(Guest Lecture) What's Available for Induction Therapy in Multiple Myeloma?

So today's topic is what's available for induction therapy in multiple myeloma. And the reason that we chose that is because in the beginning of your myeloma journey, as you're newly diagnosed and you're all of a sudden faced with this, you have to start therapy right away in some cases, or in other cases, it's caught on a random blood test. So you get to have a little bit of time to check what your induction therapy will look like. So it's been an overwhelming time and thankfully, there's a lot of choices. But we're going to be talking about what the standard of care is for most myeloma patients, how comorbidities affect what the standard of care for induction therapy might be, what does induction therapy look like for people that don't, that opt out of a stem cell transplant or choose or do not qualify for a stem cell transplant. So those are some of the things that we're going to be discussing today. But like I said, feel free to already put your question into the chat or into the Q&A box, excuse me, so that we can get started with your questions and with your questions, you can guide the session and where you want it to go. It is my pleasure to introduce our speaker to you. Dr. Nisha Joseph is an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine. Certified in hematology and medical oncology, she specializes in treating patients with plasma cell disorders such as multiple myeloma and amyloidosis. She is also an active clinical researcher in the fields of multiple myeloma, amyloidosis and bone marrow transplant. Dr. Joseph is a member of the Clinical and Translational Review Committee and the Discovery and Development Therapeutics Research Program at Winship Cancer Institute and serves as a director of morbidity and mortality conferences at the Department of Hematology and Oncology. She co-leads the Winship Summer Scholars Program, which provides high school students with a unique emerging experience in the cancer research laboratory. Dr. Joseph was named the first COREY Fellow in leukemia and bone marrow transplant prior to joining the faculty at Winship Cancer Institute and she holds professional memberships with the American Society of Clinical Oncology and the American Society of Hematology. As you can tell, she's very qualified and we're super excited to have her here today. So Dr. Joseph, thanks for being here. Thank you so much for having me. Good afternoon to everyone who's joining us. Thank you so much for sharing your hour with us. Before we get started, I just want to thank Audrey and thank the organizers for having me. This is such a great organization and program. Like I said, I did prepare slides, but we just wanted to start with Q&A because I really want this to be about you and what you want answered and what is kind of on your mind. And then happy to always transition to some of the things I have prepared to kind of round out our discussion. Perfect. Thank you. Let's start with just discussing the standard of care of induction therapy for a typical multiple myeloma patient. Yeah. So I think I was told, you know, a majority of folks on this call have newly diagnosed myeloma. I know some of the call might be more experienced, but just to kind of review what we mean by induction therapy, it might seem like a random word. Really we're just talking about the initial therapy that we're using in a newly diagnosed myeloma patient. And the goals in my mind when someone walks into my clinic is to make you feel better as quickly as possible. Right. A lot of folks who come through the door are anemic or maybe they have kidney dysfunction or maybe they're having bone pain. And so we want to site a reduce or reduce the amount of myeloma in your body as quickly as possible. Now, in general, there are a couple of things we think about when we're selecting an induction program. So one of the first decision points I think about is transplant eligibility. You know, is this someone that I that I think would benefit from transplant? Is this someone who is interested in moving forward with transplant? And then that I mean, an autologous stem cell transplant? Or is this someone that maybe is not an ideal candidate for transplant for X, Y, and Z reason? We can talk through those things because that really changes our bigger goal with induction therapy. And so that changes what we select in terms of toxicity and intensity. So after I kind of hit that decision point, the next thing is looking at the risk stratification of that patient's myeloma. And so when we talk about risk stratification, there are multiple risk stratification models in myeloma, something called the revised ISS staging system, and then a given second revision of that staging system. But in general, what I look at is disease presentation and cytogenetic risk factor. So when we do your bone marrow biopsy, we get a biopsy of a plasma cytoma in your body. One of the tests that we run is looking at the genetic changes that turned that normal plasma cell into a myeloma cell. So people often when we say there were genetics, I think that can confuse people and they think, is this something that I inherited or that my kids are at risk for? That is not what we mean. These are not germline mutations. We're talking about the mutation in the cell itself that made it a cancer cell. And so what we know when we look at those mutations is some of those mutations make a smarter, more savvy myeloma cell than others. And so broadly, we can kind of dump folks into what we say standard risk and higher risk, right, or a more smarter, savvier myeloma. And so that changes how we approach that that person's treatment, because what we have learned is those two groups of patients don't respond the same to the same therapy. And so a standard risk patient might respond really well to one therapy. But a high risk patient would not derive the same benefit. So that's kind of the second thing I look like look at. So in general, we're talking about a newly diagnosed myeloma with standard risk myeloma. The standard of care, in my opinion, is a quadruplet regimen or a quad with deratumumab, which is a monoclonal anti-CV38 antibody, and then a regimen called RVD, lenalidomide, or tesimab and dexamethasone, which I think are probably drugs that you're all familiar with. And then high risk, we know that high risk patients particularly respond well to a drug called carptalzimab, which is kind of the more potent intravenous version of bortezimab. They're both the same class of drugs. Bortezimab is also delicated to the V and RVD. And so KRD, I think, is an appropriate regimen. And then newer data from the master trial and other trials have shown really good efficacy of using a quad also in high risk of taking deratumumab again and then combining with KRD in high risk patients. And those would be those those regimens are generally for what I reserve for transplant eligible patients. Great, thank you. And very well said. Let's talk about what could make somebody ineligible for a stem cell transplant and then what the induction therapy would look like for that patient. Yeah, so I think the thing you have to understand about myeloma when you approach it is that unfortunately, though we are working on it, you know, it's not a curable disease, but we can really turn it into a chronic disease. And I'm in the camp that I think an upfront transplant can really aid us in our goal of getting folks as close to their normal lifespan as possible. Having said that, there are risks to transplant and there are toxicities with transplant. And because transplant is not curative in my mind, I need to be very certain that that patient can get through transplant safely. And so there are just certain criteria that we look at in general to determine someone's transplant eligibility. Now, age, in my mind, is not really a factor for the most part outside of over seventy seven, seventy eight getting into your 80s. I don't want to transplant folks at that age. But in general, it's not about age, it's about performance status. And if you remember, the average age of diagnosis of a myeloma patient is 67 to 70. OK, so I've had folks come to my office and say, well, I'm 70. You can possibly want to do this to me. Almost everyone is 70. Right. So if you if you're functional, meaning you can go outside, you can walk a mile, you can climb a flight of stairs, you're an active person, you have limited comorbidities. So, you know, hypertension is OK. Hyperlipidemia is OK. Dialysis is OK. Right. A good number of patients, unfortunately, end up on dialysis, hopefully for a short period of time. But if someone is older or frailer or has a health condition that maybe makes it very hard for them to move around, maybe they're they're mostly seated most of the day. Maybe they have chronic conditions that they're taking a lot of medications for. They have very bad heart failure, you know, other on immune conditions where they're on high doses of other immune suppression that would make it concerning for me to take them to transplant. Those might be reasons that we say, well, maybe transplant is not a good idea. And of course, for patients who are frail over 75 in their 80s, certainly 90s, those are folks that I routinely manage with medical therapy alone. And then, of course, there's always the patient who says, you know, this isn't a good time. I can't do transplant right now. I have three children. I work full time. And so those are those are all important things that you have to have a discussion around. Definitely. Thank you. A lot of great questions already. And I remind the audience, if you'd like to submit your question now, we'd love to hear from you. So Terry saying that they're having a lot of trouble with the steroid. Have you seen people treated without steroids because they're currently lowering the dose? Yeah, that's a great question. So I think steroids can be really hard to take. I think in myeloma, the time when they're needed the most is new diagnosis. So steroids can be very effective in myeloma, though their efficacy or how effective they are, weens with time. So, for example, someone on maintenance therapy or on a relapse regimen for years and years, I don't push the steroids forever, maybe past eight to ten months because the toxicity then outweighs the benefit. However, they're very helpful up front because they're very good at killing myeloma cells. And so we try to use steroids up front. Now, having said that, if you're having a very hard time, then dose adjustment is appropriate. So I think the things that you have to take into account, I think we're going to talk about comorbidities. For example, if you have diabetes, that might not be someone who I start at full dose dexamethasone once or twice a week. That might be somewhere where I start lower to begin with. If you're having I'm not sure what symptoms you're having, but a lot of people complain of insomnia, irritability, mood swings, increased appetite, things like that. I've had a lot of folks, particularly older folks who have trouble with insomnia. And so in general, over 75, I tend to drop that dose of steroid anyway to begin with. So I think the answer to your question is I definitely have myeloma patients off steroids. They tend not to be newly diagnosed folks, but I think every patient is different. So, you know, if you can't tolerate it, you're having X, Y and Z problem, then what I would say is I agree with the dose reduction, see how you feel with that. But if that doesn't, you know, rectify the problem and then continue to have discussions with your docs. Definitely. Thank you. They commented that anxiety, very high anxiety was accompanied with the steroids. I see. Yeah. So a couple questions here of how do you define newly diagnosed up until what point do you consider a patient newly diagnosed? And this is kind of a difficult question. That's an interesting question. I would consider newly diagnosed patients not having treatment yet. OK. For the most part, I'm trying to think through other scenarios. Yeah, a newly diagnosed patient will be someone on first line therapy or has not been started on therapy yet. OK. And can you explain lines of therapy for people that might not understand that term? Yeah, sure. So we count lines of therapy in myeloma for many reasons, and one of which is to help us figure out what you're eligible for, because some treatments are approved for folks who have moved through lines. And essentially, it's just a treatment regimen. Now, the only caveat to that is for newly diagnosed myeloma. If you have a transplant, the whole transplant piece ends up being one line, meaning induction therapy, transplant and maintenance, which we routinely put folks on maintenance therapy post transplant is one line. And then if and when your myeloma starts to relapse and then we put you on a different line of therapy, that would be your second line. So every time we switch therapy, that's the next line of therapy. Awesome. Thank you. There have been a couple comments about people who have harvested their stem cell transplant, I mean, their stem cells, excuse me, or want to harvest their stem cells, but aren't sure about the transplant. Do you recommend that all patients harvest? That's a great question. I, I think, so in general, if you are transplant eligible, I think depending on, let me put it this way, if you're transplant eligible, but the reason for not going to transplant is something reversible or has to do with your situation, meaning you had a compression fracture, and you're in a wheelchair, but you had a kyphilplasty, which is procedure that fixes that and you're starting to get strong again, but you're just not ready right now. But your doc thinks, yeah, maybe in six months with some physical therapy, or maybe, maybe down the road in a year or several years when you relapse, you'll still be young enough and healthy enough and you'll be in a better shape for transplant. That is someone I'd absolutely collect on store, right? Because I think transplant is a really potent, effective tool in newly diagnosed myeloma, but sometimes the situation isn't right. And so having that kind of backup plan. And I think for select folks collecting and storing and transplanting at relapse, first relapse is appropriate, honestly, it is appropriate for select group of patients. So I think, I think if it's something reversible like that, then yes, I think if someone is kind of maybe 75, 76, and has a lot of, it depends on the reason that they're not going to transplant, it might not make sense, you know, to collect yourselves in case you might need them five years down the road, because it's unlikely, I think that you would get a transplant. But in general, I think someone in their 60s or early 70s who thinks that they might get a transplant at first relapse, I would 100% collect and store your samples. I think it's like having insurance policy in the bank. Awesome. Thank you. You discussed Carfilzomab or Kyprolis as being used for those patients who are at higher risk. What about ultra high risk when they have double hit or triple hit? And can you explain what double hit and triple hit means? Yeah, that's a great question. So when we when people talk about double hit and triple hit, they're talking about the number of high risk mutations that you have in your mind. In general, we we put folks with one or more high risk features and kind of a high risk bubble, you know, versus standard risk. However, the master trial that I alluded to earlier, specifically looked at folks and birth stratified patients with high risk disease based on the number of high risk cytogenetic features they had. And, you know, I think though this is evolving in newer data, I think those for ultra high with ultra high risk cytogenetics, I think Dara personally, I think Dara KRD makes a lot of sense as an induction regimen. And I would I would particularly recommend a transplant for those patients. You know, at this time, things are evolving. But that's what I would do if you walked into my clinic now, I would recommend Dara KRD induction, a transplant. And then we usually for high risk patients outside of the scope of this talk for maintenance therapy, I would not use a single agent maintenance regimen, meaning for standard risk folks post transplant, standard care is Reblemit, which is that pill that many of you have had before that you take for two to three weeks on and then take a week off. In general, we use that as maintenance post transplant. What we know is people with high risk cytogenetic features one or more, they relapse sooner than standard risk folks, if you put them on Reblemit alone. And so we tend to do triplets in that setting. So something like RVD or KRD. And so for an ultra high risk patient, I might consider Dara KRD transplant and KRD maintenance, we tend to do KRD for a limited duration, I think every center is a little bit different. We tend to I tend to do that for three years. And if someone can, if the patient remains in a deep remission, I sometimes downgrade the maintenance regimen at that point. And also, I think another evolving area in myeloma is using something called MRD to define how we treat patients. So MRD is basically it tends for minimal residual disease. And it's most sensitive tests we have on your bone marrow for detecting even one myeloma solid of a million cells in your bone marrow. And so what we're learning is we can use MRD to determine who really needs to stay on triplet or continuous therapy and who maybe can come off. Because I think one of the good problems to have is myeloma patients are living longer and longer. But we tend as myeloma doctors to throw more and more drugs at you, which I know has a toxicity cost and an actual cost. And and so we need to think more carefully about who really needs all of this therapy, because not everybody does. You know, but but in general, that's how I would approach someone with ultra high risk. Very well said. Thank you. Along the lines of maybe outside the scope of this talk, but I think still related. What is the difference between induction and consolidation therapy? Yeah, it's a good. That's a great question. So induction therapy is what we use. It's essentially we're trying to induce a response. It's the first therapy that you get to start killing off those myeloma cells. Consolidation and general that's a word used across oncology as is induction. Consolidation you can kind of think is coming behind initial therapy to really drive that response home. And so the majority of times you're going to see the word consolidation used after induction therapy. So for example, I don't do this routinely, but it's done in clinical trials, you'll get an induction regimen. So let's say you get their RVD, then you get transplant. And then before you go to a maintenance regimen, so single agent relevant, they might give you two more consolidative cycles of their RVD. So slightly more intensive therapy to really make sure you have a good response before downgrading to the single agent drug. Does that make sense? I said that? Yeah, I think so. Okay. And also to the audience next, next session, which is going to be early March, we're going to be dedicating a whole session to consolidation therapy. So good questions and more more on the way. Let's switch back to steroids again, since people are curious and have a couple more questions Do you see a reduction in side effects, specifically anxiety levels, but also different side effects when changing from dexamethasone to methyl prednisolone? You know, I don't use a lot of methyl pred in the clinic more in the inpatient unit. I mean, I think in general steroids are steroids. If you if you have anxiety with one, you'll probably have anxiety with the other. But I think it's more about the dose and your own body sensitivity to that to that drug. So I haven't I haven't per se tried that specifically for anxiety. So maybe if that was recommended, maybe there's an experience there. But I think in general, it's probably more about dose reduction. And it might be about frequency, you know, some regimens do dex two days in a row, or some regimens do dex on Monday and Thursday, and maybe you're someone who has a lot of anxiety, but you know, you're getting dex on Monday and Thursday, and maybe you're someone who really should be getting dex once a week, or smaller doses spread out or something like that. I wonder if frequency and dose might help you more than than changing the classes, the type of steroids you're getting. Good point. Thank you. Steve's wondering if you've ever seen patients experience withdrawal symptoms when the steroids are reduced or stopped? Yeah, yeah, I have your body becomes dependent on steroids. So we make endogenous steroids, meaning we make steroids to keep our body running, we all need steroids. And so when you're chronically getting steroids, your body makes less, because it's smart, you can sense that it already has what it needs. I usually don't see it. Since we're talking about induction, I just want to be fully clear induction is on a super long period of time. So I usually don't see terrible induction, but sometimes in maintenance, or sometimes particularly at diagnosis, people are getting a lot of steroids to help with their pain, or, you know, or to maybe buy time before they start treatment. And so, you know, they've been getting chronically a lot of steroids. So you have to be really careful. You can't just stop steroids, you know, you need to make sure that you're weeding them or on the flip side, if you're someone who's had myeloma a long time, and have been on steroids for years and years, again, you need to be careful about, you know, the word is taper, you always want to taper it off, because you're giving your body a chance to recognize, oh, that that steroid dose drop, I'm going to make a little bit more, a little bit more. But if you shut it off right away, you're going to feel it. And what would those symptoms look like? Usually people crash. So they feel very tired. They have no energy. There might be some mood mood swing associations with that. Yeah, but it's usually just wonderful. Thanks. Terry's wondering if plasma cell leukemia is always considered high risk. Now, that's a great question. Unfortunately, yes. So myeloma cell is a plasma cell that's mutated. The plasma cells live in your bone marrow, which is the space within your bones, your blood factory, or all your blood cells are born. And plasma cells basically have a homing device, or like a piece of tape, and they're supposed to stick in the bone marrow, they're supposed to be stuck there. And so when a plasma cell mutates to myeloma cell, and then that myeloma cell has learned to escape the bone marrow, you're by definition talking about a smarter myeloma, because they're not supposed to be able to do that. And so in a majority of cases, you're going to see high risk mutations anyways, classifying that person as a high risk. But we always treat those folks more aggressively. Now, the good news is plasma cell leukemia patients are doing better and better with more of our novel treatments. And so I've certainly had plasma cell leukemia patients that we've used some carcalsimabin, I think for, you know, to induce them. But I think for most patients, they might need a little bit of chemotherapy in the hospital to at least start that reduction, and then hopefully transition them to a carcalsimab based regimen. Plasma cell leukemia, just to be clear, has two presentations. So one is called primary plasma cell leukemia, which means that that is how your myeloma presents. So at diagnosis, you already and just to define what plasma cell leukemia is, that means that if you look at your peripheral blood, your blood sample, 20% of your white blood cells are myeloma cells. And myeloma cells should not be in your peripheral blood. And so if you present with plasma cell leukemia, that's primary plasma cell leukemia, the other presentation that can happen is called secondary plasma cell leukemia, which means it happens later in relapse. So you're diagnosed with myeloma, and later down the road, as you accumulate more mutations, which can happen, the more and more you're treated, you might present a one relapse with plasma cell leukemia. So that's a different thing. Now, in general, if you have multiple relapses, that's a high risk myeloma by disease biology, regardless. But for folks who are presenting with plasma cell leukemia, that is a more high risk presentation. And so, you know, what I say is, your myeloma is aggressive, so we have to be aggressive back. Right, high risk doesn't mean, I don't want you to feel despair about high risk, it just it's good to know so that we can treat it appropriately. We don't want to under treat you. Yeah. And something that you and I were talking about at the beginning of the session is just the miracle of how far we've come in so little time. That, you know, if we were having this discussion, 10, even five years ago, you know, we weren't as successful. What we I say we you, it the the regimens were not as successful as they are now. And just these novel agents that have come out have been such a blessing to targeting this high risk multiple myeloma. Absolutely. I think in general, if you ever I have a slide, if we have time, I'll show you if you look just at the the rate of drugs being developed in myeloma, it was very flat until maybe 10 years ago, and it just has taken off. And I think for those of you, I'm sure you all are very knowledgeable, because you come to these seminars, if you're following the approvals that we've had in myeloma, I mean, every year, we're having an approval now. We just had an approval in October, and there's many to come, I promise you. So, you know, it's an exciting time, you know, if you have to be diagnosed with myeloma, it's an exciting time, because there are a lot. There's a lot of progress. And I think there's a lot of reasons to be optimistic. Yeah, thank you. So let's jump back into maintenance. I know we're talking about induction, but lots of questions. This question is about maintenance. What are your recommendations for a typical standard risk myeloma patient when it comes to maintenance? And then what's the difference? Why is sometimes a monoclonal antibody used versus? Yeah. Okay, so a couple questions within this question. So let me just take it in general. So for so what are your recommendations for maintenance? So, in general, I'm talking about transplant, if you'd like me to talk about no transplant, I can, though it's not that dissimilar. For standard risk, we do Revlimid maintenance. Now, Revlimid is the most studied maintenance regimen. It continually is shown to be effective continuous Revlimid maintenance. The recent determination trial is one example. You know, I have, there's actually an ongoing trial, and the Griffin trial has looked at DERA in combination with Revlimid. In general, you know, single agent, which I think is a good option. A single agent DERA isn't standard of care. Having said that, I have done that for select patients that cannot tolerate IMIDS. IMIDS are Revlimid and pomalidomide and cannot tolerate proteasome inhibitors, so Velcade or Exazomib or Carclosamide. And so I have done that in a handful of folks. But I try not to because I know how Revlimid acts as maintenance better. We know more about it. I have a lot of folks on Revlimid who have concerns about it. And if you want to share your concerns, we can talk about that. A lot of folks complain of fatigue. A lot of folks complain of GI things. A lot of folks just don't feel well on it. They're tired of getting infections. They just don't feel like themselves. And then I think there's a certain part of folks who are sick of taking something. You know, they've had so much therapy for so long. One thing I will say again, to go back to MRD, is that an evolving field, like I said, is how long people really need to be on maintenance therapy. So not everyone needs to be on maintenance therapy forever, right, which used to kind of be the standard. And so we're in our practice, starting to look at and we have studied looking at sustained MRD negativity, meaning people who are MRD negative up their annual resaging several years in a row, can those folks come off of Revlimid? And I have done that. And I think for a select group of folks, and then I think also just being really honest with your doc and talking, you know, these are things I cannot tolerate. And these are this is what I'm experiencing. And I have I have done dose reductions, we have done different types of dosing schedules, you know, there's what the FDA recommends how the drugs approved, and then there's the reality of the world. And so I think that's kind of the art of medicine is working with your doctor to figure out is there a schedule maybe that that would work for you. And then I think the second part of your question, if a patient is in remission, when do you think the patient should change to maintenance instead of continuing treatment? Or should the treatment last at least one year even with remission? So I'm assuming you mean here someone who was not planning to go to transplant. And so there's a couple different ways to do this. The regimens that I use for transplant ineligible patients or patients who are not going to transplant in general, tend to be DERRAREV-DEX, which was studied in the Maya trial, specifically for older patients. And then the other one is RVD-LITE, which is RVD, but on a 28 day cycle, and the doses of those drugs are reduced. So DERRAREV-DEX, the way it was studied was to continue until progression. And so what I tend to do is I do DERRAREV, and then around, like I said, eight to 10 months, I start to taper off the decks and I continue people on DERRAREV. I've had folks who don't want to do DERRA that long. And so we've done DERRAREV-DEX for eight to 10 cycles there, and then transition to maintenance. When RVD-LITE was studied, what they did was nine cycles. And if the patient has achieved at least a BGPR, which means a 90% reduction, and the amount of myeloma they had there, we can move on to rev maintenance. And so that's what I have done, kind of extrapolated that for folks who are not comfortable staying on triplets. So doing a triplet until we have a BGPR, really ideally a CR, you know, somewhere around eight to nine cycles. And if we've achieved that depth of response, we go to maintenance. If you do not have a good response, I'd be really hesitant to downgrade the amount of therapy you're getting, right? So if you're on DERRAREV or RVD, or whatever you're on for eight cycles, and you've had a 50% reduction, in my mind, it's not a good idea to stop at that time. So, you know, I think in terms of your a year, it really depends more. I'm sorry, BGPR is very good partial responses, which means a 90% reduction in the amount of myeloma we can measure in your body. So the year thing, I mean, I think, yeah, roughly a year, you know, I don't know if there's a magic number, if the response is appropriate, it can be the caveat in mind. Awesome. Thank you. And we will also have another session on maintenance therapy. I know lots of you have questions now, which is fine. But I just wanted to let you guys know that that is also on our agenda for this year. Let's see. So this question is how close are we to practice changing how close I think the question is how close are we to taking stem cell transplant as out of the standard of care? Yeah, I think this very much depends on who you're talking to. And I don't know if you have a transplant session, who's leading that one. But, you know, I think it's probably in my lifetime, I don't think that we are there yet. And I think and I say that because there has been recent data that has been touted a little bit as we don't need transplant. And I just think there are a lot of caveats in the in the study that that has led to that conclusion. One of which we don't have enough follow up on that study. So there was a study called the determination trial, which essentially was looking at the role of transplant. But patients with myeloma do so well that you have to wait a very long time to see separation of curves, in my opinion. So I still think that that transplant is standard of care, particularly for high risk patients. And I still recommend it upfront, because, you know, even I, like I said, I think delaying deferring a transplant, I have that discussion with folks who are not comfortable going upfront. But the caveat to that, that I always say is you're the youngest you're ever going to be right now. And your myeloma is the most sensitive, it's ever going to be right now. So we can control the situation. I know you can get your transplant. And I know that your myeloma will respond or is more likely to respond now. And so that's why I recommended upfront, you know, having said that we're doing a lot more trials using CAR T using by specifics earlier, we're doing a lot of innovative trials that hopefully will be out soon looking at how we sequence therapies. So can we use a lot of these new immune therapies back to back to kind of attack that myeloma not give it a break, and really move towards a functional cure. And so I think it's probably naive to think that I'll be transplanted the rest of my career. It's that's probably not true. But I don't have the time for you yet, because I still think we're we're aways from that. Yeah, it's a great question. I don't want my smile to come off as disregarding the question. I think it was an excellent question. It just is, is the most diverse and we get the most diverse answers to that question. There's camps for sure. Yeah, yeah. So that's that's the only reason. I don't mean to offend, but that's the only reason why. When we get that question, it's always going to be a different answer. So getting multiple opinions on this, absolutely, is super important. And I appreciate what you said, Dr. Joseph, I think you explained it quite well. So Bob is wondering about maintenance for high risk smoldering myeloma. And even though this is for newly diagnosed active myeloma, I think this is an important I think it's important to bring up because as myeloma research is evolving and we're trying to figure out where do these high risk smoldering myeloma patients actually belong? Let's talk about if you don't mind, what constitutes a high risk smoldering patient, and then go on to what treatment regimen or maintenance might look for them. Well, first, I just want to thank Bob for this question. I love smoldering myeloma. It's one of my particular areas of interest. So thanks for asking so small during myeloma, for those of you don't know is essentially pre myeloma. So there are two kind of buckets of pre myeloma, MGUS, smoldering myeloma and then myeloma, I kind of think of it as a spectrum, you can kind of move from one over here to myeloma. Now having MGUS doesn't necessarily mean you had myeloma, will get myeloma. Having myeloma means that you were in those stages at some point, whether we diagnosed it or not. So how small during myeloma is defined is when we do a bone marrow biopsy, we see 10 to 60% of the marrow filled with those abnormal cells. Or when we check your blood work, you have a certain degree of that M spike that abnormal para protein. But we do not see any crab criteria, right? So those are those myeloma defining events, hypercalcemia or high calcium levels, kidney dysfunction, anemia, bone lesions. And then there are a few three other criteria that we we use tumor burden essentially. So if you have over 60%, that's myeloma in the marrow. If you have a high free light chain ratio, that's myeloma. Or if you have early bone disease on imaging, that's myeloma. But so in general, test molding, you can't have any of those criteria, but you have a significant amount of myeloma in your bone marrow in your blood. So the way we restratify, there are there are in my two risk ratification models that I use the most one is called the Mayo 2018 model or the 2220 model. And it uses three risk factors. So one is are your bone marrow plasma cells over 20% is your M spike over two, and is your free light chain ratio over 20. If you have zero of those factors, you're low risk. If you have two, one of those factors, your intermediate risk, if you have two or three, you're high risk. And that low intermediate and high risk correspond roughly with an average time to progression of two and a half. Wait, yeah, four and a half, six and a half and nine years, excuse me. So for historically the standard of care for smoldering myeloma was observation, because the concern was that therapies we have are too toxic, you know, in someone who's otherwise asymptomatic. And we don't really know what this will do ultimately to the disease biology. And it's very hard for us to identify who really would benefit from treatment because this is predating some of the better risk ratification models we have because not every smoldering myeloma patient needs to be treated. Some of those folks behave more like an MGUS, for example, that they don't need to be treated. So in general for high risk, how I approach high risk, there have been two large randomized space three studies looking at giving Revlimid essentially, with or without decks, one uses steroids, one didn't, versus observation, and it showed a significant benefit in patients who were treated with Revlimid and or decks. There are ongoing trials that are looking more at more aggressive treatment strategies. So essentially treating smoldering as if it was myeloma. So this was for those of you who follow our annual meetings, two of those studies were presented at ASH last month, the ASSENT study and the GEMCDR study. For me, if a high risk smoldering patient comes into my clinic, now you asked about maintenance. So I wonder if you're if you were someone who was treated more aggressively. We at Emory are a little bit more in the limited duration less aggressive approach, meaning something like Revlimid for two years more fixed duration therapy for smoldering myeloma. And so that's what those trials showed that patients can benefit from less intensive fixed duration therapy. So for a high risk smoldering myeloma patient, I would talk to that person about Revlimid for two years off study, and then I would stop or not continue past that point. Or I would talk about a clinical trial. There are a lot of clinical trials across the country. We have two available at Emory that I'm happy to speak about if that's of interest. And there are a lot of different ones throughout both of ours are less intensive fixed duration approach. And after that duration of therapy, I would not treat further, I would watch that patient the way I watched them before I treated them with labs. And, you know, some people have issue with saying, well, you treated me and now we're just going to wait against the progression. I think we're not really yet at the point of knowing if those folks should be retreated. Right. So that's kind of, that's kind of the next step. You know, perhaps in research, we treat you, we debulk you a little bit. Now, what happens if you get back to that same point? Do we just let it ride? Or do we try to intervene again? You know, that I don't have an evidence based answer for you yet. A lot of the interventional or sorry, more aggressive clinical trials, even though more aggressive, they also are fixed duration. So in general, I wouldn't recommend maintenance. I'd recommend if you want intervention, I'd recommend limited duration therapy, and then close observation. Awesome. Thank you so much. All right. The question here is, is soft tissue involvement always considered high risk? And would the standard of care be the same as what you've discussed? So soft tissue involvement is sometimes, it depends on what that is. So sometimes people, the radiologists will read a plasma cytoma as a soft tissue mass. So so if you had a bone lesion that for example, started in your rib, and then it grew out of your rib, they're going to read that as a soft tissue mass, because it's going to just look like a ball of myeloma sticking out of your rib. And so that by definition, and I just want to make sure I'm answering your question, that is not by definition high risk. So bone lesions can grow out and look like tumors. And that is not necessarily high risk without other high risk features. So for example, sometimes, you know, people say I have myeloma in my brain, it's not a brain lesion, those aren't overly common. It's a lesion that started in the skull that grew inwards. So it's not necessarily just because I know radiologists read it that way. That's not high risk. If you have extramedulary myeloma, meaning myeloma arising outside of the bone, that I treat as high risk. So for example, if you have a lung mass, that is biopsied and that's a plasma cytoma, so there's no bone, it's in your lung tissue. Or if you have liver, I had a woman who had multiple liver masses, they thought was liver cancer, but ended up being myeloma, that's high risk. So those soft tissue masses I do treat as high risk. And then I would put that again, in that same high risk category and consider a carpe dylosomal based regimen. So something like KRD, or now even DeraKRD. Awesome. Thank you so much. We talked a little bit about MRD. Can it be used? Can it be tested using blood versus bone marrow? You guys are asking great questions. Great question. That is, we're working on that. That's kind of the goal, working on that. Because of course, the challenge with MRD is nobody likes bone marrow as I get it. Yeah, Kelly, you and everyone else has that question. Yeah, we're working on it. It's a very good question. Yeah. Steve's wondering if you could share any research going on at Emory trying to find out why African American or Black patients have twice the rate of multiple myeloma than white. Yeah, thank you, Steve, for that question. I think, you know, one of the, if I may say so myself, unique things about Emory and one of the advantages of working there is our patient population is reflective of our city and state. And so we have some of the largest enrollment of people of African descent on clinical trials of most centers across the country. And that's reflective of who we get to see at our center. And so, you know, I think when you say you're doing research, the research is to get African Americans onto clinical trials and to be participating in research, which we know is a problem across the country. There's there tends to be a lower rate of enrollment. And so that really, I think, is what we're doing in general. Now, to specifically answer your question, we do have clinical trials specifically enriched for African Americans, meaning we're trying to enroll more African Americans on those trials to see how African Americans specifically respond to those treatments. So we have a trial looking at a drug called Venetoclax, and we're enriching for African Americans, meaning for every one person who's not African American, we try to enroll two that are because we're specifically looking at that patient population and how they respond to this drug because of a higher frequency of a certain genetic change that responds well to the drug Venetoclax. So we are doing research like that. And in general, we're just trying to do research in general on black patients and make sure that they're being represented in all these trials that are that are being presented in national meetings. It's not helpful data if it's not representative of the people that we're treating, right? If everyone on the trial is white, that's not helpful, because that's not what our country looks like. Thank you very much. This is a great question that just came in our participants in clinical trials ever given placebos that may delay other treatments. Oh, sorry, I see it. I've given placebos. There, there are trials like that. But you're not going to see that in relapse refractory trials, because that's unethical. So and that tends to be in in a randomized study. So not an early phase study like a phase one or two. I'm trying to think of an example. So for example, the smoldering myeloma study I told you about patients were on observation, so not necessarily placebo, but they weren't getting treatment, but you're not going to find a trial for newly diagnosed myeloma, where the arm is placebo, right? That's never no one would ever do that trial, which is getting a trial like that, because that's unethical and ridiculous. So for the most part, in in myeloma, you're not going to be getting placebo, there might be an arm that doesn't, you know, there might be three drugs versus two drugs. So you might be randomized to an arm that could potentially be less effective, for example, but maybe less toxic. But you know, that's really our job as investigators to make sure that we're designing trials that make sense. And that's why regulatory bodies are in place to make sure that the trials that are approved that we bring to you are still at the best interest of everyone involved. Yeah, the only other thing I'll add to that is, I saw a maintenance therapy trial from quite a while ago in Europe that had a placebo as the maintenance therapy. But as you said, it's no, there's select places that can happen. And so maintenance would also make sense, right? Because, because the person's disease is under control, for example. But I think in general, you know, we don't have a lot of placebo trials. Yeah, thank you. Okay, so great question. Still coming in. I appreciate all of you. Patty is wondering if a patient doesn't know they have smoldering and go right from feeling great to deteriorating within two months to multiple fractures and feeling terrible. Is that unusual? Unfortunately, sorry. Yeah, you you answered. I agree. Unfortunately, no, that's not unusual. I mean, we see that all the time. And that's the frustrating part, I think, is we see so many people present with multiple myeloma, active multiple myeloma that had no idea they had mGus or smoldering and experienced these horrible crushed vertebrae and spine fractures and everything else. So I don't know if you have anything to add, but I'm glad that the answer is it. Yeah, I mean, I think so. So what is happening is myeloma will do this, right? I'm guessing smoldering will do this until one day it does that. And so one day it's going to take off. So that unfortunately, that's majority of the folks, you know, the new majority of the new patients I see are not smoldering myeloma, they're myeloma. And that's how they presented the challenge with mGus and smoldering is it's asymptomatic. So it's very, you know, for a lot of folks, it's not picked up until you're symptomatic. And once you're symptomatic, you have myeloma. And so, you know, we don't really have mechanisms in place or guidelines where it makes sense to screen the entire population. But for most folks who when we can catch it and smolder mGus, it's because you had a really astute primary care physician, or someone who noticed that the total protein in your blood is a little higher than it should be. Or a lot of times it's it's luck. So you see a kidney doctor because you have high blood pressure and your kidney functions a lot normal, and they just send off the panel labs and one of them is at SPAC. And we and we find it, right. So I'm sorry, I hope that happened to you. If that did happen to you, I'm sorry that happened to you. But you're not alone in that. That's very, very common. Yeah. And luckily, lots of people once they start receiving treatment, actually find a reduction of side effects, because the myeloma is becoming less and less. So hopefully that is the case for you as well. Okay. You know what, Dr. Joseph, I'm going to let you decide which questions you want to answer as we finish up. Okay, sure. I'll try to get to everybody. Okay. I'm going to read them out loud for the people that are watching. Yeah, sure. I'll just start I'll just go from top to bottom and try to get through you. So Bob was asking a regimen for a healthy patient who refuses transplant. So for standard risk. What I tend to do is, there's a couple ways to approach this. And this depends on your fitness. I think if you're I'm going to assume you're a fit, healthy person, I might induce you with DERA RVD, but do a limited duration four to six cycles to get a deep response. I would at least talk to you about harvesting your stem cells. And then what regardless of your decision there, if you've had a good response to DERA RVD, which is likely most people do, I would switch you to Revlimid maintenance. I think DERA Revdex also just as a regimen with tapering the decks off and continue on DERA Rev is is also reasonable. I mentioned RVD Lite for transplant eligible. That's really for folks who cannot tolerate transplant. And so if you're if you're fit, and it's not about that, then that might not be the best regimen. So I think something more intensive initially to get a good response and then to go on maintenance would make sense. The next question is, is maintenance therapy once a month? It depends on what you're on. But for the most part, no. So the only drug that's given once a month after six months is deratumumab. That's not routine maintenance. So in general, for example, if you're giving Revlimid, that's every day for three weeks with a week off on a four week cycle. The benefit of that is that's an oral drug. So that's not something you're coming into the clinic all the time for. And first, many of my folks who are a couple years out from transplant, I see them quarterly. So I see them every three months. I make sure their labs are okay, make sure they feel okay. And so I think that's a huge relief. You know, I mean, I think that's pretty remarkable if you put it in perspective, someone who's living with cancer is just seeing their doc pretty much for a social visit four times a year. There's a question about smoldering myeloma. So the question is, I have high risk smoldering, I'm in cycle 21 of 24 cycles. And I would agree with that. That's based off of the ECOG study. I now know why my doctor is vague about treatment beyond the 24 cycle. Yeah, I would hold after that and observe you. I get confused about references to standard and high risk myeloma. Do the latter terms refer to solely to active myeloma? So it's just kind of two different things. So once you have myeloma, we do classify you there's a staging system. But in general, we say standard risk versus high risk for smoldering myeloma, there's also low intermediate and high risk. So I know that's confusing. But for each diagnosis, we risk stratify. Because there's just such heterogeneity, meaning of just a lot of different presentations of these diagnoses. And so one shoe doesn't fit everybody. Do trials ever include people with plasma cell leukemia? Unfortunately, for a lot of trials exclude folks with plasma cell leukemia, which is really challenging. Yeah. Is generic rebel mid as effective as rebel mid? Yep, I wish it was cheaper. In MRD after transplant, how long is bone strengthening drug recommended? So this is another area probably where you're going to get different answers. I tend to do Zometa or XGV. I do more Zometa unless you have kidney dysfunction. I do it monthly for the first year post transplant, and then I go to quarterly for two more years. There are some data. So three years, there is some data about five years, I think that's older data, in my opinion. And then there's also some data that you have a deep response, you don't need bone strengthening as much. But I tend to err on over treating you just a little bit and making sure you're in a good place before I pull things back. So I tend to do it for about two to three years post transplant. As long as the person doesn't have dental issues, you know, Zometa and bisphalocinates have a risk of osteonecrosis of the jaw or an infection of your jawbone. And so if there's any risk of that, I don't push, I don't push that drug for too long. What percent of standard risk smoldering patients stay smoldering and not progressed to my moment. So it depends on the bucket that you're on. I wish I had a graph that I wanted to show you. But we tend to think of, again, low intermediate, high risk, the high risk folks are going to progress in the first three to four years, then you're going to have a bucket of folks who progress in four to seven years. And then you're going to have folks who really are behaving more like MGUS. So that's about a 1% per year. So it depends more on where you fit in that bucket than me being able to tell you the percentage. So it just really depends more on your personal type of smoldering myeloma than I you know, than your doctor could give you statistics on your likelihood. So I mean, I think the take home from the smoldering discussion is if you have low risk smoldering myeloma, I would not intervene on that. I would not treat that. And that is about observation. For the most part outside of the clinical trial, the same goes for intermediate risk, we have a trial at Emory, that is open to intermediate risk smoldering. And so I at least have that discussion. But I would not treat intermediate risk off study. And then for high risk, because of this data from the ECOG E3A06 study and the Spanish myeloma group study, I think it makes sense to do fixed duration revlimid. The only other caveat I'll make about fixed duration revlimid, the longer you're on revlimid, the more challenging it can be to collect stem cells. And theoretically, if you were treated for two years, and maybe off for many years, it might be okay. But in general, the way that the trials were designed and what I try to do in clinical practice is after four to six months of revlimid, I do I do recommend collecting your stem cells because you never know. And you don't want to be in a position where you were on revlimid for a long period of time. And then you progress down the road and you don't have that option in case we're still using it, which goes back to an earlier question. So I do do that routinely. For we're gonna have to invite you back. We have a mguz smoldering chapter and we'll have to have your expertise there. Um, one last question before we finish up. Yeah, a little bit about comorbidities. How does having kidney involvement affect how you approach induction therapy? Yeah, I think kidney involvement is very common in myeloma. I think the good news is for a good portion of patients that kidney damage is reversible. The key is to get in there quickly. And so the main challenge and folks with kidney disease, particularly that's reversible or acute, is that revlimid is not always the best drug. And we can't really dose it at high levels when you're in kidney failure. It's also challenging to get in the hospital where a lot of people tend to be. And so I for newly diagnosed folks who I'm being aggressive with, I hold the revlimid and I treat them with Dera Valcade and X, for example, for a cycle or two until their kidney function improves. And if I'm able to add back revlimid, I do. For dialysis patients, you can really dialyze, really dose revlimid. For dialysis patients, I think it's appropriate. I avoid carfilzomib in patients with an acute kidney injury. Chronic is a little bit different. So it really is just about the drug selection and making sure that you're a lot of drugs are excreted by your kidneys. You just want to make sure that you're using appropriate drugs. But I think the good news in myeloma is if you are able to get in there quickly, hopefully that's a temporary problem. Yeah, thank you very much. Is there any other closing statements you have for the group before we go today? Well, I just want to thank everyone. That was I did not expect that many questions. So I'm really pleased and happy. I hope this was helpful. Again, I'm really happy to be a part of this organization and speak to you guys tonight. I love doing things like this. I know sometimes when you're seeing your doctor to rush clinic day and you're trying to get to your infusion and your blabs and you know, you always walk out probably with with questions. And so I really hope this was helpful for you. And one thing I said already, but I just wanted to close on, you know, one of the reasons I did myeloma that I went into myeloma, excuse me, is when I was a medical student, what I learned in my textbook was the average, you know, survival of someone with myeloma was two to three years. And when I was a fellow, I was rotating and Sagerlone was clinic, who's the chair of our department, who many of you probably have seen some of his work. And I was seeing all of these patients seven and 10 and 12 years out from their diagnosis. And this was not that recently. This is a while ago when I was in fellowship. And, and they were getting they were getting on clinical trials. And they were, you know, back then they were on their tumor, bad base clinical trials, and they were responding and they felt good. And they were living their lives. And I was so excited by that, you know, to be an oncologist, but to, to deal with the disease where people are living 10, 15 years and beyond, and are having great quality of life and are getting to reach their goals, see their kids grow up, see them get married, be grandparents, it's very rewarding and optimistic. So I know that for many of you who are in this newly diagnosed place, it's really scary. It's a lot, a lot of people feel really well until this kind of comes up and hits them like a truck. A lot of people have just retired by the nickel for every time I hear that because of the average age of diagnosis. But I hope I hope you're starting to feel some optimism about the diagnosis. There is a lot of treatment options out there for you. There's a lot of information, there's a lot of support. And we're only moving and moving forward, we're only getting more and more options. And I really do think that cures is in my lifetime. And so so stay positive. And thanks for being here. Thank you so much, Dr. Joseph, we really appreciate you. This has been helpful and educational. To the community chapter, if you want to join us next month on the eighth, or excuse me, two months from now, because this chapter is going to be every other month in the year of 2023. So early March is when we're going to be talking about consolidation therapy with Dr. Rubenstein. And so you're welcome to join us. That's going to be March 8 at 7pm Eastern. Don't forget to take this survey when you log out today. It's going to be two minutes long, tell us what you liked about today, what we can do better next time and what topics suggestions you have for the future. You can also join us for other community events that we have. Tomorrow at 2pm Eastern is our understanding stem cell transplants in the black community with Dr. Yvonne Efebera. And then the 24th at 1pm Eastern, we talked a lot about kidney involvement today, we're going to be having a discussion on the best diet for myeloma patients with kidney involvement. And then the 24th at 6pm Eastern is our Florida myeloma chapter. So if you're local to Florida, or if you simply like Florida, you're welcome to join us as we hear from Dr. Baas about understanding different classes of myeloma treatment. A special thank you to our community event sponsors Bristol Myers Squibb, GSK Genentech, AbbVie and Amgen. And thank you to each of you for helping us build this newly diagnosed myeloma community. I appreciate all of you. Hope you have a great rest of your day. Thank you everyone. Take care.