(Guest Lecture): October 2023 - Extending Remissions for Newly Diagnosed Myeloma Patients

So thank you all for sticking to this breakout session. I think probably the best way to define this versus the next one, and you guys are welcome to go back and forth, I promise. This one is mainly, I'll be talking about first line therapy, so induction therapy, transplant, and so forth. Dr. Silberman next will be focusing on after myeloma had come back, so relapse myeloma, how to manage that. But obviously at the end, I'll make sure to time for questions. I'm happy to answer questions about anything that I can. Yeah, myeloma related. The solar eclipse apparently we all missed that just went by, but everything else I can talk about. Yes, indeed. So here my, I missed it. I'm sure in Seattle we wouldn't have seen it anyways, I'm guessing, right? Not on a day like this. Here are my disclosures. So again, so I will kind of, you could maybe also call this what your doctor should be thinking about when they're treating you is kind of the way they look at it. So I'll kind of focus on the doctor's approach to myeloma, and so I'll kind of sprinkle in kind of my commentary as we go. Some of you may have heard of NCCN guidelines. NCCN is a National Comprehensive Cancer Network. Fred Hutch is one of the centers, the founding member of the NCCN committee, and they basically come up with how best to treat any type of cancer, most of myeloma being one of them. And I know you don't have context, but for all the other kinds of cancers, typically there's like one or two or three options here. If you see it says primary transplant, primary therapy, and there's like 30 options between this page and this page. So it's very, very complicated. And one of the reasons we'll talk about why I do encourage patients to always get that second opinion or meet me even just by Zoom is because this is very complicated. Even for me, this is complicated, let alone for a community oncologist who treats every kind of cancer, not just this. So things that come through my mind and really anyone should think about. So question number one, should I use a triplet or a quadruplet? Some of you have heard these words, some of you haven't. Dr. Cowan briefly looked at this in his talk. A triplet is three drugs including dexamethasone. A quadruplet is four drugs including dexamethasone. So if you, the dex all of us hate, myself included. So if you exclude the dex, a triplet now becomes two drugs, a quadruplet becomes three drugs. So that's question number one, triplet or quadruplet. The answer typically is quadruplet for patients who are bound for transplant. We'll talk about that. Can I tailor the dose? So we will definitely talk about this. A lot of the, in the Q&A earlier, a lot of you described side effects that come up with treatment. Revlimid is famous for side effects, unfortunately. And so can we tailor the dose for you? Because at the end of the day, I'd rather have a patient stay on the drugs and the therapies at a dose that works for them that have so many side effects they have to come off all treatment because then I haven't done them any favors. Question number three, should I refer you to a transplant center? So again, Fred Hutch, Swedish, OHS, your examples here. There are other, Compass does some transplants I think in Eastern Oregon. So there are definitely transplant centers out there. Should I talk about transplant? And then this came up in the Q&A and I can talk about it later. If no transplant, should we try to collect and freeze the stem cells? Now question number four is what type of maintenance? So almost all of you in the audience have heard of lenalidomide before revlimid in one way or form. Is that our best bet or should we do something different or should we add a drug to it? So going through each drug kind of one by one here. So triplet versus quadruplet. So again, these are all triplets here. So you can see the DEX is here. It's, we're terrible with our acronyms. Why is the D capitalized there but lowercase there? Anyone's guess. The bor is bortezomib is the same as a V which is Velcade. So again, because all drugs have two names, right? So this is terrible and we don't make this easy and I will openly acknowledge that. But these are triplets. So Cybor-D is a triplet. VRD, many of you may have had or may be familiar with us with bortezomib or Velcade with lenalidomide. Someone had us earlier about Kyprolis, Carfilizomib, that's here. And the newest kid on the block is Dera-RD from the Maya study. There's Dera-2-MIMEB frontline with lenalidomide and DEX. And then quadruplets are basically three drugs plus ACD38 monoclonal antibodies. So Dera-2-MIMEB is there. So Dera-VRD is what I typically use for most patients. But also for example, those that Kaiser might get ESA-VRD for some of our high risk patients, Dera-KRD or ESA-KRD may be helpful. So triplet versus quadruplet. My main point is I don't care as long as there's a monoclonal antibody in there. This is one of the biggest things that we are trying to change about how myeloma is treated frontline. And I think many of you in the audience may have been treated before this was a common occurrence. Unfortunately, I think too many of our community docs don't realize that the times have changed in doing this. So we're working on educating them as best we can. But all of you, feel free to spread the word to patient support groups, to your friends, to your doctors, being like, hey, by the way, did you know that you should be using this frontline now? Because you should. So what are these drugs? Dera-2-MIMEB and ESA-Tuximab. They are CD38 monoclonal antibodies. What that means is that they are antibodies that basically, they bind CD38, which is found on myeloma cells. They just stick to it, and they either kill the cell directly, or they act as a flag to bring in the other immune cells that have been unable to recognize that the myeloma is foreign. All of a sudden, the immune cells realize something's wrong, and they kill it. Most centers do Dera-2-MIMEB. So Dera-2-MIMEB is FDA approved for first-line therapy. ESA-Tuximab is not. However, Kaiser uses ESA frontline, and this might change. Both may be able to first-line soon. Why do I bother adding Dera or ESA up front? So Dera, again, is Darzalex or Dera-2-MIMEB. ESA is Sarkliza, ESA-Tuximab. The biggest reason I would say actually is number two here, but I thought about the first one, deeper remission. So we have higher rates of complete response. That's remission where the AMP spike's gone. MRD negativity, I can talk about. I purposely didn't talk about that much in the slide deck, so a lot of people go into deep remissions. What I think is most important in the frontline, because an induction is only a couple of months no matter what, and then we're either going to transplant or do something different, these remissions are fast. With Cyborg-D and VRD, and many of you who might have had this, it typically takes about two to three months to get your first response, which is to get the numbers down by at least 50%. With Dera, I've had patients where within one cycle, their light chains have totally normalized because it really works very quickly. And so I think that, for our patients who are really so scared, all of you who have been here before know this, that's a big deal. For patients who have bone pain, for patients who have neuropathy, for patients who have kidney issues, getting into remission within three weeks and not three months is a big deal. And that's one of the biggest reasons to add these. And then obviously this is the biggest benefit long term, is that patients do stay in remission for longer. The word we use for that is progression-free survival. Again, everything about cancer is weird. For anyone in the technology field, progress is good. In myeloma, progress is not good. So progression-free survival is how long does it go before the myeloma starts to grow back again. So you get longer PFS, longer progression-free survival with this. Dr. Kavan already mentioned this, so I'm not going to go into too many details. I'd rather save time for questions. But in brief, this is the phase two study that we ran that helped prove that Dera-VRD, so a quadruplet here with Dera-tumumab, was better than VRD, which is a triplet with just no CD3D monoclonal antibody in the front line setting. And basically here, again, these Kaplan-Meier curves, doctors are obsessed with them. Kind of difficult to read, but you can see here that if you basically look at the four year mark, the second vertical line is at four years after randomization. You can see that forty, what is that, eighty-seven percent of patients in the Dera-VRD arm were still disease-free. So basically only thirteen percent of them had had the myeloma come back in forty years, versus in just the RVD arm, instead of thirteen, that was thirty percent. That's a very big difference. There's some caveats. This study used doublet maintenance for everybody, and we'll talk about that. I typically use just Revlimid for most patients. But I think even if you say that just the beginning, MRD negativity, which again we can talk about if you're interested, MRD negativity rates were much higher even after three months. So MRD negativity means basically that even with the best technology available in the US in the year 2023, we cannot see the myeloma anywhere. It doesn't mean cured, it means we just can't see it anywhere. Not even one in a million cells are myeloma, and almost a quarter of patients were able to get there only within three months of treatment, which is amazing. What about for patients who don't go on to get transplant? Because again, transplant is an evolving field. Ten years ago all we had was transplant. Forty years ago, Fred Hutch was one of the first centers in the world to do transplant, if not the first. But the fields are evolving. A lot of patients don't want transplant, or can't get transplant, or medically we feel that transplant, the risks outweigh the benefits of transplant. Even in those patients, DERA-RD, which is called the MYA, this was called the MYA trial, did really well here. So I think here it is difficult to see, and it's kind of small text, but the one in the middle here is actually overall survival. And you can see here, I can pretty read it myself, but at the five-year mark, five years into treatment, these are patients who are older, maybe frailer, didn't get transplant. At the five-year mark, 67% of them were alive who had gotten DERA-RD versus only 53% of the patients who didn't get DERA. So that's really a big deal. This is the one I love the most. Because again, it's one thing to say that yes, patients are going to live longer, but I also want them to live better and live longer. You don't have to choose between them. And so here you can see that they actually looked at pain scores over time. And you can see the blue line, there's a DERA-RD, lower is better. You can see that almost immediately this group started to have lower pain scores and it got better and better and better. So again, what I'm alluding to earlier, adding a CD38 monoclonal antibody, patients are in remission faster and they feel better faster. So in terms of triplet versus quadruplet, with that in mind, I always want to include DERA-2-membrarystotoxin lab or DERA. For patients who are relatively healthy, other 75, I tend to use a quadruplet regimen like this. I won't talk about amylose that comes up. For patients who are older or less healthy, they have a lot of, for example, other heart issues or the Velcade can cause neuropathy. So if you have a lot of neuropathy at baseline, I may say it's not worth being the neuropathy worst. So DERA-RD is fine to start with. Importantly, I think it's not, these drugs work so well with DERA-VRD, sorry. With DERA-VRD, 80, 90% of patients have a response to therapy. So you don't need, I always tell my patients, you don't need to be soldiers about this. Like, this is a give and take. With a lot of our doses, we can adjust the doses, we can make the treatment more patient friendly for you to just kind of make your quality of life better. So I would say it is completely fine if you start with a quadruplet and drop the Velcade because it's causing neuropathy or the Revlimid, I've had this happen, right? All of you know is often very expensive and they drop it and that's okay. If you drop the steroids, so we'll talk about the dexamethasone, causes a lot of side effects, including some of our research through Health Tree, through the Cure Hub that you just heard about shows that dexamethasone can predispose you to cataracts. So we're trying to use that research to help get the field to stop using dex. I should add that dropping dexamethasone is totally fine. My personal style is I try to drop the dex within one or two months. It's helpful in the beginning because it helps with pain control. Many of you who have been on it know it gives people that kick of energy, it's just sometimes helpful. And it does bring the myeloma numbers down quickly, but after that first cycle or two, they're not adding that much at all. So again, that was question number one, Trippin versus quadruplet. Question number two, how do I make the dose friendly? Again, what I alluded to in the Q&A is true. Revlimid is the same, it's not dose on patient's height or weight or anything. We just give everybody 25 milligrams of revlimid to induction. We give everybody 10 to 15 milligrams of revlimid during maintenance, no matter what their personal history is, no matter what their weight is, no matter what their height is, and that's unfortunate. And I think in real life, we really should adjust it. So, you know, deratumumab and etatutumumab can sometimes cause infections, and so we can sometimes tailor the dose or use other medications to prevent side effects. Bortezomib Velcane can absolutely cause neuropathy, so that's something that we should definitely do and make sure that we're aware of. I will say that a lot of docs in the community use Velcane twice per week. I'm not going to ask anyone to raise hands, but I bet many of you were getting Velcane twice per week during induction. We don't do that anymore. We really shouldn't be doing that anymore. The trials do it, unfortunately, and we're working on fixing that. But once a week works just as well and less neuropathy. This is new. Again, you're going to get here for some reason, not for some reason, because of me. There's a lot of stuff about eyes in my talks today, and the survey that you guys will be doing afterwards involves ocular health in terms of eye health. Velcane can cause blepharitis or stye. I've had some patients be like, every month they're getting styes in their eyes, and the local, you had them to you. Yeah, a lot of local docs don't realize. Did your doctor know right away? Or you had us the whole time, right? Okay, so hopefully one of us knew what was going on, but a lot of docs don't know this, and I think it's important to educate them that this is a real side effect. Revlimid, everyone in this room knows Revlimid has plenty of side effects. We can lower the dose very easily if needed, as low as 2.5 milligrams. And then financial toxicity is real, and there are a lot of resources that any of us, including Fred Hutch, the drug company that makes it, LLS, the Leukemia and Lymphoma Society, can help with to make this affordable. So, Dex, again, all of you are familiar with this in terms of how to make this treatment more personalized. This is how the trials go. In my mind, if there's any issues with this dose, 40 milligrams of 10 pills once a week, or five pills once a week, or five pills twice a week, I go down to 20. And if that doesn't work, go down to 12 or stop. Most of us, I would argue, are over treating our patients with dexamethasone for longer than they need, and I'm trying to be perfectly at the vanguard of changing that. So hopefully in five years, this talk will look different, but we're working on it thanks to the help of patients like you who are helping to educate us about what we should be doing differently. Other tips that come in mind for patients on dexamethasone, just to be able to stay on and deal with it. So again, sleep hygiene is very important. Taking it with meals is helpful. Steroids for some patients really cause leg swelling, so diuretics or water pills can help, leg elevation can help. Exercise came up a couple times, including Dr. Silberman's talk. That's super important because dexamethasone absolutely impairs proximal muscle strength. Some of you may have noticed that basically your upper arms and your thighs kind of start to feel flabby with dexamethasone. That's real. That's 100% real, and that's 100% the Dex. And so exercising and stopping the Dex helps with that. Dex, even once a week, can put people at risk of osteoporosis or high blood sugar, so all when primary care doctor matters. Again, eyes, I'll keep talking about that. That's a big deal. And then, of course, a patient support group. So for all of you here in the Seattle area, the Myeloma fighters are a good example of a patient support group that I think are really helpful to hear other people going through what you're going through and giving you tips on how to do with the Dex. Transplant or no transplant. This could be, I've given hour-long lectures about this. Right now, I'll try to do it in two minutes. The idea with transplant, right, many of you are familiar with this, and I'm happy to talk about it afterwards. Transplant has all these different words here. So autologous stem cell transplant, stem cell rescue, and so forth. The big point with transplant, as all of you know, with allotransplant, when people hear the word bone marrow transplant, they often think about kids with leukemia with getting a donor. This is not that kind of transplant, as some of you know. So an autologous transplant is your own cells, and the cells aren't doing the heavy lifting, the chemo is doing the heavy lifting. Right, it's a very high dose of chemo, obliterates the bone marrow, everything it sees, good and bad, it gets rid of. And the idea with the stem cell transplant is to rescue you from the side effects of the high dose of chemo. So again, it kills, yeah, this is actually, like studies have shown that it kills 99.999% of what it sees in the bone marrow, good and bad. And we just kind of help with the, we pre-collect your cells, stem cells are giving back afterwards. So Dr. Kowin talked about this, so I'll go quickly just in the idea of saving more time for questions at the end. So I don't think he actually showed this slide, right? So what's controversial, absolutely, this was, there were two studies, there was a big French study, and there was a big US study that Fred Hutch was part of, that shows that patients who get transplant aren't remissioned for longer. But here, they have tried. You know, Fred Hutch has tried, people have tried for decades to show that transplant makes people live longer. Transplant has never been shown to make people live longer. Here, for example, there's a Kaplan-Meier curve, you can see here that the two lines are the same. So if you look five years, six years, seven years out, the same amount of patients are alive whether you get transplant or not. Why, I should say, is because people can get transplant when the myeloma comes back. In the modern era, right, we have CAR T, we have bispecifics, all the cool things you knew about. So I would say that if you're going to do transplant, do it early, because after this point, I would say we have better tools available. So what do I talk about when we're talking about transplant? So I talk about other health conditions. I think a lot of patients get scared when they hear the word transplant ineligible. I think we do a poor job as a field explaining what that means. Transplant has risks. It's a mega dose of chemo, like the highest dose of chemo we ever give to anybody is for multiple myeloma during a transplant. And you know, it has a lot of side effects. And there's like a 5% risk, I often quote, of life-threatening issues or even death from transplant. And if I just said transplant's not making you live longer, we really have to talk about with each patient, do the benefits outweigh the risks here? For some patients, it doesn't. Other thing here is that for patients, and you kind of alluded to this, you know, transplant, that study, determination study, was only of patients under 65. So for patients 65 and older, there technically is no data showing that transplant is better than no transplant. So it's a very nuanced decision. And then this matters a lot, right? Are you willing to come to Seattle for two months? Do you have a caregiver? Fred Hutch does not require a caregiver for transplant. Most centers do around the country, actually. But that can be a big barrier. And then is this temporary dip in quality of life important? So it's a tough decision. Talk to your doctors about it. I'm obviously happy to answer questions about it in general. This probably comes up for many of you. What maintenance do I use after transplant or without transplant? So basically, the point of maintenance is some is better than none. The idea is that if you compare patients who are on observation after induction therapy or transplant, patients who are on some form of therapy for the long haul do actually live longer. That has been shown. Unlike transplant, maintenance has been shown to keep people both in remission for longer and actually help them live longer. As all of you know, we often do continue maintenance until progression. This is different, right? Many of you are on rev limit for years or maybe on Velcade for years. And again, here, maintenance therapy does help people live longer. This can be stop maintenance therapy. Does it have to be indefinite? So I would say, and I alluded to this in the Q&A, if you're having side effects, it is not worth suffering. I tell my patients, this is the chance where you're supposed to feel like you can rebuild your life and live your life. Easy for me to say that. Obviously, harder to live it. But this is the phase where I want people to travel. I want them to travel internationally. I want them to go see their grandkids. I want them to do stuff as they can. And if this drug, the rev limit, is interfering with your quality of life or draining your bank account, not worth it. We can find something else that works. So that is something that we really talk about. So if you're having issues with it, I don't think maintenance is worth it. There are ongoing studies that we can maybe talk about, or maybe for a round two roundtable. None of us talked about MRD that much during this morning's or this afternoon's talk. That's a whole separate day's worth of topics. But MRD negativity, again, in a nutshell, is that even with the most modern technology available in the US, which is actually a company here in Seattle called Adaptive or Mayo Clinic has a flow-based assay for this. You can't see any myeloma anywhere. It doesn't mean cured, but it means that not even one out of a million cells in the bone marrow are the myeloma. For those patients, if they're MRD negative on two separate bone marrows, I can talk to them about stopping maintenance entirely. This is an evolving topic because it's controversial. Because if I just said that rev limit makes people live longer, who am I to tell someone that I'm going to stop it for you even if I know it might help you? It's a nuanced, evolving discussion. So rev limit, we kind of talked about it in the Q&A. It's often 10 to 15 milligrams. If after transplant, typically start it within three months. If no transplant, often some people take six to eight months. I normally do six months and then move to just rev limit by itself. And then all of you know this in the room. So all sorts of issues. So this was not my idea. So rev limit is lenalidomide. It's a cousin of thalidomide. The birth defect drug from the 70s. That's why they treat you like you're some sort of a criminal to even ask for it. That's why it's so expensive. That's why for some of you who are nodding, they ask for the pregnancy tests again and again and again and again. That's why they cannot ever give you more than 21 days or 28 days at a stretch. It's because of all of these restrictions that the government placed on rev limit being prescribed. Not always practical. Many patients have side effects. Some patients have kidney disease and rev limit is not an option, in which case Velcade is fine. There is this risk of second cancers. This is controversial. So I would say the reason it's controversial is because rev limit absolutely has been shown to make people live longer. So if you do a study and you see that someone's getting another cancer higher risk with rev limit, is it the rev limit or is it that they're living long enough now that this other cancer becomes a problem? And it's really, really tricky to kind of unravel part versus parcel. I do think the signal is real. So what I do tell my patients, transplant or no transplant, is take your primary care doctor seriously, right? I think during induction, I often end up being the person's main physician for everything. During maintenance, whatever the primary care doctor says in terms of cancer screenings, I would do. Dr. Siperman brought up the 38th parallel or whatever she said, right, for all of us here in the Portland, Seattle area and above. A lot of us, I think, underestimate how much skin cancer can happen, right? We assume it's cloudy for six months a year, whatever. Skin cancer can happen. So I add in addition to normal primary care screenings, I also always tell my patients, have a dermatologist or your primary care doctor do a head to toe skin exam once a year because most of the cancers, if they happen after rev limit, are just skin cancers that can be plucked right out again. Doublet maintenance. Dr. Cowan briefly touched on this topic. So not using just rev limit, but rev limit plus something. So that's often rev limit plus the Velcate every two weeks or the Dara, the Darzalex once a month. When would I do that? So I often do it for patients with high risk cytogenetics. So this is where the bone marrow biopsy is helpful. Most centers in the country, academic centers, are doing this now. So for patients who have high risk cytogenetics, we typically give them two drugs afterwards. There hasn't been randomized data showing that that works, but there's been pretty good data showing that that does keep people in remission for longer than one might expect with a single drug. Some physicians use all three drugs, so including the dexamethasone. Again, I would say no dex in this setting for maintenance because dexamethasone has a lot of issues, including fatigue, cataracts, and so forth. But I think it is reasonable to use, for example, Velcate plus rev limit or Dara plus rev limit. And why? I can be talked about this. So yeah, it helps counteract high risk cytogenetics. So if you were to use just rev limit after transplant for someone who has deletion 17p in the myeloma cells, something high risk, typically transplant might work for one to two years. Here, this is data out of the Emory Group in Georgia. Typically you get three to four years of myelogy if you use two drugs, which is about the same as a patient with standard risk cytogenetics might get after just rev limit by itself. I'm moving quickly on purpose. I want to take time for questions. And I know I talked quickly at baseline, so at the end, feel free to have me come back to anything. As Omeda, we kind of talked about Dr. Silberman alluded to this. So I typically say two years altogether no matter what. I don't stop after transplant immediately. I kind of keep it going. My style is monthly for a year and then every three months after transplant or every three months for a year, just around that two years. I've also opened the Q&A. So for some patients, and there is evidence for this from 9WG, from our big myeloma international working group that kind of talks about this, for patients who had a lot of fractured olytic disease at baseline, I think it is very reasonable to do scans once a year, as long as the patient doesn't mind. That can be a whole body CAT scan head to toe. That could be a PET scan. That can be an MRI. Why? About 10 to 15% of myeloma relapses are what we call oligo-secretory, which means that the AMP spike or the Kappa or the Lambda light chains don't rise that much, if at all, but that's what's growing in the bone. It is possible. It's uncommon, but it's possible. And typically that happens in patients who had lytic lesions or had bone spasic diagnosis, and the myeloma tends to relapse in the same way when it decides to come back. And so for those patients, I do try to do once a year scans if I can. And I do keep checking the myeloma numbers. So I sometimes do space out of that every three months for patients who are doing quite well, but I do think that makes sense to stay vigilant for it because if the numbers start to rise, we have many excellent therapies now. For most of my patients who are having a relapse now, I don't need to ever talk about second transplant because I have so many other good therapies available. CAR T is coming and so forth, and so it's not something to be scared about. I really, patients get worried or get really nervous about these tests, and I would say there is a big difference between looking for trouble and have trouble looking for you. You've either heard this before. Most of my patients, I tell them, look, it's better to go look for the trouble because if the amp-flex starts to rise again, I know it sounds scary, but we will have caught it supremely early or we're ready to move when it happens. So 15 minutes. OK, I did it. Same quote as before. I will stop there, and I'm happy to answer questions about anything in myeloma. I will not try to govern the mic. They always talk about a second, oh, close, a second cancer after transplant, possibly getting a second, and it could, what I've heard, it's skin cancer. Is there some truth to that? It is. It's really also difficult to unravel. Is it the transplant that's putting people at risk of second cancer or the rev limit after the transplant? It's probably both. There have been some studies from the UK that show that both patients who undergo transplant and patients who have transplanted with rev limit have slightly higher risks of second cancers than those who don't. Yes. So the short answer to the question is yes. It's typically skin cancer is probably over half. I was part of our big international, Center for International Blood and Marrow Transplant research. We published our research last year. I was part of that team. About half of the cases were skin cancers. The important thing to note is sometimes they're not. Sometimes patients do have scary cancers that come back, like leukemia, something developed from this. The biggest takeaway, and I tell every patient this, who's nervous about rev limit, is in that study, and if you ever see me or follow me on Twitter or find HealthStreet, you can find me afterwards. In that study, even for those patients who got secondary cancers that we said were from the rev limit, the number one cause of death when you actually look down the line was still the myeloma, if that makes sense. So it's important to remember that at the end of the day, the myeloma is still the biggest threat that our patients are living with, that you're living with, and I would say I wouldn't withhold the therapy that you think works because of a theoretical risk that may or may not happen on the line. It's an excellent question. I hear most talk about rev limit, rev limit, rev limit. I'm on pomalist. Are they the same? In terms of the words you're saying, are they kind of the same? It's an excellent question. So no, actually. I think pomalist is a better maintenance drug for sure. Do you know, if you mind sharing, was it because the rev limit was causing issues of some way or form? They just put me straight on that. Were you on pomalist before transplant or before? No. So I think pomalist is a good bet. A lot of insurance companies won't approve it for maintenance, which is why I don't do it routinely because as all of you know, rev limit and pomalist are both made, everyone from industry left. Just making sure. If I see any BMS faces here, I'll smile at them. But yes, they're good drugs, but they're extremely expensive. I see. As all of you know. So what I was with pomalist is, pomalist probably has less of a rash than rev limit does. And importantly, there was a study from the Dana-Farber group, Dr. Sperling earlier this year or last year, that probably, at least preclinically, like in just not human trials, but preclinically, pomalist probably doesn't have a risk of second cancers, the way the rev limit does. I see. Great. So yeah, I would say if rev limit is causing issues for patients, I often then try to appeal to the insurance company and say, look, pomalist is a better bet. Pomalist is also a pill, easy to use, still expensive, still annoying. The pregnancy stuff doesn't go away, unfortunately. But I think it is a better drug. And I hope for a scenario where rev limit is just gone. I will not shut it here for rev limit when it retires from business. Thank you. Uh-huh. Yeah, go ahead, Jo. After I had my autologous transplant, I asked the transplant team, was it successful? And they said, we can't answer that yet. Now that I see about maintenance and everything else that can go wrong, is that probably why they didn't say it was successful? It's a good question. It's really difficult to say how, yeah, because the best way to tell how well something works is with this kind of a study where you follow someone for three years or six years and see what happens. Obviously, six years later, you know what happened. Either it worked or it didn't work. In real time, how can you tell if what are early indicators of treatment is working or not? Maybe I'm going to twist your question into a question about MRD. So again, some of you, maybe for show of hands, have any of you guys heard of MRD before? Yes, from you. From me. Okay. So I see a lot of hands. Okay, that's great. Okay, so we can definitely talk about that because that comes up every meeting I go to is a debate about how we use MRD. And there's two ways to think about MRD. There's ways to think about MRD as an end point. Like, oh, I achieved MRD negativity at this level. That's good. And there's a separate question of MRD as a middle point, meaning to guide decision making. Let's say, oh, my MRD level is this. I'm negative or positive. Therefore, I'm going to change what I do and do this. That second paradigm is not really ready for prime time. I mentioned that in some patients based on recent data published last year by Dr. Costa at Alabama and colleagues, that if someone's MRD negative repeatedly, there's a rationale to stop the transplant, stopping the Revlin maintenance. You're asking more here. Can you use MRD as an end point to say, hey, the transplant worked or didn't work? It's tricky. It's tricky for a lot of reasons. I think one, because the transplant, the melphalan, takes time to work. CAR T works pretty rapidly. So for CAR T and my specifics, I would say within 28 days, I can typically tell is CAR T working or not. Because you could probably tell, but the light shades come down dramatically. The bone marrow looks good and so forth. That takes time. And so achieving MRD negativity after transplant, probably about 40 to 50 percent of patients will achieve MRD negativity with a good quadruplet induction regimen plus transplant. The tricky part is even MRD negativity doesn't equal cure. One topic that Cindy was here, she's going back and forth from Health Treatment brought up, and this comes up a lot. MRD, people hear this and they're like, oh, MRD negativity is good and therefore I must achieve MRD negativity or else something is wrong. That second part is not true. Because it's possible for patients to have what we call an MGUS-like phenotype. The word for that, MGUS, have you guys heard of MGUS before? See, mostly not. MGUS is the precancerous state. There's this theory that for some patients, and I'm going to, how can I hold the mic? I'm very effusive with my hands. But the idea is that you have your MGUS, that's a precancerous condition. There's a clone that becomes myeloma. You smack down the clone with induction therapy with deratumimab and then transplant. But that MGUS that's left behind is almost like a reptilian core, but the MGUS is not itself dangerous. It's just sitting there. And so some patients may be MRD positive for years. I've had one patient who's MRD positive for six and a half years after transplant. It's a little scary because you're kind of like, oh, I kind of wish it was negative, but honestly, no. For that causing you problems, you probably have this MGUS-like phenotype. And so that's the tricky part is I don't know how to differentiate those patients in real time. So in your case, even if they'd done a bone marrow and even if they'd said MRD negative versus positive, I don't know that I would be able to say is it a failure or success or not. I would say, you know, so bringing everything back together again, Dr. Hofmeister at Emory has a nice slide of he says like, for when is transplant considered excellent versus not totally a failure? I would say that for most patients, I prefer to get at least one year of mileage out of a transplant if not two. So typically speaking, I would say people get at least two years of mileage out of the transplant, meaning they'll stay in remission. I would say that transplant did what it came for. Some patients have what we call functional high risk myeloma where the myeloma does come back within a year of transplant. And if so, lesson learned to not use transplant on that patient again and not use chemo because we have other newer tools available. But I think for those patients, I would say that would be the only scenario where I would say if the myeloma came back within a year of transplants, we did the patient a disservice. The transplant didn't work the way I wanted it to. Mine's going to work. Yes, you're going to be fine. Yeah, no, it's and it's tricky because and so what it will say, so just so that comes up, so someone has happened. I've had patients where the myeloma come back within a year of transplant. There have been a study which I don't didn't put here. Karma to cohort a looked at CAR T for patients who had an early relapse within a year of transplant and it worked as well for them as it did for anybody else. So you know that you know, the kind of high risk disease biology when it comes back early, that's often a function of the chemotherapy not working. But we have newer tools now. Car T doesn't care about chemo or not. It'll still work just as well. I've had a really severe rash reaction to linoleum I'd even at a low dose. There be any chance that palm list would work in instead? I think it's worth a shot. We don't know enough about why revel in rashes happen. So revel in it does. It doesn't just act on myeloma cells that acts on every kind of immune cell in your body basically to do something different. So in that scenario, I typically I talked to patients about how bad is a rash with palm list. There's some studies that shouldn't maybe like a 40 50 percent cross rash, which means that maybe 50 50 chance you will get a rash of palm leaf 50 50 chance you won't. I normally stop the rev limit, give it a month to wash out and then try the palm with a low dose. And if that works, then great. And if not, Velcade is an option. But I will say that again, if the rash is annoying to you there, we have Velcade other options or palm list are equally good. And I wouldn't feel like you have to have the rash to keep the myeloma in remission. If that makes sense. Would you prefer the palm list over the Velcade? It's a good question. It's up to quality of life. There's a lot of this is not go into it. I think. The palm list, I think, is probably still a little bit easier for most patients because it is a pill that you can just take and then not take and so forth. And Velcade, typically I don't do it less often than every two weeks. So that is two weeks coming into clinic for that. On the flip side, depending on your assurance, right. And everyone here is a different scenario here. Palm list can be super expensive. And ironically, for those patients, Velcade may be much, much cheaper to come in and get the injection and forget about the palm list. I think both are excellent maintenance options. Anyone else have questions? So let's see. We're in that transplant or no transplant. Where do you make that decision? And it's really difficult. Sorry. I know. I'm sorry. It's just scary. Transplant has, you know, from what I know, there are a lot of physical effects afterwards. You know, and then you look up there and it says there's no doesn't extend life. How do you, you know, trying to determine whether to move forward that way or not. It's difficult decision. It's extremely difficult. It's extremely difficult. And it's difficult because, you know, I mean, when they wrote the study, I'm sure they were hoping for transplant to make people live longer. And I really do believe this is real, that it does not because we have transplant. We always if you are able to collect the stem cells and save them, you can use it for later. Or again, by this time next year, heart therapy will be available for patients who are having their first relapse. So that might be another option as well. The way I ultimately describe it to patients is, you know, yeah, is that their threshold? So how about I'll say two things about this. So it's a very obviously personalized decision at Fred Hutch. We try to make it a little bit better. It's a little bit better for patients, but that sometimes makes it more complicated. So I am not a transplant there. Are you guys going to care at Fred Hutch by any chance? OK, right. So you've probably met a myeloma doctor and a transplant doctor. A transplant is a transplant. Everything they see transplant fixes. So they will talk about it like it's the only thing available. And the reason that we actually have the myeloma doctor to the patients first is to have them actually feel like, hey, like there are other options. Like I will take care of a patient where they get transplant or no transplant. What I typically say about transplant is for some patients, they really want to be in remission for as long as possible. And for them, that that extra three months, you know, detriment, the quality of life for moving to Seattle is worth it for them. For other patients, the fact that they're still working or still staying active, they say, look, I don't want to deal with this. I want to keep doing what I'm doing. You know, some of you may know, for example, that like the, you know, the goodness gracious, the house majority leader right now was diagnosed myeloma a couple of months ago and they keep asking, like, can you maintain his job? If you don't want to go transplant, absolutely. You probably will be able to maintain it. And so that's a big decision for things like that. What I would say then to kind of help you with this impossible decision that really will just be a matter of time. Two things I would say, one, relapses tend to occur in the same way that the myeloma initially presented. So sometimes that helps patients because if a patient was only diagnosed with just some blood work that was off or a little bit of anemia or a smoldering that became active myeloma, one could argue, forget the transplant and just keep an eye on things. For the patient who had a very aggressive presentation with, you know, lytic bone lesions and pain and fractures, I would argue for that patient, every added year of remission without that coming back is worth it. So that sometimes helps. The other thing I will say is no matter what the transplant or say, 10 years ago, probably only about 10 percent of patients who were offered transplant would decline it. Right now with my patients, it's about 60-40. So most patients still go ahead with transplant. I would say about 40 percent of my patients look through everything, talk through everything and decide it's not worth it for them. And that number is probably going to go up with coming years. So patients who decide to defer transplant, I encourage you to talk to other people here in this room or with the myeloma fighters and people here, some of you I know on the Gantt transplant and so forth. It's a very personal decision. And we are the only cancer where you guys may remember back in the 90s, we used to do the same thing. Probably you may remember with breast cancer, right, this used to be in vogue until it was shown not to help. And so now 99 percent of patients with cancer don't get this. Myelin was one of the few cases where we still offer it. And so that makes it just even more complicated. Does that help a little bit? I'm sorry, I know it's a really difficult decision. You know, it's just still it's you're talking about the presentation, right? Like so when Cheryl was diagnosed, she was kind of really more in the middle. Right. Like she didn't present with a lot of lesions. It was kind of we stumbled upon it earlier. So, yeah, it's hard to say, you know, exactly what that outcome will be, you know, at first relapse, if that happens. Right. Like, you know, you just we just don't know. But yeah, it does. Kind of help. Yeah, I mean, it's just the more information we can get and the more we talk about it, the better decision we get to make. And you're right, it is a very personal decision. And, you know, I don't it's that idea of not knowing exactly what's right. That's the part that's really hard. Like there are some cancers where you're like, yes, this is what you do. End of story. That's the only way forward. It's kind of in the middle over here. You could do this, maybe this. I agree. And it's hard because, you know, as you lose in 10 years, we'll know. So they actually are doing a study, CAR-T2-6. So by by 2030, we will know because they're doing a study of CAR-T versus transplant. That's what everybody wants to know. I want to know that too. That study is going to open next year. It's Europe only. I guess the Americans, the Americans, the Americans, the Americans, the Americans, like FDA didn't like that study. So we'll know in seven years. It's not going to help right now in this particular case. But I would say no matter what decision you make, we got you. I'll put it that way. Right. We have many new tools that are available for myeloma for surveillance, for maintenance, for treatment of relapse. When it happens, when myeloma comes back for most patients, it comes back. It's just numbers on a page. Right. It even, even if you had a history of bone fractures and so forth, a diagnosis, typically we're able to catch it with just the amp-sweat creeping it back up again. So it's caused anxiety, but nothing more than that when we treat at first relapse. So we're getting better and better at treating myeloma. I think, again, most of my patients do still use transplant as they view it almost as a kind of investment in their future to kind of, you know, downtime now to kind of help time down the line. But that's changing and probably by 2030, we won't be doing transplant. I mean, CAR T is going to win. I I'm not, I'm not at all in doubt about that. So I'm sure by this time, like a decade from now, we won't be doing transplant at all, but I think it's just what do we do until then? We don't know, because right now, CAR T is not available for patients like in your situation at this point in time.