In this episode of the HealthTree Podcast, host Jenny Ahlstrom welcomes Dr. Robert Orlowski from MD Anderson Cancer Center to review groundbreaking developments from the ASH (American Society of Hematology) 2025 meeting and what to look forward to in 2026. 

The conversation includes a discussion of smoldering myeloma and the use of teclistamab and daratumumab in the high-risk smoldering setting. Dr. Orlowski shares the 2/20/20 risk criteria, the addition of genetic testing into risk stratification and the impact of plant-based diets and exercise to slow progression. 

Dr. Orlowski shares approaches for newly diagnosed multiple myeloma therapy with the standard being quad-based therapy that includes a CD38 monoclonal antibody. Studies are now using CAR T and bispecific antibody therapy into the newly diagnosed setting. 

For relapsed or refractory myeloma patients, celmods are in development with iberdomide and mezigdomide helping to restore T cell function. CAR Ts continue to evolve with an upcoming anticipated approval of anito-cel, faster CAR T technology and in vivo CAR Ts, allowing the cells to grow up inside of the patient instead of being sent out for manufacturing. Bispecific antibodies continue to expand with studies including elranatamab and linvoseltamab and a bispecific with a new target called cevostamab. Additionally, a trispecific antibody called ramantamig is in development. 

MRD testing is being used more regularly to determine when patients can stop maintenance therapy and bespoke (or personalized) therapy is becoming more advanced for high-risk features. The show concludes with a view towards a cure in myeloma and answers to caller questions. 

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 some great news. To further our efforts to use data to develop faster myeloma cures, we had the incredible opportunity to take advantage of a very generous grant from the Roger and Paula Riney Foundation by raising $500,000 by the end of the year, which the Riney Foundation triple-matched for a total of $2 million.

We successfully met that challenge before the end of the year, and we're so thankful that you made this happen. The goal of this grant is to expand the platform to include more patients willing to use their data to find myeloma cures, provide a structure of data and tools for easier data extraction for researchers, and perform data science on the data that can uncover new findings. Our guest, Dr. Orlowski, may touch on one of those such ideas as an example, but there's so much we can learn because you have connected your medical records with the HealthTree platform.

We're so thankful for your support and for your philanthropy in helping us get to this point. We look forward to all that we can do because of your generosity and that of the Riney family and for your trust in us. Now onto our show.

This is my favorite show of the year because it helps us better understand what we can expect in the coming year. 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: Thank you very much for having me. It's always a pleasure to review all of the exciting developments from ASH (American Society of Hematology meeting) and how they impact the care of folks with myeloma. And I did want to wish you and all of your audience a Happy New Year since it's still January. And I hope that 2026 will be the best year ever for everyone in their myeloma journey.

Jenny: Thank you. We hope so too. And it's because of people like you that this is happening and progress is being made. So we're always just so grateful. Well, let me give a brief introduction for you before we get started. Dr. Orlowski is the vice chair of the Myeloma and Lymphoma Translational research division of cancer medicine and endowed professor of medicine in the Florence Maude Thomas Cancer Research Professorship in Lymphoma and Myeloma at MD Anderson Cancer Center. He's also a Professor of Medicine for both Lymphoma and Myeloma and Experimental Therapeutics, as well as the disease site liaison to the International Center at MD Anderson, where they help people travel from all over the world to this impressive cancer center. is co-chair for the NIH Cancer Therapy Evaluation Program as part of the Experimental Therapeutics Clinical Trials Network.

He's a member of Lytica Therapeutics and recently ended his longstanding role as Chair of the Southwest Oncology Group or SWOG. He participates on the Educational Committee of SOHO, the Society of Hematologic Oncology.

He is a member of the National Cancer Institute Myeloma Steering Committee and the American Society for Biochemistry and Molecular Biology. He's an author on over 400 articles, abstracts, and book chapters. Dr. Orlowski was the first to bring Velcade to clinical trials, following a successful family history established by his father, who worked on the development of proteasome inhibitors. Dr. Orlowski has received awards, including the LLS Scholar in Clinical Research, the LLS Man of the Year Award, the Emile Free II award for Excellence in Translational Research from MD Anderson, the Wuan Ki Hong Mentor of the Year Award, the Gerald Body Award for excellence in education, and the 2022 Giant of Cancer Care and Myeloma Award.

He continues leaving the field globally to bring new myeloma therapeutics to your and my clinic. And for that, we are forever grateful. You can find news and information on X @myeloma_doc.

Dr. Orlowski, we have so much to cover because there are so many things happening. So I'm not sure how you want to go about starting with this, but maybe we just start with precursor conditions.

Dr. Orlowski: I think that's a great place to start. And the exciting news is that we now have our first drug approved for high-risk smoldering myeloma, which is for right now, single agent daratumumab. And there was actually an update presented at ASH on these data by Peter Voorhees, who was actually one of my first mentees when I became a faculty at UNC (University of North Carolina). And on that analysis, they looked at the risk status by the International Myeloma Working Group 2/20/20 system. That's the way that patients with smoldering disease can determine if they're at low or intermediate or high risk of progression to active disease.

And the results of that analysis showed that indeed daratumumab worked well in reducing the risk in both intermediate and high risk smoldering. Although of note, the FDA approval is just in high-risk smoldering. So if you're in the smoldering category, definitely talk with your hematology oncology doctor to figure out what risk status you're in and whether daratumumab is the right drug for you. Plus there are lots of studies ongoing in this space with some of the novel therapies. Probably the future standard of care will be a triplet with an anti CD38 antibody like either daratumumab or isatuximab in combination with lenalidomide and dexamethasone.

And there are studies as well looking at bispecific T cell engagers and even CAR T cells in this space. So hopefully there will be opportunity for some of your patients to be a part of those trials. And again, now they can also get single agent DARA to reduce the risk of progression.

Jenny:  Fascinating. Now High Risk Smoldering Myeloma - do you want to define it for people so they understand what that means?

Dr. Orlowski: Sure. So the 2/20/20 system that I mentioned has three factors. The two means that your protein has to be greater than two gram per deciliter. The first 20 means that your bone marrow plasma cells have to be greater than 20. And the second 20 means that you're involved to uninvolved serum free light chain ratio has to be over 20. And if you have two of either of those three, then you fall into the high-risk category. So it's actually a pretty easy system to figure out.

Jenny: And have they added genetics to that as well or no?

Dr. Orlowski: Yes, there is a four-factor system which includes the results of FISH (genetic)  testing. And there was recently a paper that we were a part of looking at genomics and how the gene profile can also be very helpful in predicting risk of progression. And I think many of us in the field think that moving forward, that sequencing is going to be part of the standard evaluation, definitely at diagnosis and potentially in follow-up as the disease evolves because you can have new mutations that emerge and also new mutations that become selected out if people go on treatment.

Jenny: Are there other factors that people are starting to look at now? For example, you as a researcher looking at what else will predict for progression because this to me is one of the most confusing, I guess, of myeloma care for a smoldering myeloma patient. What kind of risk do I really have? Am I at risk? Should I consider treatment? I think you would be probably one of the first proponents to say, join a clinical trial if you have smoldering myeloma because we're not going to learn unless you join trials and we have this type of progress documented. But what other things are people looking at?

Dr. Orlowski: Absolutely, I think trials are very important. Daratumumab does reduce the risk of progression, but we definitely need to do better. I'll tell you, one of the questions I get from a lot of patients in this setting is, can I do something in terms of my lifestyle that can be helpful? And these studies, of course, are difficult to do because you have to do large trials, have to make sure that people are compliant with a diet, for example.

But it's interesting that there are data coming out, especially from Memorial Sloan Kettering, about the potential utility of a plant based diet in reducing inflammation and other markers that may translate into a lower risk of progression.

We don't know for sure that that's the case yet because again, these studies need to be done over many years, but definitely it's something that I would consider for people who do have smoldering and potentially even those with MGUS or monoclonal gammopathy of undetermined significance, which is an even earlier type of precursor. has a lower risk of progression, but still it's the most common precursor condition in this category of plasma cell disorders.

Jenny: And are there things happening with immune system function that you can determine?

Dr. Orlowski: Absolutely, with again these plant-based diets and interventions in animal models, we can see a strengthening of the immune system in part because of a reduction of inflammation. So again, reason to think that fairly straightforward interventions like changing your diet, trying to stay a little bit healthier, doing some exercise, may have a benefit and of course have other health benefits as well in terms of diabetes risk, cardiac risk, all kinds of other areas beyond the myeloma space.

Jenny:  That's great. I just know that smoldering myeloma patients are some of the most stressed patients because they just don't know, should I get treated? Should I not get treated? Am I going to progress? And if there were a rubric really that said, you have these genetics and you have the 2/20/20 and you have these other things you can measure. Yes, you know, you should really consider treatment. That would be very mind-appeasing for patients.

Dr. Orlowski: Well, you're absolutely right. We've seen this as well, that patients with these precursor conditions sometimes have a higher level of anxiety and distress than patients with symptomatic myeloma. Part of that, I think, is that in the past, we've not had treatments that we could offer them. And now with dara being approved and other drugs being studied,

I think the fact that we will be able to offer patients options hopefully will be helpful in reducing their level of anxiety.

Jenny: Great. Well, maybe we should move on to newly diagnosed myeloma. What are you seeing in newly diagnosed myeloma and what does that world-class treatment look like for you - and where do you see the field heading?

Dr. Orlowski: Definitely. Well, let's start with some of the abstracts that I thought were really interesting from ASH. And these are not yet things ready for prime time that you can get at your doctor's office, but they could be really soon. Right now, the standard of care is a four-drug combination, probably most commonly with bortezomib, lenalidomide, daratumumab, and dexamethasone.

And it definitely is an important and excellent standard of care. But we're always looking to improve upon that. And I think there were three abstracts that kind of caught my eye. One was a combination that Manier and colleagues presented which combined daratumumab with teclistamab. Now teclistamab is approved for relapsed and refractory myeloma, and it's essentially what's called a bispecific T cell engager. So it kind of has two arms, if you will.

One arm binds to a myeloma cell, it binds to BCMA. The second arm binds to CD3 on a T cell. It brings the two of them together. The T cell becomes activated and then it kills the myeloma. So it's a way to essentially boost your T cell response against this disease.

So this study looked at these two drugs in combination for older patients with myeloma that were newly diagnosed and maybe they were not eligible for stem cell transplant and the overall response rate was 100% and about two thirds of patients had either a complete remission or what's called a stringent complete remission, which means disappearance of the myeloma protein from the blood and a normal looking bone marrow. And there were some infections because both with daratumumab and with teclistumab, this can be a problem, but in the grade three or four category, which are the more moderate or severe, that was only in 14%. And we think that we can get that down even further.

So this is really a tremendous response rate for just two drugs, both of which work through an immune-mediated mechanism.

Jenny: This was some of the most exciting data I think that was presented at ASH. It was really unbelievable.

Dr. Orlowski: Really totally. I think also we'll get later to what was in the relapse setting where the same combination was looked at. Probably that's where it's going to get approved first. And actually it really looked tremendous there. We also, I was lucky enough to present data looking at linvoseltamab, which also is a BCMA-targeted bispecific for newly diagnosed myeloma. And this was now a single agent. So just one drug instead of giving people four. And the idea was that maybe this one drug would be working as well. And usually four drugs are going to cause more side effects than one drug. So even if we could get the same benefit, but with only one drug, that's a big plus.

And there also we had about an 86% overall response rate and half of those patients were in complete remission at the 200 milligram dose, which was what was recommended for further study. And because the study is still ongoing, we think that those response and complete response rates will go up even further.

So it really shows you how active these new generations of drugs are and really exciting data. And I'll quickly go to the third one because this was with a CAR T cell. There are a couple of CAR T cells being developed that target not just one, but two cell surface proteins.

So Du and colleagues presented data about one of them, AZD0120, which hits BCMA as well as CD19. And essentially in the study, they gave two cycles of standard induction, and then they went ahead and gave the CAR T cell and looked at how well that worked.

And the data again looked really exciting with almost a hundred percent (100%) of patients in a stringent complete response and 90% essentially still being without progression at three years. So we'll need more data and longer follow-up, but it looks like possibly CAR T cells given earlier are going to work even better than CAR T cells in the very advanced relapsed/refractory setting.

Jenny: That's incredible. So many new immunotherapies coming up front. We'll get to relapsed refractory where we can talk about sequencing, but I think it warrants the conversation upfront now because you're seeing so many clinical trials use the bispecific antibodies or the CAR T's in earlier lines of therapy. When you think about that, how do you think about the newly diagnosed setting for those tools?

Dr. Orłowski: Well, the exciting thing about CAR T of course, is that for right now we give the patients their infusion. There is a one month roughly more intensive monitoring period, but after that there is no continuation of therapy and people can be off treatment, which is of course when they're the happiest. And if we can give a very nice and hopefully very long treatment-free interval, their quality of life is going to be great. And we have other options now that we can offer them if they do relapse.

So to me, that's the most exciting thing about CAR T cells. We do have randomized studies ongoing that are comparing the CAR T cells to stem cell transplant as a consolidation after initial therapy and we don't yet know whether they will be better, but we do have data from the lymphoma arena where they compared stem cell transplant to CAR T cell for patients who had relapsed after their initial therapy. And in that study, there was an improvement in outcome with CAR T cells. So hopefully the same will be true for myeloma.

And that would give now two options for consolidation after initial therapy, either the transplant or the CAR T. There are pluses and minuses to both, but definitely considering the CAR T would be, I think, important.

Jenny: And you know, when you're thinking about CAR T, I know that sometimes you can get higher rates of cytokine release syndrome or the neurotoxicity type side effects if you have really high tumor burden. So I guess you could use that either to knock down the tumor burden, the CAR T itself or the stem cell transplant. What's your thinking on that?

Dr. Orłowski: I think you're making a great point. We have learned that if you have more myeloma when you have the CAR T, your risk of more severe cytokine release syndrome is higher. so knocking the level of disease down is a very good idea. also, another abstract from ASH was presented looking at some of the delayed neurologic toxicities that happen.

And it looks like part of that is related to expansion of the T cells and what's called the ALC or absolute lymphocyte count. If your ALC is higher after infusion, your risk of a delayed neurologic toxicity is greater.

That may help us identify at least some patients who are at higher risk. And that may help us because we can think about treating those people with maybe just a little bit of steroid or a little bit of cyclophosphamide to lower that lymphocyte count and hopefully preserve the anti-myeloma effect, but reduce the risk of some of these delayed neurologic toxicities.

Jenny: That’s a really important finding. Maybe you want to comment on this, but not all CAR T's are the same. You're seeing differences in some of the new things that are coming out in terms of levels of cytokine release or especially levels of delayed neurotoxicities.

Dr. Orlowski: Absolutely. So there is another BCMA-targeted CAR T called a anitocel and there were updated data from the phase two study of that CAR, which hopefully will support FDA approval. The anitocel also binds BCMA, but it uses a different way to recognize BCMA than cilta-cel or ide-cell which are based on antibodies and that one the results show again a very nice overall response rate of 96 percent in the advanced relapsed and refractory setting with three quarters of patients having a complete response but there were no episodes of delayed neurologic toxicity with that therapy.

And those delayed toxicities, by the way, can be things like Parkinsonian symptoms. They can be what are called cranial nerve palsies where you can have paralysis of one side of your face. As an example, these are not common. There may be five, six, 7%, but for the people who get them, they can be quite disturbing.

And some of them can improve with time, but others not so much. So if we could have another CAR T available that would have a lower risk of that, that would have some definite advantages.

Jenny: Wonderful. Is there anything else you want to talk about in the newly diagnosed myeloma setting?

Dr. Orlowski: Those were, think, the major interesting findings just to let people know that we're moving some of these newer technologies like the T cell engagers and the CAR T to the newly diagnosed setting. And who knows, maybe in five years' time, they will become standards of care there, which will be really exciting.

Jenny: The whole field is incredible. And ever since I was diagnosed, it's been moving so quickly and so many new options. It's incredible. Let's talk about relapsed refractory multiple myeloma. You had mentioned the teclistamab and daratumumab data in smoldering. Do you want to talk about the relapsed refractory setting?

Dr. Orlowski: Definitely. So Dr. Mateos presented these data as a late-breaking abstract. And I think you hit the nail on the head earlier when you said that these were probably the most talked about myeloma-related data from ASH. And this was from the so-called Majestic-3 study, which was a randomized phase three, which means that it could lead to FDA approval.

And essentially this was for patients with one to three prior lines of therapy. So relatively early and they were randomized either to get daratumumab pomalidomide dex or daratumumab bortezomib dex. And then the experimental arm was the teclistumab and daratumumab, the same combination we talked about in the newly diagnosed setting.

And what they found is a complete response rate of over 80% with that two-drug combination versus only 32% for the triplets with daratumumab. And the 36-month Progression Free Survival was 83%, which means after three years, only about one out of six patients had progression of their myeloma, which is just really incredible data. And if that curve continues on that same trajectory, that could mean something like a seven or eight-year average time in remission before the myeloma begins to come back, which would be some of the best data that we've ever seen.

Now about half of patients did have a grade three or four, which means moderate to severe infection. So this is an immune suppressive combination. And some of the infections were infections that we didn't used to see in myeloma, for example, CMV or cytomegalovirus reactivation.

Dr. Orlowski: So we do have to monitor people carefully and we do have to prophylax and do preventative measures more so than in the past, but really an incredible combination. would say the only concern is that only about 5% of those patients had gotten daratumumab before. And so we don't know how well this combination would work in patients who've had daratumumab previously. And right now we use dara in a lot, virtually all of newly diagnosed patients.

So as of right now, it's for a population that largely has not seen dara, but if we're going to do CAR T upfront, or if we're going to do T cell engagers upfront, then this may be something that we could then use in second line because maybe we won't be using dara in the first line in the future. So I think it's still really exciting data.

Jenny: That's incredible. And the strategy around it is shifting things around in different ways and being really creative in ways we haven't thought of before. So when you said preventative measures, what specifically, because I know patients will want to know what they can do to prevent infections.

Dr. Orlowski: Definitely. We've always, anytime we use these antibodies, we've always used acyclovir for prevention of shingles and also cold sores, which can happen. But we also would probably recommend doing IV gamma globulin, or IVIG, because these patients have low antibody levels because the drugs kill myeloma cells, which is good, but targets of these antibodies are also normal plasma cells, which make the antibodies that prevent us from getting infection.

So you do have to get started on IVIG. Some folks also recommend Bactrim or trimethoprim sulfamethoxazole against a particular type of pneumonia called PJP.

And we have to monitor for CMV. We don't routinely do prophylaxis yet because fortunately not everybody gets CMV reactivation. But if you do see reactivation and get high levels of the virus, or if there are viral-related complications, then there are drugs that we can use to treat that. So those are some of the probably minimum approaches to consider.

Jenny: Great. Do you want to talk a little bit more about bispecific antibodies? Because in the smoldering myeloma setting you talked about, teclistamab and linvoseltamab, there are more and it seems to be a very popular drug class that's expanding. It has a little bit easier access or utility in local clinics versus a CAR T, which really has to be done at an academic center.

Just what else do you want to share about bispecific antibodies?

Dr. Orlowski: You're absolutely right. So there are two other bispecifics that are already FDA approved, which we didn't mention yet. One is a third BCMA bispecific called elrantanamab. And the other, is a GPRC5D targeted bispecific is talquetamab.

So GPRC5D is a different cell surface antibody or target for these antibodies. And I think on the elranatamab front, there was one interesting combination that was presented, which was elra with iberdomide. Now, many people are familiar with lenalidomide and pomalidomide, which are the current immunomodulatory drugs.

There's a, if you will, next generation of drugs that target cereblon, which is the protein that all these drugs bind to. The two that are in trials are iberdomide and mezigdomide.

And in that study of nlranatamab with iberdomide, the overall response rate was in the 80 to 100 % range and about 40 to 50% of patients were in complete remission. The other, I think, really cool thing about these drugs is that they seem to be able to reactivate T cells even if they're a little bit exhausted. And the reason that's important is that you mentioned earlier sequencing, which I think is really going to be crucial. One of the downsides to the bispecifics

and to some extent, the CAR Ts as well is that you can get some T cell exhaustion because these bispecifics stimulate the T cells. It's kind of like if somebody shakes you all night and prevents you from sleeping. Like if your partner snores, you're going to wake up in the morning being exhausted and not fully functional.

The same thing happens with these T cell engagers and these drugs appear to be able to reverse that. So it may be that in the future, the appropriate sequence will be to do a T cell engager or a CAR T. If you get progression, then come back with an iberdomide or a mezigdomide-based combination to reactivate the T cells. And then you can come back with a different T cell engager or CAR T and hopefully have enhanced activity with that combination. So I think that's kind of really cool. And I think really that's what we're going to be doing in the future.

Jenny: That's incredible. The strategy is amazing. Can we talk about also with bispecific antibodies, just the length of utility or the length of use? Because I've heard a lot of clinical trials be developed now, so it's not until progression, it's for a certain time period or something because of the infection risk or because of those types of things.

Dr. Orlowski: Absolutely. Also these antibodies can select out myeloma with either mutation of the target or complete loss of the target, which is a problem because then those myeloma cells are invisible to other drugs that require expression of BCMA or GPRC5D, which by the way, I think gets back to one of my points earlier that we're going to be sequencing the genes of these myeloma cells, because if we know which mutations are present, that can help us in selecting the next best treatment.

There also are trispecific antibodies by the way, that are coming out. These are antibodies that also with one arm, bind to a T cell, but they have two other arms that bind two separate cell surface proteins on myeloma. That's, I think, very exciting because if you bind two targets, even if one is lost, you can still have binding to the other. And if both are there, then the strength of the binding is enhanced.

So one was presented by Dr. Krishnan. This is a drug that is called ramantamig, which binds both BCMA and GPRC5D. And in that study, there was, and I'm being sarcastic here, only a 100% response rate. And some of those patients had had prior therapy with BCMA or GPRC5D targeted treatments.

And interestingly, there was a trispecific antibody in clinical trials from China, which also showed very encouraging data, again, including in patients with prior BCMA or GPRC5D. And with the ramantamig, which is from Janssen.

The really nice thing there is that there were low levels of cytokine release syndrome because the arm of that antibody that binds CD3 is modified so that it doesn't cause as much T cell activation, which could mean that it causes less T cell exhaustion. It's kind of like your partner. snoring still, but very quietly so that you can get a good night's sleep.

Jenny: That's incredible. Yes, the field is just expanding so much. It's unbelievable. And I think I just want to have you talk about stats for a minute because some of these other drugs that were approved that we are very familiar with, lenalidomide and bortezomib and daratumumab even, some of these were approved at percentages of maybe 30-35% overall response rates.

So for you to be talking about 80%, 90%, only 100% is truly stunning. It's really incredible. This has never happened before.

Dr. Orlowski: Absolutely. And the other point to make, you're absolutely right. But the other point to make is that patients when they're relapsing now have had much better therapy than what used to be the case back then. And so that means that their relapsed myeloma is a little bit tougher than relapsed myeloma was 10 years ago.

So the fact that we're getting these 80, 90, 100% response rates is even more impressive because the myeloma is tougher at, let's say, three lines of therapy now. That's tougher myeloma to treat than after three lines of therapy 20 years ago.

Jenny: That's incredible. I'm glad you covered the cell mods because that's what you're talking about with iberdomide and mezigdomide. Is there anything else that you want to share on that or should we jump to CAR T's in a little more depth? You already talked about them, but I think there are other strategies that we could talk about with CAR T's as well.

Dr. Orlowski: Well, it's also worth mentioning that belantamab, of course, got reapproved last year. Belantamab mafodotin is what's called an antibody drug conjugate. And so it's an antibody with a drug linked to it, which is taken up inside the myeloma cell after it binds to BCMA. And that linked drug is released and kills it from the inside.

So the analogy that people draw is that it's kind of like the Trojan horse approach. And belantamab is approved in combination now with bortezomib, as well as in combination with pomalidomide. And the durability of the response with that drug in some of these combinations can be as good as some of the CAR T data.

And we're also learning to give it less frequently so that the ocular toxicity, which is one of the things to know about if you're thinking about going on belantamab patients can have blurry vision or dry eyes, which can be a little bit irritating and you have to put in eye drops. But if you give it less frequently, the severity of that is improved.

So that's another therapy that people should keep in mind, especially because it does not have any cytokine release syndrome or neurologic toxicities that are associated with it. And that less frequent dosing gets at a point that you made earlier, which is that we're learning how to do the same thing for these T cell engagers.

And I think that as we develop better tests for MRD or minimal residual disease, some of which now can be done on the peripheral blood, we may be able to get to the point where we're treating for a defined period to get to that MRD and we may then stop treatment, monitor, and consider to restart it only if there is evidence of conversion from MRD negative to MRD positive, which again would give people breaks from treatment, which is when they're gonna be happiest.

And it could extend the usefulness of a drug if you don't do it until progression, which kind of has been our practice up to now. But again, I think, know, five years from now, probably maybe even two years from now, that will no longer be the case.

Jenny: I think some interesting things about Blendrep is like you're saying, it seems to be pretty long-lasting even when you space out the dose and you all have learned how to use it in combination therapies. It's easier to administer in the clinic because you don't have some of the things that you find with the bispecific antibodies or CAR T therapies and it's not dependent on T cell function really.

So you don't have to worry like are my T cells too exhausted to use this particular drug. So it does have some great advantages in the mix. It's a great tool that we have.

Dr. Orlowski: Absolutely.

Jenny:  A little more on CAR-Ts. So we're seeing CAR-Ts like you were saying with the trispecific, you're seeing CAR-Ts and you mentioned it earlier in the smoldering setting or newly diagnosed setting, I can't remember which. Doing two different targets. We're seeing faster CAR-T cell production. What else are you seeing and where do you see CAR-T therapy heading?

Dr. Orlowski: Great question. We mentioned some of the Anita cell data earlier, which is the CAR T that has much less neurologic toxicity. Those were actually presented by Krina Patel, who's one of our own faculty here at MD Anderson. There were updates on CARTITUDE-4 presented by Luciano Costa.

This was in earlier patients with fewer prior therapies and the 30-month Progression Free Survival was 80%. Really just incredible data. And you mentioned faster manufacturing time, which is a great point. And that was in particular with the AZD0120, which was that CD19 / BCMA targeted therapy and manufacturing there was an average just under three days. Now it still takes a little bit of time after that to test the CAR T to make sure that there is no risk for infection and that the T cells are viable.

So the fact that the manufacturing time is less than three days doesn't automatically mean that you immediately get the CAR T. But definitely what's called the vein to vein time, meaning the time from when the T cells are taken out from the patient to the time that they're put back in is getting shorter which is going to be really exciting because the more quickly we get treatment into patients, the less we have to worry about the myeloma progressing in the meantime.

And one of the other late-breaking abstracts that was presented, which actually interestingly was only on three patients, but nonetheless really interesting data was with an in vivo CAR T.

Jenny:  Can you explain what that is?

Dr. Orlowski: Sure. So right now, the way the CAR Ts are done, as we just discussed, is the T cells get taken out and the manufacturing is done in a laboratory. They're expanded so that you get the number that you need and then they get re-infused. The in vivo CAR T, what happens instead is that you're injected with either a virus or other approach to get that CAR gene into the T cells in your body. So the T cells are never even taken out of your body and the expansion happens in your body and they did show activity with that approach. I think again, the exciting thing there is the potential that the time needed for the manufacturing will be much less.

And because the expansion happens more gradually, it may have lower levels of cytokine release syndrome and hopefully neurologic toxicity. Plus the fact that we're taking away all those weeks of manufacturing should hopefully make it cheaper as well, which would be more affordable for a wider array of patients.

And if we save money in one place, we can apply it to other areas to further improve the quality of life of myeloma patients.

Jenny:  I think CAR T is this crazy, incredible science and then you hear about these type of advances and it's just like sci-fi. I have a question for you.

When you think about all these different targets like BCMA and GPRC5D and all the other targets that a lot of these CAR T cells and bispecific antibodies are using, are there ways of testing to see if you have a presence for those before you get this type of therapy?

Dr. Orlowski: Sure. Definitely, mentioned that I think sequencing is going to be gene sequencing is going to be an important part of our evaluations in the future. And we can look at whether there is a mutation of the target or a deletion. Plus at MD Anderson, we have assays both by flow cytometry, which is kind of like a fingerprint approach, really as well as by what's called the immunohistochemistry where we can take a biopsy and use an antibody to see if there is actually expression of the protein. And I do think that if you've had one BCMA or GPRC 5D therapy previously and are thinking about another therapy in that category, it's really important to get that testing done because

Some patients will, as we talked about earlier, lose expression of the target protein, in which case you don't want to go on another treatment targeting that because the myeloma cell is going to be invisible. So it's a way to rationally pick what treatment am I going to hopefully most benefit from and potentially eliminate things that you will have a lesser chance of benefiting from. And that's important because all these drugs have some side effects. Why expose yourself to the risk of side effects if your chance of responding is not high. That's number one. And if it takes a month or two to know if you are going to respond to this new drug then that's another month or two delay in getting you to something better if it turns out that you do not respond. So all of these, I think, are important considerations.

Jenny: Absolutely. No patient wants to get a treatment if they, know ahead of time, it's not going to work. So clearly this is where things should be headed with the sequencing and doing all these additional testing. I think it's great. Do we want to talk about MRD testing at all and the utility? do you know, are you getting closer as a clinician and researcher to knowing what that means, your MRD positivity or negativity numbers and for how long and all that?

Dr. Orlowski: Definitely. So MRD or minimal residual disease right now, the two most common ways to measure that is by what's called next generation flow and next generation sequencing, both of which are done on the bone marrow for right now, although there are other assays coming that will be for the blood only.

I think that MRD testing is important in a number of ways. First of all, we know that if you're MRD negative, your prognosis is better than if you're MRD positive. That makes sense because less cancer is always going to be better than more cancer. But we're beginning to get to the point where we can make some decisions about treatment or duration of treatment.

And we now have a couple of studies, for example, that show that if you are what's called sustained MRD negative, which means at least two MRD measurements that are negative, usually at least one year apart, and if you're also imaging negative, like on a PET scan or an MRI, then there is the opportunity to consider stopping maintenance, for example, if people have had stem cell transplant and they've been on maintenance for probably around three to five years. So I now routinely talk to my patients that have good risk cytogenetics, which is 80%. So that's almost everybody, not quite, but close. And if they are. I pick five years, if they're five years out and they are MRD negative on to at least measurements and their imaging is fine, I give them the option of stopping the Revlimid or continuing the lenalidomide as a maintenance. Some of them say, hey, I'm tolerating it, okay, let's not fix what's not broken and they decide to continue.

But others, especially those that have some diarrhea and other issues with lenalidomide say, Hey, anything I can do to get off this drug would be great. So I think that's a new relatively example of how we can think about using MRD testing. And last year about this time, we finished enrollment to a SWOG study, which looked at this concept and we don't have the data yet because it'll be a few years. but it looked at this possibility of stopping maintenance after two years if you're sustained MRD negative. And I think especially in the standard risk group patients, it's something to consider quite seriously. So talk to your hematology oncology doctor and myeloma specialist about that option.

Jenny: Can I ask you to, when you talked about the five years, it reminded me of this. We're hearing a lot at some of these major myeloma meetings now about this functional cure idea in myeloma. So if you haven't progressed within a five year period, you know, people are thinking about calling that cure. What's your opinion on that?

Dr. Orlowski: Well, definitely if it's been five years and you're sustained MRD negative, there is a very good possibility that you could also be cured, especially with standard risk disease. You know, keep in mind that the MRD tests do have some limitations.

When you do a bone marrow, you're looking at the area where the biopsy and aspirate is done and some small area surrounding that. So there can be a sampling error because it's possible that there is a myeloma cell on the other side or one that's five inches away.

So even being MRD negative at 10 to the minus six, which is the most sensitive that we usually can get to right now, doesn't quite mean that you have zero myeloma in your body but we are seeing more and more people in that category.

And I do think that at least some of those are actually not just functionally cured, but what I call a molecular cure, meaning no myeloma in their body. And we have data from, for example, some of the CARTITUDE studies, which show after the cilta-cel cell that about one third of patients five or more years out are still MRD negative. And I think at least some of those, if not all of those, one third are potentially cured.

And if you look at the earlier cilta-cel data, that proportion appears to be higher. So I think it's just a matter of time to document that in fact these people really are cured, but we're a little conservative in using that word still.

Jenny: Well, I like to hear the word being used because when I was first diagnosed, everybody said, if you use that word, know, people are going to be mocking you. So it's great to hear that word being used in the clinic. Tell me now, we are running low on time, but I still have some written in questions that we can answer as many as you have time for. But what open studies do you have at MD Anderson that you are looking forward to?

Dr. Orlowski: We have a number of trials ongoing that span the spectrum from the precursor space to newly diagnosed to early relapse and to late relapse. Some of the ongoing research that we have, and this is both in the laboratory and some of them are in the clinic, we're interested in developing what I like to call bespoke therapies.

So these are treatments that are targeted towards one particular molecular subtype of myeloma. And the potential advantage of those is that these are targets that are just on the myeloma cells themselves, not on normal plasma cells, which means they should be much more targeted and less immune suppressive.

And we also have a novel T cell engager that we're looking to get into the clinic for patients with very rapidly growing myeloma, which is still an aggressive subtype. And then just really quickly, we're looking at new influences of the microenvironment that may help myeloma cells to survive and may suppress immune responses.

And we're working with you and your team on one of those, is uric acid, which we think is something that acts against the effectiveness of T cell engagers. And yet we have easy to use and very well known drugs that lower those levels. So I think if we can validate that with your data set that people have contributed to thousands and tens of thousands of people worth of data, I think that would be really exciting. So thank you for all that you're doing and thank you to all of the patients that are part of your effort.

Jenny: Yes, we like to thank them all the time because they're really contributing to helping us help you find out these things. I think one of the important points that you were talking about about these bespoke therapies is that myeloma is not a single disease. That is the approach where you can take a particular genetic feature or specific target and really personalize therapy. You're seeing a lot more of that approach happen. Do you want to just speak broadly about personalizing myeloma therapy before we head to questions?

Dr. Orlowski: Absolutely. BCMA, GPRC5D, CD38, SLAMF7, these are great targets that cross all of the molecular subtypes of myeloma, but they're also present on some normal cells, which is why you get some of the immune suppression and trying to come up with drugs, either small molecules or antibodies that target individual proteins that are in, example, 11;14 translocated myeloma, 4;14 translocated, 14;16, I think will be an important part of therapy in the future. We saw a little bit of that with venetoclax in 11;14 translocated myeloma.

That unfortunately did not wind up getting FDA approval, but is still a very good drug for the 15 to 20% of people with 11;14. If you have that subtype and you need a new therapy, you should definitely talk to your myeloma specialist about that. And we're hoping that newer BCL2 inhibitors that are coming may have a better benefit to risk ratio and could still be FDA approved.

And this is also important in amyloidosis where you have a higher proportion of 11;14 translocated patients. And these could also be helpful in Waldenstroms, which is a disease related to myeloma. So I think that again, targeted therapy is another approach we're looking at down the road where specific subtypes will be treated with unique drugs for that type.

Jenny: Wonderful. We have some patient questions.

Dr. Orlowski: Let's tackle them. Of course.

Jenny: - that we can dig into. So Deborah is asking for patients who are refractory to both a BCMA CAR T and a GPRC5D CAR T. Are there other types of CAR T's? And then Jeff was asking in a similar vein, what do you do if CAR T fails?

Dr. Orlowski: We do have in clinical trials a number of drugs that are targeting other cell surface proteins. Probably the best example is a drug called cevostamab, which is a T cell engager against a protein called FCRL5.

And if you do have disease that has progressed, despite GPRC5D and despite BCMA therapy, that would be probably another very encouraging drug to look at. And we talked about mezigmomide and iberdomide as the new celmods. So those would be two other drugs that I would look at. And I would also do sequencing to see because the fact that there was progression on BCMA doesn't mean that the BCMA is gone.

And it may still be worth it to revisit BCMA as a target.

Jenny: You talked about mezigmomide and iberdomide potentially bringing back T cell function. Is there anything that can bring back BCMA or GPRC5D the target itself?

Dr. Orlowski: There have been a couple of publications from laboratory studies that suggest that there are ways to reactivate BCMA. The same has been true for CD38, for example. Whether these work in the clinic or not, we don't really know yet. So I think that's too early to say. It also depends on the mechanism, because if there's a mutation or a deletion, that's probably not going to come back. But if you have, let's say, promoter methylation, which is a mechanism that turns down the amount of the gene that is being expressed, that's a mechanism that we could potentially overcome.

Jenny: Different strategies for different things that are happening. Jenna is asking, do patients with a 1Q amplification have less BCMA expression?

Dr. Orlowski: Exactly. Interestingly, 1q amplification or gain. We mentioned cevostamab and the fact that it targets FCRL5. It turns out that that gene is in that 1q region and we have reason to think that cevostamab therefore might be a particularly good drug in that subtype we're now working with the folks developing cevostamab to try to evaluate that further. There are some studies that suggest there may be lower levels of BCMA expression, but not to the point that I would not consider targeting BCMA. So definitely worth still pursuing and do not by any means eliminate that category of therapies.

Keep in mind that about 40 to maybe even 60% of patients have either gain or amplification of 1Q.

Jenny: Fascinating. Everything that you're saying are all these slight nuances about myeloma. This just reinforces to me the understanding that patients should be seeing a myeloma expert. I say this on every show, but it's true that going to a general oncologist who's treating 20 plus types of cancer are just not able to do the research and attend the meetings and you're participating in creating so much of this research to understand all these nuances. And I appreciate everything they do, but this is really such a specialized cancer.

Dr. Orlowski: Absolutely. And I also have tremendous respect for private practice and general hematology oncology physicians because I think their knowledge base is incredibly broad and frankly better probably than mine when it comes to hematology and oncology in general.

When you get to for example, high risk disease, or when you have multiple relapsed and refractory myeloma, those are scenarios in particular, also precursor disease. Those are scenarios where you definitely have a benefit from having a specialist on your team. And there actually are publications where this has been looked at, and it has been shown that care under a myeloma expert does improve outcomes by quite a bit. So definitely having a team is important and having a myeloma expert on that team is really critical.

Jenny: There's data from the University of North Carolina, I think, and a Mayo Clinic, both on that topic.

Dr. Orlowski: Correct. Absolutely.

Jenny: Okay, other questions, more CAR T related questions. So Linda is asking about eligibility. So is CAR T cell treatment available for people who have had one round therapy but are ineligible for stem cell transplant? And I think this whole, know, and Robert's also asking is CAR T safer than stem cell transplant?

So sometimes we're hearing in the clinic and local clinics that they're using the same eligibility criteria for can I send this patient to transplant as can I send this patient to CAR T and that's not really the case from what I understand.

Dr. Orłowski: So in terms of safety first, of course, a randomized head-to-head study, which I mentioned these are ongoing, will be the best way to look at that. most of the patients that I have who've had both tell me that the CAR T was easier for them to go through. Now, there are always going to be exceptions. And unfortunately, some individuals have a rougher time with CAR T than transplant. But I think on average,

They usually say that CAR T was easier. And keep in mind that these days that usually means that they're older when they get the CAR T. And usually when we are, how shall I say, more mature, we don't always tolerate therapy quite as well. So the fact that they're saying it's easier is even more impressive.

Getting back to the question of the eligibility criteria, it is correct that some insurers are using similar criteria if you're transplant eligible or if you should be eligible for a CAR T, although it's not clear that you definitely can't get CAR T if you can't get transplant.

In fact, again, because CAR T seems to be better, I think there are people who we would perhaps not want to do transplant but yet they can go ahead and get a CAR T. So I think that's an area where we in the academic setting need to try to gather more data so that we can say, hey, look, here are the data that show that those criteria are not the appropriate ones.

Jenny: Judy's asking will there be more focus on precursor conditions this year? So she's saying it's always listed as asymptomatic but then I read where lots of people have various symptoms. What's your opinion on that?

Dr. Orlowski: Well, keep in mind that the quote unquote asymptomatic is usually just based on the so-called crab and then there's the slim crab criteria. So that means that there's no hypercalcemia or kidney damage or anemia or bone lesions, but that doesn't mean that there may not be other symptoms.

If they're related to the smoldering myeloma, I think we need to be open-minded and consider treating patients if the symptom that they have is absolutely related to their myeloma. Just because they don't neatly fit into that Slim Crab doesn't automatically mean that the myeloma shouldn't be treated. But I do think that it's an area to definitely talk with an expert about.

And I do think we're going to talk more and more about precursor conditions as the number of options will grow. And definitely over the next few years, we're going to have much more than just dara for high risk smoldering and potentially some for even earlier like intermediate risk.

Jenny: That whole field seems to be evolving significantly as you try to prevent myeloma from happening in the first place.

Sharon and Catherine are also asking, what's the latest in maintenance therapy using MRD to decide on treatment decisions, but when does stop maintenance?

Dr. Orlowski: Absolutely. We did have a little bit of a discussion earlier about MRD negativity, if it's sustained and having also imaging negativity for at least three to five years, that that is a scenario where it's reasonable to talk about stopping maintenance. There is a risk that you will convert to MRD positive, but the majority of those people seem not to.

And also when we get the data from the SWOG study that finished enrolling last year, I think that will be a large study where for people that were MRD negative, we randomized them to stop or to continue their maintenance. So I think that's going to be one of the best data sets to look at and hopefully will justify stopping maintenance on a whole bunch of people.

Jenny: That answers Catherine's question. She was saying, if I'm in monthly remission on Rev and Dara as my maintenance, can I stop? You see what you were just saying, all these clinical trials really trying to answer that question. I have a question from Caroline that says, how well does lenalidomide work for 11;14 myeloma after transplant, what she's wondering is, is it worth staying on as a, you know, for potential side effects or secondary cancers versus the impact that it's actually having? And you mentioned Venetoclax. So that might be something she probably needs to bring up with her doctor. But any, any comments on lenalidomide?

Dr. Orlowski: Well, 11;14 translocated myeloma is an interesting subtype because we know that, for example, it's a little bit more difficult to get those patients into minimal residual disease negativity and a complete remission. So you may have to stay on treatment for a longer period to be able to achieve that. There are no data not right now about venetoclax as a maintenance.

I do think that lenalidomide as a maintenance is a very reasonable approach after transplant in that setting.

Jenny: We’ll end with Yvonne's question. She's asking, what about ultra high-risk patients, high-risk genetic features with plasmacytomas, and things like that? What are you seeing as the best possible treatment?

Maybe you want to talk a little bit about not just genetic high-risk, but functional high-risk when a patient receives therapy and just relapses quickly, even though they might not have the worst genetics in the world.

Dr. Orlowski: For sure. Well, ultra high risk, are some different definitions, but one of those is people who have two or more high risk cytogenetic abnormalities. Those would be folks, for example, that have a 4;14 translocation and maybe also a mutation of TP53. Just one example.

We do know that those folks have more aggressive disease, which responds well to treatment, but unfortunately relapses more quickly. And those are still folks in whom probably continuing on multi-agent therapy for many years until progression is still the best approach. There was actually one interesting abstract from a Chinese group at ASH where for these functional high -isk also patients (and functional high-risk means relapsing within 12 or 24 months of their prior therapy). What they actually did is they gave them some standard chemotherapy called DSEP and then they did a BCMA CAR T and a GPRC 5D CAR T in sequence.

So the goal is to target multiple proteins, multiple myeloma targets to go after. And the data are still very early, but it just shows you that the feeling in the field is to try to be still very aggressive in those ultra high-risk patients.

Jenny: And prior that would have been stem cell transplant and it's kind of giving everything you could to it, but with the advent of CAR-T and some of these new therapies, you have many more new tools to try.

Dr. Orlowski: And some would argue even to do tandem transplant in an ultra high-risk patient.

Jenny: Lots of different strategies. We're glad that doesn't happen. Like you said, the 80 percent of patients are in that standard risk category, but it is still a concern for friends that we know who are enduring that kind of thing. Well, Dr. Orlowski, this has been an amazing review for what we have to look forward to in the coming year. We're so thrilled and grateful to you for being such a wonderful leader in the space.

You really for decades led globally in creating these clinical trials and getting these products to market so that patients can take advantage of them. And I'm very touched every time I talk to people like you because I am so grateful that you dedicated your life to this work.

Dr. Orlowski: It's my great pleasure to do this show every year and to make sure that the wonderful news about what's happening in myeloma gets out to folks again. I hope that 2026 is the best year ever for everyone's myeloma journey. And if there's anything that I can do, I always give out my email address, is rorlowski@mdanderson.org.

Please feel free to reach out if we couldn't cover your question or if you think about a question after you've listened to this and I'll do my best to get back to everybody.

Jenny: Thank you for being so generous with your time. And we thank our listeners for listening to the HealthTree podcast for Multiple Myeloma. Join us next time to learn more about what's happening in myeloma research and what it means for you.