(Guest Lecture) What's Available for Consolidation Therapy?

So today's topic is knowing your myeloma therapy, what's available for consolidation therapy. Last time we met, we talked about what's available for induction therapy and it was a great session and there was lots of questions about consolidation therapy. I imagine today, even though we're talking about consolidation therapy, there will be questions about maintenance therapy and induction therapy, which is okay, because it's all part of the myeloma treatment. However, today we're focusing on the consolidation therapy aspect of things and this might be the one that I'm most excited for because consolidation therapy, to be honest, is the one that I know the least about. I pride myself in being a myeloma nerd. I study as much as I can about multiple myeloma, but consolidation therapy is kind of not necessarily new for me, but something that I'd like to learn more about. So I'm excited to learn with you more this session. Questions that are gonna be answered today are things such as, is consolidation therapy used for every myeloma patient? And if not, why? What are normal treatment regimens for consolidation therapy and how long do they last? When does consolidation therapy occur in the line of treatment? And what is the end of therapy? What is the goal, the end goal of consolidation therapy? And here to answer all of those questions is Dr. Sam Rubenstein. And he is an assistant professor and malignant hematologist at the University of North Carolina, Chapel Hill, and an associate member of the Leinenberger Comprehensive Cancer Center. His primary clinical and research area of interest is plasma cell dyscrasias, and he is focused on clinical trials designed to improve the standard of care with patients with those disorders. In addition to clinical trials, Dr. Rubenstein has an informatics background, which he has leveraged to develop multiple prognostic scoring tools that are useful in the management of patients with plasma cell dyscrasias. And we love innovative ways to try to understand and treat myeloma. So thank you for all you're doing, Dr. Rubenstein, and we're looking forward to your presentation. Thanks for being here. And thanks as always for having me. I'm very excited to be here. I'm gonna take over the screen share if that's okay. There we go. Okay. So I'm very excited to be talking to you guys about consolidation therapy. It is a bit of a confusing topic, bit of a semantic topic, but we're gonna show you the ropes here. These are my disclosures. Give you guys a few seconds to process that. So before we get into talking about what types of consolidation therapy we offer to patients with myeloma, going to provide some definitions about the different phases of therapy so that we refer to these terms as induction, consolidation, maintenance pretty frequently, but it's not always the case that it's clear what those mean. So induction is a general term for a therapeutic regimen that's given to a patient with active disease to help them get into remission or at least the state where myeloma is well controlled. Induction therapy often involves multiple different chemotherapy agents given simultaneously, usually for a truncated period of time on the order of several months. Consolidation therapy is often briefer, is often a higher intensity and is given with the goal of deepening remission, whether that's converting from PR to CR, CR to MRD negative CR, and then the long-term goal of consolidation is of course helping people live longer and live better by achieving deeper remission. And then the final phase of each line of therapy is maintenance, which is a reduced intensity treatment, oftentimes single agent, which is given with the goal of sustaining and lengthening remission. So a little, and of course the focus of today's talk is gonna be consolidation. So maybe helps to see all this laid out as a schematic. So the induction phase, as I said, usually lasts four to six months, multiple agents. And then the second phase of consolidation, which remember is any therapy given with the goal of deepening remission prior to deescalating to maintenance. The most common decision point that's made is whether to consolidate with transplant, which as we'll talk about is pretty much the widest used consolidation therapy in myeloma today. So if a patient doesn't undergo transplant, then consolidation usually means extension of induction. We'll talk about some of the trials today that have compared transplant to no transplant. And most of those didn't necessarily forego consolidation, but extended the induction for several additional cycles to ensure that patients who don't get a transplant are still not undertreated. And then following the consolidation phase of treatment, that's when patients will transition to maintenance, which in general is continued until either maintenance isn't tolerable anymore or until maintenance stops working. Important to remember with all of this that myeloma therapy is a marathon, not a sprint. We're getting much better at treating multiple myeloma. Every year we have new drug approvals. We're not yet curing certainly the vast majority of patients, unfortunately. So it's important that whichever route we go with therapy, we do as much as possible to ensure that it's not only effective, but also tolerable and something patients can live with. Next slide. So Audrey, despite her admitted myeloma nerd status, had mentioned not knowing much about different options for consolidation. And the truth is that's because there are not a lot of specific therapies that are deployed for consolidation. Essentially the options are for a patient with newly diagnosed myeloma who's completing their induction, is a patient going to proceed with autologous stem cell transplant with high dose melphalan conditioning. If a patient undergoes that is additional consolidation beneficial. So a second autologous transplant, that beneficial. Or is extending multi-agent therapy after a transplant beneficial. And then of course, I am not alone in being excited in general about immune therapy and myeloma consolidation frontline is a space of very active investigation for immune therapy. I'm gonna spend a little bit of time talking about that but not too much because although that's something I'm very excited about, it's something that's only in an investigational phase and may not make sense for all patients. So we'll start off by talking about transplant. So again, a little terminology, you'll hear doctors talk about transplant, you'll hear patients talk about transplant, not all those patients are gonna have myeloma. So it's important to understand a few terms when it comes to transplant. So the type of transplant that we usually will use in the vast majority of patients who undergo a transplant with myeloma is an autologous stem cell transplant. And that's a procedure in which patients own stem cells are harvested and then given back to a patient after receiving intensive chemotherapy to help support them through the effects of that chemotherapy on bone marrow. A tandem autologous transplant is when that procedure is rinsed and repeated. Upon recovery from transplant one, cells are collected, so the cells are collected at the frontline for two. Upon recovery from transplant one, conditioning regimen given again, cells given again, and then upon recovery from that more therapy is given. Allogeneic transplant is a transplant where stem cells come from another donor. That comes with some additional risks of transplanted cells attacking normal and healthy tissue, which we call graft versus host disease, and protecting patients from that requires additional immune suppression. So there's quite a bit higher rate of complications with an allogeneic transplant. I'm not gonna cover it in the purposes of, you know, in the short amount of time I have with all of you, but allotransplant has been investigated in multiple myeloma and the long story short of many, many years of intense effort is that at this point in time, we don't think the benefits outweigh the risks for the vast majority of patients, but there are very smart people who are working on trying to fix that, so it may get back in the landscape at some point. And then reduced intensity stem cell transplantation is essentially when any of the transplants that I've described are given with lower intensity chemotherapy to condition for the cells. Auto and allogeneic transplants can be reduced intensity. I'm gonna spend most of the time talking about single auto because that's what most patients who undergo consolidative transplant will get. So it's important to note that transplant in myeloma may not be for everybody. So there is a process that's, I would say these days bidirectional, used to be, you know, docs would kind of dictate who is a transplant candidate and who isn't. I would say now it's a lot more nuanced than dependent on what an individual patient wants, but there are a lot of factors that go into the shared decision of whether we're going to proceed with an autologous transplant. Of course, our priorities often will change as we get older. And in addition to that, as we get older, we accumulate more medical problems and maybe have different preferences about how much risk we're willing to tolerate. So patient's age is a very important consideration of whether to proceed with transplant or not. Of course, multiple myeloma isn't always a patient's only, or even in some cases, most significant medical problem. And so the presence of other medical conditions often influences our decision about whether we proceed or not. Most autologous transplants do require protracted inpatient stay in a transplant center or temporary relocation for a period of several weeks to the immediate vicinity of a transplant center. And there's a certain amount of social support that is necessary to make that a tenable option. So assessing that is always a little subjective and nebulous, I don't like to do it, it feels paternalistic, but it's very important to ensure that a patient has adequate social support before proceeding with an autologous transplant. And then as a function of those, what we all think both patient and the physician thinks a patient's ability to tolerate intensive treatment is the conditioning regimen, meaning the chemotherapy that patients get prior to transplant is high dose melphalan. Melphalan was FDA approved in 1957. So that's before my parents were born. So very old drug, it's old because it's good, drugs don't stick around in medicine unless they work. But because it's old, it has older chemotherapy side effects like causing quite a bit of hair loss, but additionally very profound bone marrow suppression and gastrointestinal toxicity. So making sure that patients are well consented for that and understand what's involved is very important. And then in some cases, we have alternatives of transplant, extending induction, participation in a consolidation trial, and then general weighing of the risks and benefits and how those play into an individual patient's goals of care. So I'm gonna talk about some clinical trials and there's basically two that look at the benefit of transplant in the setting of what we consider modern myeloma therapeutics, which are regimens that involve both proteasome inhibitors, so drug like Belkate or Kyprolis and in immunomodulatory drugs, so drug like Pomelist or Revlonid. So the first of those studies is IFM 2009. The F in IFM stands for French, and I don't know what the IRM stands for because I don't speak French, but it's a French myeloma study. And it was designed in 2009 and it read out in 2017. So I mentioned that because it's important to keep in mind that as we get better and better at treating people with myeloma, people with myeloma are living longer, which is great. It takes longer and longer for us to prove that therapies have advances because that requires following people until they progress. So this IFM 2009 trial, patients were randomized one-to-one to following three cycles of VRD and stem cell collection, either undergoing a transplant, followed by additional cycles of VRD, or just getting a total of eight cycles of VRD. And then following that, they got one year of lentilidomide maintenance, Revlimid maintenance, and then stopped. Many of you might be asking the question, why? In the United States, we tend to give maintenance indefinitely. In Europe, they don't do it that way. That is largely a by-product of regulatory decision-making as opposed to actual data supporting that approach. I'm gonna talk as I get into these trial discussions, which I do think are important because that's how we as physicians gather data to counsel patients in an informed capacity about whether to pursue a treatment or not. I think to empower you guys to understand how we make that decision, it's important to show you a little bit of trial data. But before I get into that, I wanna explain what some of the terms I'm gonna use to talk about the trial data mean. So when we're talking about different treatments that are being compared to one another, we need a measurement to use, right? And different trials will measure different endpoints, meaning what is the benchmark of measurement of outcome that we are going to accept will show that a certain treatment is benefiting the patient population or not. And most of these trials that I'm gonna talk about will look at two endpoints. So overall survival tends to be the thing that matters to most patients the most. That's how long patients live after they receive a treatment. That's obviously the most important endpoint to me as well when I'm counseling patients. I'm fond of teaching residents and fellows that it's not really worth arguing with another doctor about anything unless your position has shown to improve an overall survival for that patient in a randomized trial. So that's the most important thing. The trouble with overall survival is that measuring it, and this is a good problem, measuring it takes a really long time because people with myeloma are living longer and longer. So sometimes we look at what's called the surrogate endpoint, which is something that we think correlates with an increased probability of overall survival. And one of the more commonly used endpoints is progression-free survival. So that's time from receiving a treatment until the patient will have progressive disease or pass away. So either of those, whereas overall survival is only time to death for many costs. So this is the results of the IFM 2009 trial. So what the investigators saw was a significant improvement in the progression-free survival for patients undergoing transplant. So that's shown in the graph here on the left. The Y-axis is the percentage of patients who have not progressed or died. So higher numbers are better. And as you can see, the transplant arm pretty consistently at under a year post-transplant starts to outpace the non-transplant arm. The average or median difference was a little over one year on this trial. However, despite the significant improvement in progression-free survival, this study did not show that transplant resulted in improvement in overall survival. So what does that mean? That means patients that undergo transplant can expect longer periods of time until myeloma comes back, but may not necessarily accept to live longer compared to if they decide not to undergo transplant. So I remember when these data came out, I was still training to be a myeloma physician at that time. And most of us in the community did not think too hard about the null overall survival results at the time. And that's for a number of reasons. One of them is that progression-free survival is pretty important in most patients in and of itself. So the period of time that follows a transplant is generally the closest to normal life that most patients with myeloma will experience following their diagnosis. Most patients are getting single agent Revlimid, which certainly is not free of toxicity, but is easier to tolerate than a multi-agent chemotherapy combination in most cases. They're seeing physicians relatively infrequently, generally only about four times a year we see patients on maintenance. And they're avoiding the infusion center for the most part. And because of all those things, quality of life tends to be highest in studies where we measure quality of life longitudinally during the maintenance phase. Furthermore, that survival result may not apply to the United States setting. So I mentioned this trial was undertaken in France. So the average French person smokes about a pack of cigarettes a day and drinks a bottle of wine a day and still lives to be over 80. That certainly would not be my expectation if I were to do those things. And unfortunately, one problem we have in the United States is that globally our life expectancy is declining. And that's important to keep in mind because in France, in this study, the vast majority of patients who did not get a transplant frontline were still able to get a transplant when they relapsed. Generally, that is not true for many of our patients with multiple myeloma, who on average are about 10 years older than the typical patient treated on this trial. So the average age of diagnosis in the US is around 69. The average age of a patient treated on this study was mid 50s. So if you think about it, you undergo induction therapy five, sometimes more, years elapsed until you relapse. Then you have a patient who's in their mid 70s and it may not be the case that every patient after time goes by still wants to do a transplant or has avoided getting other medical complications that preclude a transplant. So for these reasons, we don't think that 80% of patients who defer transplant in the US will get one. We did not look at these data and think twice about transplant for the most part. Bottom line, study mirroring the US population and practice pattern after this was clearly needed. Also mentioned, as I mentioned before, these patients got one year of maintenance. What transplant adds to the setting of indefinite maintenance? Very open question. And so there was a trial that came out around a year ago that definitely did a better job of answering these questions as they pertained to my patients and many of you. So that's a trial called Determination. We treated a number of patients on that trial at UNC. So that was a trial in which after receiving one cycle of RVD, patients were randomized one-to-one to receive either seven more cycles of RVD, some same control arm prior to maintenance as IFM 2009, or RVD for two cycles transplant and then two additional cycles, same active therapy arm as in the French trial. However, following completion of randomization, patients got continuous Revlimid, meaning they got 10 milligrams with the option to increase to 15 until progression or toxicity, which is generally how we give Revlimid in the United States. So key points about the patient population, median age also mid 50s. So a bit of a younger population than the typical folks with myeloma that we see. However, unlike the IFM 2009 trial, the study population is more similar to American patients. Criticism of IFM 2009 is they under enrolled folks with high risk cytogenetics. That trial got about, determination got about 20%, which mirrors the general population of people with myeloma. Of course, unfortunately, multiple myeloma is a disease that disproportionately impacts black patients. And so the proportion of patients treated on this trial who are black mirrors the general population with myeloma. And then half of patients had what's called a reduced performance status, meaning the tools that we use to judge somebody's, you know, ability to conduct rigorous activities of daily living was reduced, which again mirrors the general population of people with myeloma. And then post-protocol critically, only a minority of patients, so 28% underwent a transplant relapse. And then the vast majority of patients got modern regimens. So IFM 2009 being a little older, you had many patients being salvaged with old conventional chemotherapy regimens. Okay. I'm gonna pause here for just a second to let my cat out of this room. I'm terribly sorry. I'll be right back. You're okay. We understand. Yeah, she, long story, but she's happier now. Okay. This may give you some deja vu. So despite all those differences in the populations, we see a very similar demonstration of progression-free survival and overall survival. So we see a significant prolonging and progression-free survival. So again, that means longer time from treatment to relapse or death. Unlike IFM 2009, the median difference is actually a little longer. It's about two years. But despite that, we still don't see that the people who undergo transplant have prolonged overall survival. So I think equally important to patients living longer is patients living better. Oh, I got ahead of myself there. So in any case, what about patients with high-risk disease? I made some point to emphasize that we got more patients with high-risk disease treated on determination than we did on IFM 2009. If you look at this curve compared to the general progression-free survival curve, you'll see a bigger difference in the subgroup with high-risk disease in terms of delaying progression. Some of these measurements, which are ways that we quantify that are also bigger. So this, as well as some other data, suggests that perhaps patients with high-risk disease derive more benefits from transplant. Furthermore, oftentimes it is difficult to get patients with high-risk disease back into remission following initial relapse. So this progression-free survival means a lot more to people with high-risk disease than it does to people with standard-risk disease. So this is important to keep in mind when we're thinking about which way to go. Okay, so I believe living better and living longer are equally important. And so what happens to quality of life? As you can see, so this is a measurement of a pretty widely accepted quality of life metric. QLL stands for quality of life. Patients generally had similar quality of life, whether they underwent a transplant or not, except for the more or less three-month period during which the transplant was taking place, during which the patients undergoing transplant experience a reduction in their quality of life, which having talked about the toxicities of the chemotherapy we give, makes sense. So why might transplant not improve survival? Why might you give somebody a treatment that delays myeloma relapsing, which is, that's cancer. That's for most people, their biggest medical problem. Why does getting better control over that not translate into people living longer? And there are a number of reasons why that might be. So it's important to keep in mind transplant has a very small but very real mortality associated with it, primarily due to infectious complications. I counsel patients that there's about a 1% chance that they will pass away from complications of the transplant itself. And those are for the most part patients that would be passing away earlier than they would have, were they not to undergo the transplant. It's uncommon, but if you take care of hundreds of patients with myeloma, you do see this happen from time to time. It's obviously devastating and important to digest this risk before proceeding. Furthermore, patients that undergo transplant sometimes get additional cancers that are themselves very difficult to treat that we think are caused in no small part by the transplant itself. So that's a whole separate topic that is a very active area of investigation. We're trying to solve that problem primarily by identifying people who are at high risk of it better than we currently do. And then I'm gonna show a slide later that shows that, this is probably much of the reason why transplant doesn't, the benefit of transplant and progression-free survival doesn't translate into overall survival, in my opinion, is that people who undergo a transplant because of the effects of the transplant chemo on the bone marrow are not as able to tolerate high intensity maintenance therapy, which probably means they're not as able to tolerate therapy they get later for future relapses. Remember myeloma treatment's a marathon, not a sprint. So reductions in ability to tolerate high intensity therapy means we're less able to aggressively treat myeloma down the line. And then furthermore, we're getting better. So when people relapse, they all have the opportunity to get much better chemotherapy than they did before, which means everybody's living longer, which is great. Makes it harder to measure survival benefits associated with frontline therapy. So this is that data I was alluding to. So this is the median dose of Revlimid maintenance that patients received on the determination trial. And you'll note that the folks not undergoing transplant gets significantly more Revlimid. And this is important because these dose reductions are being made in general because of reductions in blood counts. So patients are getting the same doses of Revlimid are experiencing higher rates of low white count, low red count and low platelets if they had undergone a transplant compared to those who haven't. So it may be that transplant makes the bone marrow less resilient to tolerate high intensity therapy down the line because after maintenance, when people relapse, it's the same bone marrow that has to be exposed to higher intensity therapy. So what do I recommend? Despite the arguments about the null overall survival effects, I generally more strongly recommend that younger individuals who tend to be a little more or a little less likely to experience the toxicities of transplant pursue it. And then I also recommend those with high risk disease pursue transplant. And that's because of the data that I showed. The 65 is not really an arbitrary number. That was the inclusion criteria for both the above trials. And I use that as my cut point for being more aggressive because I at least know the progression free survival advantage we saw on the two trials I mentioned probably applies to those patients. We don't have dedicated forward looking trials in older adults, which is, it'd be great to have. So for older adults and folks with standard risk disease, counseling is a little more individualized. And it really depends on what a patient and I decide is most important. What we figure out is most important to an individual patient. Sometimes that's not apparent until they've been through a little myeloma treatment. So it usually takes multiple visits to come to a definitive conclusion one way or another on which way this is going to go. But important to note, it's an individualized decision. It's not clear cut. Everybody should get transplant. That's transplant. Sorry, this is mostly transplant talk because that's as we'll see the primary consolidation therapy that's been shown to have benefit. So it's what we tend to do the most. So I'll talk a little bit about additional post transplant chemotherapy. So why would we consider additional consolidation after transplant? Transplant is pretty tough. So older trials before we had things like Revlimid and Velcade derivatives of those agents and immunotherapy, there were a number of trials that showed that doing two transplants delayed progression and delayed death better than one. And that that effect seemed to be the highest in folks with high risk disease. Furthermore, not all patients on the backend of transplant are in complete remission. And certainly not all patients now that we have MRD are MRD negative. So even Griffin, which is deritumumab frontline followed by transplant, after that about 50% of patients still have MRD. So should we be treating to complete remission or MRD negativity so that more patients get in CR and get better outcomes? It's a provocative idea, it's attractive, right? So because of these reasons, there are studies that have been done to look at being more aggressive with consolidation than just offering a single transplant. So this is a study that's from the BMT-CTN, which is the bone marrow transplant clinical trials network called STAMINA. And that's a study that randomized patients to one of three treatments, either a single transplant. So the treatment arm of the two studies I showed before, getting four more cycles of multi-agent chemotherapy after transplant or getting a second transplant. And then everybody got remanent until progression, it's a United States study, so it was designed like we treat patients in the United States. So these are the results, and this does not rhyme with the other data because unlike the other data, progression was no different, whether patients got one transplant, whether they got two transplants, or whether they got transplant and then four more cycles of multi-agent chemotherapy. And then in addition, overall survival was really no different. Interestingly, I mentioned living better and living longer are comparably important, at least would be to me if I were a patient and certainly are to most of my patients. The quality of life was really no different here either. Maybe a little reduction in the quality of life initially for patients undergoing two autos, but bounced back pretty quickly by a year, everybody had pretty similar quality of life. And that's both in the physical health and the mental health components that we use to measure quality of life. What about people with high-risk disease? I mentioned that these more aggressive consolidation strategies in older studies seemed to benefit people with high-risk disease. In general, these curves are pretty similar, there's perhaps a little bit of inferior progression-free survival. If you look at this graph, but statistically, less intense consolidation option did not perform significantly worse than the more intensive options when subjected to rigorous statistical analysis. And the overall survival, very comparable for all the patients. So even for patients with high-risk disease, we don't know that being more aggressive about consolidation has benefit. So I generally recommend against post-transplant multi-agent consolidation therapy because it hasn't been shown to benefit patients in this trial. And then I generally recommend against doing pandemoto transplant as well. Sometimes you'll have a very young patient with something like plasma cell leukemia, which is a very difficult disease state related to multiple myeloma to treat, and we will think about it. But truthfully, we have yet to formally do that, at least during my time here. We've considered it, but haven't actually pulled the trigger. So I generally recommend against tandem transplant as well. So with just a few minutes left, I'm gonna spend some time talking about novel therapeutics. So much of the current drug development in myeloma is focused on harnessing the power of the immune system, specifically T cells, to fight myeloma. And two general categories of immune therapy that are under development and that we're using for patients with relapse disease are CAR T cells or chimeric antigen receptor T cells, which are T cells that have been re-engineered specifically to attack myeloma and by specific antibodies, which are infusions of antibodies that are designed to get a patient's own T cells to fight myeloma. So one involves harvesting T cells, re-engineering them, giving them back. The other one, off the shelf. They have advantages and disadvantages that could be an hour long discussion in and of itself. So I will defer that, although I'm happy to field questions about it if any of y'all have one. So both CAR T and by specific antibodies, long story short, have been shown to result in high response rates when used to treat patients with relapse myeloma. So that means when other highly effective therapies no longer work, these therapies have been shown to get patients back into remission, help them live longer and better. So because of the encouraging relapse outcomes that we're seeing, there's very high enthusiasm to use immune therapy earlier. There's a theoretical, and I wanna emphasize theoretical, doesn't mean it's been definitively proven thought that suggests that frontline patients' immune systems aren't as heavily exposed to chemotherapy. And thus the immune therapies that harness the power of patients' own immune system may work better frontline. That's a hypothesis that needs to be tested, but there's good reason to think that it may be true. So there are a number of trials that are ongoing looking at CAR T by specific antibodies very early in the therapeutic course of patients with myeloma. I'm very hopeful that those trials will change the long-term outcomes, but I need to see the results of those trials to put my foot on the gas in recommending very early adoption of immune therapy. Because as with transplant, immune therapies have their own toxicities. They can cause cytokine release syndrome, which is a condition in which the immune system is overactive, and in its efforts to fight myeloma creates a lot of other complications in the body. Essentially, it's physiologically the same process as if the body has a significant infection except without an infection. And then both of these therapies can also cause neurologic inflammation, which can take a really long time to get better. Both of those complications are treatable, but not 100% of the time. And then long-term use of these therapies has been shown to result in a non-trivial rate of infectious complications. So there's real toxicities associated with those therapies. When there aren't other options to treat myeloma, those toxicities may be more acceptable. Frontline, when patients could defer them and do pretty well, is a higher bar to clear. So very enthusiastic about these studies. I really hope that they result in much longer remissions and cures. We don't know that yet, and we need to show it before routinely recommending it. So in conclusion, single autologous transplant is the most useful consolidation therapy currently available in myeloma. But as I discussed, whether we proceed is an individualized decision. Tandem transplant and additional consolidated chemotherapy don't seem to offer much benefit. And immune therapies are promising, but still early in development and obviously eager for the trials, looking at those to read out, as I mentioned. That's all I've planned to discuss today. Happy to answer any questions y'all might have. Thank you, Dr. Rubenstein. I'm blown away again by just the way that you convey your information. I thought it was very interesting and I learned a lot. In fact, before today, I did not realize that stem cell transplant would be considered as consolidation therapy. So thank you for clarifying that. And it looks like the questions that were asked throughout the presentation were all answered by you, but I did want to reiterate them one more time for people that might be watching the recording. And if you don't mind, I'm gonna pause your screen sharing so that people can see you. Yeah, please do. Yes. And if there's any other questions, feel free to submit those in the Q&A. I see several coming in. Keep those coming as this is your time to ask your questions and get your answers. So one of the questions here was by Anne and she wanted to know how consolidation was different for high risk or high disease burden patients. And I think you did an excellent job presenting what trials didn't really highlight that, this new determination trial that was able to give us more information. And then again, going into the, is tandem transplants really worth it or not? I think that's valuable information. And certainly you're gonna hear differing opinions across the myeloma field, but we do appreciate you sharing your opinion in a very understandable way. Yeah, so the question that was asked was what to do with high risk disease and what to do with high disease burden. So that's an interesting question because high disease burden and high risk disease are separate. Separate, yeah. Right? And they often go together, but they often don't. So, and this gets into a separate question, which is I showed differences in outcomes for high risk and standard risk. How we define high risk and standard risk is changing field wide. There are new models being developed for that every year. And then furthermore, individual myeloma doctors may not agree about what the most important high risk features are. So I'll tell you what I do and I'll tell you also with a disclaimer, it's not the God's honest truth, God's only truth, whatever. But I conceive of high risk disease as patients that have a high risk cytogenic abnormality. The revised ISS rules in some patients who possibly don't actually have high risk disease which revised ISS is the most widely used staging system we have for myeloma. So revised ISS three rules in some patients to high risk who probably don't actually have high risk disease and rules out some patients who probably really do have high risk disease. So I look at cytogenetics and basically I define high risk disease as patients having any of a deletion 17, 414 translocation, 1416 translocation or gain of 1q. So those are the four that I use to change management in terms of diverting from the standard risk pathway. So I give the same induction regimen to everybody. They all get their RVD. That's not the purpose of this talk or question. But following that, I will be more inclined to offer transplant to somebody with high risk disease. If somebody has high disease burden and they're in the same depth of response, I don't adjust my recommendation one way or another. That being said, sometimes patients with, starting with high risk disease burden, high disease burden, get to their transplant and they have a little too much disease leftover to collect stem cells. So sometimes we do have to extend the therapy in people with high burden of disease, but that's not because of the high disease burden per se, it's just because of where they tend to end up. So that's a fantastic question. I think high risk disease, because of the data, because of the data that I showed, I'm convinced that patients with high risk disease should still undergo aggressive, consolidated therapy, which is a stem cell transplant. Yeah, and I had a question to follow up on that. So double hit or triple hit, for those who don't know, are when people have more than one high risk cytogenetic. Is that true in their disease? Sorry, the last like half of that question cut out. Oh, sorry, okay. So double hit and triple hit. So double hit would be if you had two of those four that you mentioned, and then triple hit would be if you had three of those four high risk characteristics. So even with that patient population, do you still not suggest tandem transplants or super aggressive therapy? Good question. I still do not, I do not suggest tandem transplant for double or triple hit myeloma personally, because the best data we have, which is that BMT-CTN study, the STAMINA study shows that even for patients with, general population of patients with high risk disease, they don't seem to benefit. And it's additional toxicity. I, it's unfortunately a small subset of not the most common cancer, right? So getting dedicated studies of double hit or triple hit disease is difficult. The consistent theme across studies suggests that regardless of the approach, unfortunately relapses occur very shortly after implementing whatever your therapeutic option is. And then furthermore, like trials that look at stopping or truncating therapy, like the best of which is Dr. Costa's master study shows that those are the patients who are least able to come off of therapy. So I think, I think actually my interpretation of the totality of the data we have, which is it's necessarily imperfect, is that it's really important for patients with high risk myeloma phenotypes to be able to stay on therapy. When you put your foot on the brakes, those are the patients who will relapse. They will relapse the fastest. And because of that, I actually think there's a strong case made to not do a tandem because the data I showed about less therapy, you're able to tolerate after one auto on pounds after two. And so you may have a really hard time keeping your foot on the gas with maintenance, which is usually multi-agent in those patients if you've done two transplants. So I don't recommend it for those reasons. It's not to say that a myeloma doctor who does recommend is wrong and should have their medical license revoked. That's just my interpretation of imperfect data. Yeah, fascinating. Thank you. Okay, so we got another good question about, if you go into transplant with end protein level above zero, do you recommend more treatment? Great question. That's a question that's so good that somebody had to answer it with a study. And unfortunately, it's not a prospective randomized study, but it's a pretty good backward looking study, which is good enough. So that's done by my colleague, Dr. Vidge at WashU in another cooperative group setting, where they looked at patients who were not yet even in a partial response before transplant. So that's not even getting to end spike of 0.1 or zero. That's, if you start off with end spike of two, is it 1.4 or 0.8? Okay. And so what they saw on that study is that some of the patients, these are patients looking back, so they couldn't randomize. So patients for whom their doctors decided to escalate and give them different therapy, more therapy for transplant or patients who went directly in a transplant did exactly the same. So I don't think that we should be using response adapted therapy yet to determine what our long-term strategy is. We don't have, there's some other cancers where they've done dedicated studies, where they randomize people to escalation of therapy if they hit certain depths of response or not. And there are studies looking at that in myeloma that haven't read out yet, but based on the evidence we have right now, I don't recommend pursuing like a differential goal necessarily as a goal of therapy. So I hope that covers the question. So if your end spike gets the point, oh, the other thing influencing that, sorry. So the question was, if your end spike doesn't get to zero before, you recommend more after. A number of patients convert to negative just with Revlimid maintenance, even though they didn't get negative with Revlimid based induction, about 15% of patients. So it's very possible that somebody whose end spike is measurable free or even post-transplant will get complete remission or even MRD negative down the line. So escalation just comes with more toxicity in my opinion and I don't do it. Great question though. Next question, any benefits of using double stem cells after transplant? It's a good question. Hasn't been shown to reduce time to, you know, count recovery to give more stem cell dose and actually may be useful to have the extra cells in our back pocket for a couple of reasons. One is on occasion, we do recommend a second auto, not immediately after the first auto, but years in the future when patients have relapsed. If we were to attempt to collect the cells at that time, we wouldn't have very good luck. So we got to collect the cells we need frontline. And so having those cells can be for a subsequent transplant is really helpful. Furthermore, and this is like very much speculative. So bear with me here, but a number of patients who get CAR T are experiencing very prolonged reductions in their blood cell counts. And some physicians, including some of my partners here at UNC are infusing stem cells after CAR T to help patients recover from immune suppression associated with CAR T and the CAR T conditioning. So it's very useful to have extra stem cells around for that scenario as well. So I would advocate, and I think most centers wouldn't use just the standard dose and keep in the, you know, generally collect for two. Transplant one and keep the other one in your back pocket either for a second auto or first stem cell infusion after CAR T. That's fascinating. Can we just take a, I didn't know that. I mean, I've heard about it. This is like being studied. It's not like God's only truth. My suspicion is, so if I were undergoing CAR T, I would want to have some of my own stem cells in a freezer to give back to me. Yeah, that's fascinating. Okay, thank you. Do you want to ask the question, read the questions? Do you want me to, what's easier? Why don't you do it? Yeah, we'll do it. However. Yeah, you go for it. Okay, so because we're talking about MR negativity, Annabel says, so it doesn't sound like you pursue MRD negativity during consolidation treatment, just a deeper remission. Now this is the newly diagnosed chapter. So some people might not be familiar with MRD. Do you mind giving just a brief explanation of minimal residual disease? Happily, no, and I pointedly did not discuss it because I started to, and then I was like, this is going to lead to 10 more slides. So MRD, it stands for minimal residual disease. Okay, and what that means is not only as a patient in remission, but if we use, remission also, maybe people don't know the definition of remission. Remission means there's no myeloma we can see. So it basically means there's no EBSPYC, light chains are normal, and if we do bone marrow biopsy, we don't see myeloma in the bone marrow, and also we don't see any on imaging. That's basically what it means. We look for myeloma we can't see, but we have deeper ways to look beyond just using the microscope and radiology. Sophisticated laboratory techniques sometimes can find a needle in a haystack basically, an individual myeloma cell or two, where none would otherwise be apparent. So that's minimal residual disease. Patients otherwise in remission do fancy lab tests, we find a little bit of myeloma. I should mention, by the way, even people who achieve MRD negative remissions are generally not cured. So even if we're not finding it, doesn't mean there's no myeloma there, it just means we're not smart enough to find it yet. So that's minimal residual disease. And what Annabelle's asking about is a very provocative question for our field, which is, should you be going for MRD negativity, meaning you escalate treatment, change treatment, to get a patient into an MRD negative remission? They do that in other cancers, types of acute leukemia, they do that. In myeloma, we haven't generally seen that adopting a response adapted approach, meaning you treat somebody to get the maximum of depermission as opposed to treat somebody with a fixed protocol and see how well it does. Treating in a response adapted capacity has not yet been shown to result in improved outcomes. But our drugs are better now. So updated studies that are looking at that question in the setting of Thera and immune therapy are ongoing and very important. Those are the studies I'm like waiting for, the same way your kids wait for a new Disney World ride or whatever. So I really want to know the answer to that question, but I generally don't advise escalating therapy to achieve MRD negative status. Does that answer the question adequately, you think? I think so, I think that was excellent, thank you. Okay, great. Okay, lots of questions about related. A lot of really good ones in one way, yeah. Oh, sorry, did you? No, I'm just saying there's good ones, great questions. Yeah, great questions. So this one is a standard risk cytogenetic patient who's achieved this MRD negative status after induction and when their consolidation was a stem cell transplant. What comes next after that? Golden question. My answer is regardless of MRD status, I recommend patients with that type of disease characteristic go on single agent Revelemin. And I am still recommending that people in that scenario continue it until progression. There are very good dedicated studies randomizing patients to stopping maintenance at point of MRD negativity two plus years down the line. One of them's a SWOG study we participate in with Revelemin and Revelemin and DERA. And I think we'll definitively answer that question. You have other studies that are ongoing like Dr. Costa's master study, which is a little early to change practice but is very encouraging. That shows that patients with standard risk myeloma who achieve MRD negativity at two different time points, if you stop their therapy, they do pretty well for a long time. A updated, bigger, more definitive version of that study is planned, but it's probably gonna read out when my eight month old is in high school. So I think that we may reach a point where a truncated period of maintenance, meaning do it for a year or two and that type of a patient would make sense. We don't have that data yet in my opinion. Yeah, yeah. We're nearing the end of our time. So I'll just pick a couple of the questions about consolidation to finish up with. So here is what are the options for consolidation for someone who has high risk multiple myeloma but for personal reasons or other reasons does not want to undergo a transplant? Fabulous question. My general practice is to lengthen the induction. So if somebody's bound for transplant, I try not to give more than at the most six cycles of DERA RVD, because after that, it gets hard to collect cells. Oftentimes, usually we go in after four. So I'll do up to eight in somebody who's not undergoing a transplant just so that that patient is not undertreated. But that comes up extremely commonly. And just because the other thing I will say is I do advocate such patients collect their cells. Life circumstances can change and it may be down the line, whatever the logistical barrier is to transplant may resolve or get better. And you may be able to undergo a transplant later. If that is the case, not having collected cells early may make it hard to do it in the future. So I would advise undergoing a collection, but knowing that transplant isn't gonna be an option for us right now, I generally advise extending the induction. I also, what I'll say is if the induction regimen was RVD, I would have to go to the doctor for that patient, which isn't for anybody I start therapy on these days, but sometimes is for people who come see me as a second opinion. That is a scenario in which I think it's pretty important to add the DERA because there are, I didn't cover it because it's an induction concept, but DERA RVD, I'm pretty convinced is better than RVD. And if you've been induced with RVD and can't get transplant, adding DERA, which should have happened in the frontline, but could have and may have resulted in deeper emission, ought to happen at the point you decide somebody's not gonna go to transplant. I do that not infrequently for people who come to see me have gotten RVD, they decide they don't wanna transplant and they still wanna get as good of an outcome as possible. Yeah, yeah. And this is also where, excuse me, a clinical trial would be a really good option. You mentioned these immunotherapies are being tested as consolidation therapies. And it would be an excellent opportunity, I think, to be able to test that principle and be able to participate in a clinical trial to further research. Yes. Two more questions. So in the beginning, you said that consolidation therapy was more, what was the, briefer and high intensity. So is that a higher intensity than induction therapy, or is it just higher intensity than maintenance therapy, which is obviously out of lower dose? So definitely higher intensity than maintenance. Most, obviously many patients consolidation is just extending the induction. So that's no more intense than induction other than that you're giving somebody who's already had a little more chemotherapy, more chemo. So by that point, the chemo tends to be more difficult to tolerate in general. But in general, the consolidated therapies I discussed, transplant one, transplant two, those are, and of course, same chemo after transplant as I talked about that, that's more intense because bone marrow can't handle as much at that point. Generally consolidation is brief intensification to knock disease into remission. Yeah, awesome, thank you. The general concept. And then my very last question, I know we don't know a lot about the future, but do you ever see or are there clinical trials testing the role of CAR T instead of stem cell transplant as consolidation therapy? Yes, so a good question. There are two ongoing CAR T trials. There's a number of CAR T trials, but there are two big ones that are looking at frontline CAR T. One is CARTITUDE V. So that's a CILTA cell, which is Janssen's BCMA-directed CAR, or Revlimid and DEX for patients who've completed an RVD-based induction. And so that's not compared to auto, but that's for patients who are deciding to defer an auto. So sort of similar to the question that we got asked. And then another trial is CARTITUDE VI, which is the same CAR T with DERA RVD at CILTA cell or an auto. And so that may answer some of the questions about whether CAR T beats auto. There are other trials looking at CAR T one to three prior lines of therapy. So earlier relapses that are reading out, that isn't quite the question you asked. We were hopeful that some of those studies would result in cures. They have not yet, but they're with different products, and I don't know which is the right product. I like them all. I'm hopeful that one of them results in cures. And then maybe some of these frontline CAR T trials have that kind of result. Well, and also I think it's gonna be kind of a combination that brings the cure. There's so many awesome therapies being developed, and I think it's gonna be, which of these can we synergize together in a certain way to bring about cures in a majority of the patients? So it's gonna be interesting to see what the future holds. Thank you so much for your time. I know that you've generously offered to answer questions. You're more than welcome to stay during our out-of-announcement to answer questions, and I can send you the ones that you didn't get to in an email. So I do have a young child, and it sounds like I have to help with bedtime. So I can't answer the questions, but I will answer them. Audrey will send them my way. I will get to all your questions. She'll circulate them, and I'll circulate my slides. Give me a few days, but I will get to all of your questions, I promise you. Thank you very much. Are there any closing statements you want to make before we go tonight? Oh, none other than it's always a pleasure to talk to you guys. It's an honor to help people with myeloma live better and longer and help them conceptualize their disease. This is why I do what I do. And yeah, hopefully you guys enjoyed it as well. So hope everybody has a good rest of your evening. Thank you very much. We're gonna let Dr. Rubenstein go to help with bedtime. Meanwhile, we're just gonna have a couple of outro announcements ourselves. You can join us on the next time that we meet, which will be May 30th, and we're gonna be moving on to maintenance therapy. This is the big question that a lot of us have. How long do I have to be on maintenance therapy, right? So we're gonna be discussing that, new maintenance therapy options that might be coming and what's being tested in clinical trials. That's gonna be on May 30th. And I invite you to join our newly diagnosed Connect group if you haven't already. This is a way that we can stay connected outside of myeloma meetings, out of our monthly meetings, excuse me. And I think it's really cool. There's already a lot of posts there. It's an awesome way to connect with somebody who's in the same stage of diagnosis as you. There's lots of caregivers in the group and patients. So make sure to join our Connect group. The link will be coming in the email along with our slides and the recording. You may be interested in other follow-up, in other, oh my goodness, my brain is not working. You may be interested in other events that we have upcoming. Tomorrow night, we have our Northeast Myeloma chapter. So if you live anywhere from Maine to Pennsylvania, you're welcome to join us. It will not be recorded, and we'll be discussing infection risk. On the 14th is our regional SoCal chapter. We'll be talking about real-world guidance from an oncology pharmacist. And the next Wednesday is our Mountain West. So lots of regional chapters. That's Montana, Idaho, Colorado, Wyoming, Utah. We're gonna be talking about tracking your myeloma labs to make sense of it all. The link to sign up for any of those events and even more events I didn't mention is found at the bottom of the slide. Another thank you to our sponsors, Amgen, Genentech. Oh, you know what? You probably can't even see that. Sorry, guys. Amgen, Genentech, Janssen Oncology, and Avvy. And a big thank you to each of you for helping us build this multiple myeloma community. I appreciate you. I hope you have a great rest of your night. Thanks, everyone. Bye-bye.