Fireside Chat On The Future of Myeloma: What Patients & Families Should Expect Next

Joe:
We're going to take about 20 minutes to have a conversation and then we're going to have about 20 minutes of Q&A. What I'm going to ask Shaji to do is to pull out his crystal ball and to really predict the future. You've heard a lot yesterday we talked about myeloma 101. We talked about the state of the union of treatments. You're going to hear more today from doctors Lee and Janet Kinram around what is the standard of care now for frontline therapy, for relapse therapy.

But what I would like to do is try to look forward a little bit, one, to give us hope. I commented yesterday that I don't think in 25 years of myeloma I've ever seen a time as right now with the sheer number of clinical trials, the sheer number of molecules, the success that we're seeing is really extraordinary. But two, also to really have you think about some very specific things that might influence your care over the coming months and years as we think about the future of myeloma. So we want to create some hope today, but we also want to map out a little bit of where myeloma is going.

Shaji, we're going to try to cover a bit of the spectrum of myeloma. My first question for you and your crystal ball is to say right now in myeloma, we discussed this briefly yesterday, most people get diagnosed because they've had a symptom or a sign that's been going on for months. The average patient sees their primary care doctor three times with signs and symptoms with myeloma, back pain, a weakness, fatigue. As we heard from Thomas Goody, he had that pain in his arm. Are we going to now start thinking about catching myeloma earlier? Are we going to start screening for myeloma anytime soon?

Shaji Kumar:
Thanks, Joe. First of all, thanks for having me here and it's wonderful to be here with all of you. I think it's a great question because for the longest time, it didn't... Sometimes we wanted to catch the early stages of myeloma, right? I mean, it's important to keep in mind that myeloma is not something that happens overnight, right? There are conditions that precede myeloma called monoclonal gammopathy of undetermined significance that Professor Kyle described almost six decades ago, and there's an intervening stage we call smoldering myeloma where it's kind of in transition.

The good thing is we have that huge long runway where we could potentially do something. The bad thing is we don't know who has it. Most of the time we accidentally stumble upon it because your physicians have done a test and the protein is picked up, but now that we have... As you said, the treatments have gotten better and we are actually even able to show that intervening in that early stage could make a difference, I think there's a real interest in trying to screen and find people who have these early stages, but the downside to that is this is not a common cancer. So you cannot theoretically screen the entire population. You're going to a whole lot of people with small amounts of protein and worry them for the rest of their life, whereas 90% of those people would never ever get myeloma.

So I think the future is going to be a more what we call an enriched or a targeted screening, so maybe individuals with multiple family members. You already talked about African Americans being at higher risk, so maybe that is a demographic that we want to again focus on in terms of screening approaches. So identify a population where the chances are much higher and then screen them. I think it's very much around the corner. We just don't have all the precess or the puzzle together to make a convincing argument yet.
The other important aspect is it's not just who to screen, what do you screen with and when do you screen? You may have already heard about this yesterday about the more sensitive tests like the mass spectrometry, and we have shown in some of the Olmsted County population studies, if you do that test one time when you're 50 years of age, your chances of developing myeloma for over the next 20 years is practically zero. So it may be just that if you're at a higher risk, you may do a one-time screen at say 50, and then you have scored free for the next 20 years before you may want to screen again.

Joe:
Fantastic. I mean, I think it captures the whole cancer community wants to catch things earlier. I mean, I think that just makes sense, doesn't it? I just remind everybody, it took us years to determine the best way to screen for breast cancer with a mammography annually in a certain age of women. It took us years to figure out how to do colonoscopies or to screen for colon cancer, which I'm going to go through this coming week. Oh, joy, oh, bliss. But it took years to figure that out, and we're in the process of trying to figure that out because what makes myeloma even more unique than, let's say, breast cancer or colon cancer, is that very often there isn't that more clear sign or symptom that points in that direction. But because as you've said, it's so rare, we want to balance that.

I mean, if only we had a huge clinical trial that had screened over 80,000 people looking for myeloma or looking for MGUS, it would help us with the answer. Of course, I'm being a little bit sarcastic. So for those of you who have followed the IMF, you may know that a little over five years ago, we, in partnership with the University of Iceland, helped launch the largest screening trial in myeloma history, which was the iStopMM trial, the Iceland Screens, Treats or Prevents Multiple Myeloma. The short story here is that they screened over half of the population of Iceland over the age of 40 to determine is it worth screening? With the most important question being does it save lives? The answer is we don't know yet.
So the jury is still out. They still need a couple of years to process the data, but I think either way, whether it is going to be through screening or whether it's going to be through, what I'm going to share a little bit with you later when we talk about health disparities, the importance of education to the primary care world and the lay public, we all have the same objective. We don't want to wait until someone comes into the hospital with broken bones and a damaged kidney. We want to catch people as early as possible. So I think the future of myeloma has a lot to do with trying to catch myeloma earlier and to treat potentially myeloma earlier.

Well, on that note, Shaji, my second crystal ball question for you is we've had this incredible clinical trial, and I know we're going to discuss this a little bit later with Dr. Vescio and others when it comes to the controversies, but we've had a recent clinical trial that showed when we take people who have high-risk smoldering myeloma, and for those of you yesterday, remember we talked about the male risk stratification. If M-spike is more than two, if there's more than 20% plasma cells or if the free light chain ratio is greater than 20, if someone has two or three of those features, they're high-risk smoldering myeloma, that those patients were treated with just single agent daratumumab compared to what we would typically do as wait until they have active myeloma, then treat them with a quadruplet typically, that that intervention was really able to, if you will, kick the can down the road. It didn't quite, if you will, fully prevent or cure by any means myeloma, but it kicked the can down the road.

If you were going to look into the future, what does the future of smoldering myeloma look like? Not so much what are we doing today based on that study and waiting for the FDA approval, but in general, do you see us catching, if we catch myeloma in that earlier stage, treating it the same as active myeloma, because you led one of the biggest clinical trials in the area of the ASCENT clinical trial, or are we going to partially treat people to delay them to getting to myeloma or is it going to be a combination of both?

Shaji Kumar:
I think it's most likely to be a combination of both. I think the critical change that I think will happen over the next few years, and there are already ongoing efforts to make that happen, is to have a lot more specificity on that test, more accuracy of the parameters that Joe just talked about, the 20 to 20. Can we have additional information about the patient and the two and the cancer that will allow us to say very accurately who is going to get myeloma, who is already crossed that threshold that we no longer can just try to kick the can down the road, just we have to treat them like myeloma and we will treat those people like myeloma? We may call them myeloma and not necessarily keep them in that diagnosis of smoldering myeloma.

For the remaining patients with smoldering myeloma, there's always... One of the concerns we haven't treated smoldering myeloma for such a long time is because we might harm them rather than help them. So identifying the group of people who very unlikely that they will actually get myeloma during their lifetime, we want to accurately identify them and again, tell them that, "Don't worry anymore. We are just going to watch you still like a muggers but not necessarily do anything." The people who are in between, I think we need to do something about it.

There are two things we can consider doing. One is to, as Joe said, kick the can down the road. Can we delay the things? So if that person has a risk or would likely to get myeloma in the next 10 years, can we make it 20 years instead of 10 years? If it's five, can we make it 10? There may be some individuals where the cancer hasn't quite crossed the threshold where we still have an opportunity to cure the disease, so to speak. We are already starting to talk about cure in myeloma, so it's not a leap of faith to say that we can actually cure it in a much earlier stage. I think that's where we might borrow some of the treatments that we use in myeloma, but use it in a little bit more intelligent fashion and try and eradicate the disease completely so that the rest of the life, the patient has never to think about the risk of myeloma.

Joe:
Beautifully said. I think if I can put an extra plug in for what Beth shared with us yesterday about shared decision-making, and this just doesn't only apply to smoldering myeloma. I want to really emphasize this in general in all of your treatments. Now that we have so much choice in myeloma, when we talk about matching choice to what you prefer and what you want, that matching becomes really important because I bet if I sat down with a group of you today and started just doing the numbers and saying, "Okay. You've got smoldering myeloma. You have a 20% chance of this becoming active in the next two years. Do you want treatment, yes or no?" I'm going to suggest most of you would probably say no.
Well, what if I raise that to 40%, to 60%, to 80%? That's where there's going to be a greater variation and it's okay. You may want to be the person who says, "Look, Doc, right now I'm living my best life. I'm having a great time with my grandchildren," or "My business is going this way. I think I would rather kick the can down the road. I'd rather have a lighter treatment that I can keep doing all the things that I'm doing and have it delayed." Versus someone says, "You know what, Doc, look, that risk scares me. Let's do it. Let's go big or go home. I want to get fully treated." Both of those philosophies are absolutely acceptable, which is why when someone says, "What is the best treatment?" Well, it's hard to say what is the best treatment because it really depends, right?

It's like when you ask your waiter or waitress at a restaurant and say, "What's the best thing on your menu?" Well, it depends, right? Maybe you don't like shrimp. Maybe you don't like this. So your preferences have to be matched to the options that you have. Now, you own a restaurant that has one thing on the menu, thanks for coming out, you don't have any choice, right? When we started treating myeloma 20 years ago, there was one or two things on the menu. Now with this portfolio, we want to empower you to help you understand that you're not diminishing the strength of your treatment by intervening with your preferences. If anything, you're strengthening your treatment by being able to choose the thing that matches your lifestyle.

So again, that's a bit of a commercial for shared decision-making, but I just think that's really important because sometimes we might think that, "Oh, there is the best treatment and then everything else." We're in a situation now where you have so many different treatments. There are a lot of great things. There are a lot of great things to eat on that menu and it's somewhat subjective as to what is going to be best for you.

All right. Shaji, next question of the future of myeloma because I want to get to our Q&A in another five, seven minutes or so. We've heard all these great things about CAR T-cell therapy. You've been a participant in the trials. I know Dr. Lee has been a participant in the trials, Dr. Vescio the other one's here today. It proved itself and people have had multiple lines of therapy. It's even now proven itself as early as first relapse as I shared with them yesterday that the indications of cilta-cel and ide‐cel. Are you going to predict with your crystal ball here that we're going to be doing CAR T-cell therapy upfront and that we might actually be able to get rid of stem cell transplant? I was waiting. I was waiting for the lightning. Okay. Very good. So, what do you think? Do you think in five years from now we're going to stop doing transplants and just do CAR T upfront?

Shaji Kumar:
I think the first part is easier to say. I think that CAR T-

Joe:
This is being recorded by the way. No pressure or anything.

Shaji Kumar:
No, but I think as you said, the CAR T has proven itself, right? I think we've seen some really wonderful results and we saw some people, some patients who had received CAR T and has had no treatments for five years with no trace of the disease. It's a fraction, but a sizable fraction. Almost a third of the patients in that trial reached that milestone. So I think it's only natural that we think about using the CAR T earlier on and it's only a matter of time before we think about using CAR T as part of that initial treatment of myeloma to control this.

What is stopping us from doing that today? We have the CAR T in the clinic. The reason is it does come with its own package of side effects and some of those side effects can be quite a bit of a problem, especially things like Parkinson's and other neurological side effects that we certainly don't want to have that risk if... As Joe already said, with the current treatments, we are making patients live 10, 15 years, even 10, 15 years for the myeloma to come back the very first time. In that scenario, to give somebody a Parkinson's diagnosis or something along those lines right in the beginning is probably not the right thing to do.

How do we actually make it happen? One, we have to improve upon the CAR Ts to make it more effective, more safe, more importantly, and especially these kind of side effects we talked about and it is happening as we speak. Now, we used to use viruses to actually randomly make that genetic material change. Instead, now we have much better technology that does not include virus and which is very targeted manipulation of the gene, which allows these CAR Ts to be safer. I think over the next two to five years, we will be at a point where we will have CAR Ts which are more effective, very much more safer than what we have today and that's when we are going to start thinking about using CAR T earlier on after the diagnosis.

Now, let's say if we get to that point, can everybody get CAR T as the part of the first treatment? Maybe not because there are a lot of other things that goes into that mix, right? Can the patient sustain the side effects that can come with some of these CAR Ts? Can the patient travel to a center that can give the CAR T? So a lot of other challenges that can still be in the way, but in principle I think it's quite likely that we will start using CAR Ts in the earlier as part of that frontline package and you'll hear about what is being used currently in the breakout sessions as well.

Joe:
Fantastic. I, by the way, completely agree with you. I mean, I think we need to make it even more effective and safer. It's hard to say even more effective when we've seen 90% of people responding to something, but we want to set that really high bar in that high standard.

Shaji Kumar:
I'm not avoiding the question of the transplant. The transplant.

Joe:
You avoided. Yeah, that's what I was about to say. Yeah. You should run for office. You're good at avoiding questions. I'm sorry, did I say that? My thoughts being broadcast? Did you all hear that? Yeah. Do you think that we're going to abandon transplant?

Shaji Kumar:
I think we will abandon transplant as part of the initial treatment of myeloma, but I don't think we will abandon transplant as a treatment option because again, as you said, we are curing some, we are not curing all. Until we are curing everybody with myeloma, we are going to throw out any treatment.

Joe:
Yeah, I think that's a really important principle is that in general, in a disease we've not yet cured, I don't want to take anything off the table. There are some patients... We've talked about these great... And I know Dr. Lee will discuss it at the frontline session. Just to give an example, I just a patient actually recently in my clinic, myeloma's weird, right? It's different in different patients. We have some patients that for some reason we can't quite understand. We give them that best quadruplet possible, whether they're getting DVRD or ECKRD, all these different four-drug alphabet soup combinations that we give and their disease still doesn't respond very well and yet we do a stem transplant and they really respond.

It makes me think that there's some forms of myeloma that the biology of the myeloma is just very responsive to that old-school melphalan chemotherapy and not as responsive to certain treatments. I do like the idea of keeping, but I also do think, and I'll go out on a limb saying this, that I really do think the role of stem cell transplantation is going to continue to shrink over time. For the financial types in the room, I wouldn't be buying transplant stock right now as it were. That's not to dish transplant and that's why I was waiting to be struck by lightning by the transplant gods. I've been a transplant for over 20 years and I believe it, but I do think we have gentler and more effective ways to treat transplant.

Shaji, my last question before we open up for Q&A, so if we can get our mic runners ready, Michael, et cetera. It's always nice to ask Mike to do mic running. Okay. I'll keep my day job. All right. No worries. I still am a myeloma doctor. I'm not a comedian. We talked yesterday, Shaji, quite at length and I explained for quite a while yesterday the whole concept of MRD, minimal residual disease. For those of you here yesterday, this concept of being able to do a test to look for tiny little bits of myeloma left and how we're already starting to see clinical trials being designed and processed to incorporate that in decision-making. So the question for you about the future is do you think we are going to be using MRD significantly more to make decisions about do you get this treatment or do you not get this treatment or can maybe we even stop treatment versus continuing treatment?

Shaji Kumar:
Absolutely. I think minimal residual disease or measurable residual disease as some people would like to call it, I think it's going to be here to stay and a very prominent part of what we hope to attain with the treatment for our patients. So I think there are multiple ways we might end up using it. One is to decide early on which kind of fork in the path do we take. We already have some clinical trials showing that the MRD testing before deciding on the transplant could have implications as to what you choose to do, transplant or not transplant. We know the MRD can be used as a measure of, again, how deep the response is and how long the response lasts so that we can stop treatment. I think increasingly, almost all the trials that are being designed for the newly diagnosed myeloma patients include some element of MRD-guided discontinuation of therapy. I think that is going to be the future.

Now, this other important aspect is when do we restart treatment? Right now, we start treatment only when patients start having some of the same symptoms that they may have had in the beginning or the protein has increased considerably, but we may get to a point where we might start intervening when the MRD becomes positive. So there might be a setting of where we talked about intervening early that might happen even in the setting of someone who has already been diagnosed with myeloma and has been treated for myeloma. So I think there are multiple places where we may be using it in the actual practice, but immediately I think where it's going to make a huge impact is how we do clinical trials. The clinical trials are increasingly looking at the MRD as a way to measure or compare the different treatments so that we can get the new treatments to the clinic much faster than what we have been able to do.

Joe:
Yeah, that's fantastic. If I could even take it a step further, and I know we're not quite there yet, but this is again part of the work that we're doing the IMF and partnering with others is I would love to see a day where an MRD test is just like taking a blood test and not requiring the bone marrow to do it. Obviously, the bone marrow is the headquarters of myeloma, so we get the most information there, but sometimes the headquarters there can be leaks as it were out into the peripheral blood. I know for some of the work, for example, we do in our lab is that we are trying to look for even the tiniest amount of evidence of myeloma in the peripheral blood and I think that will open the doors of more routine MRD testing so you don't have to get a needle in the backside every time we want to look for MRD testing. I really do think it is going to have a huge impact.

My last comment about MRD, I can't help but say it because the IMF led this process was to work closely with the FDA to say that in clinical trials when we see patients respond and we measure how many patients get into MRD negativity, it predicts how well patients are going to do. By using that as, if you will, a marker of what's going to happen later, a predictor of what's going to happen later, it can speed up how quickly we develop drugs. So back to what I said earlier about clinical trials. If I want to test that clinical trial I told you about where I take the standard of care drug A and now I add drug X to A in the intervention arm, that trial might take eight years before we figure out that A plus X was better than A.
But if we could predict it early on and know within the first several months that because this many people got into MRD negative with A plus X and only this many with A, that the benefit's going to be there, you can imagine how much faster it is. It's like predicting the end of the game at the end of the first quarter, which we all could have done at the Super Bowl last year. Sorry for any Chiefs fans, thanks for coming out. But anyway, the point being that that could really, I think, propel the development of drugs earlier so that if we can predict that this is going to work just by how many people respond. All right. It's time for Q&A. Sylvia is flat waving her number four, so it looks to me like we've got a question right at the back. That may even be Richard, I think I can see you. How you doing brother?

Richard:
Hey, thank you so much, Dr. Joe. Always informative presentations. You're fantastic. So the question that I have, and so I'm very excited about the prospect of better testing for asymptomatic diagnosis, but I wonder about the gap in people who are symptomatic like Thomas and myself who end up being diagnosed very late because of just the lack of testing to really bring out the disease. So I wonder about SPEP, whether that would be something that maybe if Thomas's doctor, maybe my doctor had given me an SPEP test, whether I would've been diagnosed earlier and whether that would be something that would make a big difference because a lot of us we're presenting with symptoms and we're still being diagnosed late. So, what can we do to fix that problem?

Joe:
So I think what you're asking both is should we be looking at testing earlier on and what do we test with, which I think you raised a little bit, so maybe I'll let you answer that, Shaji.

Shaji Kumar:
Yeah, I think part of it is too, I think the gap in terms of, again, myeloma is not a common thing. So if you walk into your primary care physician's office and say a back pain, myeloma is probably nowhere on that list of things they're thinking about. So I think the key thing is just education. I think the more we convey or be part of some of those general medical primary care sphere, so to speak, education in that I think would be the major thing to do. I think just making sure that people are aware of these different conditions that could lead to some of these symptoms we see in myeloma. So if they do the X-ray or they don't find anything or if they go down the list of things in orderly manner so that this is part of the testing that they do is the testing for myeloma, I think that's a-

Joe:
Richard, part of our approach to do that was both to educate the general public and in particular those who are at higher risk, older individuals, individuals of African descent, et cetera, but also to educate the primary care world to say, "Don't dismiss this person with pain because they may have multiple myeloma," because we want to find that balance, right? We have young Black men diagnosed with myeloma. We also have young white women diagnosed with myeloma, right? So it's not that those are the only ones at risk, and so we're trying to find that delicate balance, but I do think your point's well taken.

I'll add one point to this, that Shaji and his team at Mayo Clinic don't even really do the serum protein electrophoresis anymore or the serum free light chain assay, which the two that should be done together. They've now taken another step to do this mass spec testing, and that mass spec testing may make it easier in the long run because it's a single test. It could be done very quickly. It could be potentially added to other tests that are being done. So that may be part of the future. All right, Mike. Mike with the mic.

Speaker 4:
Yeah. Hi. Thanks for being here. So I was diagnosed in October of 2023, standard triplet, dara, Revlimid and dexamethasone. I was told I'm in remission. I don't really know what that means. My doctor has never mentioned MRD. I had a bone marrow in June. So really my question is what should I be asking going forward and what does remission really mean?

Joe:
Do you want to start with that?

Shaji Kumar:
Sure. No, I think when we talk about remission, again, we're talking about the disease that is quiet or maybe MRD positive, maybe MRD negative. But what I think the key questions you need to ask to understand that is how is my myeloma being measured? What are the tests that we are using? Is it the M-spike? Is it the free light chain? Are there myeloma cells still in the bone marrow? I think you can certainly ask was MRD testing done?

Now, again, the MRD testing, as we said, it'll likely be a big thing in the future. Does 100% of the patients today get MRD testing? Not necessarily, because sometimes if you decided, okay, you're going to get four cycles of the triplet, you're going to get a transplant, you going to get a maintenance, and you don't have any high-risk features to start with, knowing that MRD result might not change the treatment, it might give you the reassurance that you're less likely to have the myeloma come back soon if it's negative. So not everybody might routinely do it in their practice, but it shouldn't stop you from asking about that. So I think those are the main things. Now, what are the measurements that they're using to observe your myeloma? The blood tests. What do they see in the urine? What do they see in the bone X-rays?

Joe:
Yeah, I think that beautifully said. The only caveat I always add to when we have these discussions on MRD is that... I don't know if you remember that old advertisement I want my MTV, right? I always wanted to make that to I want my MRD, right? So I want to be careful that people don't leave, like going back to every community oncologist represented here, and you're saying, "I went to the conference this weekend and Dr. Kumar says that you're going to do my MRD testing for me." Let's be careful, right? It's not that it's revolutionized what we're doing. We know it's a powerful tool, we just haven't fully understood how to use it yet. So it's not a bad thing that your doctor hasn't done it.

It's a good thing that they've told you you're in remission. They may assume that you know what that means, and that's part of why we're here this weekend. That's why yesterday I showed the difference between an M-spike and light chains so that we know what's being followed. We can work with you and you can work with Missy in the info line here if you want some help looking at what those numbers are so that we can make sure you understand it. Yara, I think, has the next question.

Speaker 5:
Yes, thank you very much. Excellent presentation by both of you. I'm a very unusual three-drug approach to my treatment of both multiple myeloma and amyloidosis on the sidelines and I'm curious about the treatment I'm getting. That is I have the 11;14 and I have a combination of dara, dex and Venclexta, I think I'm not... I know if I'm pronouncing it right. It's been a very remarkable thing in putting me into remission. I wondered what your opinion is of that unusual three-drug treatment with my type of chromosomal defect and whether there's any literature on the long-term effects of that somewhat different treatment regime.

Joe:
Well, if only we had someone on the stage who led the studies with venetoclax or as you've just described. Oh, Shaji Kumar happens to be with us, right? Isn't that ironic, don't you think? Boy, I'm hitting a lot of songs today. Anyway, Shaji actually led many of the studies and the very first and most important study in translocation 11;14 multiple myeloma with venetoclax, so I'm letting him take this one.

Shaji Kumar:
No, I think, again, just going back to that you said initial about the two things happening at the same time, that's about five to 10% of the patients. So it's not uncommon thing because the root cause is the bad plasma cells making protein, but in the setting of amyloid, it's that your body is reacting to that protein in a little different way. Now going back to the 11;14 and the use of venetoclax, I think you are on the right treatment. It's probably one of the most effective treatments that we have, the combination of daratumumab and the Venclexta for someone with 11;14 translocation. So we do use it often. We don't use it in the beginning primarily because the Venclexta is still not approved by FDA for use in myeloma amyloidosis, but we know it's effective.

There have been some trials that did not turn out to be positive because of trial design problems, not necessarily because of the fact that the drug does not work well in patients with 11;14 translocation. So long-term effects, the venetoclax or the Venclexta has been around for a long time for treating patients with chronic lymphocytic leukemia, and those patients often get this treatment for long periods of time. Right now, there's no literature to say there's any irreversible long-term side effects of Venclexta. Certainly has some side effects as you're taking it, including some low blood counts and so forth. But again, I think you're on a good treatment that, as you said, seems to have worked remarkably well for you. So that's great to hear.

Joe:
Fantastic. Question number three over here.

Speaker 6:
Good morning and thank you to the IMF for putting this together and everything you do. I do have a question around... You talked a little bit at the end of the talk about the speed of analysis of clinical trial. By the way, I'm a caretaker. My beautiful wife is here with me, who's a patient. In that speed of analyzing all the data and coming takes eight months to understand that, is the IMF involved in any initiative to working with whether it's ML or AI companies to accelerate perhaps some of the analysis and come to either predictive or prescriptive conclusions about that faster, if you will, if there's anything going on there?

Joe:
Absolutely. In fact, it's a tremendous question. So if I understand your question correctly, what can we do to accelerate the results of these studies and find ways to obviously make a big difference? I think the one thing that comes to mind, what I just briefly mentioned before, was this notion of using MRD as a clinical trial endpoint. After we made the case to the FDA and had the discussion with them, now we're seeing more than ever drug companies and others putting together clinical trials that use MRD as the endpoint.

So instead of saying, "Let's wait to see what fraction of patients stay in remission over a year, over two years, or what the average is," now based on the MRD studies, we know it's not perfect. MRD is not perfectly predictive in every patient. I always give that caveat. Remember I commented yesterday that those patients, it's almost like they go back to MGUS. They still have a tiny amount of disease, but it's the Bambi. It's not the Rambo. Remember we said there's that little bit that is actually not going to hurt, but I think that's been a major step forward.

I think secondly, and Shaji, I'll let you comment if you have other thoughts on this, I think secondly, to be very blunt, it is a very competitive space right now in doing clinical trials in myeloma, which is good, which is good for all of us that there are a lot of new molecules, a lot of new studies, a lot of... It's an area where we know we can see considerable improvement. I think that in of itself has caused us to say, "Let's get through these barriers that have historically slowed down clinical trials." Why do clinical trials only have to be done in very large academic centers?

Again, I'm not trying to be a commercial here for City of Hope, but let me just give them as example in this region is they said, "Look, instead of having to schlep everybody out to Duarte, which is on a good day in Los Angeles could take two hours from here, right now, let's extend City of Hope into Orange County into other areas and have more peripheral centers based with clinical trials so that people can enroll on closer to their homes, closer to the areas which facilitates enrollment, which ultimately ensures that we have a greater representation and indeed speeds up the process."

So I think there is an impetus in all of us to say, "Let's get to these results quicker." Some of the ways they're designing clinical trials with different endpoints, some of them is moving clinical trials into the community. Some of them are efforts to increase, as I shared with you earlier, diversity in clinical trials, because sometimes the FDA might say, "You know what, you did this clinical trial, but there weren't enough Americans represented on the trial." Without that, we can't really make a comment here. So we now have to in sense go back to finding, "Okay. Let's do more trials with them." Had we done that from the start, it might have facilitated. I don't know, Shaji, if you have anything to add there.

Shaji Kumar:
No, I think you hit on the two major points. I think the biggest thing is accrual. If we can get patient clinical trials completed fast, we get the results fast as well. Then I think one other thing I might add is that we want to get all these new treatments that are approved into the community as fast as we can, because the next trial is going to use that as the known experimental arm, so if that's already not adopted in the community, that becomes a challenge as well. So I think that's part of the education part that we have to do as well.

Joe:
We'll take one last question and then we'll give you instructions about our breakout. So Yara, I think, has it over here.

Speaker 7:
First of all, thanks to everyone in this organization. It's my first year and I'm grateful for the amount of information I'm receiving. Thank you.

Joe:
Thank you.

Speaker 7:
Question is does AI technology or could AI technology play a role in R&D or any part of this process at all?

Joe:
Well, if only we had a station outside of these doors where there was a computer set up to connect you to an AI chatbot that interrogates the Myeloma.org website to answer questions. Again, I'm being a little facetious here, but yes. So there is no doubt that when it comes to education and awareness that AI is going to play an incredible, or it's playing it already, not just through the chatbot. But sometimes I say the IMF is trying to beat a human chatbot of bringing together the masses of information from all these different centers.
Diane showed that incredible world map with all of the connections around the world, because some of the principles of AI is to collect information in a way that one individual could never collect. One person can't learn it all, but integrate it we can. So from an educational standpoint, absolutely. Shaji, I'm going to ask you to answer it from a research standpoint. I know there's some really fascinating things happening in particular through Mayo Clinic looking at ways to incorporate AI into our research in myeloma.

Shaji Kumar:
Yeah. I think the multiple by places the AI can touch in terms of the R&D starting all the way from selecting out the best molecules. In the past, we would have maybe 70 or 100 or 1,000 different molecules that we want to go through in different testing. Now we can use AI-based approaches to say, which one or two or three of them is most likely to be a good candidate so that you just move them along. So the whole process of clinical trials actually becomes faster from the early part of the trials.

The second is matching patients with clinical trials. You saw the spark cures. That's also in a way using AI to connect the right patient to the right clinical trial. We are looking at AI as a way of looking at the electronic medical records to find out, okay, without even... Who are the patients who might need to be screened? Who are the patients who are at higher risk of developing myeloma? We are using the AI to interrogate a lot of different variables in terms of lab results, the patient characteristics, the tumor genetics, all of them can be put together. That's a vast amount of data that manually, it's very difficult to understand patterns, but AI can tell us, "Okay. This patient may not do very well," or "This patient might actually be best treated with this particular three-drug combination." So any aspect of diagnosing, developing new treatments, AI is going play a major role going forward.

Joe:
I'll give you one last example and then we really have to go onto our next session. Remember how I commented about the iStopMM trial? So they screened 80,000 individuals for MGUS right across all of Iceland. You can imagine the mass of that database. It's unbelievable. One of the things that they used AI to do was to develop a calculating tool that based on features of someone's MGUS, what was the likelihood that doing a bone marrow is going to give us any more information to make the determination if they have smoldering myeloma a lot? Because the difference often between MGUS and smoldering is just the bone marrow test that shows more than 10% plasma cells, and so they fed this all into their AI system. Now we can use this calculator that says, "Okay. I have a patient who has this, this, and this. What's the percent chance that doing a bone marrow is going to give me any more information?" What's allowed us to do, I think, is to do less bone marrows.

There are patients with MGUS we've said, "You know what, based on this calculator, the likelihood that you have smoldering myeloma is so low. Let's not do the bone marrow test. I know you're dying to have this needle stuck in your backside, but let's not do that." Again, I'm not trying to make light of something that's so serious, but those are the kinds of things that AI can help us in, even pragmatically in the clinic.