Today's topic is know your myeloma therapy, pomelist or pomalidomide. Pomalidomide is a familiar myeloma therapy, but perhaps one that isn't frequently as used. Today we're going to be learning about its mechanism of action, efficacy, and side effects from Dr. Svamsanka. It's important to me that myeloma patients and caregivers are actively aware of what medicines are being prescribed to them and put into their bodies. It allows you to better understand what's going on in your body, what's going on with your disease, and have more empowered discussions with your doctor. It is now my pleasure to introduce our featured speaker to you. Dr. Atiyah Svamsanka is a graduate of Thule Longhorn University in Thailand. She completed her residency at Albert Einstein Medical Center in Philadelphia and a fellowship at Roswell Park Comprehensive Center in Buffalo, New York. She joined the Indiana University School of Medicine in 2003 and currently serves as an associate professor at the IU School of Medicine and researcher at the IU Simon Cobran Cancer Center. Dr. Svamsanka's research interests are in the molecular mechanism of drug resistance in multiple myeloma and precision medicine. Her clinical expertise includes myeloma, cell transplantation, and immunotherapy. Dr. Svamsanka, thank you so much for being here today. The time is now yours and I look forward to hearing from you. Thank you so much, Audrey. And thanks so much everyone for joining. It is a privilege to spend an evening with you. I think in my time zone it is evening, but maybe for some of you, you're barely leaving work yet. And share what we know about homolidomide and hopefully having plenty of time for you to also share your experience and go through questions you might have. Whether it'll be about homolidomide or something that relates to it or other aspects of myeloma, I welcome all of those questions. The slide I have hopefully isn't scaring anyone away because it does have some graphs and so on, but I don't plan to spend extended time with the slides to go very much deep in detail. I want it to be a point of discussion. I'm gonna start sharing the slides. Okay, I was just gonna, perfect. Tell me that I haven't shared what I was saying. Yes, you knew that. It would help to share. Okay, so I should also mention that not only I see patients over at Indiana University, I also have a privilege of seeing patients over at Richard Radebosch VA Medical Center, which is really just a block away. So taking care of veterans there. Okay, doesn't want to go forward. Okay, so I don't wanna scare anyone about all of these diagrams either, but I wanted to mention that homiletamide belongs to a family of drug called IMITS or immunomilitary agents. And the reason that they're called that is exactly because they don't just work directly to kill myeloma, but they do a variety of things to activate the immune system, such as they actually stimulate natural killer cells and natural killer T cells to have the immune system come in and help committing cell killing. In addition, if you think about myeloma cells as hanging out, just like weeds in the garden, hanging among other plants, myeloma cells take advantage of other neighboring cells, including the stroma where they attach themselves to, and also other cells around them to end up supporting their own growth. The drug in the family of IMITS actually disrupts that interaction. It makes the cancer cells not adhere as tightly to the stroma. It makes them not able to enjoy all of the secreted factors that promote their growth. So all in all, we, with this group of agents, ended up about nearly two decades ago with agents that did not just kill the cancer, just like old-school chemotherapy, but something that's actually pretty specific to this cancer and works by multiple ways. So since the early onset of the first in class agent, thalidomide, there has been two other sisters that got approved, which is linolytomide or Revelemed, or antipomalidomide or pomalist. And if you look at what the pomalidomide looks like, it really is a combined sister between thalidomide and linolytomide. I'm hoping that most of you did not need to take thalidomide anymore, but some of you might have started on the journey with IMITS with the thalidomide. It was the first one in the family, but also was the most difficult one to use. And there are many side effects, constipation, neuropathy, sedation. So the second drug, linolytomide, was sort of a sister that is as far apart based on the chemical structure. From the first one, it was based on the chemical structure from thalidomide. Sort of one on the left hand, one on the right hand, and that was why it was chosen for development. Even though of the three sisters, pomalidomide is the strongest one as far as its activity to stimulate the wound system or kill the cancer, it really was chosen for development a little bit later, because it has a part of it that looks a little similar to thalidomide, and that was raising concern about its potential overlapping side effects. So the three sisters are still available today with pomalidomide actually being approved as to use in a later line, mostly after patients have already had linolytomide. And we will look at the clinical trial data that led to its approval in a little bit. So the three sisters, I was telling you that they belong to the same family, but they're kind of different. We talk about the potency and that ability to activate the immune system and killing cancer. So it goes in rank, thalidomide, holo-violinolidomide, and pomalidomide is the strongest. Neuropathy was most significant with thalidomide, and that was exactly why second and third generation agents were so needed, because that was an unintentional side effects. It was what we call an off-target effect. You don't need to have neuropathy for the drug to work. So if we could find an agent that works similarly, if not even better, but also avoiding toxicity, that would be important. Now, the blood clot risk stands all through. Although it was reported first in the linolytomide and continued to be an issue with lenolumide, by then it was so clear that this group of drugs shift the clotting and bleeding sort of balance towards promoting clots. So all of the patients who are taking medications in this group were then required to have prevention type medicine that's used in conjunction with the medicine. And these could be aspirin, could be injection of blood thinner, or something called Levenox, or it could be an older blood thinner called warfarin where patients need to have their levels checked. The level is called INR, and it is important to be sure that it is not too high or not too low. Newer medicines that have already been used in other diseases, not only in treatment of blood clot, but also in age of population, a medicine in the group of what we call DOAC. Many of you might've heard about these medicines on TV commercials, Revaroxaban or Somranto or Apixaban, its trade name is aliquist, are already started to kind of get adopted as the prevention type choices. All of these medicines will suppress the blood cell production, and we call that myelo suppression, which means that if we're suppressing the normal blood cells, there are gonna be side effects that relates to low blood counts. You know that low white blood cell increased risk of infection, low red blood cell cause anemia, and patients can be often experienced fatigue. Low platelets can cause increased risk of bleeding, particularly since we have our patients on medicine to prevent blood clot. Now the interesting thing, particularly between Revlimid and Pomelist is how they're cleared from the body. Revlimid is cleared mostly by the kidneys. So in patients whose kidneys aren't perfect, you will need dose adjustments, you will need lower dose so that the drug is not filling up in the bloodstream causing side effects. But Pomelidomide is an interesting one because it is mostly cleared by the liver. So many of our patients with myeloma whose kidneys don't work well. And when they don't tolerate Lenalidomide or progress, when they go to Pomelidomide, they might find that they don't need a dose reduction, that they can take the standard approved dose, just like patients whose kidneys are working well. But the caveat is it is cleared by the liver. So patients whose liver is not working well may not be the right candidate for it. There are not a whole lot of experience of usage of Pomelidomide in patients with liver failure. So even though there's a recommendation for using lower dose in patients with bad liver, it's not clear how low you can go. So this would be the group of patients that I probably look past Pomelidomide and try to look for other agents instead. Now, all of them are bad to take when you're pregnant. And luckily, I'm hoping that most of our patients are not going to try to get pregnant, but the reason that there is pregnancy category listed is because Pomelidomide was actually first approved in 1950s. Weirdly enough, as a medicine for morning sickness, and when I tell that to all of my patients, they look at me very weirdly because they just couldn't imagine such a drug being used over the counter, but also for pregnancy. It's really because Pomelidomide at high dose is actually quite sedating. So it wasn't that it was really coming down the stomach so much, but it actually just made ladies who were suffering from morning sickness sort of slept with the first trimester. Unfortunately, that is also such a critical time that the fetus is being formed. So babies were born with limb defects and that really led to the black walks morning. And also now you are all, whether you're taking Lenalidomide or Pomelidomide are actually registered with a particular side effect monitoring program called the REMS program. So that was the story behind it. But goes to say, we have agents in the same family, newer agents, a little bit more potent and different in some way to what we've already had and end up getting used a little bit later just because of the way it's developed. Pomelidomide was mostly tested in patients who have already had Lenalidomide. A question, sorry to interrupt you. We just got a patient question about what does DVT mean on those slides? Oh yes, I do apologize. DVT is deep vein thrombosis. And that's really the blood clot in the veins. Typically they happen in the legs. And this is probably why, you know, your doctors are always saying if you're traveling long distance, sitting in the car for a long time, you better park and get out of the car, stretch around if you're flying, use compression socks or be sure to get up, walk to the bathroom, come back, that kind of thing. But the blood clot can happen. Outside the venous system as well, there's slight increased risk of arterial clots and that stroke, that's heart attack. And this is why it's important for our patients who might have already had risk factors for these clots. Say for example, if you've already had blood clot before, you've had history of stroke or heart attack, then your doctors are pretty proactive about being sure you're on the right kind of prevention. And there are many choices, going from aspirin, over the counter, all the way to injectable form, but thinner. So not all of them have been compared head to head, but they all work better than not to be on it. And this also means that say, if you were scheduled for a clonoscopy and you're taking Revlimid and your GI doctor said, it doesn't matter, they really don't worry about your chemo, they don't wanna mess with it, but they want you to stop the blood thinner, say a week before you come in for clonoscopy, you're gonna call your oncologist and say, my GI doctor really need me to stop blood thinner. Do you want me to continue on the cancer treatment or do I need to put a pause on that? Because I mean, oftentimes this group of medications are commonly used in the cancer world, but less so outside. So other doctors may not always know that you really have to be on these agents just because you are taking this type of therapy. There are also some of my patients who were say, taking what they know already for atrial fibrillation. And their cardiologist said, well, since we have converted your heart to regular rhythm, we don't need you to be on blood thinner anymore. The first thing you do before you say thank you doctor, is say thank you doctor, but let me talk to my oncologist because they may actually need me to be on either that same blood thinner for a different reason or switch to something different as long as you're still taking this group of medicines, you should really be considering prevention. And there are some patients who are, even with the right kind of prevention, end up with blood clots, particularly serious blood clots, then this group of medicine may not as it's really be the right choice for you. So it is with a little bit of customization depending on the patient's risk. I'm seeing the question, the transcript has too many errors. Okay, just keep talking, it's okay. And I wanted to apologize because I think part of the transcription error may also be my accent because most actually will not necessarily recognize my Thai accent, but afterwards, if there are any particular slides that you like to have, and you want me to create a little blurb to describe what I was talking about, I would be more than happy to do that. And Audrey can make it available to anyone who's interested, okay. And in addition, it's not necessarily your accent because I don't think the transcript recognizes these complicated words and medications and myeloma vocabulary, you know, like I don't even think it gets myeloma right. So it's not good. Okay, but really, if it doesn't sound clear and if the transcription does sound really weird, please feel free to just pause me. And we can go over what wasn't clear, okay. Now, there's a story behind how Pomolist was developed. It's actually not that new a drug, it's almost a decade old now. When it was first approved, it was approved because of this landmark clinical trial that was using Pomolist plus low dose dexamethasone to compare with just dexamethasone alone at high dose. And it was hard to think that at that time, we actually called this 40 milligram a week of dexamethasone as low dose, because I think most patients would say that that is plenty high, no pun intended, but it does keep them high as well. But before we come down to the once a week dexamethasone at this 40 milligram, the so-called high dose dexamethasone that was a controlled arm on that clinical trial was a 40 milligrams, you take it four days in a row, and then put a pause on it for four days, go back on it again four days, all four days, that kind of thing, and you do it three different series in a month. So that was needless to say very difficult, and also unfortunately not very effective, but that was the control arm on that clinical trial. Since then, there have been developments of other things to combine with the pomalidomide after the first doublet, the pomalidomide dexamethasone was approved, and we'll go through those clinical trials, but you'll see that every few years, we seem to learn a little bit more and have different ways to combine pomalidomide with other things. And the primary group of drugs that end up getting combined with it are the antibody treatment, because I was telling you that pomalidomide activate the immune system by stimulating NK cells and T cells. Well, the antibodies in general bind onto the cancer cells once it gets into the circulation, but then it's waiting for the immune system to combine recognize that cancer cells that's marked by the antibody for destruction. So the two things are synergistic because they're actually helping each other out in the way of killing off the cancer cells. Let's talk about the first clinical trial that was nearly 10 years ago. So this was what we call a phase three study. What that is, is it's comparing, it's challenging existing therapy, asking a question whether the new drug or drug combinations would perform better. That study was done in patients with myeloma who have already progressed on at least two other lines of treatments. And good number of them actually received lenalidomide and verticidim already, but they did not need to progress on it. Now, they could also be the people that stopped therapy because they didn't tolerate it and progressed within 60 days of treatment. The regimen they got was a four-milogram, which is a standard dose of homolytomide, and they take it daily, three weeks in a row. So day one through 21 and off seven days. The control group was, as I was saying, those four-day series of the Jackson-Method for seven four days on, then off, then on again for four days, all four days, and on again for four days. And the treatment continues until progression. That data shows that on this left hand, you see what we call progression-free survival curve. The top line reflect patients who continue to be in remission at any given time when they're taking the combination of homolytomide dexamethasone, while this lower black line reflect the group that took dexamethasone alone. And there's clear and early separation showing that the new drugs, the regimen that has homolytomide actually perform better to keep patients in remission. Not only that, it actually translates to longer remission. So that was why homolytomide dexamethasone was approved. There, well, there are, I see in the chat that there are questions about the- Don't worry, we'll get to that. Yeah, we'll get to that. I promise I'll get to that because I have one of the slides that was really talking about blood clot issues. But I think it's good to talk a little bit about why homolytomide that had better efficacy got developed later. It was really because there was such a concern about side effects of the thalidomide. And when I was showing you the chemical structure of homolytomide, it actually looked a little bit like the thalidomide. So the intention for drug development then was to go as far as possible to the other sister that looks so different from thalidomide. And that was why lenalidomide or Revlimid actually was chosen for development and take onto clinical trial first, even though homolytomide was sort of was looked at first. But when lenalidomide was already approved, but patients were failing it over time, homolytomide was sort of pooled for development later, specifically for patients who've already failed the lenalidomide or Revlimid. And until these days, that is really how the package insert is. It also exclude patients who've had significant neuropathy, whether it would have been from the lenalidomide or from lenalidomide or from another group of drugs, the proteasome inhibitor or mortisimit. So, I mean, by then we learned that neuropathy is bad in myeloma and stopping the drug doesn't make people always feel better. So it is important to put extra caution and choose the drug that probably doesn't have as much side effects in that regards. But I hear you, it's why not save the best for last? But that's the story of where we are. Okay, so that was 2013. We did not stay with that regimen for too long. We move on to the combination. My forward slide does not want to go forward. Okay, so these were the side effects and many of you who've taken the drugs would have already experienced this. I was talking about suppression of the black counts and that's why this meotropenia, which means low neutrophils, neutrophils are infection fighting cells. If you're taking formalitamide, comparing to if you were just taking the dexamethasone, there's higher degree of suppression of the neutrophil production. There are also more fatigue, sort of malaise, not feeling great and higher risk of infection. Now, luckily these side effects are manageable, meaning that they're usually not to the point where patients need to stop therapy. They can be managed by holding the medications, allowing the black counts to recover and adjust the dose. Formalitamide is approved at four milligram, but it does come as three, two and one milligram capsule as well. So just be looking out for these side effects if it would happen to you and definitely please discuss with your physician. Many of my patients early on when this drug was approved got worried that if they weren't telling us that they didn't feel great, that they would actually be taken off from the agent or from the clinical trial. But the concern though is without adjustment of the dose appropriately, you end up getting significant side effects that may preclude the doctor from ever using this group of medicines again. So we also don't have a way to measure the blood level of these agents. So we go by how your body experienced the side effects and kind of modified accordingly. So let us be part of your team. Tell us how you feel and we'll help supporting you through such a treatment. There is, so do I, well, I will, I promise. There was a question about aspirin with formalitamide. So I will kind of get to that. Don't, as you see the questions come up, don't worry about them. We have time at the end and I'll moderate those. So no worries. Okay. So we did not, I probably was jumping the gun. So we didn't stay with the doublet for too long. We realized that with myeloma combination therapy that attacked the cancer cells by different ways, help making the treatment work better. So this was a study called Eloquius which was bringing the doublet, the formalitamide and the dexamethasone together with an antibody called daratumumab. Many of you have probably been on this or heard about this. It's an agent that bind onto a particular protein on the surface of the cancer cell called CD38. That antigen, that protein is expressed greatly on the surface of the cancer cell and it's not expressed a whole lot on any other cells in the body. So it's used as a target and the antibody is more like an arrow looking for the target. It binds onto the cancer cell and helps calling the immune system to come in and clear it off. So the combination was very started on what we call a phase two study which means that everyone gets all of these medications. And it was trying to compare experience with patients who were getting just the two drugs. And just like what the original clinical trial of the two drugs was, most of these patients have already had Revlimid. Most of them have already had vertizema and a good number of them actually were refractory to both. And even in that significantly bad situation at the time because we didn't have as many choices, response rate was quite fantastic. It was 69%. So that was pretty exciting. And also not only the response rate was good, patients also stay on remission for average 13.6 months. The adding of the antibody did not seem to increase the side effects significantly. So because of the promising signal, the triplet combination got then explored further in what we call phase three clinical trial. And if you start back to the homolytomide dexamethasone being compared to single agent dexamethasone, this time we're comparing homolytomide dexamethasone and that daratumumab with just the two drugs. Daratumumab in this new version was given as an injection rather than the IV. That gives such a huge benefit comparing to the IV in that you don't have to stay for a long time at the infusion center. There is also less infusion reaction comparing to the IV form. Infusion reaction with antibodies can cause people to feel the flu-like symptoms, fever, and some may have shortness of breath and wheezing. So this is a very important point which could be pretty serious for patients who may already have baseline cardiac or lung problems. So the triplet was compared to just the two drugs and patients again take the treatment until progression. And that graph comes right back, that Kaplan-Meier survival curve. This one is looking at patients who stay in remission without progression. The top line is the group that took three drugs, actually improved that progression-free survival by a fold. And when you look at just why, it's obvious that most of our patients had such deeper remission, meaning that if the drugs are effective at killing off more cancer cells, then that should hopefully allow those cancer cells that are left behind to be suppressed and patients last in remission longer time. Unfortunately, still a good number of patients with long enough of a follow-up may relapse at some point, but long remission like this with a regimen that's quite manageable, particularly for homologamized oral, dexamethasone that's used within this oral, and the daratumumab antibody down the road after the first six months of therapy becomes just a once a month injection. So it gives patients a lot of convenience and flexibility. So we are definitely a lot better at keeping our patients on this journey with good quality of life. Still, side effects, when you combine things, we need to expect side effects that are brought about by every component in the regimen. That antibody daratumumab, when it's used together with formalitamide, increased risk of infection. It drops the neutrophil count a bit more and increased fatigue. There also may be slight increase in the GI side effects. The formalitamide itself caused quite a bit of diarrhea in some patients, and adding the daratumumab may up that signal a little bit. But I highlight infections because that is what we encounter in keeping patients on treatment for a long time. So prevention is key. Some of your physicians may opt to give patients prevention type antibiotics, particularly in the first one or two cycles to try to get patients through that tough phase where the cancer cells are not yet fully controlled and the body is still gonna see some side effects. Once patients get past that first few months, usually the blood count holds better. And if the dose modification needs to happen, sometimes down the road, if patients are only on one or two milligram of formalitamide, because they struggled with side effects earlier, but their cancer is not yet in full remission. They're tolerating treatment better now. There may be an attempt to kind of escalate back up. That's entirely possible. So prevention, I was saying, is the key. Some patients may also end up getting what we call IVIG or infusion of antibody molecules because they're not making enough of good antibodies when the body is making the wrong kind of protein because the myeloma cells were there. There's usually a suppressed production of the normal ones. So a little bit of a replacement may help prevent infection. Most of you are probably taking a medicine called a syphon beer to prevent shingles. That is the right thing to do. Vaccination to boost up the immune system, whether it be flu vaccine, COVID, pneumonia type vaccines, those are all sort of something that we can do to keep patients on this journey safely. Another antibody that's been approved together with formalitamide is something called elatuzumab. It isn't used as frequently as the daratumumab because it doesn't really have what we call single agent efficacy, meaning that elatuzumab itself really doesn't work well unless it's used in combination of other medicines such as formalitamide or linalitamide. And it's a newer one that's been approved in combination with formalitamide. So it's not quite clear whether it works well in patients who have already failed daratumumab, but you might hear your physicians talk about finding the right partners. And when they're talking about formalitamide exomethazone, they may mention about this particular antibody which has been very well tolerated. So side effects wise, it's really not that terrible. And comparing the progression-free survival, comparing just the two drugs and the three drugs, the three drugs work better. So it goes to say, if you're on formalitamide exomethazone, you probably have another agent in your recipe, whether it'll be daratumumab or elatuzumab, or this is really showing that same kind of graph with the top line showing better overall survival. And that's the group that got the antibody together with the formalitamide. But I was mentioning other regimens that you might be on or your doctors might talk about combining with formalitamide. They are not approved as a triplet combination because most of these have been studied in phase two clinical trial, mostly combining themselves with agents that have already had a strong footprint in myeloma, such as the drugs in family of prism inhibitor, that is the vortisimab or Velcade, or isosomib or Nilaro, and the carfilzomib or Kyprolis. That one is the intravenous one, and all of the three probably has the strongest efficacy. Now, because three was good and mean two was better than one, three was better than two, you can imagine the oncology world is asking, well, is four better than three? Well, that has not been studied in formal phase three type clinical trials, but data from phase two. So smaller group of patients looking at the four drugs together show that they have great efficacy, but certainly higher chance of infection and more side effects. So these are probably right now reserved for patients who have more rapidly progressing disease, and younger patients who probably will tolerate the side effects a little bit better. So we talked about the good things about this group of drugs, and mentioned a little bit about maybe the not so good things. So I wanted to bring us back to talk about the embryo toxicity, of course, with the leading agent in the group, the little white, and these were the pictures of children that were born in that 1950s, when a little white was used over the counter for morning sickness. And also the comparative study that was done in monkeys where they're given a little white during that first, first one third of the gestational age, and you can see that in high animals, there's also limb defects. But that might actually be why, outside of the use for morning sickness, it actually works in myeloma, because part of the limb defect will start to be related to blockade of new blood vessel formation. Apparently, when we form limbs in embryo, in fetus, you have to form blood vessels to go along with the limb that's extending. So by not having new blood vessel, it cause defects. But we know that in myeloma, the cancer cells are trying to form new little blood vessel channels to steal the nutrients, to use it as pipeline, to degrade the waste, and that really helped them expand and grow. So that property that the little white showed was called antiangiogenic property. So it blocks the new blood vessel formation and help finish myeloma. So just be careful. Don't let your medicines be taken by mistake by anyone else. And whenever you need to do that RIMS program, and most of my patients are so annoyed by it, I am too, but now we know why. Now, we have to talk about rash, which is seen a little bit less with formalytomy comparing to Revlimid, but this is something that if it would happen when you start the agent at home, please, please don't wait, call your doctor because it can actually expand and get worse and cause the skin to be peely. And patients have the skin that looks like they have 30 degree burn, that could actually lead to quite terrible long-term complication. So I said that formalytomy probably has a little bit less frequency of rash reported with it, but also know that it was not ever studied in patients who had extensive rash with Revlimid. So say if you had rash, terrible ones when you took Revlimid before, and now you're changing your oncologists, your new oncologist is now saying, let's start formalytomy, please, please remind them that you had terrible rash before, because you might need some desensitization. There are some strategies where oncologists will work with the immunologist to be sure that this kind of agent gets started safely. All right, and we talked about thrombosis, that's black blood. A little bit hard to predict in whom it might happen. In myeloma, it's probably 10% or so of patients, particularly in patients with active disease who will experience black blood. And that is just for myeloma itself. So as we layer complexity of treatments that we use on top of that, and also patients who are hurting a lot and do not want to move around very much, variety of reasons make us need to think about prevention. Now, black blood, I was saying, it usually happens in the legs, but it doesn't always just stay there. Sometimes it shoot up to the lungs and cause what we call pulmonary embolism. So if you ever find yourself having swelling of the legs, particularly when it's one side more than another, particularly if it's causing pain, don't wait, let your doctor know. If you have sharp shooting pain in the chest when you're taking a deep breath, it can be pulmonary embolism, let your doctor know. Choices of blood thinners. There was a question about, well, aspirin, and this Levonox and Warfarin, what is better? Choices we don't know. There have not been clinical trials that looks at all of these choices side by side, but they all have been shown to be better than control. So at least aspirin, 81 to 325 milligram are probably something that everyone should consider in patients who have already had more risk for black clot than otherwise general aspirin would be considered appropriate. Those are a step up. The injectable form of heparin can be difficult to use because you have to give the shots to yourself. And depending on your body size, it may be twice a day. So the inconvenience is real. And that's why a good number of patients who failed or were considered to have high risk of clot where aspirin wouldn't be sufficient, they may go on to receive Warfarin. And I was mentioning that that one does require the follow-up with Coumadin Clinic to be sure that the level is right. But newer agents hopefully make life easier. And that would be medicine in the group of the aliquist, Sarelto, and we call them DOWAC. There are many choices within that group. Cost of these newer agents tend to be concerned. Aspirin costs partly anything. Newer agents tend to have financial burden. So that will be another factor to consider. I don't think that any suggestions your doctors have given you were wrong, but I think it's probably explaining why not everyone takes the same thing. So more than anything, be looking out for the clot symptoms. And myeloma doctors always try to find ways to group our patients into the low risk, the high risk, so that we can actually all manage our patients in the same way. It's not always easy because even though there's some scoring system that's taking into account of some of the risk factors on the host, on the patients such as body size and the history of clots, whether they have any, you see, we see as like the category, do you have a medipore, do you have those peak lines, do you have something in your blood vessel that dangly and blocking the venous drainage that was gonna be a problem. Or if you have femur surgery, hip replacement and knee replacement, or you actually were on aspirin and you failed it, or you were on warfarin and you failed it, you have risk factors that tip you over to the high risk and then that in up forcing our hand to use a more aggressive blood thinner. Also, if you're using this image, the homolytomide, the linolytomide together with higher dose of the steroid, or if you're using it with this Evo, which is the red blood cell stimulant, it has the name of Aranaz or Procreate Evo, those increased rates of black blood as well. So depending on where you fit in this big scheme that dictates the different choices. I probably have most of my patients on the aspirin between the baby aspirin, 81 milligram or the full dose aspirin, and only people who've actually had history of blood clot, I would put them on full anticoagulant. Now, second cancer is what we don't talk about a lot. Having one cancer is already bad enough. Why are we talking about second cancer? It's because there's signal of second cancer with linolytomide. With homolytomide, that signal is not very clear because it hasn't really been used as long, hasn't been around as long, but please don't forget the cancer screening when you're doing so well from your cancer from your myeloma perspective, it is important to look for anything that's preventable. So we don't always know when second cancer is gonna happen and in who, but certainly for patients who've also been exposed to high dose chemotherapy, that risk does go up. And there's financial side effects. This is an issue that is so near and dear to my heart and also to many of you, particularly as we're talking about using medications in combination, the cost on the left hand is the annual cost, it's a cost per year and it's a cost of the single agent. So the more agents we combine, the longer we use these agents because patients stay in remission longer time, we're gonna be driving the cost. So there's not an immediate solution, unfortunately for the financial side effects, but really this is a point to also compare and contrast different agents and discuss well with your treating physicians. There are co-pay assistant program out there and if any of you feel that rather than solving the problem just for you by looking at co-pay assistance, but also take it up to be part of solution, this would also be where patient advocacy comes in, health tree has access and representation that would actually make your voice heard when it comes down to the financial side effect as well. So it doesn't have to be patients either, it can also be caregivers. The right hand is showing that this isn't just for myeloma, every new drugs that have been approved in the past they keep the cost goes up and not only the cost when it's approved but also the cost increase over time. And well, generic version of Pomolase has been approved, it's just not yet available and hopefully this will change pretty soon. Pharmaceutical companies are of course going to war to figure out who gets to hold the patent and to what, but hopefully in the near future, we will have this generic version that drives down the cost because the cost of production itself really isn't. Isn't that high, Indian company, this Natco company is based in India and they were of course making the generic version of Pomolase and this is the unit of monies in rupee and 20,000 rupee is 200 bucks. That's less than really your heart medicine or your blood thinner even, and far less comparing to what we're paying in the US. So that's what I was thinking when I think about Pomolamide. And I think Audrey, I ran way over my talk time, I was hoping that I can cover some of the questions so please keep them coming. Yeah, let me moderate those for you. That was an excellent presentation. I think you covered a lot and we had a lot of discussion and in-betweens during that. So no worries about running a little bit over time. One of the questions that was asked that I just wanted to touch on a little bit more, why is Pomolase not used more often? We see that it's efficacious, we see that it's tolerated well, why don't we see it more and why is it in front line? Give us some reasons. Yeah, okay, all right, VMS is gonna kill me. I could talk about the science but also I think a lot of drug developments are also partly mediated by the strategic planning of the pharmaceutical companies which respond to their shareholders. So if you want purists from the science standpoint, I'm gonna say that because Pomolase look a little bit like a hybrid between the little Mike and Revlimid and if we're worried about side effects of the little Mike then you want a second drug that looks so different and that was like Revlimid was pulled off the shelf for that purpose. But if you were to say, well, now that we know the little Mike can cause neuropathy and so far experience with Pomolidomide has been pretty decent, neuropathy that was a concern really wasn't seemingly as big a deal, particularly if we watch patients closely, if we do a dose reduction. I think it goes to the second marketing kind of approach to this in that it was actually never studied. In frontline or in patients who have not been on Lenalidomide because so far it's only you have to bend on at least two lines of therapy and those may include Velcade or Revlimid. Now there's gonna be unique group of patients that really is really not a good choice such as patients with terrible kidneys while you dose reduce Revlimid. Some patients even with the lowest dose of Revlimid they still have significant side effects. Pomolidomide may be a better choice because it's mostly metabolized by the liver. But it's sort of, you can take my answer as a purist or you can take my answer as that this is what pharma marketing looks like. Now, if and when the drug becomes generic, if there would ever be an investment to go back to the drawing board in Duke-Linford trial that was truly comparing the two drugs in the space where you don't have to fill one before you can tap into another that might change everything. Right. But even now that the generic version is approved is still not accessible. So hopefully a lot of push from patients like yourself from caregivers to bring this issue to the forefront will help the FDA, will help the pharmaceutical companies think about approaching drug development differently. Yeah, I appreciate your authenticity in that answer. Thank you. One of the patients is wondering if pomolus lowers white blood cell counts. And it does. Now, luckily not permanently. It actually slowed down the neutrophil development. So if you think about how our stem cells inside the bone marrow make white blood cells, they kind of go through different stages before the actual neutrophils get kicked out to the circulation to go fight infection for you. So medicines like this slow down that process. So your neutrophils are not making as much and there are also selections coming out to the circulation. Medicine like Nalazda is a growth factor for white blood cells. So you're pretty much just kick the bone marrow and say, go make more white blood cells. So hopefully you can actually still tolerate the pomolidomide without such increased risk of infection. Now, if the neutrophils drop pretty low, most of us would probably still put a temporary pause on the pomolist and maybe do this Nalazda, get your white blood cells up a little bit before starting again. It's kind of hard to continue with the pomolus and also give the growth factor and think that we're always gonna come out winning. It usually, unfortunately happens the most when you need the drug the most because when there are a lot of cancer cells in the bone marrow, the bone marrow just isn't so healthy to be making blood cells. So it's already under attack. Many patients have already had low blood counts to start out with and we're coming in with agents that's gonna go after the cancer, but also at that time, slowing down the white blood cell. So oftentimes after you sort of chew off some of these cancer cells, your bone marrow looks so much better a cycle or two later. So you might find that you could tolerate the full dose of pomolidomide without as much problem after that initial phase. Also, I was saying that particularly for any of you who are taking pomolidomide X-medicine together with the monoclonal antibody, with the Darcelex, at the beginning, it is also given weekly through on a lot of treatments for the right reason, but it also makes it harder to get through with this side effect. So that's why everyone needs to be monitored closely. I usually like to check patients' blood count weekly when they start a regimen like this and back off when I need to or use medicines like Elastide, but hopefully you don't have to always use it. And if you find that you're responding great to the treatment, but oh geez, you're on Elastide every month, probably by then your cancer doctor will be thinking about cutting back on the dosage because maybe you're more sensitive to it because of the way you're breaking it down and maybe you don't need as much of the medicine to still continue to have a good effect on the cancer cells. Yeah, that makes sense. There's several questions about combinations. So I'm gonna kind of go through them and see what you think about them. So one of the patients is asking about Benetoclax. It's not currently, for those who don't know, it's not currently approved within the treatment of multiple myeloma, but many doctors use it for patients with translocation 11, 14, because it's very efficacious. So have you ever used or have you ever considered using the combination of pomalidomide and Benetoclax? I think that is a great question because of course, in that group of patients with such unique translocation, Benetoclax is a medicine that really shut down the particular genes that's turned on with that translocation. And when I say translocation, it means that these are two pieces of genes that are on two different chromosomes. They should have never seen each other. And somehow in the genetic chaos of the myeloma cells, you actually have the two protein fused together. So the problem is this, in this group of patients, it brings the two genes that one is an on switch and the other one is the cell growth signal to automatically really jack up the proliferation. And if we could just shut that down, then even without other chemotherapy, that Benetoclax alone could work. It works even better when you combine it with something, but it only is beneficial in patients with that specific translocation. Doesn't seem to expand its benefit to the group that doesn't have it. And in fact, in the group that doesn't have it, clinic large clinical trial would end up showing that we probably have hurt some people because they didn't derive benefit, but they also got the side effects. So I think it is with a little caveat as we're gonna go forward, exploring who's the right partner for Benetoclax that needs to be in that specific group of patients. So most data right now are in combination with the group of prorosome inhibitor, whether it'll be the Velcade, Brutizomib or the Carfilzomib. This is also because that group of drugs has quite excellent activity that's unique in the 1114 patients. Before we even had Benetoclax, the 1114 patients before we had the Brutizomib was actually once categorized as high risk because they just didn't seem to do very well or as well with chemotherapy, with the transplant or at the time with Belinomide, who knows whether Revomid and Pomogetomide have actually really overcome that fully. But the experience was quite different for when Brutizomib came about because it really worked quite well in the 1114 and that's why now that we have the specific off switch with the Benetoclax, it sort of makes sense to combine it with a drug that works specifically well too in that group of patients. But there are small clinical trials that look at combination with Pomogetomide. So I'm sure that if your doctors are grabbing on to a combination, it is with rational thinking for why using it together, but this is also why it's not approved together. It's really not studied in that way. And I think the future development of Benetoclax is gonna be interesting mostly because I don't know that each white partner is gonna actually be a Pomogetomide. I'm concerned that with Pomogetomide, you do need to have steroid with it and Benetoclax actually increased with risk of infection quite a bit. So you wouldn't be on two drugs, you'd be on three that has Benetoclax, Pomogetomide and Dexamethasone, whether we end up causing too much infection is just unknown yet. Yeah, I would just, Dr. Svantezaki, you can tell the passion that you have for this and I just, I love it. Thank you for doing what you do. Let's talk about, you mentioned Carfilzomib, combinations with Dara, Carfilzomib, Pomogetomide and Dex. Yeah, so these quads sort of like, you know what? We grab the strongest member of every family and we just put them together. So you're like super cocktail. Well, it really does have quite significant efficacy response rate in patients who are what we call triple class refractory people who've already failed, Lenin-Wolfe-Mind and Lenticinib. In phase two, clinical trial was pretty good. It's sort of almost 80% and 80% in that group is, it's not 100, but it's pretty good. Now the issue really is, it is really hard to get patients through when we deal with infection because you're having big whammy hit on the immune system as well. So to me, this is the choice reserved for patients who are young, fit and they probably have a really explosive relapse of myeloma so that we cannot possibly consider using three drugs and then moving on from there to entirely different strategy if the three drugs doesn't work. So your doctor is sort of like, I'm gonna use all of the great tools I have. But if you think about just how hard the three drugs were based on reported incidence of infection and so on, and I think the fourth drug does make it even harder. So it's just a point to be careful. But I'm glad that there's such a clinical trial because I think we can't approach everyone in a similar way and regimen that has carfiocemi pomalidomidexamethasone even without the Geratumab end up being used in patients who might've actually had Revlimid, Velcade and monoclonal antibody already. Many of you probably have been started on that regimen that has four medicines already to start out with. And they're the older family of each, the older members of each family. They're the Revlimid, they're the Velcade, the steroid, and then the antibody. Then if it doesn't work, where do you go from there? So you do have a choice of grabbing stronger members. Say for example, Revlimid you have a stronger member being the pomalidomide, stronger member of the participant class would be cariprolis and even a consideration and of course the steroid is there. I long for the day that we don't have to use steroid but then have a choice of antibody in case patients did not fail it. If patients flat out fail Geratumab because they progress while they're on it, I usually don't continue it. I probably end up moving on to the three drugs that is the KPD, the cariprolis, pomalidomidexamethasone. So these alphabet soups is really all mixing and matching mostly because people got different things by the time they relapse, you need to customize it. Right, and this shows the importance for patient education and empowerment that they're understanding how the drugs are all related and then why different drugs would be used in different cases and then advocate for themselves. I think I'd rather use the stronger members if I'm qualified to do so, you know what I mean? And just kind of have, there's risks and benefits to each of these combinations and then deciding with your doctor what is right for you instead of just letting the doctor dictate to you what should be done. Let's talk about Dexamethasone. Yeah, let's talk about Dexamethasone just a little bit since you mentioned it. How, what is the dose of Dex that you recommend with DeraPOM and how often? Okay, so on, I mean, we still go back to, we base our experience on the clinical trial. And I mean, I think the 40 milligrams a week is absolutely a standard dose. I would probably say though that most patients probably couldn't tolerate that dose very well, particularly overextended amount of time. I mostly go down pretty quickly to 20 milligram or start there in patients who might've already had bad experience from Dexamethasone because of course, by the time you get to a point where you sort of have had Dexamethasone with your other component. And I mean, that's why I was saying that it is sad to say that we thought of this 40 milligrams once a week as low dose when it was compared on clinical trial because it's plenty high. And most often times it's even if patients say, I'll take it doctor, their spouse would call me and say, please, please stop. So be sensitive about this and definitely please don't take your Dexamethasone at like 3 p.m. because you're in for a long night to either take it early in the day or you take it just as you're gonna go down to sleep because hopefully it peaks in the circulation within one to two hours and it actually lasts in the body for about eight hours. So hopefully you kind of either take it early in the day and have a restful sleep or take it so close to the time you sleep and just somehow hopefully sleep through it. Many of my patients in out needing sleeping aids, whether it'll be a little touch of Benadryl Ambien, you name it. But I think it's not just the lack of sleep but also Dexamethasone is causing this like extra impulsiveness, titrariness. Don't feel good. Most people would say, it's not that I'm high and I'm like ready to work. There's a sense of everything is not right and patients perceive it but they can't control their mood. So I usually like to go down pretty quickly and I usually probably keep patients who are taking it long-term probably about that eight to 20 milligram. The number of you odd because it's a four milligram tablet and I don't like people breaking the tablets. I just round it up or down. And there are also some patients who will not tolerate the Dexamethasone. So our turn to choice may actually be Pritnesone. It's actually less potent. But so when you compare milligram to milligram you'll need higher milligram of the Pritnesone but it actually has shorter have life. So many of my patients actually do way better with a lower dose and more days of the Pritnesone. It was used for maintenance therapy before. So before we have the relevant maintenance therapy it was Pritnesone. It was actually every other day and you sort of take your 20 milligram every other day. Most patients actually do okay with that. It's also the dose that's used quite a bit in rheumatological conditions. So we adopt that dose really from the rheumatologist but it is hard to get by with medicines in this group without steroids because I'm telling you this when Pomoliss was tested alone, it really didn't work. Right. Really, really need a little jab of a steroid for that synergy. It doesn't have to be much but I was to say. It definitely serves a purpose but we're excited for the day when we find a different way. I know, right. Or actually I'm long for the day where, I mean, we are telling our patients that they can achieve remission and be in remission for so long that there comes a time where we say, you know what? For patients who achieve such deep remission that there's a way to back off from therapy and treatment break because it is this cumulative side effects that becomes a problem. And I think for most patients, if I was to tell you that you're gonna experience quite a bit of side effects but it can be three months and you and I, we don't have to look at this choice again. Most people would say, oh, go as far as I need to go. It is this sort of, it's not the end of the world but I don't feel good kind of thing. Or in many of my patients, it's the, I will have diarrhea at unexpected time and wherever I go or I'm taking my spouse out on a date, I will need to know where the bathroom is kind of thing that I think really wears people down mentally. So your quality of life is so important to me. I think everyone gets to remission not for the sake of just having undetectable end protein but you wanna have the quality of life to be able to enjoy your remission. So it is important to figure out the right dose for you for the time. Yeah, definitely. Two more questions. I know we're a little bit over. So if you just have a couple more minutes to spend with us. One of the questions since we're talking about quality of life, this person is on POM, DARA and Dara tumor Mavindex and has done so little because of COVID. They're asking, do I still have to continue without participating in normal activities? So what's your suggestion to this patient and other patients in the same situation? I'm so feel for you. I will tell you that two years ago, when this, when COVID first hit, I was really very much a no to everything doctor because I was just so worried because, we definitely saw our patients on the ventilator and we've lost patients because they've done everything right. They did their vaccinations and whatnot, but really they end up still struggle with serious complications. I think we've come a long way. I think we know a lot more about immune response to vaccination. I'd probably say any of you who haven't had vaccine, please go ahead to get vaccinated. By now the safety data is beyond player. The biovalent kind is out and that now is what we recommend to our patients because it combines the activity against the Delta variant and the Omicron variant. And the Omicron is the variant that is less sensitive to the older version of the vaccine. So please think about it. Now we're also lucky enough to have provalentic monoclonal antibody, something called Epochel that is its trade name and has actually been approved for almost two years now. What it is is it's really antibody already made against COVID. So for example, if we were concerned that you may not be making enough antibody against COVID, even if you already got vaccinated, this is sort of like a given in antibody. It doesn't stimulate the immune system to make more, but it's there as when I tell patients, they say you wanna have enough money in the bank for usage. And if we're concerned that you may not have enough, this is a top it off to hopefully reach a gap. And it should stay protective for six months or so. So it can be given again every six months, for example. So you don't have to choose one or another, being able to make your own antibodies key. So vaccination booster, but also think about this provalentic infusion is an injection. And also we are lucky to have access to home testing kit. And there are treatments that work for COVID. So say, if you really feel like you're gonna have a family get together, and while everyone knows that you're in a compromise and they have taken good care of themselves, they're just an unknown factor. So you being able to also check yourself, if you're concerned about the exposure, or if you were coming down with the clutch, we're heading into the cold months. So symptoms of the cold and COVID is just difficult to differentiate, just test yourself. And if it's negative on day one, 72 hours later, test again. Reason is this, the treatment works if you started within the first five days of the symptom, not five days from your testing. So if it's positive, you will be able to get treated and also be able to hopefully stay on quarantine so that you're not giving it to anyone else. So I think we've come a long way to be able to tell our patients that it's not always no anymore, that you can live your life to a degree, but assess the risk as you navigate through your days or your activities, know who are in your circle, and set up some prevention. And if all things fail, early detection and get treatment is key. We would definitely put a pause, typically on patients' cancer treatment if they are also fighting COVID, because it is so critical that we get the immune system to fight off the infection as soon as possible so the treatments will happen later. The downside, unfortunately, is what to do when the cancer is progressing rapidly and also there is an infection. That's usually, unfortunately, the group of patients that tend to do the worst. Statistically speaking, patients who are in remission, not on as much chemotherapy, they actually tend to not get into a serious problem. So my long answer as to stay cautious, but live your life. And since you rely on the people in your circle to keep you safe, maybe also take an opportunity to encourage them to also get vaccinated. Oh, I think you're on mute. Thank you. Isaac, thank you so much for your answer. I do apologize. We're not gonna be able to get to everyone's questions. There's a lot of great combination questions here. Maybe I can email you just a couple of questions, Dr. Svanasankar, and get your quick answer on those later. But the last question was the combination of pomalidomide, dexamethasone, and isotoxamate. There we go. So, you know what? First, I should say this is such a panel and you're so engaged and I love it. Because I think we are learning from each other. So isotoxamate is another monoclonal antibody that binds onto the similar antigen on the surface of the cancer cells after tumor map. It binds onto the CD38. So the tricky business comes down to, there's not a lot of data in patients who have already had their tumor map on whether a switch to isotoxamate works to work. So certainly, pomalidomide, dexamethasone, plus isotoxamate would work better than pomalidomide, dexamethasone. Particularly in patients who have never had antibodies before. I struggle with defining whether that would be a good recommendation for patients who plan out fail, the monoclonal antibody. But in my practice, if patients struggle with side effects to the deritumumab or say if they've already been exposed to deritumumab and they stop it for one reason or another and now they're progressing and they're about to start on pomalidomide, dexamethasone, and I'm looking for the third partner. I mean, I think unless they completely fail the deritumumab, I think both deritumumab and isotoxamab are potential choices. Now isotoxamab, at the time that the deritumumab was only used IV, isotoxamab was sort of a niche drug. It was actually quite good in that it doesn't cause as much infusion reaction. And so we can actually get our patients treated faster. It can run faster. You don't have to hang out at the infusion center and become good friends with your infusion nurses. But now that there is a subcutaneous formulation of the deritumumab, so the time issue is sort of like solved. So I have to confess that I actually don't use isotoxamab as much, but is it wrong to use? No, not at all. Awesome, thank you so much. Thank you for your preparation and just your sharing your expertise and knowledge here tonight, Dr. Svanasankar. We're really grateful for you. And as you leave the session today, was there anything else that you wanted to add, Dr. Svanasankar, before we leave today? I wanted to tell everyone who is joining that really, I'm hoping that knowledge is power and everything that I'm saying today, hopefully will be something that will come obsolete in the near future when our treatments keep getting better and better. Living with cancer, living with myeloma is such a demanding journey because there's uncertainty around. So what the next corner is, when the next corner is gonna be, when the next treatment, when you need to think about what's next and of course, relying on numbers like the M protein is just testing because it's not all rigid rule, right? That there's no safe number per se. And even when we say people are in remission and we're so happy about it, I wish I could say that those cells would never grow back. In reality, they might. So I usually tell my patients that the people who tend to do the best in my experience with them are people who could set aside the time to take care of themselves and also the time to not think about their cancer, but also think about their other aspects of life because myeloma is a small part of who you are. It doesn't actually define everything about you. And really having us being part of your team will help us customize the care that would be specific to you. My baby's calling for me. Yes, you have to go and I know it's me too. No, no, no, it's great. Thank you, Dr. Savana Sankai. I really do appreciate your time and shared knowledge and shared advice. You guys can meet us in two months, excuse me, in November. We're gonna be continuing this Know Your Myeloma Therapy series and talking about deritumumab, which has come up multiple times today. And then in our upcoming events in less than an hour, we have another event, which is our CellCal Regional Chapter. We're gonna be discussing equity and advocacy and why it matters. Then tomorrow we have two different events. At 1 p.m. Eastern is our Stem Cell Transplant Chapter. We're gonna be talking about the true costs of a stem cell transplant. And then the 14th at 7 p.m. Eastern is our inauguration of the Myeloma Kidney Involvement Chapter. We're gonna be talking about if Revlimid can be a successful disease for myeloma patients that have kidney involvement. I'd like to send out for any of those events and even more events I didn't mention is found at the bottom of this slide. I do encourage you, if you're logging out, please make sure to fill out a survey. Two to three minutes it takes. Just a couple of questions and we really value your feedback. Zoom will prompt you to take that survey. A special thank you again to our sponsors, Bristol Myer Squibb, GSK, Genentech, Janssen Oncology, and Abbe. And a big thank you to each of you for helping us build this myeloma community. I hope that you have a great rest of your night. Thank you, everyone. Thank you. Thank you.