(Guest Lecture): August 2022 The Role Of Maintenance Therapy after SCT

As you know, today's topic is going to be the role of maintenance therapy after stem cell transplant. This is a popular topic that gained a lot of interest really quickly. And again, I'm glad you guys are here taking time out of your day to either listen or participate. Why is maintenance therapy so strongly recommended after a stem cell transplant by lots of physicians? And how long do those physicians wait to give maintenance therapy after the stem cell transplant procedure? For how long is maintenance therapy given? Today, we're going to meet with Dr. Sam Rubinstein, who's going to share his professional opinion with us. Dr. Rubinstein is an assistant professor, malignant hematologist at the University of North Carolina, Chapel Hill, and an associate member of the Leinberger Comprehensive Cancer Center. His primary clinical and research area of interest is plasma cell dyscrasias, which includes multiple myeloma. And he is focused on clinical trials designed to improve the standard of care of patients with these disorders. In addition to clinical trials, Dr. Rubinstein 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. Dr. Rubinstein, we look forward to hearing from you. And there's lots of interest in this topic today, so I'm sure you're going to do great. No pressure. Thank you so much for the kind and thorough introduction, Audrey, and it's my pleasure and privilege to give this talk to all of you today. I just want to emphasize what Audrey said, which is that, as with many things, excellent myeloma doctors can disagree in good faith about a lot of things, including all the excellent questions that Audrey posed about maintenance. So this is, I think, a pretty balanced take on the topic. But just want to emphasize that this is, even though I think it's pretty balanced, it's my own take. I'm going to share my screen real quick, so give me just a couple of minutes to make sure that the talk is uploaded. Okay, so I'm going to talk to you all today about the role of maintenance therapy after stem cell transplant. These are my disclosures. One of these, I'm going to be talking about one of their products. That's Daretumumab. It's a drug I use a lot of. It's a great drug. It actually is not that useful in maintenance. You'll hear more about why. So even though this is my potential conflict of interest, as you'll see it, I'm not going to be talking about myeloma, but if anything, I'm saying things that they would not want me to say in the purposes of this talk. So before diving into maintenance, I'm going to go over an overview about how multiple myeloma is managed. So multiple myeloma is the second most common blood cancer in the United States. So approximately 30,000 patients are newly diagnosed with multiple myeloma every year. And when we meet a patient for a new consult, there's really three things that I endeavor to get them to understand about the disease and its management at the end of the visit. So the first point is that multiple myeloma is not a cancer that we can cure. It arises from a type of white blood cell called a plasma cell. Plasma cells are hardwired to make antibodies as long as you live. So, sorry, that means when they turn into cancer, it's very difficult to kill 100% of the plasma cells. So that's not a disease that we can cure. However, even though we're not so good at killing 100% of the plasma cells, we're pretty good at killing 99% or more of them. So this is a cancer that's very treatable. Outcomes of patients with multiple myeloma with modern myeloma regimens have been improving dramatically over the last 20 years. To the point that particularly patients who undergo stem cell transplant and some case series are living on average in excess of 10 years following diagnosis. The third point draws naturally from the first two, which is that this is not a cancer that we cure. It's a cancer that's very treatable. But because we have a hard time getting rid of all the myeloma cells, achieving the best outcomes typically requires continuous therapy in some form. And that's where maintenance comes in. So this is just one slide about how multiple myeloma arises. So, or at least our general theory about the model about how it generally arises in most people. So plasma cells are these cells that are shown right here. They look sort of like clocks with the face off to one side or fried eggs. It's actually the pathologists who look at these slides on microscope love to make corollaries to food. So they refer to these shells as cells and shaped like fried eggs. So the way a plasma cell works is in response to an infectious process or an immune stimulus, be that an autoimmune disorder, or in theory of vaccine. I'll note that vaccines are specifically are not implicated in the development of multiple myeloma, but they do stimulate our plasma cells to produce antibodies to protect us from getting future infections. In some cases, an infectious stimulus can overstimulate a plasma cell population so that it makes too much protein. So over time that population of cells may accumulate mutations that cause it to grow and eventually has the potential to invade surrounding tissue. And when that population of plasma cells starts to invade surrounding tissue. That is the process that results in multiple myeloma. So 30,000 for view of the management of this disease, particularly in the frontline setting. So when we meet somebody with multiple myeloma. The first step is to get them into remission that is achieved within induction regimen induction. As the name implies, is intended to induce a remission. Typically induction regimens involve multiple different chemotherapy agents, but are given over a defined period of time, usually three to five months which corresponds to four to six, three to four week cycles, depending on the individual regimen that's used. Following induction patients who are interested in appropriate candidates are referred for consolidation therapy with high dose melphalan and ontologist stem cell transplantation. And then following recovery from stem cell transplantation. We typically recommend the vast majority of patients go on to receive maintenance chemotherapy. And although there is some controversy regarding duration, the majority of myeloma doctors, and the best clinical trials that we have suggest that most patients should remain on maintenance as long as the disease is well controlled or in remission and maintenance is typically advised to be continued until a patient relapses. Key point is that because this is a disease that most patients live with for many years or even decades, and it does require in most cases continuous therapy to achieve the best outcomes. This is a marathon and not a sprint and minor adjustments are often necessary investments in helping patients remain on appropriate therapy that they can tolerate and support their quality of life as long as possible. So before diving into the dedicated slides on maintenance I do want to talk a little bit about transplant and its role because this talk is going to be focused on maintenance regimens that are given after transplant. So stem cell transplantation and multiple myeloma, as I mentioned, is a consolidation therapy. So what consolidation means sort of like contained within the word itself, it solidifies our position of remission with the goal of deepening it and prolonging it. A key point distinction is that the type of transplant performed in patients with myeloma is something called an autologous stem cell transplant. And this means that the cells that are given come from the patient themselves. So this is not a transplant that is given from cells derived from a donor. So patients own stem cells are harvested and used to rescue the bone marrow from the effects of intensive chemotherapy. So why do we do stem cell transplant if we don't cure patients, as I mentioned before. So, these are two recent and very large randomized controlled trials, comparing frontline stem cell transplantation to deferred stem cell transplantation meaning give a patient induction, collect their cells, patients are randomized to getting the high dose transplant and cell back or keeping the cells and using them later if they wish. And you'll see these two curves look very similar, even though, unfortunately, the New England Journal decided to transpose the colors of the control arm over the last five years. So, in both cases, the top line is transplant, and the bottom line is, is no transplant. I want to explain exactly what these curves are because I'll be showing a few of them over the course of this presentation. So these are what are called Kaplan-Meier curves, and these are how clinical trials represent time to an event. So, if we start at the beginning with 100% of the patients, as whatever event we're looking at starts to happen, the line reflects the proportion of patients who have not experienced the event. So, in the case of these curves, these are looking at an endpoint called progression free survival, which is essentially time from an intervention in this case transplant to either relapse of disease or death. So every time this line goes down a patient has either relapsed or has passed on. You'll notice these tick marks, those are patients being censored out of the study, which means either they have reached their point of maximal follow up, or they have chosen to leave the study for one reason or another. And what you'll see on both of these curves is that the transplant arm is solidly above the no transplant arm. And what that means is that patients are taking more time to progress after they've had a transplant. So transplant across a number of studies prolongs time to progression. However, time to progression may not necessarily result in patients living longer. So this is overall survival, which unlike the prior curves is simply time to death. As you'll see, both of these curves are nearly identical for transplant and delayed transplant. People in the myeloma community are on both sides of whether this result will hold up, or whether this will diverge over time. That is a big discussion that would require its own talk. So I'm going to defer it. I just want to emphasize, however, before we dig into the maintenance topic that transplant may not be the right procedure for everybody. We know that it prolongs the first remission with high confidence, but we don't know that it makes people live longer. So depending on an individual goal, patient's goals of care, transplant may or may not be the right approach and I would encourage you if you are considering transplant to have a balanced discussion with your physician regarding whether transplant is the right approach for you. Okay, so that's the introduction. Now I'm going to move on to a discussion of maintenance, which as I said initially is usually given as long for as long as a disease remains in remission. So before we talk about maintenance, I'll define maintenance. So the spirit of maintenance is a lower intensity treatment. So induction I mentioned multiple agents shorter period of time maintenance is something patients have to learn to live with usually for a period of many years. So it's typically a lower intensity treatment that's given to sustain a remission that has already been achieved with higher intensity induction or consolidation therapies. So, there are a variety of different regimens that are given as maintenance to patients with multiple myeloma after transplant. And we're going to talk about what I think are the most widely used ones. So because multiple myeloma is not usually cured, achieving the best outcomes often requires continuous treatment. Combining multiple drugs at higher doses indefinitely. So we need to treat this disease more or less continuously giving multiple drugs, as those are done in the induction setting forever is not always feasible. The more chemotherapy agents we use, the more toxicity we expose patients to. Additionally, most of my patients like me, but not enough to spend time in my infusion center versus at their home, or with their family. Time in the infusion center is precious, and the more infusional regimens we give, the less time patients have on their own. That is real toxicity that most myeloma physicians take very seriously. And then of course, there's no free lunch and medicine, both from a toxicity perspective and a financial perspective. The more drugs we give, the more money we cost both the healthcare system and individual patients, so we are mindful of that. And when it comes to maintenance, for this reason, we think it's better to be on fewer rather than more individual drugs in most cases. So, that should be Revlimid in parentheses, not lenalidomide, my apologies. So, let's talk about Lenalidomide or Revlimid. So this is the widest used drug for post transplant maintenance. In keeping with the prior presentation, it's oral, so it keeps patients away from the infusion center in most cases. Revlimid is one component of the induction regimens that we most widely use for patients with multiple myeloma. So when it comes to maintenance, Revlimid is a drug most patients are used to, and they know to some extent what toxicities they're going to be dealing with. And that helps prepare them to be on it for a long period of time. And I think most important reason that most patients with multiple myeloma should be on Revlimid for maintenance is Revlimid is the only drug that has been shown in a randomized trial to prolong overall survival in the maintenance setting. Most patients care about two things, living longer and living better. Living better requires generally careful adjustments by physician and patient to the maintenance regimen. Living longer, Revlimid is the only drug that's been shown to result in that following stem cell transplant. So here are some more of those curves that I showed before. So this is a large study from the United States Cooperative Group to C-A-L-G-B. It was led by Phil McCarthy who practices in upstate New York. But it was a national study and took 460 patients and randomized them to indefinite maintenance with continuous Revlimid at a 10 milligram dose or placebo. The curve on the top left shows progression so that's proportion of patients who are alive and still in remission. As you can see the Revlimid curve quite a bit above the no Revlimid curve. Median Revlimid almost doubled the remission on this study and in magnitude did so by a period of 30 months, which is between two and three years. In addition to prolonging remission, Revlimid resulted in an improvement in how long patients live. And that's reflected in the separation in these curves on the bottom right that show patients receiving Revlimid are less likely to have passed away over time compared to patients receiving placebo. There are a number of maintenance studies that all came out around the same time. Some of them did not show advantages in overall survival. So to settle the question of what the effect was, some researchers combined the results of all these trials and said if we put them all in a basket and treat them all as if they were the same, what would we have seen? This is a research method called meta-analysis and that just refers to combining multiple studies into one study. And this took three studies, the one I presented, a study from France and a study from Spain. There are subtle differences in the design of these trials, but in all of them, patients were randomized to receive Revlimid or placebo. And what they found when they pooled the results of all these trials is that even though some of the individual ones did not show that overall survival was longer, in aggregate, the three trial results put together showed that Revlimid is associated with an improvement in overall survival. Blue curve is Revlimid, yellow curve is placebo. As you can see, patients receiving Revlimid are likelier to be alive. This first curve corroborates or backs up what I showed earlier, which is that the time until progression for patients getting Revlimid is quite a bit longer, again, an average of just under 30 months in aggregate. So Revlimid is the only drug to show this effect and it makes people live longer. There are other drugs that have been studied in the maintenance setting. None of them have shown this. So that's the benefit, but as I mentioned before, there's no free lunch in medicine, and as many of you likely know, Revlimid is associated with significant side effect potential. So there's really two kinds of side effects that it's important to get patients to understand. Common things that are manageable, but they are likely to experience, and then rare things that are potentially very difficult to deal with, that are small but real tail risks associated with an intervention. So the most common side effects that patients with Revlimid will experience are far and away fatigue. I think the majority of my patients experience fatigue that if we were to stop the drug gets better. Revlimid can suppress the normal and healthy bone marrow cells. So you can see reductions in the white cells, red cells and platelets. Reductions in the white cells are associated with an increased risk of infection. Furthermore, Revlimid can be challenging to tolerate from a gastrointestinal perspective. The most common gastrointestinal side effect is diarrhea. However, Revlimid can also cause nausea, vomiting and abdominal cramping. A fourth very common toxicity that I'll mention here is rash. Rash is more common when we start Revlimid than it is in the maintenance setting. So most patients, if they were going to get a rash, will have had it when Revlimid was given during their induction. The key point to consider is that usually when we have a rash to a drug, that means we might be allergic to it. With Revlimid, that's not what it means. A rash that occurs on Revlimid reflects the immune system getting used to taking Revlimid and typically will resolve if the drug is continued. So we'll commonly help help a patient remain on Revlimid by giving them antihistamines, topical steroids or even systemic steroids, meaning oral steroids, to control itching and other symptoms that can be associated with the rash. And over time that rash will typically go away. So those are the common side effects. I'll also mention one more. Individuals, and it's in the vein of rash, individuals with dark skin, so Black people, people who are of South Asian descent, people who are of Latin American descent, will commonly experience a darkening of the skin. This can, is thought to be only a cosmetic effect. As with the other rash does not reflect an allergy to the medication or an impending harm, but can be very cosmetically disturbing. So that's something to prepare yourself for if one is in that category of patients. Rare but potentially devastating complications of Revlimid include clots, most common location being in the legs but also those can travel to the lungs, and sometimes in rare cases occur in arteries in the heart or the brain. That is a risk that is associated with Revlimid, mostly when it's given in combination with higher doses of steroids. It's not often seen in the maintenance setting, but just to be safe, we recommend all patients that take Revlimid or a related drug, take a medication to prevent blood clots. Different physicians use different ones. I typically use aspirin unless a patient is at particularly high risk for clots, in which case I'll use a stronger blood thinner. And then another rare but potentially devastating side effect of Revlimid is secondary cancers. So patients that take Revlimid for treatment of multiple myeloma are at an increased risk to develop a second cancer in the future, unrelated to the multiple myeloma that we think may have been caused by Revlimid. So that's obviously a very devastating side effect and one that our group at UNC is very interested in understanding better, so that we can prevent the small but real number of patients who get this from having this devastating complication. Here's a rundown from two randomized trials of the types of second cancers that can happen in patients on Revlimid. What I want you to notice is that the numbers here are rather low. So on the left you have the first Revlimid maintenance study from 2012, and you see that a total of 18 patients out of 231 got some sort of a second cancer. Many of these were treatable. The breast cancers were all localized, the melanoma localized, and furthermore, the patients who did not get any maintenance did also get some second cancers. So the difference between these two arms is 12, which over the size of the study is an increase of between 5 and 6%. Specifically, on the right I have a newer study, this is the one that was just published in the New England Journal a few months ago. This study didn't compare Revlimid maintenance to no maintenance, it compared transplant to no transplant, but all the patients got Revlimid maintenance and those who got it after transplant were at increased risk specifically of developing myelodysplastic syndrome and acute leukemia, which are other blood cancers that are unrelated to multiple myeloma. So that was 10 out of 365, so a little under 3% of the patients got that. So a rare, but very possible and when it occurs potentially very difficult complication. Last thing I will note about this, not to trivialize this potential, this is a real tail risk that I discuss with every patient before I put them on Revlimid. This risk is accounted for in the trials that show that Revlimid in aggregate results in prolonged life expectancy for patients that have multiple myeloma. So even though Revlimid can result in this complication, in aggregate a patient can expect to live longer with the diagnosis of myeloma taking post transplant Revlimid than they do taking placebo. So thoughtfully, we usually recommend continuing with this drug unless a patient is at particularly high risk of developing a second cancer, which is certainly some of our patients. Next I'm going to talk about a class of drugs that are sometimes used in the maintenance setting. These are the proteasome inhibitors. So these are drugs that are widely used in treating multiple myeloma. There are three of these drugs and they all work very similarly in terms of how they attack myeloma in the myeloma cells. One of these drugs is Bortezomib or Velcade that's given subcutaneously. Another one is Exazomib or Nilaro, that's a pill. The third one is Carfilzomib or Kyprolis, that's intravenous. And all of these drugs may have role in the maintenance setting for an individual patient. But as we'll see the data supporting them is not as strong as the data supporting Revlimid. So Bortezomib or Velcade is a drug that the majority of patients with multiple myeloma are familiar with. It is a drug that's been widely in use as part of the frontline therapy of multiple myeloma for over a decade. In the maintenance setting, however, we don't have that much data. So unlike Revlimid, this drug requires a patient to go to the infusion center. Furthermore, when it was being developed, it was given intravenously and at that point in time had quite high rates of causing peripheral neuropathy or nerve damage. Now that it's given subcutaneously, it still can cause that toxicity but does so at lower rates. So the only data that we have comparing Velcade maintenance to an alternate strategy comes from this very old European trial called Hovon 65. And this wasn't exactly a clean comparison of Velcade maintenance to no maintenance like the trials I showed you earlier with Revlimid. This compares getting Velcade in induction and maintenance to getting a different induction regimen called VAD. The V does not stand for Velcade, it stands for Vincristine. That's an old regimen that we don't really use very much anymore. I've written for it once in my career. So it compared bortezomib based induction and maintenance to this VAD regimen and thalidomide. So not lanolidomide, thalidomide. So the results here, which I'll show you, do hint at some benefit to Velcade in patients who have what we consider to be high risk myeloma. So high risk refers to risk of therapeutic resistance and relapse. And we consider the factor to be most consistently associated with risk in myeloma to be the chromosomes in the myeloma cells. So DNA is the code that tells the cell what to do, and that lives on a structure called the chromosome. And multiple myeloma cells commonly have abnormalities in the chromosomes. Virtually every myeloma patient's myeloma cells will have abnormalities in the chromosomes, but some of them we note are associated with an increased risk of relapse and resistance therapy. And three of them that were investigated on this trial were the translocation 414, deletion 17, and deletion 13. Deletion 13 we don't consider high risk anymore, but at the time they did. So these are the results of that trial and what it showed was a modest improvement in overall survival associated with getting the Velcade-based regimen, which confusingly is PAD. A little aside here, Velcade is actually a UNC drug. We're very proud of it here. And all drugs start by having an alphabet soup sort of name, and the original name of Velcade was PS41. So that's why even though the generic name is Velcade, the regimen was called PAD that contained Velcade. So the top line is the Velcade-based regimen, as you can see, associated with slightly better survival. On the right here we see the results for patients with high risk disease. So remember, we don't consider deletion 13 to be a high risk abnormality anymore. So focusing on the bottom two curves, what you can see is that arm B, which is PAD, for those that had deletion 17 and 414, is associated with improved overall survival, and that it's more pronounced in the patients with deletion 17. So the real caution is that you'll notice that the numbers of patients with high risk disease on this trial are very small. So we have 35 patients on each arm with a 414, and then an imbalanced but similar number in total of patients with deletion 17p, about 60. So there are numbers of patients, but it's a real effect. And some people think that because of this data, it suggests that proteasome inhibitors are very important for patients who have multiple myeloma and high risk abnormalities. So I mentioned that one reason why there wasn't much enthusiasm for studying Velcade is that it's a drug that forces people to go to the infusion center. And so now we have an oral proteasome inhibitor called Ninlaro or Exazomib. Exazomib is a pill that works in the myeloma cells the same way that Velcade works. So when this drug was being developed, we had a lot of enthusiasm that we could have all oral regimens for patients with multiple myeloma. Unfortunately, however, this drug has been studied in a lot of different clinical trials, and this is getting into my take on the data. There may be myeloma doctors who disagree with this, but there's a pretty consistent theme that when you look at trials that use Ninlaro and trials that use Velcade, what you see is that the benefit associated with adding the drug with Ninlaro is lower. So even though it avoids the infusion center, it doesn't do as good of a job as Velcade does at treating myeloma. And so this drug, it's been studied in the maintenance setting with the hopes that it could be a pill that could work for people that, for whatever reason, we didn't want to use Revlimid or perhaps individuals with high risk disease. And compared with placebo, after transplant, Exazomib has been shown to prolong remission by less than six months. So remember, the Revlimid curves that I showed you demonstrated Revlimid on average results in remission longer by 30 months. So a little over two years better in terms of the benefit to patients in prolonging remission. And Exazomib also, unlike Revlimid, did not have any effect on prolonging survival. So this is just that information shown as a curve. As you can see, there is a difference in progression-free survival, but it's quite a bit subtler than the difference that was shown with the monolidamide drugs. So you'll notice that the time here is shorter because patients are generally progressing faster with this drug. So that's Exazomib, as you can probably tell. I don't have a lot of enthusiasm for using this drug personally in the maintenance setting. So that's the proteasome inhibitors on their own. What about in combination? So combination regimens, one could say violate the spirit of maintenance, which is deescalated therapy that's supposed to liberate one from the infusion center. So we're giving patients who may need a little more therapy to keep their disease in remission as long as others. And specifically, those are the individuals with high-risk disease. So patients with high-risk disease are thought to be a population that will not perform optimally in terms of how long the disease can be controlled with the standard approach of Revlimid maintenance. So different centers will recommend, in some cases, combinations of Revlimid with the proteasome inhibitor rather than simply replacing Revlimid with the proteasome inhibitor. So two regimens I'm going to mention that do that are Velcade and Revlimid and Carfilzomib and Revlimid, both of which have some data supporting their use in the maintenance setting. So this is the data about VR maintenance, and this is small data from a single center, Emory. It's a big center, so I guess it's the size of maybe two or three normal myeloma centers, but it's still one center. And you have to take that with a grain of salt. A good, but politically correct joke about Atlanta is not coming to mind. I do like it there very much. In any case, what we see on this trial is the patients that got dual maintenance with deletion 17P, that's one of those higher risk abnormalities, had a relatively preserved progression-free survival compared to the typical outcomes of patients with high-risk disease, which was a median progression-free survival of less than two years. At two years, nearly 80% of the patients have not progressed that received dual maintenance, which is better than what we call the historical standard. And then the vast majority of patients with high-risk disease are still alive on this regimen. So this, in the view of some myeloma physicians, supports giving Velkin and Revlimid maintenance and combination to patients that have high-risk disease. What about Carfilzomib and Revlimid? So these are data from one of my favorite myeloma trials, it's the Forte trial. It's an Italian trial, and it's relatively complex. It had two randomizations. One of them was to Carfilzomib and Revlimid versus Revlimid alone. So unlike the NUCCA data here, this has one arm. This is a comparative trial, which compared Carfilzomib and Revlimid to Revlimid and asked the question, what does Carfilzomib add? And so what was seen was a meaningful prolongation in progression-free survival, meaning patients were less likely to die or progress if they got both drugs. And this benefit is pretty modest, so it's a one-third reduction in progression, but that's real. And so for patients for whom progression may occur faster or may be accompanied by disease that's more difficult to treat, so those with high-risk disease, this may be worth adding the extra drug and time in the infusion center. So this is what we call a forest plot, and it's called a forest because it's got all these lines in them which are sort of like trees. So what we're looking for here is consistency across groups, and as you can see, these black boxes that represent how the patients do are essentially in the same place for all the groups, including critically individuals with high cytogenetic risk. So for those with high risk, the benefit here is very similar to the overall benefit, small number of patients, but suggests that even the benefits seen in the trial overall probably does apply to the folks who would need this type of regimen the most. So those are proteasome inhibitors and Revlimid. I'll briefly talk about daratumumab, which is a drug that many of you are likely quite familiar with. It's a monoclonal antibody to CD38, which makes it a targeted therapy to myeloma cells. It is a great drug that's widely used front line and in patients with relapse disease and has been shown to benefit patients in those settings. There have been studies of daratumumab single agent as maintenance. It's given once a month and does require going into the infusion, but because it's only once a month, maybe a little less burden. Unfortunately, those trials have not shown that getting daratumumab indefinitely benefits patients. So this big European trial called Cassiopeia is sort of like Forte, a little more complicated with multiple randomizations, but the patients that got a little daratumumab for their induction did not benefit from getting more daratumumab after. It may not be the best drug on its own to keep disease controlled for a long time. However, what was seen with this drug when it was developed in relapse myeloma is that it works much better in combination. It plays better with others than it does on its own. And so dedicated studies of daratumumab in combination with Revlimid, there are multiple of them, we're actually participating in two of them at UNC, are ongoing and a very important result that the field is waiting for a bated breath. So I've talked about a lot of different drugs. So I'm going to just, this is perhaps if there's one slide to summarize all of it, this would be the one to internalize and review. Revlimid has the most benefit both in prolonging progression and in causing survival, no other, causing improved survival. No other agent produces the same improvement in overall survival that Revlimid produces. All have different side effects, which may be particularly important to individual patients, because any given patient's risk of one of these might be higher than others and that absolutely should influence how we decide on maintenance regimens. So I spoke about clots in second cancers, I spoke about neuropathy with Velcade. It's also been associated with low but non zero risks of pulmonary and cardiac toxicity. Exazomib, you'll hear a lot that it doesn't cause neuropathy. It's actually not true. It just causes neuropathy at lower rates than Velcade does. And the other side effects, you know, that Velcade has, which I didn't touch on, but are similar to Revlimid actually, diarrhea, low blood counts, fatigue. Exazomib has all the same, has the potential to cause the same side effects but at lower rates. So, for philzomib has the unique potential to have a pretty decent rate of cardiac toxicity. In clinical trials it does this between three and 5% of the time. So patients that have cardiac disease may not be the right patients to use KR maintenance. And then of course route of administration is important mostly because anything other than PO necessitates a visit to the infusion center. That's the only options there are Revlimid and Exazomib. And although they've not been directly compared, Revlimid has been shown to prolong survival and Exazomib hasn't. So this is the comparison. We'll probably talk more about the benefits and risks of different drugs when I get to Q&A. So a couple things that are coming down the pipe that I don't think quite ready to be used categorically. So, so you'll hear myeloma doctors talk about this concept of minimal residual disease. What does that mean? Minimal residual disease refers to myeloma that we can find when by conventional criteria so labs, marrow biopsy imaging, a patient will appear to be in remission. So it's a catch all term. There are many different ways to measure it. So there are two commercially available tests, flow cytometry and next generation sequencing based. Both of those are generally performed from bone marrow biopsy samples only. In some cases, the NGS next generation assay, which is also called PRONASeq, can be done on the peripheral blood, but MRD testing means a bone marrow biopsy in most cases, except the investigational ones. So good doctors disagree on whether testing for MRD is useful in making decisions at all. And even among those who think it's useful, that's my camp, people have different views on how one should use those results. So this is a powerful tool that I think will be standard of care in the foreseeable future. But there are clinical trials that are being done that will help show us how best to use it that I don't have results for yet. So I don't want to say it's not ready for prime time because it is useful to know, especially if a patient is struggling to take their maintenance for one reason or another. Just how much disease they have left. That's the setting in which I find it the most useful. So I'm not going to say it's not ready for prime time. It is. But we're still learning the best way to target, to use MRD. And, and I imagine questions might come up about that in the Q&A. I'm not really going to say more until then. I'm a clinical researcher, that's why I work here. So I want to emphasize that although a clinical trial may not be the best treatment option for all patients, all patients should be offered a clinical trial when a change in management is being considered. And maintenance is no exception. Even though all these maintenance drugs are old, even daratumumab, which is I guess the newest kid on the block in this space, has been FDA approved for eight years now. There are still many important questions to answer. Is adding daratumumab to Revlimid beneficial in maintenance just like it is in relapse and frontline induction? What's the best approach for patients with high risk disease? I showed you the slides that support using proteasome inhibitors. Note the very small number of patients. We still don't have a lot of confidence about that. Those management strategies and ongoing trials are investigating how important that is. And then for the last slide I think this is the most important question in maintenance. We're kind of using Revlimid in most patients as a blunt tool. That trial shows overall survival advantage to giving Revlimid indefinitely, so we tend to advise that for most patients. However, it probably not as the case that that is the right approach for every individual patient and MRD is a tool that we're going to be using at some point to figure out which patients we can advise to stop earlier, which patients need to continue, which patients might need to have their maintenance escalated. So those trials are really important. And please, if you're considering a maintenance trial, make sure you ask your physician about a clinical trial. So that's all I had planned. Guess I ran a little longer than my goal of 35 minutes, so I apologize for that. So you have me for question. Awesome. Well, that was an excellent presentation and I really appreciate the way that you spoke in terms that patients from all stages of their myeloma journey would understand. It's really helpful to have a baseline understanding of what you're talking about. I know some physicians get really passionate about it and your bright minds sometimes speak in language that we don't understand, but I feel like you did a great job in communicating effectively to us. So thank you. Well, thank you. I did get nervous about the number of Kaplan-Meier curves, but I thought it was going to be cool. No, I thought they were very easy. Well, I thought they were relatively easy to follow along with and I think you explained them well, so thank you. One of the questions that I see repeated throughout the chat and I just want to say, the patients right now that have entered their questions already have done a great job, but please remember that Dr. Rubenstein is not your personal physician, or even if he is, this is not a clinic. So when you do ask your questions, please make sure to ask them in a general manner. Instead of a, this is my personal situation, what would you recommend for me? Maybe you can turn it into, if there were a patient with this genetic, Oh my gosh, what am I saying? Characteristics of the myeloma. What would you do in this case? I will do my best to translate them into more generalizable. Yeah, I want to emphasize, I don't know y'all from Adam, your doctor does, so they know you best and of course you know you better than your doctor does. So, yes, I'm going to speak in general terms and try and try and address things most generally if I can. Okay, let's dive in. All right, and I would just like to say I don't know why the raise hand was option was on because I'm not actually. Yeah, so just write your questions in the question and answers and I thought I turned that raise hand feature off so anyway sorry about that. The question I see repeated is, is pomalidomide, does that have the same results as linolytomide and Can you speak to that as a maintenance therapy? So that's a good question. Pomalidomide, I don't have data about what its efficacy is in the maintenance setting. It doesn't, the decisions that were made when pomalidomide was being developed about how to develop it were to study it after patients were refractory to Revlimid. So we don't have the big prospective trials with hundreds of patients looking at pomalidomide in the maintenance setting specifically. However, I do, I do sometimes use pomalidomide in my practice and maintenance. That's generally when a patient is refractory to their frontline regimen, and I need to transition them to something including pomalidomide, and we're looking for an oral maintenance regimen on the back end. So that is the setting which I will personally use pomalidomide, however I want to emphasize there's not great data. That's almost like a tendency. So generally with patients that are refractory to their induction regimen, my practice is to continue a form of that regimen on the back end just as patient gets their RVD frontline, our maintenance is a sort of a form of that regimen and that it's one of the same drugs. So if we need to salvage a patient gets RVD and is refractory, we give them KPD or Derek KPD, then we may continue POM or POM in combination with something else for maintenance. Yes, it is very likely an effective maintenance drug. I don't have same kind of data for it that I have with Revlimid. That's interesting. Can you briefly explain the relationship between pomalidomide, pomolist and Revlimid for those who aren't familiar? So pomolist is to Revlimid sort of what Kyprolis is to Velcade. It's a little bit of an oversimplification, but essentially it's an updated version of Revlimid. So it does a little more efficiently at the cellular level does what Revlimid does to kill myeloma cells, which I'm not going to get too much in the weeds, but it basically interferes with a signaling pathway that tells myeloma cells to grow. And pomolist does that a little better than Revlimid does, or can do that after Revlimid stops doing that. But it's been shown to work after Revlimid stops working in a variety of settings. That's a different question than if we lead off with the same drugs, is it going to be better just because it's newer? In fact, pertinent to drugs I discussed, this is an argument people made about carfilzomib vis-a-vis Velcade for a long time, because it's newer and better and has better binding characteristics that it would do better frontline. A huge trial of that carfilzomib LendX versus Velcade LendX called Endurance. That read out at ASCO 2020, the first big meeting of the coronavirus pandemic, and was totally negative. Getting carfilzomib frontline did not help vis-a-vis Velcade. And we don't know if the same result would be seen with pom. It hasn't been studied. And the folks who would sponsor such a study were interested in doing it, which, yes, I helped a lot of patients. But it's a strategic landscape and you have to make certain decisions, I guess. Yeah, yeah. So to be clear, because this attendee is wondering if MM markers went up on maintenance of Revlimid before stem cell transplant, would you still think of using that? I think they mean therapy. So if they were refractory to Revlimid in their induction therapy, you would then not use that as the maintenance therapy, but switch maybe to something else such as pomalidomide. It would depend on what is meant by markers going up and what the setting was. I could engineer a setting in which I would do it, but to give a general answer, I generally would not do that. Generally, if Revlimid stops working before a transplant, I think it's possible it could work after, but it's less likely to. And the reason it's possible to work after is that multiple myeloma is, we think of it as one disease, but really in an individual patient, it's polyclonal, which is medical jargon for its multiple different subpopulations. And it may be that the dominant population before transplant is not sensitive to Revlimid, gets knocked out by the transplant, and then what we're left with later is a Revlimid sensitive population. That's theoretical. I personally think if it doesn't work before transplant, it's too risky to try it for maintenance after. And I generally, I sometimes will advise dual in that setting if there's a separate agent. Like, so I have patients, for instance, that get RVD in their refractory to it and then we'll add DERA RVD and they'll get, you know, back into remission. Those are patients I might do DERA and R because there might be something about the synergy between those agents that's helpful. That's my philosophy. This is something that we don't have good trials of though. Yeah, most patients respond to their induction and most patients stay in a response by the time they get to their transplant and designing a study, a high quality study focused on those patients who are refractory would be very challenging. Yeah, I want to comment on one of the clinical trials that you mentioned and I see somebody else has the same question. I thought no placebos were used in myeloma clinical trials. So when you brought up that the placebo was used in the approval for Revlimid maintenance, that kind of shocked me. How is that? Not anymore. Okay. Okay. At the time that Revlimid study was designed, so hindsight's 2020, right? So at the time that Revlimid study was designed, we didn't know if maintenance prolonged PFS. We didn't know if maintenance prolonged OS, which is overall survival. There were other studies of different maintenance drugs. So the things that were used before Revlimid was developed were like low dose Melphalan and interferon and these old drugs you don't hear of very much. And thalidomide, which is challenging to give indefinitely because it causes nerve damage at pretty high rates when it's given indefinitely. So we didn't have a good like potentially tolerable drug out there till Revlimid and people would argue about how necessary maintenance was. So that's why we were able to do a placebo controlled trial at that time. I will say there are, it's a minority, a very small minority of myeloma physicians, but there are still people who don't think maintenance is necessary out there. I can count them on one hand, but you could, yeah, and one of them is quite influential. So you can seek out that opinion, but I think with the randomized trial that shows that Revlimid prolongs survival over placebo, it's pretty hard to give placebo as maintenance. Unless it's very, yeah, definitely. But I would say there, there may be placebo controlled trials, but no patient should be treated only with placebo on a clinical trial. Yeah, yeah, I especially, they get like, cancer. Yeah, maybe trials of like XYZ regimen plus placebo or minus or plus some active agent. Those are plenty of trials like that, but nobody should be getting only placebo at any point in their myeloma journey as part of clinical trial. No risk of that if you go on a trial today. Yeah, yeah. If you are complete response, does the same maintenance philosophy apply? So I think people are confused about like, after stem cell transplant, you get, you know, you get lots of tests done to decide how effective was that stem cell transplant? Does the effectiveness of the stem cell transplant affect the maintenance therapy that you will go on? Good question. So those curves I showed with that showed that people live longer, that applied at all depths of response. So even if you're in a complete remission, I wish it weren't true, this weren't true, but it is very likely true that your multiple myeloma will relapse. And delaying that significantly results in improvements in survival. So my general practice is if patients are in CR, or even in an MRD negative CR, meaning they're in remission, and we use these fancy techniques to test their bone marrow for extra myeloma, we don't find any. I don't have data to tell me that's not a patient that's going to benefit from maintenance. So, so, because we know we're not curing even the patients who get in these deeper missions. Eventually most patients in those deeper missions will eventually relapse, and they may relapse in longer periods of time, the relative benefit may be lower. So, this is my general recommendation. I don't think I ever recommend no maintenance but in some cases if a patient's really struggling, and they're in a deep remission, I'll usually check for MRD and if that's negative then sometimes we'll talk about, you know, do we want to take the chances on a faster progression to have you have higher quality of life and some patients choose that. So it's an individualized discussion, the general response to transplant in and of itself does not determine our maintenance strategy. Okay. I would like to just mention I know sometimes it's hard to talk about overall survival. When it comes to these kind of sessions, patients have mixed feelings about it I mean it's good to know and at the same time it's very difficult to know because what we're talking about is inevitable and I think it's very difficult for people. I see that there's a comment here, somebody who's recently diagnosed with still coming to terms and confused about what seems like a contradiction, that multiple myeloma is treatable but not curable. I don't understand what keeps people from surviving it and it's difficult to talk about these kind of things. I think you hit it in your last answer that unfortunately it keeps coming back, and myeloma is a very smart disease. We need to be smarter in how we're treating it because it evolves. And, and it takes time to know so to this patient. It's okay that you're still coming to terms with this. It's complicated, it's difficult and I'm glad you're here learning more about it today. Yeah, well I'll say is that, you know, we're so it's easy for us to get enthusiastic as doctors because the outcomes for patients have gotten better over the time, I'm not that old I have involved but I'm not that old. So even in the time I've been doing it patients outcomes have gotten better. We have lots of very effective drugs that wouldn't even have when I started not very long ago. Some of which are even at the level of being FDA approved, but it's important to know that progress meets still still means that we have a long way to go. The best. Again, I mentioned this in my presentation to most patients, the two things that matter is living longer and living better. So, trials and treatments that show that they can do one of those two things we consider to be very important. So we're better at making people live longer but it still does generally require continuous treatment exposure to drugs that have these low but real risk of bad toxicities, and we need to do better to get to a place where we're treating people for shorter periods of time and can stop and get people back their lives. We're not there yet. That's the goal. The next question is what determines the drug dosage and maintenance schedule. Good question. The standard starting dose for most patients is 10 milligrams continuously, meaning with no of Revlimid, no break. We sometimes need to adjust that if a patient has renal dysfunction or kidney disease, because Revlimid is cleared from the bloodstream by the kidney. If we have impaired kidney function you may need a lower dose of Revlimid. Another thing that influences it is how patient tolerated Revlimid during induction. Some patients need Revlimid to be reduced during their induction. Those people, I will usually use a reduced dose on the back end. The other thing I'll say is that there's an alternate maintenance regimen that gives three weeks on one week off. There's data showing that that prolongs permission, but at three years did not prolong overall survival. It's a British study, and there's many caveats even more than the French study. I'm not going to get into the differences. My guess is that if they designed it a little differently and use different induction it probably would have shown an overall survival benefit, but it didn't. In any case, three weeks on one week off is a fair way to dose Revlimid. If somebody comes in for a second opinion, their first doctor's doing it, I don't make the change. I do 10, 10's got I think the best data, three on one off, not wrong. Great, thank you. There are so many excellent questions here. I know I'm looking at them and I'm like, boy if I had another hour I can maybe get to all these and do a fair job. Maybe we could do one more and can you give them my email? Sure, if you feel comfortable. What you could do is maybe you can email. Yeah, you can do that and you can maybe email me the unanswered questions, and I can maybe get you my answers to those questions after the fact. Yes, that would work. Okay, yes. I'll take one more now. There's one that multiple people have asked them. I'll take it now. Okay, how about Why is Dex commonly added to maintenance therapy? Great question. I'm not really sure. I don't tend to. So Dex, there's a lot of, a lot of, so Dex is the oldest drug for myeloma, the first drug for myeloma, and it's still part of our treatment regimens. People keep asking the question doesn't add anything to modern myeloma regimens. So the theme of those studies, even some involving anti CD38 monoclonals is that adding Dex deepens our remission. So if we take Dex versus no Dex we get to a deeper place, but it doesn't influence long term outcomes. So, in fact, there's some studies, and they're using Dex doses we don't use anymore but there's a famous myeloma study, E4A03 that's a Vince Rajkumar study, or he led it a lot of many other people participated in obviously, but it compared very high doses of Dex 40 milligrams daily for four days to the more standard dose we use now 40 milligrams once weekly. So, more Dex was associated with better responses but actually inferior survival. So that probably doesn't apply to like 40 versus 20 once a week. 20 probably isn't, it's not like we can go all the way to zero based on that result. But the principle is that Dex helps us achieve a response, probably doesn't help us stay there. So, I don't basically don't ever give Dex in the maintenance setting of transplant. I shouldn't say ever because there's some cases in which I need a full like DeraPom Dex to get somebody to transplant and then I might continue DeraPom Dex after, but I have a very low threshold to stop it for toxicity. Honestly, the patient doesn't need a good reason they can just ask, can I stop Dex and I say yeah, as long as they're the response, I don't believe long term Dex does much. Okay. Is there anything else that you'd like to say as a closing statement before I close with my outro announcements? I want to thank, so first of all I want to say I admire patients with multiple myeloma, you guys are dealing with a really difficult disease. And it's one of the reasons that I do this. Of course the science and drug development is interesting but you all are very pleasant population of patients to deal with, especially considering the difficult disease you're dealing with. So I want to thank you for being that way and also for being such eager participants in clinical research we would not be improving patients outcomes if it weren't for your efforts. I completely agree and there's lots of thank yous coming in so we're grateful for all of you for attending here today and thank you. As mentioned, I will get those questions to you so that you're able to answer those. And I'm even thinking I mean this is such an important topic and there's so much interest in it. I wonder if we do a part two next month. I was going to choose options during and after stem cell transplant when you don't have support at home, which I believe is important, but I wonder if we should continue the momentum of this and continue to talk about this role of maintenance. Yeah, you definitely should there's so much to discuss and there's so many active and important trials in this space that are enrolling right now. I love, I'm an academic I love talking and listening to myself talk, but also, as you can tell, there's a lot of live controversy in this field so yeah it'd be good to get a different voice, maybe a maybe a female myeloma doctor can do it. There's a lot of good. We'll see. Yeah, yeah, you don't need another white guy to give his client you can find somebody else. Yeah. I'm happy to, I'm happy to chat anytime. Thank you, Dr. Rubenstein I really appreciate you taking time out of your day to prepare for this and speak to our group. Just a reminder to all of our participants as you leave this session today. We appreciate you taking two to three minutes to fill out a brief survey about your experience with today's event. The upcoming events you might be interested in on the sixth is the myeloma financial chapter. We're going to be talking about support and resources for your myeloma treatment. This is an extremely important session we're going to be talking about pharma and support programs that can help you pay for medications if you're paying out of pocket expenses. Then at that same day at 7pm is our minimal residual disease chapter. We're going to be talking about what to do with minimal residual disease with Dr. Luciano Costa, who has done several clinical trials trying to figure out the answer to this question. Then the seventh at 1pm Eastern is our cell and neck sore group, and we're going to be hearing from Dr. Craig Cole about cell and neck sore carfilzomib and dexamethasone which are some drugs that we talked about today. 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 site and will be included in that follow up email. Thank you to our sponsors, we're still Mary Squibb, GSK, Genentech, Dance and Oncology and Appy. And a big thank you to each of you for helping us grow this myeloma community. I appreciate each of you and hope that you have a great rest of your day. Thank you Dr. My pleasure. My privilege to spend some time with all of you. Thank you. Thank you all. Bye bye.