Dr. Robert Orlowski joins the HealthTree for Multiple Myeloma Podcast to share the recent announcements from the American Society of Hematology meeting and what we have to look forward to in 2025. He shares new approaches for high risk smoldering myeloma that may include near-term FDA approvals for daratumumab and the triple combination of isatuximab/lenalidomide/dex. He also describes CAR T approaches in smoldering myeloma and the pros and cons of that treatment approach. 

He describes the importance and data showing that quad therapies are the new way to go for newly diagnosed patients. He shares many updates for relapsed and refractory myeloma patients including the use of maintenance therapy (with a two-drug combination with daratumumab and lenalidomide), new bispecific antibody results for teclistamab, cevostamab and talquetamab and the importance of having multiple targets for immunotherapies. He shares how MRD is being used as a new clinical trial endpoint, how blenrep (an antibody drug conjugate) is likely to make a comeback, and how new CART therapies like anito-cel are looking promising. 

The show is full of gems that patients will want to know like why you may be able to stop 24-hour urine testing, why new monocloncal protein testing like mass spectometry is more accurate, the infection prevention (and lengthening of life) from IVIG, lower rates of cytokine release syndrome (CRS) when CAR T is given after stem cell transplant and how the new drug class called CELMods can actually re-activate T cells. 

This is a show not to be missed by one of the top myeloma experts in the world.

Jenny: Welcome to today's episode of the HealthTree Podcast for Multiple Myeloma, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom.

Now, before we get started with today's show, I'd like to share how HealthTree Foundation is the market leader in digital health advocacy and what that even means. HealthTree has a unique technology experience and a large software development team.

What this means is we can create technology that removes barriers to research, cutting the time by more than half to complete a research project and providing our technology tools to analyze very large sets of data that might not be available for a single institution.

Our goal is to provide the data and support that researchers need to cure myeloma faster. In 2018, we built a research portal called the HealthTree Cure Hub Registry. This is a way for every single patient to contribute to research, whether you can join a clinical trial or not, and we've had great success so far.

We currently have over 10,000 patients participating in the HealthTree Cure Hub Registry. And with that participation, we've been able to complete over 170 myeloma surveys or studies in partnership with over 150 investigators involving 72,000 patient participants just like you. These discoveries are changing clinical practice.

Now, this year we will have a significant focus on immunotherapy. So if you have had a bispecific antibody, please join that study and if you've had CAR-T therapy, we will be opening a study on that by the beginning of March this year. Now onto our show.

This is my favorite show of the year because it helps us better understand what we can expect in 2025. This will be a fast-paced show covering many different topics, but Dr. Orlowski is the absolute best at making these topics easy to understand. We'll have a full show transcript that you can reference at a later time and we'll be sharing some of your pre-submitted questions.

So Dr. Orlowski, welcome to the program.

Dr. Orlowski: Well, Jenny, thanks very much. It's always a great pleasure to do this show every year. It's probably not too late in January to wish everybody a Happy New Year. And of course, our best wishes go out to all the folks in the Los Angeles area, especially the myeloma patients who are impacted by the terrible fires out there.

Jenny: What a crazy tragedy. It's incredible.

Let me give you an introduction for you before we get started. Dr. Orlowski is Vice Chair of the Myeloma Lymphoma Translational Research Division of Cancer Medicine and endowed Professor of Medicine in the Florence Maud Thomas Cancer Research Professorship in Lymphoma and Myeloma at MD Anderson Cancer Center. He's also Professor of Medicine for both lymphoma and myeloma and experimental therapeutics. He's the disease site liaison to the International Center at MD Anderson.

Some key appointments include, there's so many to mention, but I want to include some of them: Co-chair of the NIH Cancer Therapy Evaluation Program in the Experimental Therapeutics Clinical Trial Network. A member of Lytica Therapeutics, Chairman of Millennium Independent Data Monitoring Committee. Chair of the SWOG Group and the Barlogie Multiple Myeloma Committee, which is a national program for evaluating clinical trials, so it's a major responsibility. He is on the educational committee at SOHO, is a member of the National Cancer Institute Myeloma Steering Committee, a member of the editorial board of the publication Hematology, and is a member of the American Society for Biochemistry and Molecular Biology, and FASEB member in Houston. So there are so many more committee positions he holds and too many to mention, but he's an author of,over 500 articles, abstracts, or book chapters.

You may not know that Dr. Orlowski was the first to bring Velcade to clinical trials, continuing a family legacy of his father who had conducted laboratory research that laid the scientific groundwork for the development of the first proteosome inhibitor, which led to the development of bortizomib. So I always think that's an amazing fun fact about you.

Dr. Orlowski has received many awards, including the Leukemia and Lymphoma Society Scholar in Clinical Research, the Leukemia and Lymphoma Society Man of the Year Award, the Emil Frey III Award for Excellence in Translational Research from MD Anderson, the Waun Ki Hong Member of the Year, Mentor of the Year Award, the Gerald Bodie Award for Excellence in Education, and the 2022-2023 Giant of Cancer Care in Myeloma, which is incredible. He continues his lab research in myeloma, is now performing significant research on a myeloma lymphoma therapy that I hope he discusses for heat shock protein called HSP70 and is moving that towards the clinic.

You can find news and information from his daily newspaper on Paperli called Myeloma Daily or find him on X at @myloma_doc. So with that, let's get started.

And I am going to let you share your favorite topics that both came out of the recent Ash meeting and other things coming out of 2024, but really a look ahead at 2025 where you see things going. So I don't know if you want to start in the precursor condition stage or have any thoughts about that, where you'd like to start.

Dr. Orlowski: Definitely. I think going to the precursor area is a good place to start. And I think there were two abstracts that I thought were very interesting there. One, which may change practice very soon.

The second will take a little bit longer probably, but the one that's going to probably change things a little bit sooner was the results of the phase three AQUILA study, which looked at daratumumab as a single agent for patients with high risk smoldering myeloma. And many people who are in the myeloma area are familiar with daratumumab. It's a CD38 antibody, which is used both alone and particularly in combination in the newly diagnosed and also relapsed and refractory setting.

Here, they used it as a single agent, as I said, for high-risk smoldering, and the results were quite impressive with a prolongation in the time to progression, as well as some differences in overall survival.

The tolerability of the drug is very good. Because this was a Phase III study, we're expecting that the data will be filed with the FDA.

And if the FDA agrees that the data look really good, it could be the first approval of any drug for high-risk smoldering and probably won't be the last because we're also expecting - I don't know if it'll be this year or next year, but there was the so-called ITHACA study, which looked at lenalidomide and dexamethasone as the control arm versus isatuximab, lenalidomide and dexamethasone. And isatuximab is another CD38 antibody.

So that study has finished enrollment. We don't know the data yet because the follow-up is ongoing, but I think we would expect that Isatuximab with lenalidomide/dex will probably be better. So then you would have single agent daratumumab or an isatuximab-based triplet to pick from for the high risk smoldering category.

Jenny: And just the significance of this, I mean, it's been forever that it said if you have smoldering myeloma, regular or high risk, get treated in a clinical trial. There's really nothing that we know of right now. So this would a big game changer. 

Dr. Orlowski: You're right. It has been forever because there have been no prior FDA approvals in the space. So it would be really nice to have something that could delay the time to progression. It's even possible that some people who get treated may never progress to active disease, although we don't have long enough follow up to know the answer to that question yet. But we can hopefully be optimistic.

Jenny: Wonderful. Are those the two that you wanted to talk about in smoldering or did you have a second one?

Dr. Orlowski: Well, one other study to keep a watch out for is a trial that was called CAR-PRISM. And this actually looked at a BCMA targeted CAR T cell, the cilta-cel type of CAR T for patients with high risk smoldering.

This was a very early study, so that's why I mentioned that this probably won't have immediate effects. But in the first six patients that were reported, all of them were able to achieve MRD negativity or minimal residual disease negativity at 10 to the minus six, which is the deepest level of response that we can measure. And so, definitely very encouraging.

We need of course larger numbers of patients to be treated and longer follow-up, but definitely something to look at. I think one has to balance the excitement of that with the potential risks of the CAR T. There's more information coming out about delayed neurologic toxicities with some of the CAR T's.

And of course we know that there is a very small, fortunately, but not zero risk of second cancers. So that's something to keep in mind as well, considering that even among the high risk smoldering, some of those patients would never progress. So we do wind up treating some people who perhaps may not need treatment, which means we need to get a little bit better at predicting who will progress and who will not progress.

Jenny: It seems they see a difference in the neurotoxicities with the high-risk smoldering patients compared to the other types because I've heard a lot of physicians say, well, I'm seeing that more in patients that have really high tumor burden or things like that. So I'm curious.

Dr. Orlowski: I didn't look at the data. So far, not so much, but keep in mind that the patients were a small number, again, only six patients at the beginning, and the follow-up was relatively short.

So I think that we need to see more people and a longer period before we can hopefully say that there's less neurologic toxicity in the smoldering setting. Although if it has to do with BCMA expression in certain parts of the brain, which is one of the current working hypotheses, it may not matter what stage of the disease you're treated with, you may get the same risk.

Jenny: That'll be so fascinating to learn. I think that's incredible. Do we want to move on to newly diagnosed patients and what you see as the major advances for them?

Dr. Orlowski: Definitely. I think in general, it was a relatively quiet ASH (American Society of Hematology meeting) for Phase III studies in the newly diagnosed setting. One trial that I think is worth mentioning was of the IMROZ data, which was for MRD negativity.

IMROZ, you may remember, was for transplant ineligible patients, and they got either VRD, which is bortezomib len/dex, followed by len/dex as a continuation of therapy, versus the experimental arm, which was isatuximab with VRD.

And then after that, as a continuation, they got isatuximab with lenalidomide/dex. And the presentation, which I was lucky enough to be able to make, showed that the quadruplet with the anti-CD38 antibody had a higher rate of MRD negativity at both 10 to the minus fifth, as well as 10 to the minus six.

And interestingly, if you were MRD negative on the quadruplet and converted to MRD positive, you still did better than if you were MRD negative on the triplet and converted to MRD positive. And that could be either because you still have a deeper level of response with the CD38 antibody, or it could be that the antibody changes the microenvironment of the tumor.

So even if the myeloma cell doesn't respond as well as it should and maybe has some resistance, if the microenvironment is still different, meaning that the neighborhood where the myeloma cell lives is tougher and more difficult for it to survive, that could explain why we have that difference. So I think that was one study that was interesting.

And then the other phase three study that was reported out was one that was a little bit similar in design. And instead of isatuximab as the CD38, it used daratumumab. So this was the phase III CEPHUS study.

It also was for transplant ineligible patients, but it was a little bit of a different population because they did allow transplant eligible patients who didn't want to do a transplant and also excluded frail patients. Whereas the MRI study had about 20 to 30 % of patients who were actually considered frail.

But here too with Dara VRD, the DARA VRD was superior to VRD. So essentially the take home message is we've seen from past ASH meetings for transplant eligible patients that quadruplets are the best way to go. And now we have data for transplant ineligible patients that the same is true.

And one of the concerns about using all four of these drugs upfront was always, gosh, you know, people will still relapse and will we have something left for them? And one of the ways that that was addressed is that in the MRI trial in particular, PFS2 was looked at.

That means how did people do on whatever treatment they got after their disease progressed on the first line therapy and the people who got the Isa/VRD still did better on second line. So that shows you that even if you use that quadruplet upfront, patients will still do better later on. And I think we expect that that will translate into a better overall survival benefit.

So I think those were the main take-home messages from the newly diagnosed setting from ASH from this year.

Jenny: Great. It sounds like quads are here to stay. Are there any conditions where a patient shouldn't get a quad? Because it seems like you should give it to every newly diagnosed patient now using one of those monoclonal antibodies. I think that the vast majority of patients should get them.

Dr. Orlowski: I could imagine that if somebody has really severe neuropathy coming in, because most of the quads that have been used include bortezomib, which can worsen neuropathy, that you may want to be very judicious in the dosing or maybe not give it at all. You know, if people have poorly controlled diabetes, I think we have to be careful about the dose of dexamethasone.

Sometimes with lenalidomide, patients can develop allergies. So those are considerations, but that's a relatively small proportion of people and most folks should get the quadruplet.

Jenny: Okay. Well, it sounds like everyone's decided and should be implementing it, right? And for those who are seeing a general oncologist and not getting treatment from a specialist,

I always say this, but you should be consulting with a myeloma specialist like Dr. Orlowski every time you are making a treatment decision, especially, you can go get your infusions done closer to home or whatnot.

But this is imperative that you have a specialist on your team. And you're going to hear more about why that's so important. But this is why. Because sometimes a general oncologist might not be up to speed with this data and still be giving triplet therapies, for example.

Dr. Orlowski: Totally agree. Great point to make.

Jenny: Well, let's jump into relapsed refractory multiple myeloma. There seems like there was a lot and maybe the majority of the content from this conference was about this topic. Where do you want to start?

Dr. Orlowski: There was a lot. You know, I think if I could, I would mention one study from the maintenance setting which was the phase III AURIGA study. And this took patients who were MRD positive after transplant and randomized them either to lenalidomide alone or to patients who got Dara with lenalidomide. And as you would probably expect, the dara and len group did better.

We are very close in SWOG (Southwest Oncology Group) to also finishing enrollment to a study that's comparing lenalidomide to lenalidomide/dara right from the beginning of maintenance, irrespective of MRD status. And that will be an interesting study, although it might be a couple more years before it reads out.

So for those people who do get a transplant and think about maintenance, a combination like len and dara may be a reasonable way to go. And hopefully we'll push out the need for the next line of therapy. And at that point we would get to the relapsed and refractory setting.

Jenny: And then some patients are asking for how long do you do these things? But we'll get to those questions at the end.

Dr. Orlowski: Great question.

Jenny: So things seems like the immunotherapy bulk of the treatment landscape is growing and with more options, more different types of classes, more targets. So I'm not sure where you want to start because there's a lot to cover.

Dr. Orlowski: Yes, there definitely is, which is great news for people who do have myeloma relapse. One of the drugs that will likely make a comeback is belantamab mafodotin, which is an antibody drug conjugate.

It's kind of like a Trojan horse where the compound, the antibody is taken up inside the myeloma cell. The drug that's attached to the antibody is released inside and it kills the cells from the inside. The drug was originally approved as a single agent. There was a randomized study which was positive but not positive enough. So it was temporarily pulled off the market. but now we have two large studies in the early relapsed setting showing that combinations with belantamab are better than other combinations, not just in progression-free survival, but also in overall survival. Plus with less frequent drug dosing, some of the ocular effects are less severe.

And those effects can be blurry vision, dry eyes. So those are things that sometimes did interfere with people's quality of life, but now with less frequent dosing, that seems to be more manageable. So it's not yet been reapproved, but certainly with two phase three studies, the data really looked quite good.

Jenny: This brings up a good point that you just made. And some of this is learning that by implementing this in the clinic and then you learn, we're going to space out the dose or we're going to lower the dose or things like that. You go from a clinical trial that's just a single agent, they're testing out doses or using their optimal dose and then you're combining it with other therapies so potentially you can lower the dose and still get the same impact. I just think that's a really fascinating learning process.

Dr. Orlowski: Absolutely. I think every drug that we currently use is used in a different way than it was in the first studies. So as an example, know, bortezomib used to be IV, now it's subcutaneous. Daratumumab was IV, now it's subcutaneous. Isatuximab is coming out with a subcutaneous version. Selinexor, which we used to give twice a week, now is almost uniformly given once a week with similar efficacy and much better tolerability. And again, that's why your earlier point about at least consulting with a myeloma expert is important because these nuances are really well known to people who see lots of myeloma patients, but may not be as familiar to people who are in practice that see the full range of cancer patients.

Jenny: Well, I don't know how it's humanly possible. You're covering a lot of innovation that has happened in the space. And you think about people who are treating 25 plus different kinds of cancers. It's tough. I totally agree.

Dr. Orlowski: I have huge respect for the community, hematology, oncology doctors, because I know I wouldn't be able to take care of every cancer walking in the door. And I think especially those of them who are willing to learn and reach out for help, those are the people I really take my hats off to.

Jenny: Me too. It's incredible what they do. Now, should we move to bispecifics?

Dr. Orlowski: Yes, definitely. There is a lot about bispecifics. One presentation which came from one of our faculty, Oren Pasvolsky, looked at the use of teclistamab in patients who were a little bit older with relapsed refractory myeloma.

And what they found is that in general, there was a good progression free survival and tolerability with that therapy, even in older patients. And one other abstract that's worth mentioning, although it's not a treatment abstract, it's more of a supportive care abstract, but there was a study of IVIG replacement.

And many patients who are getting CAR T and bispecific because these therapies impact normal plasma cells as well as myeloma plasma cells, you get low IgG or antibody levels, which makes people more susceptible to infection. And in this study, they were able to show that not only did the IVIG help to reduce the risk of infection, but patients who got it also lived longer. And so that really gives a strong argument for us to be as liberal as possible. Sometimes there are shortages of it, but especially if people have an IgG level below 400, and if they're having infections when they're on CAR T or bispecific, it's really an important part of the care of these patients.

Jenny: Yes, I totally agree. IVIG is really, really important. So you should be talking to your doctor if you're on a CAR T or if you're on a bispecific antibody, that should be part of your discussion.

Dr. Orlowski: Now we all need additional targets. Most of what we have seen up to now are BCMA and GPRC5D targets. There was an update on a bispecific called cevostamab, which goes after a different protein on the cell surface called FCRH5, sometimes also known as FCRL5. And one of the reasons new targets are important is that what the myeloma cells sometimes do to develop resistance is that they will mutate either BCMA or GPRC5D or just delete the protein altogether.

And then those cells essentially become invisible to a CAR or a bispecific, but they will not mutate other proteins. So having a selection of different targets is helpful. And the cevostamab study did show that the drug was continuing to show activity. The response rate was a little bit lower than what we had seen before.

But when you consider that there were also more patients who had had prior BCMA and GPRC5D targeted therapy, I think that's understandable. And it looked to me that there was still an opportunity for that by specific to make it to the clinic.

And very briefly, I think one other BCMA therapy that was exciting was the update on anito-cel (by Kite Pharma), which is another CAR T. That one has been showing an almost 100% response rate. It's kind of interesting because most of the other CAR Ts use an antibody fragment to recognize the protein target on the myeloma cell.

And sometimes those antibody fragments can cause an immune response. Anito-cel uses a different construct to recognize the BCMA target, and that construct may be a little bit less immunogenic. And so if those T cells hang around longer, that may be why patients are responding better. And definitely we can use more therapies with a 100.

Jenny: It's incredible. And you see some of the neurotoxicities with cilta-cel (Carvykti) and some with ide-cel (Abecma) (not as many it seems like), but I think they had nothing really. It's incredible.

Dr. Orlowski, Yes, anito-cel data so far look better in terms of neurotoxicity. Of course, again, you know, the numbers of patients and the follow-up is not quite as long. So I think we have to be a little bit cautious, but it definitely looks exciting and it would be a great thing to have available in addition to ide-cel and cilta-cel.

Jenny: You see more development happening. Do you want to talk about the multiple targets too in the CAR T space? Because you were talking about that for bispecific antibodies, but that's happening too in CAR T, right? Not all are being developed to target BCMA.

Dr. Orlowski: Totally right. There are a couple of products that are out there targeting GPRC5D. We already have one FDA approved GPRC5D drug, which is talquetamab (a bispecific antibody). The problem with that is it has to be given continuously. And because the target is expressed on skin and other tissues, you can have rashes, taste changes and people sometimes lose quite a bit of weight.

And with a CAR T where the drug may be around for a shorter period, we expect to see some of that, but hopefully for not quite as long a period. And the initial data with the CAR Ts to GPRC5D also look encouraging and there are registration studies underway. They haven't read out yet, but I would expect that probably sometime next year, if the data continued to look good, we would have a CAR T approved against a non-BCMA target, meaning GPRC5D.

Jenny: And then do you want to talk about dual CAR T approaches or what your opinion is on that?

Dr. Orlowski: Totally. You're bringing up a really fascinating area.

Just like we don't anymore use single agent chemotherapies alone, right now, most of the CAR Ts and bispecifics that we're using go after a single target. The problem with that, as we mentioned earlier, sometimes the myeloma cells can mutate or delete a target, and therefore having something that goes after two targets makes it more likely that you will be able to kill all of the myeloma cells.

And there are data already combining, for example, teclistamab and talquetamab, which are GPRC5D and BCMA bispecifics that look quite exciting. So now there's a variety of CAR-Ts out there. One product hits CD19 and BCMA.

Others are attacking both GPRC5D and BCMA. And I think they're exciting because beyond just the resistance mechanisms, we know that each patient has myeloma cells that can have a range of expression. Some of the myeloma cells may have more BCMA, but less GPRC5D. Others may be the opposite. And then you've got everything in between.

So by hitting both, you're essentially attacking a broader range of myeloma cells and making it more difficult for them to become resistant because you're going after two different targets at once.

Jenny: Absolutely. Can you talk a little bit about sequencing? You went over bispecific antibodies and we have more coming out. You know, there are three approved and now more still in the pipeline.

And then you have the CAR-Ts that are growing in number and availability as well for even the FDA approved ones. How do you talk to your patients about that? Do you suggest the CAR-T first? Do you do bispecifics? it based on a slot open or the nature of their disease? How do you make those decisions with your patients?

Dr. Orlowski: I think that's a really important topic that a lot of people are working on and that we still need to figure out better.

But in general, the field has come to feel that if you are able to do both, that you should probably start with the CAR T first. And if there is a relapse after that, to think about going with the Bi-Specific. And the reason is that if you do the bipecific first, it sometimes can be a little bit difficult to collect enough T cells that are healthy and that can expand and be activated afterwards to do the CAR T at that time.

So sometimes you don't have a choice because there is still a manufacturing period for the CAR T. And if somebody has myeloma that is very rapidly progressing that maybe will not respond, for example, to bridging therapy.

You have to do what you have to do and you may have to go with the bispecific because it's off the shelf. But some of these newer products that we mentioned are going with a faster manufacturing time and every day or week that we're able to cut off the period, it's called the vein to vein time, meaning how long is it between the T cells being taken out of the patient's vein until they get put back into the patient's vein.

If we can get that period down to a couple of weeks even from the current of about four weeks, that gives us more flexibility and maybe would have us need to do less bridging therapy. So that's another way to consider how we could make outcomes better.

Jenny: We did a lot of videos while we were at ASH and one of those was about trying to predict who will respond to CAR-T therapy and who won't. Can you address that a little bit about are there factors that we should be testing for prior to CAR-T?

Dr. Orlowski: Definitely. Great question. We've actually covered a couple of those because if you have low or mutated expression of the target protein, then that can predict for a lower response.

Sometimes what there have been descriptions of include alterations of NF-kappa-B signaling, TP53 mutations are usually poor risk, and certain other key transcription factors when they're lost can predict for a lower response rate.

So I definitely think we need more research here because we're not yet at the point where on an individual basis, we can say, Mrs. Smith, unfortunately, your mutations in your myeloma mean that you will not respond at all. We can predict a lower or higher likelihood of response.

But I think if we keep working on that and refine our predictive capabilities, we will get to a point where we'll be better at selecting what's best for an individual patient.

Jenny: That takes us to this personalized medicine idea. And when you think about all newly diagnosed patients, they will probably will benefit from quad therapy. But then for those relapsed/refractory patients, I know you're working on a personalized approach more with the deletion 17P, and maybe you can talk about this shock protein target.

How do you see the field evolving when it comes to that type of development? Every patient I think would love to go in and say, take my genetic testing, here's my disease, what should I take?

Dr. Orlowski: Definitely. Well, one thing to mention that has nothing to do with the predictive part is that we're getting better at using DNA from blood to predict mutations in myeloma.

We're not quite yet at the point where we don't have to do bone marrows, but I think that at least the light is there at the end of the tunnel. And we may in the future be able to do this just with peripheral blood testing, which would be really cool because nobody likes to get a bone marrow. And I can tell you as a doctor, I don't like to order it unless I have to.

But I do think that we are going to be able to be at a point where we can better predict what is the best therapy for each patient. One of the reasons we haven't gotten there up to now is that frankly, we just didn't have enough therapies to pick from that were very active. And so we just combined everything to try to get the best responses that we could.

But now especially with these immunotherapies and different targets, which roughly work similarly well, we're in a better position to say, hey, if we've got three or four things that will give you a 70 to 80% response rate, it's probably not the same 20 or 30% that are not responding, and we can predict which therapy will be best for you.

So I think we're going to get there. We're not quite there yet in 2025, but I can certainly see it happening before the next five years elapse.

Jenny: And do you want to talk about the treatment that you're working on?

Dr. Orlowski: Well, one of the therapies that we're developing, and this is in part with support from the Leukemia Lymphoma Society is an antibody to heat shock protein 70 which acts as a way to boost the immune response against abnormal proteins in the myeloma cells. So we are looking to hopefully soon take that to the clinic, but at least in the laboratory, the results look quite good.

Jenny: That’s great. I hope you make fast progress on that. It's wonderful. CELMoDs seem to be coming out as a new treatment option. Do you want to cover that at all?

Dr. Orlowski: I think it's definitely worth mentioning that iberdomide and mezigdomide, which are the two CELMoDs that are furthest along in development, are in registration enabling studies now. They seem to also, I think very excitingly, be able to stimulate T cells that may have been previously exhausted.

And the great thing about that is one of the problems now in relapsed myeloma after CAR T or bispecific is that oftentimes the T cells are exhausted. And if they're tired, giving another immunotherapy that requires them to be back in the ring and fighting hard is difficult. But if you can combine, let's say a different bispecific with iberdomide or mezigdomide and reactivate the T cells, then you're overcoming that exhaustion. So I think to me, that's one of the really exciting parts about those.

And they seem to work well even in patients whose myeloma is progressing on either lenalidomide or pomalidomide. So we could still use len and pom earlier and maybe the iber and mezi would slot in after them. Or if the data looked good enough, maybe they would jump ahead of len and pom. That's a possibility as well.

Jenny: Well, it’s so great to see more therapies becoming available. It's just very hopeful as a myeloma patient. I had another question for you. I know everybody wants to understand the role of transplant and how you're thinking about transplant. In this age of new immunotherapies, I watched one of the videos that we did that was talking about just very early data, post stem cell transplant, and then going to CAR T and the impact.

What is your opinion as we sit today in now 2025?

Dr. Orlowski: An important area of research with lots of studies ongoing. We would all like to get rid of stem cell transplant and high dose melphalan, but at the same time, it's still a very effective therapy clinically and also relatively cost effective, which is not unimportant given some of the costs that we're seeing.

It'll be interesting to see the randomized data. I think for patients with standard risk myeloma who were doing really well with transplant, those may be patients who at least in the short run would still go the transplant route, whereas the high risk patients whose benefit from transplant is decreased, those may be the people who get either CAR T alone as consolidation or maybe a transplant followed by CAR T.

One of the nice things about CAR T after a transplant is that those patients have very low rates of cytokine release syndrome because the level of disease burden is so low that you don't get a lot of those inflammatory proteins. So the safety is much improved as a result.

Jenny: That’s fascinating. I hadn't thought of that. Let's move on to MRD. know that earlier in 2024, there was a meeting hosted by the FDA.

Now with all these therapies and the longer efficacy, they're looking for ways to run faster clinical trials and MRD might help with that as an earlier endpoint. Do you want to share your opinion on how MRD is affecting the clinical trials that people are now running or the impact of care generally?

Dr. Orlowski: Well, I think you've made a great point. And in fact, the FDA has accepted now MRD as an important endpoint for clinical trials that was a result of the effort of a lot of people, but in particular, the International Myeloma Foundation and Ola Landgren, who's now down in Miami, were major drivers of that.

The benefit is that we will still be collecting the progression-free survival and overall survival data, but now we'll be able to get earlier readouts and hopefully approvals based on the MRD negativity rates. The nice thing about that is that if we can get therapies approved sooner, they'll be available to more people and hopefully will make a bigger difference.

There is a small risk that we may approve something that looks better based on the MRD data. But then when we look at the progression free survival data, the data may not be different and it'll be interesting to see how that's handled. But one of the big benefits now is that people are doing so much better with myeloma, which is of course wonderful. The only small downside is that if you have to wait longer to know if a new drug is effective, that actually delays drug development.

So having this earlier time point overcomes that and hopefully will bring us much closer to a cure. So definitely an important step forward. And many studies now are using this early MRD readout in order to get results out there faster. That just makes so much sense for patients. And sometimes patients don't know that it takes eight years or 10 years to hit some of these progression-free survival or overall survival.

Jenny: Patients are living longer which is this awesome life blessing that we're living longer, but still a challenge for running these clinical trials for you to get your results.

Dr. Orlowski: We don't want to rest until we've hopefully cured everybody. And so the sooner we know if a new therapy looks promising or not, the better. And the MRD will definitely help us with that.

Jenny: I think one thing that was interesting about this ASH meeting also was that we saw tons of results about real world data.

So I don't know if you want to share what you learned about these study results while you were there, but I was fascinated by it and obviously we're interested in more of that because we have this platform (the HealthTree Cure Hub Registry).

Dr. Orlowski: I think real world data is really important because we know that patients who enroll our clinical trials are on average a little bit healthier and therefore have better outcomes than patients who are not eligible for trials. The other factor to consider is many trials now that are international have a large component of their enrollment in Europe where there is a low, for example, representation of folks of African descent. And we don't always know if data from a predominantly Caucasian population will be equally applicable to African-Americans, Hispanic-Americans, and Asian-Americans.

And so real world data is something that really helps you in that because you can look at people with more ethnic diversity and that look more like the patients that come into the office of the average hematology oncology doctor.

I do joke though because people throw the term “real world” around quite a bit. And I joke with some of my MD Anderson colleagues because they publish papers where they talk about real world data. And I asked them whether they think that MD Anderson, even if these are patients that are not trial eligible, is it really real world compared with people, for example, out in the community?

So I think that some standards of what we call real world may be interesting to implement. But the more we know about the outcome of patients in the real world, the better.

Jenny: That’s great. Do you have anything else you'd like to share before we go to caller questions? Because I'd like to leave a few minutes for some writing questions that we received. So do you have any summary you want to share?

Dr. Orlowski: I’d mentioned two other abstracts that I thought were quite interesting.

One was around 24-hour urine collections, which nobody likes to do on the patient's side. And it turned out in the analysis that was reported, the 24-hour urine didn't really contribute very much to the determination of response. So I think that that will help to push forward a movement to get rid of that.

And we may not completely get rid of it because it still sometimes helps to know how much protein, for example, is in the urine, but at least we could reduce it down to like once a year or once every six months.

The other interesting abstract right now, the response criteria require one measurement and then a second one as confirmation.

And the problem with that is that if you have to do two blood tests, first of all, you’ve got to get poked twice. Second of all, there's a further delay in determining if there is progression or not, which means a delay in getting onto the next treatment if indeed progression is happening. And in this abstract, they really found that that second measurement also added little to the calling of progression.

So if that's adopted and we are working on new response criteria for the field, that will help because we'll be able to decide more quickly if somebody is progressing and get them onto a hopefully better therapy more quickly.

Jenny: That’s actually related to one of the questions that I'll get to. that's great to know.

I think it's a great review, what you reviewed.

I have some additional questions and we'll just jump into it. I think Jessica and Phyllis have, similar questions. So Jessica is wondering if a patient's MRD negative is seven years, would you stop maintenance? And then Phyllis is saying, I've been on Darzales Fast Pro and my numbers are looking good. What goes into the decision to stop? And I know you can't answer specific patient treatment questions, which I don't want you to do, but just general guidance about how you think about those things.

Dr. Orlowski: There are a number of abstracts now and papers that look at if people have sustained MRD negativity. And there's a difference in what time period people look over. Some of them are over three years, some of them are five years. But it's clear that especially if you have standard risk molecular features at diagnosis and you have sustained MRD negativity over a few years, the risk of relapse is low if you discontinue maintenance.

So it's still a discussion to have with your physician and with your family. And I do think that MRD testing on a more regular basis, particularly of the blood would help because we would all feel better if we could catch MRD conversion to positivity and restart maintenance at that point.

But I think in the past, I would have said, no way, you have to do maintenance until progression. Now, again, I can say, well, I think that there is light at the end of the tunnel. And especially for the good risk patients, there may be a good argument to at least consider stopping.

Jenny: That kind of goes into Linda's question where she said, when will ClonoSeq, this MRD test that you're using through a bone marrow biopsy, when will it have better availability? She was wondering too, do I have to have a baseline for this test so I can track it over time? And I'd like you to share a little bit more about the blood-based MRD testing.

Dr. Orlowski: So for ClonoSeq in particular, you do need a baseline sample because it's a technique that identifies the abnormal gene that is produced in the myeloma cell. And if you get a bone marrow at the time of MRD negativity and you can't detect it, then you don't know which are the normal sequences versus the abnormal sequences.

Now, if you haven't had that done at baseline, it sometimes is still possible to get a slide from that original biopsy from the pathology doctor and send it off and have the analysis done. So that's a way to work around if you didn't have the assay done before. But it does require a baseline sample at some point to identify the protein or the gene in those myeloma cells. is FDA approved and available. Right now, it's predominantly done on the bone marrow. We know that it can be done on the blood. The blood in general is about 10 times less sensitive though. So we're not quite at that point yet.

Other assays that are also being looked at in the blood include mass spectroscopy, which is a more sensitive way of detecting the monoclonal protein than the electrophoresis and immunofixation tests. So we're getting there. We're getting there soon.

Jenny: That kind of folds into Aridia's question because she's wondering at what point when you start relapsing, do you decide it's time to re-treat (or start new treatment)?

She's gotten RVD, stem cell transplant, her numbers are going up. what's your cutoff? Do you wait for this 0.5 monoclonal protein that means an official relapse? Because when we look at our data, people are starting at .38 on average to restart treatment, whether they hit the 0.5 number or not.

Dr. Orlowski: I think whether you start treatment again depends on a couple of factors. First of all, if people have symptoms, let's say they have a new bone lesion or they have higher calcium or their kidney function is declining or their blood counts are worsening. That's a scenario where I would not wait for the magic 0.5 gram per deciliter number and I would start much more quickly.

If the only thing that's happening is you have a small increase in the protein, you may have some flexibility to change the dose of maintenance if that's where you are, or add a little bit of dexamethasone or add a third drug and maybe not go full bore with another three drug or four drug regimen. So that's kind of how I would approach it.

In terms of using MRD, again, it depends a little bit on molecular features because if you've got a tenfold increase in MRD and you've got molecularly high risk disease, I'm more likely to want to do something there than if you have an increase with standard risk disease.

Jenny: Great answer. That makes a lot of sense.

Joan is asking, would you do a second CAR if the first one didn't work or just go to straight to bispecific antibodies?

Dr. Orlowski: Great question. It depends a little bit on the initial CAR T and what we know, if anything about the factors that led to that. One thing that would be important is let's say the first CAR T was a BCMA. If there is no BCMA expression on the myeloma cells and that assay is now available at many places, then obviously the answer is, gosh, you I wouldn't do another BCMA no matter what. And that would include a bispecific.

And then you have to look at the GPRC5D. But in general, especially if it didn't work at all, as opposed to it worked, but then people relapsed, if you had no response whatsoever, I think trying to go after the same treatment modality again would be problematic.

Jenny: I know you have to go. We have several other questions, but I'm going to potentially email those to you and maybe I can pass that along to the people who asked. So I just want to thank you for your spectacular work as always in the field of myeloma. I'm just so grateful.

Dr. Orlowski: No, it's my pleasure. And thank you for everything that you and your colleagues at HealthTree do for myeloma and now for some of the other diseases that you're covering as well.

Jenny: We are just so thankful that such talented people like you are in this space. It's just incredible what you do. So thank you for participating. And for our listeners, we thank you for listening and know that on the next show, we'll be sharing more about the changes in myeloma therapy. And thanks for joining.