlier criteria that was used, the Mayo 2008 and the Pithema criteria. The bullet points just show what was what's used in order to generate that the risk score. And then more recently, there's the Mayo 2018 and you can see that was slightly changed to better categorize high risk smoldering patients. The important thing is in a set that we did at NIH where we actually looked at well how well if there's more than one risk criteria that doctors can use and patients can use to determine if their smoldering myeloma is low, intermediate or high risk, how do they correlate with each other? And interestingly enough, the correlation between all three models was really poor. So the concordance rate was only about 17% and that's what this picture here shows. And so it's not so surprising because again we're not, none of these risk models really look at the underlying biology. So again myeloma and there's a spectrum. We have in general MGUS and smolder myeloma, which for the most part is observation as the standard of care. Then here where I have maybe treat. So that's the high risk and I personally do not believe in treating high risk smoldering myeloma outside of a clinical trial. I do believe wholeheartedly 100% on clinical trials. So I actually recommend all my patients enroll on a clinical trial, but if clinical trial is not an option, I think observation is the next best. I think personally, I think the worst thing to do is to receive treatment outside of a trial as a standard of care or anything like that. So really there's a new paradigm, I think, approaching multiple myeloma where to remind everyone this whole definition of smoldering myeloma way back was really defined by only six patients. And that's how we know smoldering myeloma. And it's, I think it's very much a somewhat arbitrary definition or basic definition of smoldering myeloma. And it's, I think it's very much a somewhat arbitrary definition or bucket that we use to help us sort of think about diseases. But really we're getting to the point where I think this whole smoldering myeloma is going to dissipate. And really we're going to identify patients who either have an M. gust-like indolent disease or early diagnosis of multiple myeloma, say like a Steve-0 multiple myeloma. And this is definitely going to happen as we understand more of the underlying biology and molecular genomics to be able to identify those patients accordingly. So the future really of smoldering myeloma is in the generation of myeloma defining genomic events. So there's novel whole genome sequencing allowed for the identification of cases of M. gusts which would progress versus those which would not. For example, in stable versus progressive M. gust cases, there is like no activation of an important pathway called APOPEC genomic signature. There's no template of insertions, rare involvement of single variant hot spots and rare occurrence of chromatripsis. I think I know this sounds like gibberish. In some ways it is. The point is that these are signatures that are really that we see a lot more in multiple myeloma. And those patients with smoldering myeloma that have these signatures are probably really closer to the end of multiple myeloma rather than the typical case of M. gusts which really never progresses. So perhaps the real question is not whether and how we should treat smoldering myeloma, but rather how do we identify patients with myeloma defining genomic events. And once you do that, you treat them the same as you would treat multiple myeloma with the best treatment available at the time. So here's some technologies we're working on in Sylvester and Miami, Florida. So one of the issues or problems with studying smoldering myeloma and M. gusts is on average, the percentage of bone marrow plasma cells to study is very low. And so it's very difficult to isolate these from all the normal cells in the bone marrow. And that's what really causes problems when we try to do things like whole genome sequencing. So this was a recent kind of technology. This paper was published in 2021 from our group and a bunch of our collaborators. And basically it uses a novel technique to be able to use what we call low input DNA in order to sequence these patients tuners. And here is just an example of what was seen in a pilot study. So smoldering myeloma cases, those cases that remain stable for many years compared to those cases that progressed to multiple myeloma. You can see here that their signatures, their genomic signatures look different. And that's what all these different plots basically show you. And the main, the reason I have this up here is not to look at each column, but rather to realize that it is really different. And here on the right, it basically looks like copy number changes. And again, there is a difference. And so how do we put all this together? What are myeloma defining genomic events? I borrowed this slide from Dr. Langren. And here he has it very simply put. These are all the different genomic events that you can see in different stages of the disease. And as you can see with the check marks, those stable smoldering myeloma cases and even MGUS cases, they really lack some of these more intricate and complicated genomic alterations. And these alterations range from, to give you sort of a layman's term, anywhere from specific DNA changes like mutations that we all heard of on the news and whatnot, all the way to catastrophic chromosomal events where whole chromosomes either get deleted and multiplied, get added on to another chromosome. And we see a lot of that in the multiple myeloma cases compared to those precursor cases that don't end up turning into myeloma. Here is basically another plot on that study that shows you that if you have stable smoldering myeloma, then based on the genomic signature, none of these patients in this small set develop multiple myeloma compared to those who had that progressive genomic signature. So where did all this lead us practically speaking? Well, in Miami, this lead us led us to the TRANSFORM study, which some of you may have heard of. This study is really an observational study, open about a month ago here at Sylvester Conference of Cancer in Miami. It's a natural history study, meaning there's no treatment involved in this. But our aim is to enroll a thousand patients and use whole genome sequencing to define the presence or absence of these myeloma defining genomic brands. Really the goal is to develop a molecular marker of individual patient's risk of developing full-blown myeloma. Obviously, this will be open to patients with precursor disease, untreated, MGUS, and smoldering multiple myeloma. On the left pictorial shows you the basic diagram. Patients get enrolled, they get a bone marrow biopsy, and all the really the clinical labs you would have done. And that's repeated on an annual basis, five years. And on this picture, the bottom, basically, I will show you at which times we get research samples and each time we get what we call the myeloma clinical blood work, which most of you are getting anyway. And this, you know, this just to be clear, we're not, it's not like we are testing for these signatures in order to be eligible for the trial. Rather, we are monitoring patients, kind of like what's called a natural history study. And results as we get it, we may get the results nine, you know, six to nine months after the bone marrow samples. And that kind of tells us where we are with sort of studying this large cohort of patients to making sure that our genomic signature holds up. And, and would give us more power to characterize the other important clinical parts that come with, with those genomic signatures. But at the end of the day, some patients who have the high risk signature may actually want to be treated for, you know, because of that, because of that finding. And so along those lines, we are developing this is not open, we are developing the revive study, Dr. Langren is the principal investigator of, and it will actually incorporate by specific monoclonal antibodies and combinations to treat patients who have high risk smoldering myeloma, not only based on the clinical markers we talked about, but also by these genomic events identified. The primary endpoint will be MRD negativity. And as I mentioned, only patients with this high risk genomic signature will be enrolled. So in summary fairly soon the diagnosis of smoldering myeloma is likely to dissolve patients disease will be categorized as either M. gusts like or early myeloma using underlying molecular genomics and biology. So patients determined to have early myeloma will be able to be treated using the best approaches at the time for treatment of not newly diagnosed multiple myeloma. As drug development, especially in terms of immunotherapies improves patient outcomes and patients diagnosed early will most likely derive the greatest benefit. The horizon looks very bright, not only for the treatment and functional cure of myeloma but the prevention of multiple myeloma and craft from the start. And those lines just want to shift over and let those of you who don't know about Sylvester in Miami, let you know what's been going on over here. So, our program is, we're not young, but our program is young, about a year, year and a half. Dr. Langren was brought down from Memorial Sloan to lead the myeloma program here in experimental therapeutics. He relatively soon after recruited me where I was the head at the NIH in myeloma to come here and help him build the myeloma program and clinical trial research Sylvester along with a slew of other very talented people that we have in our program right now. And we really have two major focuses clinical trial research and drug development. In addition to myeloma based computational translational research. We have many phase one and two trials, smoldering, we diagnose, we have a new lab refractory. We have trials incorporating small molecules and also immunotherapies. Our trials really focus on the translational genomics research focusing not only on sort of driving precision medicine and finding the drugs focused on patients particular myeloma alterations but also identifying molecularity which cases are early in myeloma progress to overt myeloma. And for those again who may not know we have many satellite stations also we offer telehealth appointments from across not only the country, but the world. We are mainly based on the main campus downtown Miami but, but I have patients and we all have patients in all the different satellites where they can receive chemotherapy and our appointments, where we are still using telehealth a lot. And a lot of times patients don't have to even come downtown and can see us by telehealth. So with that I would really first of all, like to thank all patients. I've been doing this for a little while and I can tell you that I would not be where I was without all the patient support that I get. And especially those who have enrolled on the clinical trials that I have led and conducted. So I really thank, thank you guys. In addition, of course I think the team, we are definitely a team here I can't do any of this on my own. Needless to say, including our warrior and Chief Dr. Langren and all the other myeloma doctors and the research support staff and clinical support staff. And lastly, I'd like to thank you for giving me the opportunity today to give a talk. Thank you Dr. Xanjian that was an excellent presentation. I have several questions for you so does the audience so I'm excited to get started. One of the first questions that I have is, why do we not screen for MGUS? And I know that this is something that the PROMIS study is looking into. That's being hosted at the Dana-Farber Clinic up in Boston. But what is your thought on screening for MGUS especially once we understand this genomic marker that you were talking about? Would you see it as beneficial that we screen the general population for MGUS? Thank you, Arjun. I think that's a great question, because that's like the logical question. Like, we're finding all these patients on trials, right? Like I mentioned even the initial PLCO study. The reason is because in medicine, I know it's hard, it's a concept that's really hard to grasp but in medicine, just because you know doesn't necessarily equate to actually living longer or being better. And so the only way that you know that that is going to be true is if you do a massive study, because myeloment and even MGUS is still relatively in a low percentage of the population, that study has never been done. But that being said, I think even more important, you know, is the Icelandic study, where they are actually screening, you know, almost the whole population. It's a small population. I think it's a couple hundred thousand who own Iceland. And that will give us, with the data is already coming in, and we see different incidents and prevalence. Then really what's going to happen is, it's not only what X percentage of MGUS or smoldering or whatever is identified. But in the long run, did it benefit those patients from learning that early? I think that's the key because on the other hand, what's wrong, there's a lot that can go wrong about just like knowing if it's not going to make you live longer. I'm talking about everywhere from psychosocial stress of knowing that you have it, all the way to financial. I mean, myeloma labs, as cheap as they are, they add up, you know, and then you because that means you have to be monitored every three, six months, whatever, right? Not to mention if things are identified, you're getting bone marrow biopsies and all that. And at the end, if that all that stuff doesn't really make any individual live longer, we just don't know. It may, and if it does, and it's worth it, don't get me wrong. But it's just that we don't know. And I think, I think just like the initial studies in MGUS and myeloma, which were really based on the Mayo cohort. I think you need some kind of cohort to actually show that pans out before it's sort of used in a more general population. Yeah, that makes sense. That makes complete sense. Thank you. What role can myeloma vaccines play in precursor treatment? I'm assuming, I'm assuming the question is based on like anti neoplastic or anti myeloma vaccines. I think, I think there's hope. I think there are some studies that we're looking at it. We don't have really any positive results from it. It's neither in smoldering myeloma nor in multiple myeloma at all. I think, so this is my, this is my personal take on vaccines. I think it's some day for myeloma treatment. I think someday we may get there where we can use it. But I really personally don't think we're anywhere close scientifically to really be able to manipulate vaccines in such a way that really gives us meaningful results in the clinic. Yeah, that makes sense. Okay. What about circulating plasma cells and blood as another high risk marker for smoldering myeloma? Absolutely. So for those. So just real quickly, plasma cells come from B cells. B cells, you know come from the, you know progenitor B cells come from the bone marrow, they hone into the lymph node where they mature. Some set, as they go through the lymph node, some set of them become memory B cells and kind of hang out in tissues and lymph nodes and stuff. And some set of those actually become long-lived plasma cells. So they come out of the lymph nodes and live in your bone marrow. That's why we do the bone marrow biopsy. But the point is, you should never really have plasma cells, even like, you should just never have plasma cells in your blood. If you have plasma cells, especially barren plasma cells, it's usually not a great sign. Great. We have a couple people asking if we can get copies of the presentation, the recording will be sent out to all registrants via email. Several questions about that transform study. One question is if they're not in Florida, are they able to participate from other parts of the country? And then another question is, do they have to have the high risk multiple or standard multiple myeloma or could it be just the standard risk, smoldering? Right. So the transform study itself is a natural history study, so no treatment. Actually, if you got treatment, that would probably kick you off the study, which is fine. So the first question, you can live in Alaska and still participate on the study if you can come to Miami, if you feel like a vacation from the cold. You have to come, I mean, I think at least annually for the bone marrow biopsy, so it doesn't have to be like every three months. So we do need to monitor you, but I think those can be done by telehealth throughout the year, but it would necessitate a bone marrow biopsy done like in Miami. And then it's open to anyone that has either MGUS or smoldering myeloma irrespective of the clinical risk. Okay. And then regarding the other clinical trial that you talked about, have you decided, has your team decided which by specific will be used and how can people get involved with that study as well? So there's only so much that I can probably say since it's not formally out, but it will be one of the better known BCMA based by specific antibodies. But it actually, interestingly enough, Audrey, will be actually a multi-plenum. So it won't just be one. We are actually, at least as of today, we will have two different, at different times, two different by specific antibodies targeting different antigens. I just, I'm excited. I'm excited to see the results and how patients respond. Another question regarding the transform study. We have a patient on the call that is actually enrolled in the trial. Are you able to tell us how many patients have enrolled so far in this trial? I think right now we have about 20 to 25. Okay. We have a little while ago. Let's increase. Let's do this. I'm excited. I need your help. Okay, we got it. We're going to work with our chapter and we're going to get some people enrolled in this. It's going to be exciting. Tell me why KRD instead of VRD. I mean, we hear VRD used so much in active myeloma treatment, and you hear KRD as well, Kyprolis versus Velcade. Is it because of the neuropathy that these high risk smoldering myeloma trials are using Kyprolis or do you think Kyprolis is more effective? What's your opinion on that? Yeah, this is really one of those things, depends on who you ask. I can just tell you, I've been using it for about 15, oh near 15 years, okay. I'm very experienced with it. And I personally, anecdotally, at least feel like it's a better drug, both in outcomes and also toxicity. I think the one toxicity that everyone rightfully so is concerned about is cardiac. But really, if you know what you're doing, kind of, meaning if you're careful, that's why I had the last bullet point if you remember about thrombo-prophylaxis and about volume and intravenous fluids. And then you're careful about who you enroll. You don't want to enroll with someone who has heart failure at baseline who's 85 years old on a KRD study. But otherwise, it's definitely my, I don't personally, I don't use VRD at all anymore. And for some reason, if I have to treat a patient who can't receive KRD, then if anything, I will use the quadruplet diuretumum on my VRD. I don't use VRD alone. I just, I don't know, in my hands, I just get much better results with KRD. Yeah, that's awesome. Thank you. Deborah is asking an important question and I'd like to kind of tie it into one of my questions as well. So she's talking about regarding your statement that you wouldn't treat a smoldering myeloma patient outside of a clinical trial. She wants to know why if treatment could delay progression or eradicate myeloma for that patient. And my question that I was going to ask you is, there's such a risk of treating smoldering myeloma. So, I think you just answered the question yourself by your question. Like how do you, because there is that, we saw in those studies, there is a possibility that by treating high risk. Because everything is sort of, how should I put it, what's the legal term with like, with, I forget now how that's saying. How does that go with like, with reasonable doubt or whatever like, it's because we don't really, so there's only really two randomized studies that were significantly, in my opinion, flawed, I presented them, that actually showed treating myeloma is better than not treating. But the problem is those studies did not use effective myeloma treatment. I don't believe, and we don't know in the long run really, really, if that, you know, if that's really going to make patients live longer. So, I wouldn't treat it because if I would treat smoldering myeloma, I would want to treat it the same way we would treat newly diagnosed myeloma. And right now you really can't because that randomized study has not been done. So even our study looked great, right? Care, like, and that's why people are like, well, why aren't you using that? It's because even though it looks really good, and I think it's probably real, we just really can't with that. I have to be, I have to put my academician hat on. And I have to say like, you know, you really need a randomized study to prove that probably. I personally think that, you know, one way is like, okay, so this is how it's been going, right? We've been showing that two drugs, or three drugs are better than two in relapsed refractory myeloma. Then we showed, we had to prove, we had to show that, I don't know why, in newly diagnosed myeloma, right? And then now, and then we have four drugs in relapse, and then you show, now we're showing four drugs actually better in newly diagnosed. And so do we, the question is, do we really need to go through that exercise of like showing that, oh, now we should use one drug, and then until the study comes, it shows two drugs is better than one and then three is better than two. I think, I think it's ridiculous because the diseases are so similar. I mean, there is the same disease. It's not even amyloid versus myeloma. And so I think you'll never be able to, so like the way the drug development goes now, you would have to really duplicate every study that's been done in newly diagnosed and smoldering myeloma in order to actually have a standard of care treatment and regimen. I think what's going to happen is, like I said, instead of doing, instead of focusing on the treatments that we use for high risk smoldering, I think, I think the key is in defining, getting rid of smoldering myeloma and categorizing those patients molecularly as either, you know, myeloma or not myeloma. And then using whatever state of the art treatment is at the time for newly diagnosed myeloma in that patient population. Yeah, it's interesting that you say that, you know, I hear different things from other myeloma specialists and it makes me wonder, you know, how far away are we from these changes, you know, how exciting it sounds, but then again, the reality of it all. Well, the reality is it'll take some heavy lifting, but the evidence will speak for itself. And so once that's the thing, we need to get data at the end of the day and the data will speak for itself. Yeah, yeah, definitely, definitely. A lot of questions about testing in the precursor field. How often would you require a bone marrow biopsy test from an M.GUS patient? That's a good question. So it really depends on that risk. So my M.GUS patients, I kind of run them through my mind through the original Mayo sort of risk criteria. So what I mean by that is you basically look at three things. This is true also, this is important at diagnosis. Not all M.GUS patients even need a bone marrow biopsy. So usually I don't get a bone marrow biopsy if patients have low risk or low intermediate risk and kind of higher up in age. I don't. And then I get them on all the other ones. And so the things, so if you have like something like say high risk M.GUS or something, then I usually would check, I personally check labs like maybe the first two, like I would do one in three, this is a new patient, one in three months and then another one in another three months and then I would go to probably six months for a few times and then a year and then just look for stability. What we do know is you don't want to lengthen it out more than a year because there was a recent study that actually showed, you know, from Dr. Langren and I worked on it too, like that risk, we risk prognosticate, but it's not something that you do at diagnosis and you forget about it and it always stays the same. That risk is actually dynamic and can change. Bone marrow biopsies. Well, probably patients don't like bone marrow biopsies so this question is always really hard. Like clinically I would say, and like if I was at the NIH where we did our clinical trials and stuff, I would say annually just like transformed study. I think it's kind of hard to ask that from like all patients, not on a clinical trial, so maybe then every few years. Yeah, it really depends on the patient. And what about smoldering myeloma, would you increase the frequency based on the risk? So, so, so with smoldering, with both, I can really use this and it's like this strategy where we really look at the labs, and when I say labs, not just the multiple myeloma labs but also other things like renal function and anemia, or hemoglobin rather, right, because there's always that gray zone, right, patients have a little anemia but doesn't qualify for multiple myelomas. So, so if those don't budge a lot then every few years, as soon as the moment I see, you know, something that's out of the normal for that patient, I would have a light, like sort of light trigger to initiate a bone marrow biopsy. And of course, along with bone marrow biopsy imaging is super important. I really personally don't get anything. I push hard to get a PET CT. And then skeletal surveys don't mean anything for me nowadays. And so that just put that out there too. Yeah, okay. One more question to go along with that discussion. How close are we, again this is very hypothetical, but how close are we to getting rid of biopsies and just using blood tests? I mean, I know you've, you've heard of that. Do you think we're, I don't think we're close, I think, I think we're much closer in order being able to like monitor myeloma that way. Yeah, I think because unfortunately at the end of the day, the tissue itself like you think about, think of like breast cancer right I mean, at the end of the day at some point you need, you need the breast tissue right to diagnose breast cancer and really unfortunately myeloma is the bone marrow. That's, that's really the organ from myeloma so I mean, I think it's some, I think it's inevitable that you will always need one. The real question is whether we'll need it, like all the time to do things like MRT testing or not. I think, I think we're probably, I don't know, probably about anywhere between three to five years away from that. Yeah, yeah and I only laugh because we get this question every event, I mean, everybody is ready for those bone marrow biopsies to go away. So lots of people are asking for the information to enroll in the study so I'll, I'll connect with you after this event make sure I get all the links that refers them to the transform study that where they can enroll. And that way, with that, so the first step to that, for that honestly would be to, to request a new patient visit with our group. Okay. So, it's this isn't, it's not really like some, it's not like for example, the data farmer study where you know you can kind of register abroad and stuff this is sort of more like a traditional trial where you would actually see the doctor and then if you're interested, you're okay. It would initiate clinical trials.gov or something. You know, I don't know if it's on clinical trial, it should be, it will be I don't know if it's on there right now. The best thing to do is to reach out to. I'll give you the information but it's the best thing to do is to reach out to our clinical trial coordinator for it. And they can send like, like for example we can set a potential patient maybe they're not sure if they want to come. They can always actually set up a telehealth visit before with one of us to discuss the trial, and then after that we can kind of share the inform consent. You know, if that's something they were interested in. I think that's the best way to move forward. Yeah, the best. So, so, in summary, best way to move forward is have that have it anyone interested should should email which I'll give you the email, our clinical trial program manager for it. Yeah. Okay, perfect. There are so many excellent questions and I wish that we could answer them all. I'm going to give you a couple more before we leave that's okay. So Jenny here is saying she has IgG lambda Ben Jones hasn't been treated yet but I think her question echoes within other questions that I've seen in the chat here. Am I causing irreparable damage to my kidneys by not treating versus treating. And I see other questions in the chat you know, am I hurting myself more by not being treated than being treated. And how can they wrap their minds around whether treatment in the high risk category for example, whether again that's a great question that like we just don't know right unfortunately we just didn't know. I think there's evidence of like for example renal dysfunction or that goes along with actually what we were talking about before, like patients may have something like monoclonal gammopathy of renal significance as they call it or whatever. I think if you can get, if there is objective data that sort of like for example light chains are causing myeloma kidney, then in itself is enough to call it not like mg, you know RS or whatever but really just called myeloma and treat from myeloma. Like, like, I kind of agree with this, like, like there's no sense in waiting for the crowning to raise from 1.5 to two, because that's what the criteria says. Before it's called crab if you know that it's the plasmus, you know, the monoclonal protein that's causing the renal damage, then you should just like not be treated like with monotherapy or something like that you should get treated for full blown myeloma. Interesting. Another question here is, you know, would you advise a patient who has no symptoms no fatigue works full time continues to work out daily to start a clinical trial. If you don't mind I'll answer something real fast and then you can put in your, your two cents. I talked to patients a lot that have this conundrum. One of the things that I recommend is if you feel the call to be in a clinical trial to help further myeloma research. There are quality of life studies there are like this. What did you call it natural history studies that you can be a part of in order to further myeloma research and be monitored in a way without having to receive treatment. If you feel like you want to participate in myeloma research but don't want to receive toxic treatment. Not, not would be one of the ways that you could contribute. What else would you add to that Dr. Kusumji. I agree I mean to go back I mean there's different motivations like even in these questions right. Some patients, and this is, I experienced this a lot like when I was at the NIH, which is, which is 100% referral center. And I think that we have sort of patients that can't even like, comprehend idea of living with a pre cancer in them, and not doing something about it. And then, and then there's folks who are like, why am I going to try to fix them that I don't really see it's broken right now I feel perfectly fine. You know it's a difficult question to answer. The important thing is that patients are informed, you know it's kind of sort of like, well we don't know this is why it's a trial trial similar to this, this was the kind of side effects that patients had this is the benefit that we know or we don't know. And then there's, you know, if you don't get treated on the clinical trial, which is what I'm assuming the question is geared towards. Then this is probably an average was going to happen or not. Yeah, the very patient physician decision to treat on the trial for smoldering. Yeah, yeah. Well I see a lot of people in the chat to you know explaining their personal circumstances and that's why I think it's really important, I will include how to reach out to your institution to be able to secure a visit because consulting with the multiple myeloma specialist about this, even if you have smoldering myeloma is incredibly wise. I think you're asking incredible questions. And I think you deserve more one on one time with a specialist that can answer these questions for you. And so we are going to be providing the multiple myeloma specialist directory and also the contact information for Dr. I think I'm not know it's already. But again, like what we were talking about before this started I think patients may not always realize that doctors get it wrong. I think I've caught many, many misdiagnoses. I'm just trying to echo, I mean even if you so that's the other problem is everyone, I don't know, in Miami everyone's a myeloma expert, you know what I mean, I don't know what that means. It's funny but it's not funny right because patients think they're going to some something called an institute or whatever that, oh they must know and then but they don't. I mean the doctors are not really experts in that. It's really important to go through an organization like you to really figure out who the experts are. And if nothing else to get a second opinion, forget about trial but second opinion on just the diagnosis in itself. Yep, yep we want what's best for our patients and their families and we'll do everything we can to do that. So thank you Dr. Kazanjian we really appreciate your time and knowledge that you shared with us today. So, my group can meet on next in September, we meet every other month. So we will be meeting in September, and possibly talking about monoclonal gummopathy of clinical significance. This is something that's been highly requested by the group. And something that's pretty still unknown but I'm going to try to talk to a couple doctors that wrote different academic papers about it and try to see if they would be willing to come to talk to us because if it's being requested by my group it's important to me and I want to be able to speak to this. You may be interested in other health tree myeloma community events that are coming up on the 19th tonight at 630pm Eastern is our Florida myeloma community chapter, we're going to be discussing cancer survivorship and how to optimize our wellness. This event will not be recorded so if you want to attend please make sure to attend live. Tomorrow at 1pm Mountain is our Mountain West myeloma chapter we're going to be having an open q&a with multiple myeloma specialist Dr. Sporoff. The 21st at 2pm Eastern is our African American myeloma community chapter. We're going to be talking about black myeloma health and how to empower the village. On the second at 1pm Eastern, we're entering August and we'll have our myeloma financial chapter and be talking about how we can capitalize on life insurance to pay for myeloma care even when that person continues to be alive that it doesn't have to be just at time of death and that's how life insurance policy comes into play. The link to sign up 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 that I've been mentioning. And then our community event sponsors we give them another thank you Bristol Myers Squibb, GSK, Genentech, Janssen Oncology and AbbVie. A big thank you to each of you for helping us build this community. Thank you so much for joining us today. I hope you have a great rest of your day. Thank you for your excellent questions that provided a great discussion. Take care everyone.