(Guest Lecture): A Discussion of Two Case Studies | MCRT Webcast: Why Physicians Are Optimistic About Newly Diagnosed Myeloma

Well, good morning, at least it's morning where I am here in Seattle. I want to thank you so much for this great privilege. Thank you to the Milo McCrack for inviting me to be part of this program. I think both Drs. Farrow and Libby mentioned, you know, what a great honor and how a little bit intimidating this crowd is. And I think I'm the newest kid on the block here. So it feels wonderful standing on the shoulders of the giants who've kind of spoken ahead of me and have gone ahead in this field. And it really is a very exciting time for our patients. And I know a lot has been discussed this morning. I was happy to hear the presentations. And I think the cases that we're going to talk about will help kind of solidify some of the information that's been presented in hopefully a way that can be easier to understand in the setting of patient stories. So with that, I'd like to welcome back Drs. Bergsegel, Dr. Farrow and Dr. Libby, and we'll move on with our first patient story. So this is a story of a 50-year-old woman. She was a schoolteacher who developed back pain back in the spring of 2014. And you know, like a lot of patients, she kind of sought to go a more conservative way. She tried physical therapy, some massage and over-the-counter pain medications with things like Tylenol, ibuprofen. Her pain continued to worsen in early summer, so she did end up getting x-rays that showed multiple compression fractures. But the decision was made to just continue at that time with physical therapy. By midsummer of that year, the pain was just significantly worse, and she was now presenting with new symptoms of nausea. And so her primary care doctor got some additional labs at that time, and they were notable for a new anemia, so the hemoglobin of 7.6, new evidence of kidney injury with the elevated creatinine of 2.4, and hypercalcemia with value of 12.8. So this prompted further workup. So she had a bone marrow biopsy that showed 10 to 20% plasma cells. Cytogenetics and FISH were normal. There was evidence of a monoclonal protein with an M-spike of 3.3, and in immunofixation showed IgG kappa. She had elevated serum kappa and kappa-lambda ratio, and the beta-2 microglobulin was also elevated. She had further imaging that showed just diffuse lytic disease in her bones, including her spine, her hips, sternum, pelvis, proximal femurs, and multiple compression fractures. So with all of this information, she was diagnosed with IgG kappa multiple myeloma, and based on her baseline characteristics, she was classified as ISS stage 3 at that time, back in 2014, but if we were to apply it to the revised staging system now, she'd be considered a revised ISS stage 2. So before kind of moving on to what her induction treatment was and what her course was, just I'd like to throw out, you know, I'll point it to Dr. Libby first, but certainly any of our panelists, you've heard throughout the morning there's different approaches. But Dr. Libby, maybe if you can start, what would your approach be for induction treatment for a patient like this? What are some factors that you consider in making that decision? Three drugs, four drugs, if you can comment on any of those things. One thing I want to say, first of all, can you hear me? Yeah, it looks like you can. Yeah. Okay. This is so classic, because somebody has back pain that doesn't get diagnosed. It's a little surprising, but not really hardly at all. They saw that she had compression fractures in her spine. I don't, this is actually a patient of mine, that she had compression fractures and they said, well, you've got compression fractures. The reason for that is women get compression fractures from estrogen deficiency or menopause. She was pretty young to have that, but chronic back pain is just so classic in myeloma and it's just so frustrating that the diagnosis is often delayed and there are more fractures. So what would I treat right now? This is a classic presentation. I think, I didn't, I think her genetics, yes, they were normal. So this is a standard risk myeloma patient, two out of three, roughly, patients with myeloma have standard risk. They're the patient to do especially well. And I would use, I would use RBD, standard RBD therapy. There's no reason to use more aggressive treatment. I would follow the algorithm that I showed earlier after, would collect her cells and then depending on her response, discuss with her the option of transplant, whether or not to do it, depending on her response and her personal feelings. Dr. Farrell or Burksiegel, any other additional comments? I'd like to make a comment. And, you know, I study genetics, it's one of the main things I do. And at the Mayo Clinic, the fish is, you know, it's very rarely normal. And, you know, if this was a patient that had been referred to me from another hospital, I would wonder, there's a lot of variability in different places as to how well the fish is performed and often they don't isolate out the myeloma cells specifically and then they get false negative results. And in a case like this, you know, if her fish showed that she had a T414, for instance, or she had the lesion 17P, she would switch from being, you know, the revised ISS stage two to actually high risk disease, revised ISS stage three. And actually right now, I think we and probably others, there's a clinical trial open called CARMA four, which looks at actually using upfront CAR T cells in newly diagnosed patients if they have revised ISS stage three. And so in a case like this, if she were to come to me today from another institution and get my opinion, I would say I'd like to repeat the bone marrow biopsy at the Mayo Clinic and really make sure that the fish was normal before deciding. And if she did have, you know, high risk disease, RISS three, but, you know, she didn't go on a clinical trial, I would probably, I would try and see if I could give her a four drug combination. So DERA, RVD, and that's not necessarily covered by insurance and so it may or may not be approved, but that would be the approach I would take. If she, on the other hand, if she had standard risk disease, I'd treat her just like Dr. Lube said. Sure. So she actually ended up going, getting started on Cybordy. She had that some renal problems at the start. And so she was on cyclophosphamide, bortezomib, and dexamethasone. And she got that for about seven cycles. She initially had a very good response with her M protein decreasing, but it plateaued a bit. And so, and her kidney function had improved. So she actually was transitioned then to bortezomib, linalytomide, and dexamethasone, and she continued that for four more cycles. At that time, she had some restaging bone marrow that showed that her bone marrow biopsy was now less than 1% plasma cells. The M spike had improved, though it was still detectable. Her capillite chain had improved to normal. And so at this time, we would categorize her as having a very good partial response or VGPR. So what is there? I guess at this point, I just open up to the crowd. I know we've had different talks, and Dr. O'Leby went into a big talk about transplant. But in a patient who's had almost a year of induction treatment now, what are some of the options next, or what would you recommend next for her treatment, whether to continue on or go towards maintenance or go for transplant? What are some of the thoughts about that? Well, hopefully, there's been a discussion about the pros and cons of transplant with the patient. And if she is interested in maintaining that option, then she should probably collect her stem cells. Before, she's had a lot of exposure to Revlimid because it can deplete the stem cell pools. There are times where even with our best attempts, we're not able to collect enough stem cells. And oftentimes, we can get enough for two transplants if we catch them, if we collect it early enough. Dara-tumumab has also been reported to decrease stem cell pools, so the quadruple regimen of Dara and lenalidomide, although I haven't seen the data on that, may make it particularly challenging. So as Dr. O'Leby said, you can collect and bank them, even if you aren't motivated to go on a transplant right away. She's relatively young, so I would probably push her more towards doing it rather than just postponing it indefinitely. One thing you don't want to do is wait until you have a lot of morbidity and then from your disease progression and causing problems, it can make that treatment harder to withstand. And once you break a bone, you can't unbreak it again, like a compression fracture. So you do want to get treatments before a lot of that problem develops. You bring up some good points, Dr. Ferro. Thank you, Dara. So for patients who are starting their initial treatment, maybe with a local oncologist who may not be aware of all the kind of intricacies related to transplant, when would you recommend a patient seek out a transplant or someone at a transplant center to discuss these things? I have a lot of patients who get referred to me early in the course of their diagnosis, and we don't usually consider collecting stem cells until they've had a good course of induction, at least four or five cycles, but preferably before they've had a year of treatment with Revlonet or Deratumumab. So, you know, at least from an informational standpoint, it doesn't hurt to talk about things early on and get educated. So she actually did go on to get a transplant with high dose melphalan in July of 2015, after which her M-spike then became not detectable or too small to detect. And so at this point, I think, Dr. Ferro, you did talk about maintenance treatments and some strategies. So what would you kind of recommend for her or any of the other panelists about maintenance at this point? Well, that is a super hot topic. I'll let Dr. Libby go first and then I'll editorialize. Yeah. Well, one of the things I think that if you've gone through a transplant, one of the ways that I think is that if you've gone through a transplant, I want you to get the most bang for your buck out of that. It's quite a journey. And we can we can prolong the response, the benefit that you get from a transplant in terms of we can provide by using maintenance. And what's the what's the clear cut benefit? No question. Benefit about a transplant right now is that it takes a longer time. It takes longer for the disease to return. If you get at a transplant to standard therapy than if you do not get a transplant plus standard therapy. You don't live any longer based on the study that we've focused on today, but it will be longer before the disease comes back. And what that could mean is you have a longer, very high quality of life. You're just taking a pill every day or you get a shot every other week, which would be Velcade without steroids. You live a pretty darn normal life. That's that's a big major goal. So maintenance will tend to give you will in general give you a longer time before the disease returns. And because we're using low dose therapies for maintenance, I my routine is to recommend it. Most patients, Revlimid is the standard maintenance that's administered in high risk patients at a minimum. I recommend that you take a shot every other week. The last one is a high risk treatment. And that's from Velcade is administered every other week. High risk, meaning people with translocation 414, 1Q plus or del17 P, which is perhaps the worst player in the cytogenetic abnormality list. I will I will play devil devil's advocate on that because I think from patients perspective, I think that's a great point. If we're talking about patients, that's a great point. I will I will play devil devil's advocate on that because I think from patients perspective, I think that's a standard recommendation and I do the same. But but I think it's important to understand what we know and what we don't know and make an individualized decision with your with your cancer doctor. So I what I showed and I think that what Dr. Libby showed too is that maintenance therapy doesn't make you live longer. It keeps your disease and remission longer. And so is how important that is that to you if you if you're monitoring your disease, you're you're you're paying attention to how things are doing. Even if you do this this new MRT testing and you can see small changes, then you're going to be able to see the changes. And then you can see small changes, then you always have the option to go back on therapy at a higher dose or back on maintenance or back on a combination therapy. So we shouldn't get too dogmatic about saying you have to do this because I have some patients, I recommend it in everybody. At least they try it. I've had some patients who just feel sick all the time on Rebellimid and they're just not good for their quality of life. And they don't want to be therapy. And then what happens is their disease comes back sooner, but then they have to bite the bullet and kind of deal with it in a more intense way. I think it's a very personalized decision. And I think it's important to understand that and make the decision about what's best for you. In the end, it may not matter. What may matter more is that you get all the treatment options that are out there that you don't skip anything that's potentially beneficial. But the sequencing, the timing of them may not be as important. Yeah, I'd like to I actually agree with both Dr. Libby. I think they said the same thing in slightly different ways. And it's also what I believe. You know, in general, you know, I prefer to do upfront transplant, as in this case, and I prefer to put patients on maintenance, not because it necessarily makes them live longer. But there's absolutely no question that it keeps the disease away longer. And and the first remission tends to be the highest quality remission. And I think, you know, also, given how much things are changing right now, I think you heard from Dr. Libby, the excitement about these novel therapies that that are coming down. It actually makes a difference. You know, if you relapse in, you know, four years versus two years, because the therapies that will be available to you in four years are probably going to be much better than the ones available to you in two years. And so there's an in a time when the therapies are changing so rapidly, I think there's a little bit added benefit to delaying the time before the disease recurs. I would like to say that that there have been studies that show, for instance, made analysis by McCarthy that after stem cell trans autologous transplant myeloma that maintenance does significantly prolong survival. So I don't think that that we know for sure. I agree. After transplant, there is some data that indicates that there may be an overall survival benefit of maintenance, but I don't I'm not sure I've seen that replicated, but it's worthwhile considering. Dr. Birx, I will also mentioned early on about potential availability of a clinical trial and I and I just want to second that the that sentiment. I think the only way we're going to know how to sequence these treatments, how to combine these treatments is really if we get people on clinical trials and learn from what we're doing. I think that the centers that provide clinical trial as an option are generally providing top notch care. So I would definitely encourage everybody to at least consider it and think of the additional effort to enroll in a study is acceptable to you. And then the final thing that we haven't talked about too much that which is also consideration, you know, as physicians were advocates for our patients and we're always pushing for as much as we can get. But these treatments are all extremely expensive and there is a societal cost of going on more and more therapy. If there's not a clear benefit, I think you should ask, you know, what are you actually what are you actually accomplishing? There's some logic to doing if all else is equal to sequencing therapies to do your cheap treatments first and then do your expensive treatments later on. Because the later treatments tend to be less long lived and all else being equal, you would want to be a little bit more economical that way. I just want to put it out there because I think that we sometimes neglect that and the overall financial burden on society is enormous from from some of these new treatments. Yeah, that's a great point, Dr. Farron. I know we have, you know, some attendees from different countries as well where the system's different. So I really appreciate that additional comment. So to move on with our case, so she did go on maintenance lenalidomide. And actually she's been on since about three months after her transplant in 2015 and has been continuing on maintenance and a complete remission now and doing quite well. So, you know, for obvious HIPAA reasons, you can't put pictures up there, but she is a schoolteacher and again, doing very well. Her kidney function improved her pain from her bone disease is improved. I think the biggest pain that she's dealing with lately is probably with distance learning as a schoolteacher. So I think a couple takeaway points just to highlight from her story is, you know, she did present with what seemed like a very high disease burden evidence with, you know, all that bone disease, anemia, hypercalcemia, you know, classic kind of symptoms. But that it doesn't necessarily mean that it's irreversible. So the goal would be that with treatment with optimal control that we can get patients back to even potentially pre-disease states and that your induction treatment may need to be modified in the beginning. You know, whether that's because of how you present with, you know, your organs involved or if you're not having an optimal response, but that also doesn't mean it's going to dictate how you respond to subsequent therapies. So let's jump into our second case. This is a story of a 42 year old man. He again started with back pain in the spring of 2010 and kind of went again a very similar route of trying physical therapy, seeing a chiropractor over the counter medications and whatnot. But by January of 2011, the pain was significantly worsening and he ended up going to the emergency room where a CAT scan was done that showed diffuse bone mats, some pathological rib fractures and a soft tissue mass along the right posterior ilium. And a biopsy of this mass was done that showed plasma cells that were capillite chain restricted. So he went on to get further workup, a bone marrow biopsy showed 20 to 25 percent plasma cells, normal cytogenetics. Fish did show a translocation of 1114. There was no M-spike that was detected, but he did have elevated kappa and kappa lambda ratio and calcium, creatinine and hemoglobin were all normal. So he was diagnosed with capillite chain myeloma. So his kind of first set of treatments, he actually enrolled in a clinical trial with his induction treatment. And so he got the backbone of cyclophosphamide bortezanib and dexamethasone with the addition of doxorubicin, which is kind of an old chemotherapy agent. He got that for four cycles and went on to get consolidation with the high dose melphalan transplant in August of 2011 and started maintenance therapy. Unfortunately, by December of 2011, he progressed with hip pain and this was consistent with progressive disease. So just to kind of throw out to the group in this and someone who's young like this who didn't get what you would expect in terms of a long response with his induction treatment and transplant. What are some of the treatment options that you might be considering at this time or, you know, what are some things that approaches that you might take now in someone like this? Well, the one thing I would say, and then I'd like to hear my colleagues speak, but is I'm sure all three of us this story, we're worried. So something's really wrong. This is not good myeloma, even though the testing that we did to start with suggested that it was going to be very treatable myeloma. Something is very wrong. We're dealing with a very different and enemy here. Now step out. Yeah, and I guess I, we have, if this patient was, you know, presenting now, we also have clinical trial for patients that relapse, you know, so shortly after their transplant again with CAR T cells, they're trying to move CAR T cells earlier up in the course of people who have high risk disease either by genetics or functionally like this. And so I would consider them high risk and I would, you know, look to see if there was a clinical trial that he'd be eligible for. So, yeah, so, so this is a kind of patient where obviously you would not consider a second transplant, which since the duration of remission was so low clinical trials are always appropriate, but the patient didn't have treatment with what's now sort of standard upfront therapy with proteasome inhibitor and, and a thalamid. So it's, it's still possible the patient will have an excellent response if they get back on a therapy like that. I would like to say to that. I think it was leaf that had that that great slide that I have to get from him where you're throwing darts at the dart board and then the bottom part says, you're throwing it the Lord has lawyers on it. I have a patient who's like this very very much like this who relapse immediately after an upfront transplant and standard risk genetics. I literally threw a dart at the dartboard because I, this was several years ago I was not sure what to do. And he, and I put him on elatuzumab. I don't even know why I did it, but I, I just did it. And, and plus an immunomodulatory drug either Revlimid and pomalidomide immediately responded. He shouldn't have it was very surprising but he immediately responded to amplicity or elatuzumab plus either Revlimid and pomalidomide and he went for many years in remission with that combination. So, yes, you can we can turn things around because we're using. When you do that, I switched him to something with completely different mechanism of action from mouth land the drug that we use in transplant, you may go to a different mechanism of action and, boom, everything changes in the patient response. So this patient actually went on to get an allogeneic transplant he was seen it at the Hutch so you know being center of transplants and back in the time. So, I think we can have a whole roundtable just on transplant options and considerations and certainly aloe transplant in the setting of myeloma is also very controversial topic so I won't really even approach that during this few minutes, but he did go on and have a transplant in 2012 and he actually had a fairly good response with that. So he had about four years where his disease is well controlled. And then in 2016 he relapsed with the new plasma cytoma along the chest wall and a biopsy at that time showed a new mutation with the Dell 17 P. So he ended up getting radiation and started systemic therapy with deritumumab, pomalidomide, and dexamethasone. But Dr. Brooks, I wonder if you can comment I know in your talk you talked about the clonal tides that can happen and just kind of the significance I guess of a new mutation, with his initial diagnosis. Sure, yeah. The, and that is basically our concern is that, you know, the, with every relapse, there's the concern that the mutations are acquired or grow out. And that's the, you're seeing in this patient deletion 17 P is is one that we're really worried about because we don't have good treatments for it. And the, yeah, so that. And that's actually one reason we would like, you know, as much as possible to prevent relapses from occurring, particularly in patients with with a genome is unstable and they have high risk disease. But that combination that he received is a very active one. And I think a good chance it would work. And what impact, you know, he obviously got agents that he hadn't seen before in very good anti myeloma therapy but does the Dell 17 P how does that impact what you would choose in terms of combinations of treatment or which, which classes you would, would you use You know, I think we know chemotherapy, which would be, you know, mouthful and doxel cyclophosphamide really doesn't respond to the deletion 17 P image, you know, by themselves really actually don't work that well either. It seems proteasome inhibitors work and we think immune therapies like their tumor map work. You know, perhaps I might have been more inclined to also include a proteasome inhibitor in this combination. But I think the data to map is a good choice. I think when you've got the leach and 17 P. And, but I think we all we know it, it still isn't the answer. And we need I think we need to find better things. So, he actually didn't get much out of that combination so the dear to him a pump a little my deck some of his own, about three months with treatment still hadn't had a significant response. So he was started on car fills and the little So, at this point, now we would consider him to be pen to refractory so he's had both one a little my palm a little mind are two big image he's had Bortezumib and car fills and they've are two, you know, produce them inhibitors and then also anti CD 38 monoclonal antibody in terms of So, I guess opening it up again to the panel what are some treatment options at this point. You know what, what can we do. Well, maybe I'll just continue and say he does have the T 1114 chromosome translocation and the meta clocks has been shown to be active in patients with that subtype of multiple myeloma. And it has been made available from the company to be used in those patients, although it's not approved by the FDA. And so if there were obviously there's a clinical trial of an anti clocks I'd get them on that but if there was not a clinical trial, I would see about getting him. Veneta clocks. Probably use in with dexamethasone. I want to second what leaf just said I think and we probably didn't spend quite enough time so far talking about Veneta clocks it, it is a very exciting drug another super exciting drug it, it may be the first truly targeted therapy in multiple myeloma. Because only really you only get a good response with translocation 1114 it changes the playing field because now when I hear about a patient like this say I didn't know him but he's referred to me. And I, the first thing I'm going to do is see does he have 1114 that's going to be the top of my mind, because we can give potentially this targeted therapy we have a study, you can get in the study great if you can't get in the study I would still recommend it. It's just a pill. I often combined it with Velcade but that's potentially, it's very close there's a number of studies with Benita clack serve and collect a very exciting drug in, in, in this group of patients with 1114 and by the way, it's a significant number of people, it's maybe 30% 30 or 40% of patients with multiple myeloma have this so it's going to be probably going to be a major addition to our treatment toolbox and in the foreseeable future in the next one, two or three years at the most I would think, certainly hope. So, I was the one last thing I guess I would say about him is, I have, I have a patient like this probably more than one but the one I always think about the patient almost identical to this. Who, not only had he failed a transplant but he'd also gotten car tease and got another so at this point a patient like this who got car T cell therapy got about a year and a half out of his car T and then relapse, but lo and behold he had 1114 we put him on Benita clack and he's back in a remission. It's unbelievable. But it's great. I think you might have spoiled the ending for this patient because it's a very similar trajectory but we did have a few other pit stops along the way so just to kind of close them out so he did end up having, again the new litigations to control the disease at first there was some consider he did end up going kind of getting conventional chemotherapy, which he had no response to which Dr. Roussica you kind of alluded to with this deletion 17 P. And then he went on to clinical trial that was looking at a new novel, small molecule agent in combination with some, you know, approved medications and again didn't get much mileage out of that treatment, either. And then he was ended up getting on a car T trial here at Seattle, and immediately went into complete remission and was in complete remission for the next couple years. And then most recently had a relapse. And as you know we just discussed he with that translocation 1114 was started on Veneta clack and Bortezumib and is again back into having a very good disease control. And just kind of sum up so our patients can see our attendees can see, you know, over the course of about nine years since he's been diagnosed he's obviously gone through multiple lines of therapy. But, and at times, have had had had had treatments that are a bit more intense and labor intensive for him. And at other times, you know was still able to maintain good quality of life and continue doing the things he loves and surfing and seeing his family and enjoying that time. So, my last question to the group I guess, you know, for someone who's gone through all these treatments. What are some of the newer drugs or mechanisms or targets that are in clinical trials are in the pipeline now that you guys are most excited about seeing in the near future. Well, the thing that the next therapy or another therapy that definitely is very high in my mind right now is something called bite therapy BITP. And so it has many similarities to car T therapy in how it works. But it's not as in some ways, it's going, we hope it's going to be easier to administer, and you can give it over and over again. It's still somewhat early in clinical trials but there have been some dramatic responses. And so bite therapy. In my mind is one of the most exciting therapies that will be is being investigated all over the world and there are literally dozens of fights there's at least a dozen bite different bites that are being studied right now. So it's a very intensive investigation with this form of therapy, which is has similarities to car T, but it's, it's different. It's only available in a clinical trial. So, it would be something that you'd have to go to a research center to get this therapy. So the other thing that I was referring to is that by specific antibody. Yes, we have, we have multiple antibody therapies already available for my alone on this patient had their tumor map for example, most antibodies, naturally, are so called IgG antibodies they have two arms on them and they can stick on to two antigens of the same molecule by specific antibodies been engineered so it sticks on to the myeloma cell with one arm and sticks on to their own T cells from their immune system and brings the immune cell effector cell to the myeloma cell and induces cell killing, which is essentially the same thing that a car T cell does a car T cell, you've actually engineered the lymphocyte itself the T cell to have the antibody stuck onto it, and then that will attach it to the myeloma cell and kill the myeloma cell. The problem with that approach is that it's expensive you have to engineer the cell. You have to get the lymphocytes out of the patient engineer it and then put it back into them so it's a very laborious process, whereas a bite antibody, you can just get get it off the shelf and inject it into the patient. Yeah, I think what's particularly exciting about these these sort of T cell therapies that you're hearing about the car T and the in the by specifics is that there's a lot of room for improvement, there's different antigens that the antibodies can be directed to this And so you can see as opposed to sort of the empiricism that that characterized the first 50 years of myeloma, that there's really rational drug development that can be done with these therapies that that I think gives us all great hope for the future. Again, our patient, you know, I think that some take home messages so he is again able to enjoy quality of life at this point he's surfing he's enjoying his kids and able to actually see and enjoy his grandkids which is something he didn't think would be possible at nine years ago And he was first diagnosed. So, I think a couple take home points again, just that there's a variety of different treatment options and combinations based on disease characteristics as well as patient factors. And I think we've all kind of alluded to it's really important to be in contact with a specialist who specializes in myeloma. And I think that's a great point, you know, even if they're going to be working with your local oncologist but there's so many moving parts, new treatments new therapies new combinations that it would be really beneficial to have at least an expert opinion and touch base every once And my other point is always always consider clinical trial option at any stage of your treatment so even if it's induction or at your relapse, or if you've relapsed multiple times. There's always you know, look, looking to talk with a physician about clinical trial enrollment. And again, you know, I think to emphasize that we've been talking about there's a lot to be optimistic about our goals are to maintain good disease control, while And I think that's a great point, you know, it's important to have a good quality of life. And that's always kind of something that we're trying to balance at the forefront. So, I like to think yeah. And I think one thing I wanted to add to that is that for our attendees who are in other countries, I think could clinical trials or that's the best way to go often because many countries cannot afford the therapies that we have and it's really the only way you can get access to these amazing treatments If I was in a different country. Most countries really the therapies that we routinely use in the United States are not routinely available. I would go to the biggest myeloma center in the country and try to get on the studies as soon as I could because that's going to give you the state, the very best care that's that's available In the United States, I would point out, I'd like to point out that really if you if you really want to look for these these cutting edge therapies that are available only in a clinical trial, you have to go to you in general to a university center and And that's because only a university center can afford to have 10 1520 trials for myeloma open at the same time they're just not most centers aren't going to have enough most private practices just aren't going to have enough myeloma patients to really be viable as a major research center. So please remember that that that you really need to go to a big myeloma center and I strongly recommend going to a myeloma center for a second opinion if you're in search of the very best therapies. Dr. Lee, thank you. And Dr. Herth Libby and Burks Hagle and Dr. Farrow. Thank you so much. Great ideas for these different patients. And as you can see, everybody's treated differently, you know, as you can see, it's, it's a lot. So I echo consider a clinical trial always even as a newly diagnosed patient.