(Guest Lecture): June 2022 - Measuring Serum BCMA for Non-Secretory Myeloma Patients with Dr. James Berenson

our questions in an organized manner. Today's session is going to be about measuring serum BCMA for non-secretory or secretory myeloma patients. Non-secretory myeloma patients are hungry for other ways to monitor their disease apart from a bone marrow biopsy. Thankfully, research in myeloma has discovered a possible way to make that happen. So today, Dr. Berenson is going to expand on what he and his team have found regarding the measuring of BCMA and how it relates to monitoring myeloma, including non-secretory myeloma. I'm looking forward to learning from him. A brief introduction, Dr. Berenson founded the Institute for Myeloma and Bone Cancer Research in 2003 and serves as its medical and scientific director. It's a mission-driven 501c3 nonprofit institute committed to the advancement and committed to advance the monitoring and treatment of multiple myeloma by connecting possibility through scientific innovation leading to personalized and continuous optimized patient care. Dr. Berenson has authored nearly 300 peer-reviewed publications, contributed to multiple book chapters, served as a member of many organizations, including National Institutes of Health Center for Scientific Review, Clinical Oncology Study Section, Scientific Boards of Multiple Myeloma Research Foundation and International Myeloma Foundation, served on both the foundation and scientific boards of the LL, Linc, Leukemia, Lymphoma and Myeloma Society, LLS. And Dr. Berenson is a section editor for the Supportive Cancer Therapy and Editorial Board, has many credentials and is very qualified to be with us today. With no further ado, then I will turn the time over to Dr. Berenson. Thank you for being here. Oh, it looks like you're muted, Dr. Berenson, if you don't mind. All right. Good afternoon or evening. Can you hear me now? Yes, perfect. Yes, thank you. All right. It's my pleasure to present work we've been doing on a new biomarker, which we've been actually studying for over 11 and a half years now, almost 12 years. And we stumbled in on this through work we did early on a BCMA targeted therapy. And the thing we thought is, if this was in the blood, it may interfere with the ability of that particular drug to work. And that turns out probably the case 12 years later. But we found that this was an excellent way to monitor the disease and predict outcomes. And I'm going to show you some data specifically related to non-secretory in a moment as well. So if we can go ahead and get the first slide up. So the standard tests for falling myeloma are to measure these monoclonal proteins or antibodies that are coming out of the tumor cells in the bone marrow, and then go into the blood or urine, either as whole antibodies, which are those triangular shaped things. And the pink guys are the short chains, which are otherwise known as the light chains. And the longer guys in the light blue, those are the heavy chains. So when you say a myeloma is an IgG kappa, it's because this part is C gamma. So that gives us G. And the light chain was named after two guys originally worked on this. One's last name started with a K and the other with an L. So we had kappa or lambda. So you can have a G, either kappa or lambda, or most commonly an A kappa or lambda. But some people only have light chains, maybe 15% of myeloma. So this stuff in the bone marrow, the red part of the chicken bone goes into the blood and the light chains can fit through the membranes into the urine. And then you can measure them either as whole antibodies, and that's by a protein electrophoretic method in which you separate the proteins based on size and charge. And then you get with Bob Kyle, the old grandfather of myeloma calls the church fire peak. And that's the M protein. Or you can measure the antibodies in the blood. And those antibodies in the blood, whoop, you're going, yeah, there we go, called, those are measuring the amount of IgG or IgA or IgM. And that's called the quantitative immunoglobulins or the QIGs, if you will. And then on the bottom, you can measure the light chain using a free light chain assay from a group in England. And that can be done the urine or the serum, but usually we now restrict that study to the serum. All right, go ahead in the next slide. So the problem is these tests are not that accurate. They're really slow to detect changes in clinical status. For example, the half life of the monoclonal antibody is about a month. So it's really too slow to effectively guide therapy on a day or week to week basis. So it's like with a monoclonal antibody, that is the M protein, it's like you're looking at light from the sun. And that just takes too long to get a read on what's happening with you in a time friendly matter if you need to change therapy. And then the serum protein electrophoresis, if you've seen those, it's pretty subjective how you call an M protein. The amounts of IgG, IgA, and IgM are problematic from two aspects. One is the reagents vary from lab to lab and month to month. So at 1,700 IgG, maybe at 2,200 the next month on the same sample. And you're measuring not only the IgG of the myeloma, but remember you're making a lot of other normal antibodies. And this test doesn't differentiate between the normal and abnormal. The serum free light chain has a lot of variability without really changes in the clinical characteristics of the patient. So it really becomes problematic to note that 500 that went to 800, is that really a real change? Or is it going to go down to 500 again? And then in patients with kidney failure, it's really hard to figure out how to use this test. And that is a commonplace event in myeloma patients. And then last, there's really no consistent method to interpret the results. Do you use the amount of the involved? So if you're a lambda patient, you just count the lambda. Do you use the ratio of the two? Or do you use the difference between the lambda and the one that isn't the myeloma, the cap? Well, remember, a lot of that lambda also can be normal antibody. The 24-hour urine collection is not reliable. You and I know we've had urine spill in the elevator, in the bathroom, in the clinic, let alone what happens at home. And you got to dinner and you forget it. It's not really very accurate. And again, the same limitation on the protein electrophoresis and the serum holds for the urine. What do you call the monoclonal component of it? Next slide. So these tests really are not that great, but we believe the serum BCMA will help a lot. And one of the reasons for that is it turns over much more rapidly the M protein. And secondly, you can see in the third row, you can use this in people who don't make an antibody that is their non-secretory. So they don't make an M protein or a light chain. And that is certainly not only occurs upfront, but over time, your cells get really poopy at making heavy chain and light chains. And many patients become either what's called oligosacretory or non-secretory. And we know that this is a consistent assay to measure outcomes, both in terms of survival, prognosis, and to monitor your disease. And really importantly, in the second to the bottom row, these results are independent of kidney function. And that's not true of free light chain. And the results are very tight. There's not the kind of variability you see certainly in the serum-free light chain and with the subject of M protein. So next slide. So what is this BCMA? Well, it's a protein that is stuck on the outside of the cell membrane in the bottom left. It stands for B-cell maturation antigen. And the reason it's called that is because you may know myeloma is a mature type of Y cell called a B-cell. And then normally that BCMA is bound to a number of proteins that are fertilized that drive B-cell growth called April in bath. But what happens is, as you've seen in the very bottom left, they could be clipped off, scissoring, if you will, shed off into the blood as serum BCMA. And that has a lot of implications for treatment in the biology of the disease. So for example, in the bottom left, the shed BCMA we've shown actually paralyzes your immune system because what does it do? It prevents that fertilizer April in bath from driving normal B-cell development and probably is one of the causes of the immune deficiency of myeloma. We know that this is elevated in myeloma and related cancer in the third bullet on the left. We also know from work we published, it's very low in kids with primary immune deficiency or adults, and you can track those patients as well. But we also know from our own work, it's shed very rapidly into the blood. So again, the advantage here is time that you're looking at like the light from the sun instead of the light in the next galaxy like with M protein. And it's very convenient. It only takes the tip of your pen here, amount of blood to measure this. Let's see if I can get the top of the pen. You don't need a whole gob of blood to do it. And yet you could leave it up on the bench top in our lab for a month or two and it's really stable. So it's a very convenient test. All right, next slide. So basically the bone marrow with the plasma cells, the BCMA is shed in the blood. You can draw the blood. You send it to the lab and you run what's called an immunoassay in which you have an antibody on the plate to BCMA. It's similar to what they're doing to measure antibodies for COVID. And then they put some serum on top of it. And then the serum has BCMA in it from the solubilized BCMA in the blood and it sticks. And the bluer the more of the BCMA in the blood and that's not such a good thing. So you can measure it quickly and then you can easily get the results in a few hours. And you'll see in a moment it's very good at predicting outcomes and monitoring our patients. Next slide. So this is some data we published a few years ago. This is data from Health. We have a lot more data on like a thousand patients now, but this is healthy donors, so-called MGUS, that is monoclonal gammoth, they've been determined significant, smoldering myeloma and active untreated myeloma. And the red numbers are the averages for the normals, the pre-myelomas, the patient's not requiring treatment, that is smolders. And you can see the untreated and the numbers are quite different. And good news really for a test is there's a lot of variability, particularly in the active patients. And that turns out to be very useful predicting outcome for these folks. Next slide. So here's just an example of time to the disease worsening. And this is a number we picked at 595. And that basically represents people who have really high numbers. This is 25% of our patients in the setting that we published. And basically their time to progression or really death from any cause is way longer if they're less than that than if they're that or higher. It's about four or five times higher. So this is a really good separator in terms of the progression of the disease based on what your number was when you walked in the door to start a new treatment. So this is a number that's gotten at the start of a new treatment, regardless of the type of treatment. The next slide. Now, does it actually with monitoring tell you something? Yeah, if you monitor it and it goes down by more than 50%, either at four, eight or 12 weeks after you started to treatment, if it goes down more than 50 in the blue line, you have a much longer time of lacking progression than if it does go down by less than that, which is kind of a demarcation. That's how we say patients respond in myeloma to the M protein go down 50. We just chose that number, copycatting the numbers you use for following M protein. Now, on the other hand, if it goes up, does that tell you anything? And that is in the next slide. So the next slide looks at a 25% increase in BCMA. And again, this predicts a really short time to your disease worsening. You can see the marked difference there. And these are folks that have had a lot of treatment. So again, if your number goes up by more than 25%, either four, eight or 12 weeks, you're only going to have less than a two month time to the disease worsening. And it's about seven months if it doesn't, and it's quite a difference. Next slide. Now, as clinicians, we want to know as soon as possible when our patients are worsening, so we can get them off ineffective therapy that may have toxicity that they don't need and get them on to a new therapy that might work. So BCMA, again, compared to standard markers, it turns over much more quickly in the blood. And the other thing, I didn't show you the data, but it shed much more quickly off the tumor cells in M protein, which means it's a much quicker determinant of progression than is the conventional M protein. And so this is a study we published where we compared our marker to conventional what's called International Myeloma Working Group Criteria, or IMWG criteria. And we were faster in two thirds of cases, and we were never slower than standard tests. And the average was several weeks. And in this setting, that's of great importance because again, you don't want to stay on therapy any longer than you need to. Okay, next slide. So patients with non-secretary myeloma, as you well know, they do not make monoclonal proteins. So you can't measure a disease with measurements that rely on measuring a monoclonal protein, either the whole antibody or the light chain. And there are a slew of other patients who have what's called a legossecretory disease. They have small amounts of protein that you cannot accurately assess as you treat them to see if they're responding or not. So we actually did our own study to look at what the numbers are, at least in the setting of a patient starting new therapy in the setting where they had failed other therapy. And this is patients getting 122 different new therapies. And you can see that the patients of only about a third of them were accessible by M protein, only less than two thirds by serum-free light chain, and about a quarter were not accessible by either. Whereas all of them, you can use BCMA and you can track it. So a lot of patients, even if they have a protein that's there, it's not high enough to use either for their clinician or they're not allowed on clinical trials because they don't have a measurable protein. Okay, next slide. So this is just a couple of examples of patients who had non-secretory disease. A patient on the top, I just saw her this week, Julie, I've been following her now for about 10 years, continues to be in complete remission. And she presented, you can see with about 20, 25% plasma cells and a PET scan that lit up. And then her BCMA initially was about 140. The average new patient again is about 500. So that's a good sign that it was low. And she again had a nice response and her BCMA dropped to about 20. It didn't go to zero because if you recall early on, the average normal patient has BCMA of about 35 nanograms per milliliter. And the reason that's present, because we all have normal plasma cells shedding off the normal plasma cells, BCMA and the blood. In fact, many patients went low because they don't have any antibody, particularly after a lot of chemotherapy and antibody treatments that kill normal plasma cells. They don't have plasma cells. So they don't shed any of this and they run low. And the bottom patient is one of my favorite patients, Bob, a psychiatrist from Oakland and Berkeley. And again, you can track his disease. He's now out 16 years. So you can see we've been doing this for a while as this data only is out to about seven years here, but it beautifully tracks his disease, the PET scan and the plasma cell loads, which can be quite variable. The other nice thing about the BCMA, unlike plasma cell loads on bone marrow, which may vary from location to location in the marrow, the BCMA is kind of a general number of shedding of everything coming out of that patient's bone marrow. Next slide. So this also is useful for patients with smoldering myeloma. This is data we recently published on our own patients and I'll show you some blinded Mayo Clinic data. And basically we were able to show that at levels above about 137 nanograms per milliliter in the red line, those are patients who did not transform. And basically you can see those a lot more of those patients in that red line are transforming than our patients in the black line, which are the group of patients who had less than that number. So this is a determinant of risk to transform and smoldering. And similarly in the next slide, this is data that we have from the Mayo Clinic and blinded study showing the same kind of thing. Their cutoff was 128, but they show a difference in transforming to active myeloma on the left. The red line represents patients who had lower levels. In this case, the blue line higher levels. And one can see that the averages were two to three times longer if you had lower numbers than 128 versus higher numbers. And the right hand side looks at survival and you can see a difference between about seven and 12 years in this study. This is an older study. I think the numbers would be better for survival now, but this is bank serum for many years from the Mayo group. And similarly in patients with, if you will, pre-myeloma with MGUS. In the next slide, you'll see that you can predict the same thing. So on the left hand side is represented patients who they cut the median here. So it was half the patients had numbers that were less than 77, half had ones that were more than 77. And you can see the vast difference. The red line again is lower numbers, the blue line's higher numbers. And we're telling you the transformation risk is way higher if you have a higher number than a lower number. And then on the right hand side, you can see that really predicted survival was double if you were less than 77 than higher. So this is a test that can be used in all sorts of situations and plasma cell dyscrasia. We've also used this for Waldenstroms, for amyloid, for chronic leukemia, and a variety of other disorders. Next slide. So the BCMA test is elevating patients with variety of plasma cell dyscrasia. It predicts both progression free and overall survival in myeloma. You can now track patients with non-secretory disease effectively. More patients are valuable with this test than conventional M protein or serum free light chain assays. And because it turns over so rapidly, you can find changes in the clinical status of patients more quickly than with conventional M protein measurement. And again, as I showed you just in the last few slides, it predicts who with MGUS is going to get myeloma and who with myeloma not requiring therapy, so-called smoldering multiple myeloma or SMM, it will predict your chances of getting active myeloma. And then I want to mention in the next slide a couple of books that my wife put together. She's an actress, but because every bit of her family's had myeloma, Waldenstroms, and MGUS, she decided to devote herself, and she did this as a labor of love for free, to write a book about myeloma from both the patient's perspective in the first half of this book and the last half as medical information from health care professionals. And then she just completed a book for the caregivers called You Have What, again, with the same idea to help caregivers learn about myeloma. Sorry for that Sunset Boulevard honking. And in the last slide, I'll leave myself open for lots of questions. By the way, we've done a ton of research on COVID-19 vaccinations and boosters, and I'm happy to take any questions you have about COVID-19. And a lot of that's been published, too. Wonderful. This is really exciting, Dr. Branson, and thank you so much for both the time you dedicate in research and also for being willing to speak with us tonight. I have a couple questions of my own. Meanwhile, you're welcome to write your questions in the chat. I see that there are some questions already, which is great. Or you could virtually raise your hand if you would like to ask a question directly to Dr. Branson. If you just raise your hand physically, I won't be able to see you. But if you click reactions, if you're on a desktop or laptop computer, there's a little smiley face. It says reactions. If you click that and then raise hand, I will be able to see you. If you're on a mobile phone, I think you click more, the three dot icon, and then raise hand should be near the bottom. One of the questions that I had, I think I share with Vicki. So Vicki, I'm going to turn the time over to you to ask the question that we were talking about in the beginning. Okay, cool. Thank you, Audrey. I actually have that question and several others, but I have to start by telling Dr. Branson that you are a rock star. And I can help it. I have to tell you, you know, I was a Beatles fan and George Harrison, my favorite, but you are miles above. And this is a thrill for me to hear you speak. Okay, my first question is, I've been hearing about this for several years, long before I became a Nazi reader. Why isn't this standard? Why aren't we able to get this test? Well, the reason you're not able to get it quite yet is it's we are now commercializing it. So the Institute license off the intellectual property to a company called Onco Tracker. And the Onco Tracker group then licensed it up to the binding site group, which is the same group that makes your free light assay. And they're busily putting together the final touches on the assay. And it should be available next year. We do it routinely here on site, but that's not an approved. That's what we call ROU, or R-U-O, sorry, research use only test. So you can't use this to make clinical decisions yet, but that test is rapidly being put in commercial mode. And I expect it to be in the hands of pathological labs and clinical laboratories next year, hopefully earlier next year. But I would not like, I wouldn't want to tell you that date yet. But I want you to know we have a full throttle effort at the binding site to do that because, you know, we just don't have a group large enough to commercialize something. And there are experts at it. They brought us the free light assay, and they're busily putting the final touches on this assay. And we've been, you know, working with them for a number of years and formally for about two, but I've been titillating them about this assay for about eight years talking to them about it. But, you know, it takes a while to generate all this data. And as you can guess, we've fortunately been banking samples here for about 15 years. And most of our colleagues never did that. So we have the luxury of having 40,000 samples to pull out and look at. And that's pretty cool when you want to look at things like, you know, what happens to patients over time, who have had MGUS or smoldering myeloma, or what happens with different types of therapy? Does it work if you have, say, Darcellex, just as well as if you have Revlimid? So we have all that data too. And if I could- Vicki, before you go on, let me ask a couple follow-up questions to that that are shared by the group as well, just so we can stay on the same subject. And then I'll give you an opportunity to ask a different question. Dr. Berenson, do you see this test being covered by insurance, or do you have an idea of financially the impact that would have on patients for this test? Because, you know- Well, I'm not, that's not my bailiwick. I mean, obviously, eventually you want to get FDA approval and be able to get it so it's reasonable. But that's really in binding sites domain. So I'm like the research guy, and I'm not- No, I understand, but I just wondered if you had- I mean, it should become a route. I mean, this is going to be used well beyond myeloma. We started on that, but it's clearly a great assay for immune deficiency. It clearly works great in CLL. We published several papers with chronic leukemia, the most common type, and amyloid and Wallenstrom's, and probably for rejection as well, transplant rejection, although we don't have enough data on that yet. But I expect that that will be the case. So I would expect that- I mean, these guys are really- The good news is the binding site are really the golden people to know how to get approvals from all these regulatories. That's what they've done with their free lives. So they've been there, done that, whereas it's a big black box to me because I do research, science, clinical, and preclinical. I don't do this kind of stuff. No, yeah, I understand. I just wondered if there was talks of that. I mean, the good news, you guys have to know it's in really good hands. These people are great people. They're really straight laced. They do good science, so they're not like just prominent straws or, you know, all those things. And I feel that also validates us that we got these guys as our partner and not some fly-by-night diagnostic company in the middle of Hoboken. I won't speak too badly about Hoboken, but you know. One other question. I mean, you mentioned you see this filtering into other diseases. Do you see this as a test being used outside of the US as well? Oh yeah. I mean, we have patents all around the world and they're certainly actively, you know, getting it approved in every place that they possibly can. So I expect this to be a worldwide test and that's their view of it too. Their view is it's going to be used just as often as you're doing free lights. You're going to be doing this and maybe more often. One of the advantages here is you don't have to worry about kidney failure. That's a big problem in my alone. Yeah. Well, thank you. Vicki, sorry to have interrupted you. You can continue with your questions and then we can keep going with the group's questions. Cool. Thank you. I was wondering about macrophocal myeloma. We keep hearing now about myeloma that does not show up in the bone marrow, but shows up in other parts of your body. And I was wondering if the BCMA test will pick that up even though a bone marrow biopsy would not. You're really smart to ask that. So Sean's a perfect example. He was having more rib pain and the rib pain was causing him quite a bit of distress. His markers, which had been present, had disappeared at that point. And he then had a BCMA that was going straight up. And the BCMA going up was associated with a PET scan that lit up like a Christmas tree in certain spots. And yet his bone marrow was totally normal. And so we have, this is not a disease. Unfortunately, I had a brother and sister about leukemia. And in that case, it's like the wallpaper. It's all the same color. No matter where you look, myeloma is very heterogeneous. And that's why things like MRD assays are problematic and using bone marrow percentages are problematic. Whereas BCMA gives you a whole body read on your level of plasma cell load. And that's why it's really useful. Whereas macrophocal, you can miss it. It's basically focal areas of myeloma and in between you have normal marrow. And there are certainly about 10 or 15% of myeloma patients like that who need treatment. Sometimes you get away with just radiating those spots if there's few of them, which I hate radiation in general for myeloma, but that's the one group sometimes that can be helpful. Is that, just to be clear, is this the same as extramedullary disease or is this separate? No, no. We're talking about areas in the bone marrow that in between, there are islands of myeloma in between you have normal marrow. Extramedullary can be, there's several definitions of that. One is in which you have disease that's extending out of the bone. And the other is in which you have disease that starts in the liver. So there are in the pancreas or in a vital organ. And if you have diseases extending out of the bone, people do quite well. But if you have disease that went through the bone marrow into the blood, and then went to the liver, not so good. So there's kind of two different forms of extramedullary disease we talk about. And would this soluble VCMA be able to help monitor extramedullary disease as well without so many... Oh yeah. Yeah. I mean, I saw an example that today, those people usually have levels that are 8,000, including this woman today, which is not good. And whereas people, again, the average myeloma and relapse runs about 300. Interestingly, over time, there is some drag down on VCMA a little bit over time. So the average in frontline 500 and relapse is about 300. And that's similar to what happens with M protein and Freelight. They go down, but they go down more precipitously faster than they do in myeloma over time. So many patients do become non-ereligo secretory over time and they get lulled to sleep. They're fine. And their doctors think they're fine, but they're not really fine. And this would help say that, nope, your VCMA is going up. This is not such a good thing. Yeah. One of the questions here, do regular cells secrete VCMA? Yeah. That's the point, you guys, is that normal plasma cells, half percent of your marrow is normal plasma cells and they shed it as well. So we can't do an MRD assay. We do have patients that run levels below detectable and those people have mighty low IgG levels, especially people in complete remission. Sometimes they don't restore their normal antibodies. And of course, as you might know, some of the newer treatments like Darcelex or Clisa not only target the abnormal plasma cell, they indiscriminately target the normal plasma cells. So you don't have normal or abnormal plasma cells. I always show two canisters in the clinic rooms. One has the cotton balls and the other has the swabs. And I go, the swabs are the myeloma cells and they get knocked out just like the cotton balls and you can't measure it in the blood of either. And so therefore these people run low antibodies and their VCMAs are very low. Thank you. Is there a numerical measurement of this? One of the questions here, is there a numerical measurement of the specificity of VCMA on cancer cells versus normal cells or is that not? Yeah. I mean, the concentration or the expression is higher on a myeloma cell than a normal plasma cell. And there is kind of what we call an exponential rise. So if you look at bone marrow, as we published this on the percent of marrow, the numbers kind of go like whoop. So as you get really more and more bad myeloma, there's more and more of it per cell. And there's more density on a myeloma cell than on a normal plasma cell there is. That's true. Thank you. Paul is wondering, how does this test track against next generation sequencing testing? Well, the problem is we're not an MRD test. We never will. And I don't really care if we're not, but we can't tell you you have zero disease because there's VCMA on normal and abnormal plasma cells. We do know if you normalize your VCMA, your outcome is identical to those people who have a complete remission. There's no difference. And I'm certainly not one of the people in the world who thinks that MRD is the be all end all that some of my colleagues do, just like the transplant article that just came out that just busted transplants, which I've been saying for 22 years. You know, as my good friend Gio said, it's not about more, it's about being more specific. We want to kill the myeloma and only the myeloma in the bone marrow. That's what we need to do. So it's not going to be a, it's not going to be a MRD or if you will, a genetic test. It's not. Okay. But it is a predictor. So, you know, we have data. In fact, I was just looking data on a new paper. It was actually set in the New England journal in a couple of days, a new treatment for myeloma. And that new treatment, we're able to predict outcomes based on BCMA. So we know that if your BCMA is high, your chances of responding to drugs is pretty lousy. And, you know, similar to 1114, on the other hand, that translocation being associated with a great response to Ben Klextor, Venetoclax, a leukemia lymphoma drug, and a subset about 20% of patients have this specific genetic marker. They do great. We think that BCMA may help, although so far it seems to be indiscriminately a pretty bad marker, regardless of what you're getting. Interesting. Let's talk a little bit about how you personally monitor, go back to how you personally monitor your non-secretive patients. Are you, as well as the soluble BCMA, are you also doing bone marrow biopsies, PET scans? How do you monitor and how often are you monitoring these? I just talked to Julie, the first curve on this week, and I said, you know, it's been so many years. Why don't we cut the frequency of the bone marrows to once a year? Because, you know, it does hurt and, you know, you're traumatizing the same area. Because people in myeloma used to live two years when I started doing this in 85. Now you guys live forever. And getting 40 bone marrows is really not a lot of fun. So we generally start out every three to six months and probably move up to annually, especially we have BCMA. We PET scan people, which is a fair bit of radiation, quarterly or every six months initially, then annually. But again, that's a lot of stuff you probably don't need now. I can't, you know, we don't have FDA approval, but certainly the data says it's going to work. So we monitor with those tests. Obviously, we monitor their blood counts or chemistries or kidneys and all that stuff as well. And if they got specific symptoms in the bones, we'll get more imaging of an MRI type of an area that may show a new lytic lesion. And then another question that I had, you know, you talked about how it could show like who's going to go from MGUS, you know, the progression of myeloma. Could this also be used for a patient that's in remission that perhaps has a Mardin negativity? And then you could be able to see like, oh, it looks like it's indicating perhaps a relapse. Right. No, obviously that's what we're seeing is we are seeing that, that it is indicating. And then how often do you recommend they be tested in remission in order to accurately? We follow patients at least monthly. And if it's going up, we'll repeat it. But our patients are coming in at least that frequently for an antibody or something else or Zometa or Xtiva or something. So active patients at least get a monthly monitor. The other thing is we do, unlike my colleagues, we try to monitor patients on new treatments frequently the first month, every week. And most importantly, we want to make sure we have numbers before they start a new cycle. My colleagues tend to actually measure it on the first day of the next cycle. And then they go, whoops, your disease was worse. And I go, well, why are you still treating them with that drug? I mean, that doesn't make any sense. So we don't, we don't do that in our clinic. Do you see, and again, I know this isn't your, your expertise, but do you see this test getting to patients in clinical trials? Oh, it already is. We're using it in lots of trials and it's been used in a bunch of trials. So that's really validated within, within your clinic and outside, or just- Yeah, yeah. And outside as well. People are using this with CAR T cells showing it effectively monitors the disease. And certainly it's being used in non-CAR T cell trials as well. We just published the first perspective data from our, our lanolinamide trial with Roxolitiniv or Jackafy. And now we're seeing the same thing with Jackafy alone, a Jack inhibitor that we're using to treat myeloma, which has been used for a lot of different indications and hopefully myeloma soon as well. Interesting. Thank you so much. We have a macrophocal patient here today that was excited to hear about us speaking to this subject. So great question again, Vicki. They were wondering, currently MRD negative, but bone lesions have been appearing on the skull. Would you recommend if this was your patient, a BCMA test to help monitor the disease? Well, of course I would. I discovered the one thing. But I think it's a- It would be helpful to this patient. Also, they could be actually CT guided into an area of possible involvement to see if there's really tumor there. And the problem with the MRD assay is you go, wow, it's negative, but how do you know two inches away that in the macrophocal lesion, there wasn't a bunch of myeloma? I mean, it's kind of, in my view, it's like, what does that really be? It's interesting, right? Especially with a disease like myeloma that is all over. It's not a solid tumor that you can, you know, check. I mean, I think, I mean, I think one of the false, one of the assumptions, which I believe is false, that because something happened that you have to get there in order to do better. So what the hell does that mean? People who get MRD negativity do live longer. Now, did you actually have to get all of that treatment and get MRD negative or is the biology of your disease such that if you never got treated, you wouldn't live longer with something else? Similarly, people who get osteonecrosis, the jaw, which I'm really expert on, those patients who get this, the two or 3% of myeloma, they actually live longer. They do much better with their myeloma. But do you want to really get that? Not really. Does that mean that you had to get the drug and get it to live longer? Not necessarily. Maybe the 3% of people who get it may have done better from the start if they never got seneta. They may have a biology that says that. And that's why all these trials where you do transplant versus no transplant or more drugs, you don't see these survival advantages because a lot of this is biology. It's not really the treatment. That's not to say you don't need any treatment, but it says that treatment can be much different than is generally given in this country. Thank you. Another question was, do non-secretary patients have statistically lower life expectancy for myeloma? I believe that answer would be no, but what is your insight on that? My answer is they don't. And Julie and Bob would say no, but there is certainly data now to show that's not the case anymore. Nope. That's exciting. It's just like people with lousy chromosomes now, but that doesn't necessarily mean you're going to... The woman today was in, she had a P53 I go, that doesn't necessarily mean anything bad anymore. People with this 1114 marker where you give them the benetoclax, first it was a good marker, then it was a bad marker. Now with the new targeted therapies we have for that genetic marker, it's become a good marker again. So things change. Now, as drugs emerge, they really do. For example, our new treatment with Jackify, the people who respond, they have really lousy chromosomes. So it may be lousy chromosomes, may be a, hey, you're going to do well if you get this. So I think as drugs emerge and have different mechanisms, what are bad markers and they no longer be bad markers. Do you consult via telehealth or can other countries come to visit you? I do it all. Yeah, I do telehealth around the world and then I run around the world, although since COVID I'm just running around the world. But yeah, I do telehealth stuff. I like to keep myself honest by seeing real people. So we see about 125, 150 patients a week and I monitor them all. So I'm very hands-on and I think if you're really going to be an expert, it isn't like when I was at UCLA and pretended to be one, but really the interns, residents and fellows were doing it and I was in the back room writing papers. Because it really does give you a completely different perspective on treatment of a disease when you're handling the patient and you're seeing them every day in clinic. You get a whole new perspective on drugs, side effects, hassles that people and their family go through to deal with their disease. Yeah. I think you had a really great question. Does treatment with anti-BCMA drugs such as BlendRip have affect the BCMA test results? That's really a good question. We don't really know the answer, but there is enough BCMA. There is enough, that's how I got in this initially, to actually suck it up. So it could bind to the BCMA and you could get some limitation of the assay. I saw a paper like that recently from Israel where the BCMA levels were zero on a CAR-T cell treated patient and I'm like, your assay either was not very good, which it probably wasn't, or maybe all your BCMA was actually bound to the T cells targeting BCMA. So you falsely think things are great and they're really not. I don't think we have a clear-cut answer on it yet though. It also though would bring me to tell you the amount of drugs you need, like with BlendRip and some of these bi-specifics may change over time. Because if there's enough BCMA in the blood, you guys, it may be as that BCMA number drops. And I've told this to the people who make BlendRip, it means that you may have- That's what you mean, the continuation that I asked you about? Excuse me one second. I'm on the conference call. No, no, no, no. I just meant after whatever- Okay. Yeah. Sorry, guys. That's okay. So I think that the amount of BCMA may be able to tell us how much drug. And it may be that you need a bunch the first couple of times you get it. And as your BCMA level goes down in the serum, you may have less binding to your BCMA targeted product and therefore you can use less antibody and things like, as you know, BlendRip can do a lot of damage on the eyes. And maybe with lower doses, we're not going to see that because you don't need as much the second or third month as you did the first month. Interesting. Okay. That's a really good question. Does your test measure free BCMA in the blood or measure the B still attached to the cancer? Well, that's even a more complicated question. Our test measures BCMA in the serum, but it can be bound to a lot of other things in the blood. It can be bound to those other drivers of B cell development, like the ligands I mentioned earlier, April and Bath, so they can bind it. And so we're not for sure just measuring the BCMA that's free of those ligands. We're certainly measuring it free of the cell. It's not cellular bound, but it could be bound to other proteins that naturally. So BCMA, when serviced, naturally binds to Bath in April, which drive the development of a B cell into a late plasma cell to make antibody. But if there's all this BCMA in the blood, it may bind to those guys and they may be measuring bound. And in fact, in that regard, the work we've done in immune deficiency is interesting because we've shown that kids with immune deficiency, they have sky high levels of these Bath and April's and it's probably because they don't have any BCMA shed. So they have all this stuff in the blood that's really high because there's nothing bound really high, which suggests that we're probably measuring mostly free, but we don't really know for sure. Yeah, thank you. There's several questions just again on the timing and I know you can't be specific on like the date, but for example, Anne's question, are we close to using this test for clinical trials in general as an equivalent to monitoring the MSPYC? I mean, what's the timeline there that you see it really taking off? 23 next year. It'll be because it's, we cannot run tests here unless patients have a group like Mayo or some other group where they have IRB approval to get research when they ship it, but you can't go to Dr. Smith and Pocatello and get a test unless Dr. Smith's group has sounded okay for research because this is not an approved test yet. Yeah, it's not yet. Okay, wonderful. There's a couple other questions that will kind of that are a little bit different from what we were talking about, but I think I'll hit on them if you want to comment. The first one was, can you comment on the Mount Sinai case of a patient developing Parkinson's like toxicity three months after the BCMA directed CAR T cell therapy? You know, it's so hard. You know, I get like my nephew is one of those crazy anti-vaxxers and he writes me that somebody with myeloma got leukemia and I'm like, I don't know what that means. Three percent of people in that transplant trial, you know, who are on the transplant arm of the New England Journal, they got leukemia or pre-leukemia. So is that really an outcome from the treatment or is that just something else? One of those two patients I just showed you who's on an anti-CD38 antibody, the non-secret, he just got Parkinsonism. I have no idea what, I don't think that's from the CD38. Right. I mean, you know, until you do a big study, you don't really know anything about these anecdotal things. I do think we're going to learn that these things aren't as safe. They may, they made out to be, you know, I do think you're right about that for sure. Yeah. Is there a better low radiation scan technology coming of age now that has resolution comparable to PET CT scans? There's a lot more attempts to do that. That's for sure. So yeah, I mean, it's coming. It's not here yet. You know, it's coming. Somebody asked a question about the name of that drug for the 11-14 people and that's called Ben Cluckster or Venetoclux, which actually my brother with leukemia got it, didn't help him now, unfortunately, but it's called Venetoclux from AbbVie. Very well tolerated. The other cool thing is we're learning and unfortunately my colleagues haven't learned as well. You can use really low doses of a lot of these drugs and they work great and therefore you really reduce the side effects. And for me, that's really about every myeloma drug from pomolus to Revlimid to Velcade to this drug, Ven Cluckster. We don't use standard doses. We don't think that the necessarily ones you have to give people and the companies never compare them because they don't want to find out that less is more. There's nothing really in it for them, but I do think that's the case with most of these drugs, with most of these drugs. I was just getting that for the proper spelling for that. Thank you. Okay, another question was, let's see, kind of as I mentioned before, there was that question about extra medullary disease. What is your protocol for maintenance therapy? How do you feel about maintenance therapy? What's your protocol? I actually ran the first maintenance trial in the world for S.W.A.G. back 30 years ago this year. You tend to show that prednisone every other day improves survival. So I do believe in maintenance. I tend to keep people on the same drugs they've been but without the chemo. So if they've been on Velcade and Dex and say Dex Doxil or Cytoxan, I'll continue the non-chemo Velcade and Dex, but I usually give them every other week. The Revlimid we do continue. I don't use 25. We give people 10 even for induction. Daratumumab, I think you also need to keep people on that too, keep that going. So I'm not, I do think maintenance is important. I think eventually we'll have therapy like I compare it to going to the county fair and when you go into the arcade and the clowns come up and you bash the clown back down, we're going to have treatment like that. You will not have to have any therapy in between so that you really, really need to think about the future as one that I think will have drug holidays. And it used to be said in the transplant group, you're going to get a drug holiday. Well, we know that's not true anymore with Revlimid maintenance, but I think eventually we'll come back to this. We'll be reassured with drugs we know will work every time and that you won't have to be fearful that you're going to have long-term sequelae because you're not going to get them many, many times. You'll just get them intermittently, but we're not there yet. We're just not there. Yeah. Interesting. A COVID question, Kat says, in regards to COVID, do multiple myeloma and smoldering myeloma patients obtain a good response to the vaccination from what you've seen? We actually published, we published the seminal paper on that actually in leukemia about six months ago. So it turns out that less than half of myeloma patients will get a decent response. 95% of our controls did. About a third of patients or about 25% of patients had a little bit and about a third, they had no response. But it turns out the booster we're just sending this paper in today, the boosterized patients do really well. So the boosters really work. And the other things to note are that the boosters and the treatments with the two first vaccines are much better with Moderna. Moderna wins hands down over Pfizer for myeloma. We don't really know, we developed our own assay for this actually. We don't really know whether these assays hold true for Omicron. We're developing a new Omicron assay. However, we also know that the half-lives of these antibodies shoot down much faster in myelomas than normal. So every 60 days you're going to go down by half. In normals, it's about 100 days. So it's longer in normals. We also give Evishelled to patients. We know especially patients, somebody just asked about Evishelled. The antibody levels go up to thousands. Whether that's protected, we really don't have enough data. It looks like in general, and immunocompromised folks, they help quite considerably. If you haven't been vaccinated, they're not going to do anything, and we don't give them to unvaccinated folks. But if you're vaccinated, Evishelled's probably a pretty good thing. Paxlovin we're using in all of our patients now, and it's probably helpful. They say again, unvaccinated, it probably doesn't help very much. But I do think that vaccination is a good thing to do. However, I must temper that by telling you, if you're on an NICD38, you're not going to have a response to vaccination. Because again, it wipes out the plasma cells that you need to generate an antibody response. So we have published data both in the setting of the first two doses and the booster. If you're on sarclisa, or you're on Darcelex, or Faspro, you're probably going to need Evishelled. It's probably not going to work. Interesting. The Evishelled antibodies included in the antibody testing, we'll be finding that out very soon with both of our assays. I don't know the answer to that quite yet, but we've certainly got studies going on in our lab on that right now. Yeah. I also see a question about how often patients should get the booster. I believe the current FDA protocol, they just changed to three initial shots and then two boosters, if I'm correct. We don't really know anything. I think that you probably, if you could be monitored, would help tell you. But it's probably going to be, it's going to be dependent on what you reach. If you're like me, I don't, unfortunately, Omicron in January, I'm up to 10,000, so I'm probably not going to need one until next year. Whereas if you have a myeloma patient with a poopy immune system, you only may get up, and the protective levels, at least for the first assays, were 250. If you got up to 500, you're going to be below that within three to four months. Below 250, you're going to go down by half. It depends on where you got to, but the boosters are clearly winners. Recent papers show the two first two don't clearly do as much as the third vaccine. So it's the third guy that's really helping people a lot. It really does help. That's great. Thank you. I know there's several other questions, but we are nearing the end of our time, Dr. Berens, and we're going to have to invite you back, your popular speaker. Thank you so much for all of your research and all of the happenings that you're helping, all of the things that you're helping make happen in myeloma. It's really exciting, especially you've been in it so long. Would you say the future is hopeful? I would. Oh, yeah. The survival when I started was 25 months, and hopefully soon it will be 25 years and 50 years. Yeah, I love it. And then the 85 when I started. Wonderful. Thank you so much. All right. Be well. Thank you for having me this afternoon. Yes, thank you. Take care. Bye-bye. All right, Cruz. So next month, we're going to get together to simply connect and get to know each other better. It's going to be a more casual setting, and I'll get that date to you shortly. And then the month after that, we're going to be inviting a speaker to come talk about MRD testing with Clonoseq. So like Dr. Berenson said today, that CRBCMA is not really related to MRD testing, but with all the bone marrow biopsies that you are getting done in order to monitor your non-secretory myeloma right now, let's also talk about MRD testing when it comes to those bone marrow biopsies. Again, that date will be published shortly, and I will let you know. You may be interested in other myeloma crowd community events that we have upcoming. On the 21st is our Plasmacyloquemia chapter, and we're going to be just talking about updates in the PCL field. That's at 1 p.m. Eastern. That same day at 7 p.m. Eastern is the launch of our Amloidosis chapter. We're going to be hearing from Dr. Jeffrey Zander about connecting, educating, empowering a community of amloidosis and just kind of facts about the disease and what the future is like. And then the 23rd at 2 p.m. Eastern is our African American Community chapter. We're going to be taking our fitness routine to the next level with Vanya, who's a fitness expert. The link to sign up for any of those events and even more events that I have not mentioned is found at the bottom of the slide and will be included in the follow-up email that I've been mentioning. Another thank you to our sponsors, Bristol Myers Squibb, GSK, oh hopefully you can see that here, GSK, Genentech, Janssen Oncology, and Avvy. And a big thank you to each of you for helping us build this non-secretary myeloma crowd community. I appreciate you. I hope you have a great rest of your night. Thank you everyone. Take care.