Myeloma expert Robert Orlowski, MD, PhD of MD Anderson Cancer Center shares what was both learned from the recent American Society of Hematology meeting and what patients can look forward to in 2024. He shares key findings for smoldering myeloma patients about risk of progression with MYC and LAMP5 genetic factors. He shares data about how a plant-based diet can have impact on myeloma and how bispecifics are being used and sequenced in the clinic. 

Dr. Orlowski shares how the use of quad therapies for newly diagnosed myeloma patients can provide better remissions and new approaches to maintenance therapies following an initial therapy.  He also shares a new BCL-2 inhibitor in development and a new antibody drug conjugate in clinical trials that is useful for del17 patients. He reviews the new CELMoD category of drugs and reviews additional innovation we can expect in 2024. 

 

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, and we'd like to thank our episode sponsor, GSK, for their support of this program. 

Now, the new year is a wonderful time of reflection. I started HealthTree as Myeloma Crowd in 2012, two years after my myeloma diagnosis.

Now so many years later, it's just been extraordinary to see that we've built three extensive pillars of support, the first being personalized support and education with this podcast, HealthTree University, and others, the second pillar being a meaningful patient-to-patient connection that include our Coach program and many other programs as well. I've done a lot of reflection in the past, I would say, six to eight months. It's really our third pillar, our powerful data platform called HealthTree Cure Hub that is really going to help us advance a cure for multiple myeloma.

We internally developed this cutting-edge technology and software to make a data portal possible to provide myeloma researchers with this anonymized data from thousands of us as patients. Today, over 13,000 of you have joined this platform, and our goal by the end of 2025 is to include 25,000 patients in this platform. It means these researchers can search the data to see what the optimal therapy might look like for newly diagnosed, standard-risk or high-risk patients, or learn what's happening in the real world with patient side effects, or they can invite you to participate in a survey to answer very important questions.

So what I'd like to invite you to do in the new year is to join HealthTree Cure Hub. And now I'd like to begin our show with Dr. Robert Orlowski. Dr. Orlowski, welcome to the program.

Dr. Orlowski: Well, thanks very much, Jenny, for having me again, and Happy New Year to all of your listeners. Hopefully, this will be the best year so far for all of your myeloma journeys. 

Jenny: We hope so. With so much innovation happening, we just know that we need to stay as current as possible. This is my favorite show of the year. This will be a fast-paced show, but Dr. Orlowski is the best at breaking things down to be understandable, and you do this in such a remarkable way. So let me just give you a quick introduction before we get started.

Dr. Orlowski is Chairman and Director of the Myeloma Section and Professor of Medicine in the Departments of Lymphoma and Myeloma and Experimental Therapeutics Division of Cancer Medicine at MD Anderson Cancer Center and has led the myeloma and lymphoma program since 2007. He has been honored with the endowment Florence Maud Thomas Cancer Research Professorship. He's also a disease site liaison to the International Center at MD Anderson.

He serves as the chair of the Southwest Oncology Group, which is called SWOG, which creates clinical trials from multiple centers and is a member of the American Society for Biochemistry and Molecular Biology, member of the editorial board for Expert Review of the publication Hematology, member of the NCI Steering Committee, a member of the Medical Advisory Committee for the LLS, Scientific Advisory Board member for the HealthTree Foundation, reviewer of the ASH Abstract Review Committee, and a member of the AACR Clinical Trial and Translational Center Research Grants Scientific Review Committee. There are so many more committees, but he's also an author on over 420 articles, abstracts, or book chapters. 

Dr. Orlowski has received many awards over a number of years, including the Leukemia and Lymphoma Society Scholar in Clinical Research, the Leukemia and Lymphoma Society Man of the Year Award, the Emil Frei III Award for Excellence in Translational Research from MD Anderson, and the Waun Ki Hong Mentor of the Year Award, the Gerald Bodey Award for Excellence in Education, and the 2022 Giant of Cancer Care in Myeloma.

So now you can find news and information from his daily newspaper on paper.li called Myeloma Daily or find him on Twitter, now called X at @myeloma_doc. 

So let's just jump right in. We have a lot to cover, and as you said, 2024 is going to be a very exciting year. So should we start with just precursor conditions, or where would you like to start? 

Dr. Orlowski: I think that's a great place to start because there's a lot going on there. I think if I had to highlight two areas, I would say, first of all, that we're starting to get smarter about being able to predict who will progress to active myeloma from a precursor state and who will not. There's a couple of abstracts from ASH that I thought I would highlight. 

One was from Daniel Wong from Australia, and they found that cell-free MYC gene copy number was a good predictor for high risk of progression and also for diagnosis of newly diagnosed active myeloma. Although this assay isn't yet ready for prime time, I think the two major points are that it really underscores the important role of the MYC oncogene in myeloma biology, and equally exciting is the fact that a blood test now may be able to become available from that, which will certainly be a lot easier and a lot more popular than the dreaded bone marrow aspirate and biopsy.

The second abstract I'd probably highlight from the predicting perspective is one of our own studies that looked at a gene called LAMP5, or lysosomal-associated membrane protein, that turns out to be especially highly expressed in newly diagnosed and relapsed refractory myeloma and is associated with a higher risk of progression and with an inferior prognosis. We also developed an antibody that recognizes this protein, which we were able to convert into a drug therapy that worked in a laboratory model. So it's not yet ready for prime time to go into patients, but I think, again, it shows that we're able to better predict, and potentially some of these predictive genes and proteins could be targeted with new therapies. 

Jenny: It's so exciting to understand better, especially at the beginning of treatment or at the smoldering stage even or even as a newly diagnosed patient which path you should take. I think that's one of the most challenging pieces from a patient perspective, but also from your perspective potentially. How do you treat this disease? 

Dr. Orlowski: I definitely agree. I can imagine it must be very frustrating from a patient perspective to be told that you have a form of myeloma, even if it may not be clinically active, and that your doctor is not going to be treating you, because at least as of right now, we don't have an approved standard of care, but we can stratify patients into those who are at low, intermediate, or high risk of progression. 

I would say that definitely those who fall into the high-risk category, and possibly some of those in the intermediate risk category, should consider clinical trials. There are many active options out there. The U.S. National Study right now is comparing Revlimid and dexamethasone with Darzalex, Revlimid, and dexamethasone. A similar study was completed in terms of enrollment, and we don't yet have the final results, but it may lead to the approval of a different combination, Sarclisa or isatuximab, with Revlimid and dex, which would be our first FDA-approved therapy for smoldering disease. That would be really exciting. 

Jenny: Wow, that's fascinating. I wasn't aware of that. Wonderful. Thank you for doing this important work to find this higher risk of progression with the LAMP5 work that you're doing. That's so wonderful to have that happening. 

Dr. Orlowski: Well, it's definitely a team effort. I think one of the questions that patients often ask when they're diagnosed, and this is true with precursors as well as active myelomas, is there something that I can do to improve my chances? Diet is often a question that comes up, and we've not always had very good answers. 

But over the past few years, there's been more and more information about possibilities that a plant-based diet may be healthy and may have some positive effects on the myeloma. Actually, for those of you that are on Twitter, or of course now it's called X, I tweeted about a recently published paper on January 3rd. This was by Castro and colleagues, where it was published in the journal called Leukemia. They looked at dietary habits in a very large study that was co-sponsored by the National Institutes of Health as well as the AARP. The study found an association between a plant-based diet and a decreased risk of myeloma. 

An association, of course, doesn't mean that one is directly linked to the other, and we don't yet have information saying that if you switch to a plant-based diet, you will have a better outcome with active myeloma or that you will have a lower chance of progression from a precursor state. But frankly, if I were in this situation, and I tell my patients the same, if you are able to switch over to a plant-based diet, I would probably recommend it because, first of all, it's going to be healthy from a number of different medical conditions, including diabetes and coronary issues, but may also have a benefit to your myeloma with a lower risk. I can't think of a way how it would hurt the situation. So just something to think about as well. 

Jenny: Well, thank you for the advice. I am taking that advice. I have started a plant-based diet since the beginning of the year. I have to say it is not easy, it takes more planning, but I'm feeling great. So whether it helps my myeloma or not -- and I've seen a lot of work be in this area of progression prevention, it seems, and it's something that patients can do, right? 

Dr. Orlowski: Well, definitely kudos to you. I haven't had the strength of will so far to do that. A plant-based diet, it doesn't mean that you have to be vegetarian necessarily for every meal, but if you do reduce processed sugars and protein from non-plant sources for at least some of your meals, that may be easier for those of you who, like me, don't have the optimal level of willpower.

Jenny: Well, my husband looked at my sweet potato creation last night and was just like, "What is this? You’re going to eat it anyway. It's okay." Well, okay, wonderful. Is there anything else in the smoldering myeloma or even MGUS stages that you'd like to talk about? 

Dr. Orlowski: I think those are the major new developments. Certainly, as I mentioned, there's a lot of research here. People are looking at bispecifics in these precursor stages. We'll talk about bispecifics later in the program. There are even one or two CAR T-cell trials. So definitely look into, if you're in this category, what research trials are available in your area. And you should definitely consider to enroll, always weighing, of course, the risks involved with each of the therapies. 

Jenny: Well, I want to just echo your comment about clinical trials that you made earlier. I think patients should always consider them as a treatment option. I think we're to the point in myeloma care where there are so many wonderful options that are standard of care. All these clinical trials are just pushing the field forward and more and more so. Anything you're going to get in a clinical trial could be just early access for some of these newer therapies. I would just encourage patients to consider it, whether you're smoldering, newly diagnosed, relapsed, it doesn't matter. You should consider a clinical trial as a treatment option with your doctor. 

Dr. Orlowski: Definitely. Maybe we can move over to newly diagnosed symptomatic myeloma at this time, if that's okay with you. 

Jenny: Yes, for sure. 

Dr. Orlowski: I think there were two really important abstracts that were presented. One was at the so-called plenary session. For those of you that don't go to these large annual meetings, the plenary session is where the top four or five abstracts across every disease that is covered by the meeting is presented. There also was a late-breaking abstract. Both of these involved addition of a CD38 antibody to a triplet for newly diagnosed myeloma. The plenary session involved adding isatuximab to carfilzomib, lenalidomide, and dexamethasone. Then the late-breaking abstract involved adding daratumumab to bortezomib, lenalidomide, and dexamethasone. Both of the studies really showed that adding the CD38 antibody made a big difference for patients with newly diagnosed myeloma. 

I'll give you just one piece of data. This is from the study with daratumumab. The overall rate of complete response with the triplet in that study, so the triplet was bortezomib, lenalidomide, and dexamethasone was 70%. For the quadruplet with daratumumab, it was 87.9%. That's a pretty big improvement and definitely, I think, should make everybody think of using a four-drug combination if you've got newly diagnosed myeloma that's symptomatic, unless there is some really dramatic contraindication. Let's say for the sake of argument, for example, that somebody has really bad neuropathy, you may not want to use bortezomib, but otherwise, the quadruplet really is the best way to go. 

Jenny: The typical length of time before you try something else or go to transplant is four to six cycles, or what do you typically do? 

Dr. Orlowski: One of the standards has always been to do about four cycles, and many of the studies are designed that way. I personally don't go by that rule of thumb in every patient because it really depends on where the myeloma starts out in terms of disease burden and also how quickly it responds. Sometimes people can have symptomatic myeloma with just 10% plasma cells, and sometimes you have people with symptomatic myeloma and 90% involvement of the bone marrow. The 10% patient is probably going to achieve a complete remission more rapidly than the 90% involvement patient. 

Also, the molecular risk can be important because the standard risk patients, of course, still have a better prognosis than the molecularly high-risk patients. That's another consideration. Hopefully, the goal is to achieve a complete remission and, if possible, minimal residual disease negativity or MRD. If after four cycles, you're tolerating the regimen well and you've got a really good response but it's not quite all the way to a CR, why not do a fifth or maybe even a sixth cycle as well and get it down even lower? Because we know that, in general, the less disease you have, whether you do a transplant next or not, the better will be your outcome. It makes sense, right? Less cancer is always going to be better than more cancer. 

Jenny: Absolutely. Well, it's nice to see that that personalization is happening.

Dr. Orlowski: Definitely. In terms of the transplant, yay or nay, there wasn't a lot of new data at this ASH meeting about whether we should or should not be doing transplant. I still tend to practice with the notion that, if you have good-risk disease and you get into a complete remission and are MRD negative, you should have the option to do either a harvest and hold and not do a transplant and go right to maintenance. Or, if you prefer to get the transplant out of the way, it's certainly fine to go ahead and do it. Whereas, if you have high-risk, molecularly high-risk disease, or if you have standard risk but you don't achieve a complete remission, then probably adding the transplant at that time is a good idea. 

Jenny: That makes a lot of sense. It seems like the data is not quite there yet with all these immunotherapies. There's just not that proof yet that you can bring these up to that first set of therapies and achieve the same type of remission. Also, you can think about extending that remission out with transplant or even with that good response. Then, in the meantime, all the data is coming out over the next few years while you're in that remission. 

Dr. Orlowski: You're definitely right. I would just highlight one abstract at the meeting where this was actually a study done in China, but it's with a CAR T product that is now undergoing trials in the U.S. This is the so-called fast CAR T, which is a CAR T that is made much more rapidly than some of the current FDA-approved CAR T's. It recognizes both BCMA and CD19. 

In this small study, it was only about 20 patients with newly diagnosed myeloma. The follow-up was still relatively short, but the response rate was 100%. The stringent complete response rate was 95%. That sounds like it might be even better than the quadruplet of the daratumumab with bortezomib, lenalidomide, and dex. That doesn't mean we should all be rushing out to do these CAR T trials up front because we need to know how durable the response is, number one, and then to make sure that there is effective therapy if people do relapse. But I do think that it's definitely worthwhile thinking about these immune therapies early.

Just as a little shameless plug, we just activated a trial with a BCMA bispecific. This is with linvoseltamab, which we're doing in what's called a window trial. So we're taking patients with newly diagnosed symptomatic myeloma, and rather than do the quadruplet, we're doing the BCMA bispecific first. If they get an excellent response after two cycles, they continue on the bispecific, whereas if they don't get a good response, then we switch them to standard of care. The goal is to really see whether one of these new immune therapies can do as well as these quadruplets or, who knows, cross your fingers, maybe even better. 

Jenny: Wow, that's fascinating. That's the one from Regeneron, correct? 

Dr. Orlowski: Correct, yes.

Jenny: Wonderful. Well, that's a wonderful strategy to see if using these up front is best, because I know you hear people talk about the immune system status and having a stronger immune system when you're first diagnosed, and that might be a wonderful therapy. I know everyone's kind of thinking about bringing these things up. What a wonderful strategy. Thank you for mentioning that. 

Dr. Orlowski: Well, you're right that it looks like patients' immune systems are healthier earlier, and if you look at some of the CAR T data, for example, with ide-cel or l or cilta-cel, when they were moved from the late line to earlier lines of relapse, the efficacy did improve. So this is another way of trying to do the same thing which is to move it even earlier with the thought that there may be less T cell exhaustion and less T cell damage in newly diagnosed patients who haven't gotten treated with a bunch of, for example, steroids, radiation, other drugs that can impact T cell health. 

Jenny: Can I ask your opinion about maintenance therapy when you think about that? Because as you walk through that strategy that you use, like if you're high risk or you're standard risk but you didn't ever achieve a remission, you think about the transplant, how do you look at maintenance therapy after that first line? Do you just use a single drug? Do you use multiple drugs? For how long? What do you do there? 

Dr. Orlowski: Great question. Typically, the current standard is considered to be single-agent lenalidomide for patients with standard-risk disease, whether that be after a transplant or after induction therapy. For patients with molecularly high-risk disease, the approach in the field has been to use lenalidomide with a proteasome inhibitor like bortezomib or carfilzomib. But more and more, there are data about lenalidomide with daratumumab as a maintenance therapy. Although I don't think that everybody is switching to that combination yet, I do think that there is a feeling among the experts in the field that that trend will probably happen.

Now, long-term, if you ask me where I think we're going, what I'm hopeful is that we will incorporate some of these immune therapies into our upfront treatments, and we will get such a huge reduction in the level of myeloma that we won't need to give maintenance therapy. People will be able to have what's called a treatment-free interval and will be able to monitor their disease burden with blood tests looking at MRD measures. If somebody converts from negative to positive, then that may be a trigger to think about maintenance therapy. 

Jenny: Well, that would be absolutely fabulous if you didn't need that. That would be incredible to have that treatment-free period. I think it helps your body just kind of recover so you can even hit the next therapy as well. That would be fantastic. I'm so happy to hear you say that. Wonderful. 

Dr. Orlowski: Yes, definitely. Everybody feels best when they're off of therapy and with as little myeloma as possible. 

Jenny: Yes, I know it's not always possible, but what a wonderful thing. Are there other strategies that you have or you use to personalize treatment from the beginning? Because I remember just being newly diagnosed and having physicians tell me that your first treatment is your best treatment and so how do we optimize it. What other strategies do you try to use? 

Dr. Orlowski: Well, right now, as I mentioned, the quadruplets are probably the best way to go. We don't yet have ways to personalize those treatments for individual differences in disease biology. However, I do think that we're moving in that direction. I'll give a few examples. Probably the best one is for the patients which is about 15% who have 11;14 translocations. Those patients have myeloma that is much more dependent on BCL-2 expression. Venetoclax is the obvious drug to consider there, although unfortunately not all of the studies with that have been positive, but there is a different BCL-2 inhibitor that was presented at ASH. This was a drug called sonrotoclax. Not quite as easy to say, but this was presented by Hang Quach from Australia and it had a good overall response rate at the recommended phase 2 dose in the relapsed setting. 

So I think hopefully we'll be able to investigate that drug since, unfortunately, as you probably know, the so-called CANOVA study, which was the most recent attempt to look at venetoclax in relapsed refractory disease, unfortunately, although there were some indications of a positive result, they probably were not sufficiently positive to lead to an FDA approval. 

There also are other approaches. Gareth Morgan's group reported at the ASH meeting about a strategy that they are looking at targeting pinocytosis for RAS-mutated myeloma. By the way, that's almost 50% of patients who have some kind of a RAS mutation. We know that those RAS-mutated patients have disease that is less responsive to proteasome inhibitors, and many of these are now in development and hopefully soon to go into clinical trials. As far as I'm concerned, the earlier you use them, the better. So what we may have is a quadruplet as kind of a backbone that everybody gets and then we may add a fifth drug that is targeted to the molecular features of the patient's own myeloma.

Jenny: That's wonderful. This is why patients need a myeloma specialist on their team. I just don't think it's possible to be seeing a general oncologist who's treating 20 plus different types of cancers and have this level of knowledge about myeloma and the nuances because every myeloma patient's myeloma is different. So it's just proof to me that you really need a myeloma specialist on your team. 

Dr. Orlowski: You know, there are some wonderful community hematology/oncology doctors who are very involved in myeloma and have lots of myeloma patients. But it's always worth asking your doctor how many myeloma patients he or she treats just to get an idea. If that number is low, then having either an in-person or, now very often you can do this remotely, having a remote consult so that you can at least have the confidence that what you're doing is the right thing would be really, I think, important to reduce anxiety levels and sometimes potentially change treatments to something that could be better. 

Jenny: Well, I agree. And even if you want to get treatment in your local center or community, you can do that. But I think consulting with an expert like yourself at decision, key decision points, whether you’re newly diagnosed or you're relapsed is really critical because you have this depth of knowledge and it's what you focus on all the time. So there's just no replacement for that kind of pattern recognition that you're seeing in your clinic. It's just critical, in my opinion, for patients to do that for themselves. 

Okay, well, should we move on to relapsed myeloma and maybe earlier and then moving into later relapses? 

Dr. Orlowski: Definitely happy to do that. There were updated data from the Phase II CAR T 2 trial that were presented. This was in two different cohorts, one of which had one to three prior lines of therapy, and the other were patients who had early relapse after their first line treatment. These were all patients getting second line BCMA-targeted CAR T cell. Now, the number of patients in each of these cohorts was only around 20. So we definitely want to see the larger study results that have been presented and that really have been announced as being positive. But the overall survival in those patients with a 24-month follow-up was anywhere from 75% to 84%, and the overall response rate was 95% to 100%, which again, suggests the possibility that earlier use of these CAR T cells will give you a better outcome. 

The other nice thing about that is that if you use it earlier, you may have a longer treatment-free interval than if you use it later. Definitely be nice to get the approval for both ide-cel and cilta-cel in earlier lines of therapy, which we think may be possible later this year, probably in the second half of the year rather than the first half, and so that will give earlier line patients the first shot at CAR T cell therapy. 

A couple of advantages to doing it earlier. First of all, we talked earlier about T cell health. Probably your T cell health will be better in earlier lines of therapy. The other thing that you can avoid is in later lines when the myeloma can be more aggressive, sometimes it can be a problem to have to wait for the manufacturing period, because if the myeloma is progressing more rapidly in the meantime, you may have to get what's called bridging therapy. But sometimes in earlier lines of therapy, the myeloma is not that aggressive and so you can have a little bit of period off of treatment before you get your CAR T without the need for bridging, although definitely there are a lot of options for bridging. So again, hopefully by later this year, we will have earlier line of therapy BCMA-targeted CAR T cells FDA approved.

Jenny: That would be amazing. I know just based on those results, that those are really impressive results. So that'd be wonderful to have this available at earlier relapse because those other studies were four plus lines of therapy. So that's a lot of treatment. 

Dr. Orlowski: Definitely. Now, for later line of therapy, first of all, there are some novel drugs out there that you should watch out for. I talked earlier about the new BCL-2 inhibitor, sonrotoclax. For those of you that have 11;14, all of you I'm sure know about lenalidomide and pomalidomide, but there are newer drugs in that category that also bind cereblon as the target protein and seem to have more potent effects than len and pom. The two in particular are iberdomide and mezigdomide. Niels van de Donk presented an iberdomide maintenance study, which looked at various doses and found a number of very well-tolerated doses and what looked like very good efficacy. 

So for those of you that have just undergone stem cell transplant or who think that you may be undergoing transplant later this year, there is an international study ongoing right now comparing lenalidomide to iberdomide. Plus, I'll put another shameless plug in to our SWOG study which is comparing lenalidomide to lenalidomide with daratumumab. So those are two large maintenance study options that you would have. 

Now for the relapsed setting, mezigdomide is another drug that looks very active and it's in this category of so-called CELMoDs or cereblon modulating agents. There are a couple of national studies of mezigdomide combinations. The paper that was presented at ASH by Paul Richardson looked at mezigdomide with either daratumumab or with elotuzumab. The elo data, frankly, were a little bit disappointing because the response rates were not that great, but the data for mezigdomide with daratumumab were quite good with response rates in some cohorts in the high 70% to high 80% range, and so really a very active combination. 

The other thing that I think was really interesting about mezigdomide, and this has been in part published and in part presented in abstract form, is that mezigdomide seems like it can activate T cells. The reason that's important is that some of the immune therapies that we've been talking about, including bispecifics and CAR T cells, can cause T cell exhaustion. Let's say for the sake of argument that you're on teclistamab and the myeloma progresses, not because there is a mutation or loss of BCMA expression but because your T cells become exhausted, trying to bring in another bispecific, which will also then rely on T cell health, may not be the best approach. But by adding either an immunomodulatory drug or one of these CELMoDs that activates T cells, you may actually be able to recapture response. 

There were data presented at the meeting looking at teclistamab with pomalidomide and talquetamab with pomalidomide, where the overall response rate was in the 80 plus percent range. And so really something that looks interesting and may inform future sequences of therapies if, again, you have something like T cell exhaustion. 

And then probably the last new drug I would briefly want to mention in this new drug setting, there are a couple of what are called trispecific antibodies. So a bispecific, like it sounds like, binds to two different proteins, either BCMA on myeloma and CD3 on T cells or GPRC5D on myeloma and CD3 on T cells. But there's a number of trispecifics that can really bind to three proteins. One of them, which is a Janssen compound, actually bound to BCMA and GPRC5D and CD3 and the results with it look quite promising. The reason that's interesting is that not every patient's myeloma expresses high levels of both proteins. Some patients may have high levels of one but low levels of another. So if you pick the wrong one, you may have a lower efficacy. But if you've got a molecule that hits both, then there's less concern that a low expression level could undermine the activity. So that's kind of cool. 

And then I'll just mention one other drug. One other drug to quickly mention is belantamab mafodotin. Now all of you, I'm sure, remember that this originally got single agent approval. It's a BCMA antibody drug conjugate, sort of like a Trojan horse approach, where it's taken up inside the myeloma cell and releases a toxic drug that kills the cell from the inside. But then the drug got pulled off the market because there was one phase three study that was positive, but not positive enough to be considered successful. But we now know that there were data announced, although not presented, from the so-called DREAMM-7 study where belantamab with bortezomib and dexamethasone was better than bortezomib and dexamethasone for progression-free survival as well as overall survival. 

Just earlier this month, there were data published about belantamab with pomalidomide and dexamethasone that had an 85% response rate. I tweeted about that on the 6th, if you follow my Twitter account. And it seems that there is a possibility, therefore, that the belantamab may make a comeback. The reason that's interesting is that belantamab is another drug that doesn't rely on T cells for activity. So in terms of sequencing, if you've just progressed on a bispecific and your T cells are exhausted, belantamab may be a reasonable next step. 

I should say, by the way, these are all hypotheses that I'm mentioning. We haven't proven them yet, but there is at least some science and biology and logic behind them. 

Jenny: It's fascinating to watch the evolution of that. I have a few other questions, follow-up questions for what you're saying about the trispecifics. So I know you said it was the three -- it seems very similar to that, like a dual CAR T strategy. Has that made any progress? Because I think at the beginning when they started talking about CAR T's, they were talking about, let's do two targets at the same time. I was just curious about that. 

Dr. Orlowski: Well, definitely. So I briefly mentioned the fast CAR earlier, which is a dual BCMA and CD19 approach. There are folks that are looking at targeting both BCMA and GPRC5D. So there is some progress there. Hopefully, we'll see even more at this coming year's ASH in 2024 back in San Diego. 

Jenny: Yes, that's the best place for ASH. Absolutely. Are there other targets besides the CD19 that you talked about, like either CS1 or some of these other targets? Does anything else look promising? I'm just curious about that. 

Dr. Orlowski: CS1 or SLAMF7, which was targeted by elotuzumab, people have been looking at that as a target. At least at our center, E.J. Shpall and Katy Rezvani looked at that as a target. What they found in preclinical models is that there was very rapid emergence of myeloma cells that no longer expressed CS1 or SLAMF7. So I think that one is a little bit less popular, but there definitely are others. One I would briefly mention, which was CD70. A number of groups have found that CD70 is expressed at high levels, in particular on the 4;14 translocated myeloma, which is one of the higher risk features. The so-called Myeloma Solutions Fund has supported research in that area. We actually have a CD70 NK or natural killer cell CAR in the clinical trial arena right now here at MD Anderson. So if you have 4;14 translocated myeloma, it's definitely something to think about.

Jenny: Okay. Just curious about that. It's interesting to see these therapies evolve. You talked a little bit about sequencing. Can you talk about sequencing? Patients are trying to figure out what they're doing at every step. Hopefully, they have a myeloma specialist on their team that can guide them through that process. But it's a wonderful problem to have that you have so many different treatment options. Can you speak to how you determine what should come next? Like for the newly diagnosed patient, and then they've relapsed, and then do you do a bispecific? Do you try to do a GPRC5D and then go to a CAR T BCMA? Or like, how do you think about that, and how do you figure that out for your patients? 

Dr. Orlowski: Right now, all of us in the field still practice with the goal of giving the most active therapy as early as possible. In deciding on the next line of therapy, what you really look at is what's the biology of the disease? How rapidly is it progressing? Is it standard risk? Is it high risk? What treatments did the patient have before, and how did the patient tolerate them? What treatments did the myeloma become resistant to? So it's a combination of disease factors and patient factors. But some of the concepts that I've mentioned, I hope will be emerging more and more, where we'll be using measures of T cell health, as well as expression levels of some of the targets that we've talked about, which include BCMA, GPRC5D, CD70, as ways to try to figure out appropriate sequencing. So these are all concepts that are in development.

Just as one example, there is an abstract at ASH that suggested that patients with 1q gain or amplification had reduced levels of CD38 expression. That may suggest that maybe something like isatuximab or daratumumab may be less effective, although actually isatuximab has really good activity there. So one has to always be careful because these laboratory studies are really important to do. But cell lines and even samples taken out of patients are not quite as good a model as the patients themselves. I think that goes back to one of your earlier points, which is the need for continued clinical trial research to understand how these approaches are best used in people. 

Jenny: Absolutely. This is how you make progress in the care that you're delivering. It's because patients have joined these clinical trials and participated, and now you know the answer. So it's best for patients and best for the research, which is best for patients also. So that's fantastic. Just a quick question. I know we want to talk about testing methods, but you've mentioned T cell health over and over again and it's so important for patients responding to these immunotherapies. Is there anything a patient can do to improve their T cell health? 

Dr. Orlowski: Great question. A couple of studies have been published just recently looking at CAR T efficacy. I tweeted about one earlier this week that looked at CD8 T cell expansion and health as a more important determinant of successful CAR T therapy, even compared with persistence. Unfortunately, as of right now, we don't really have good information about how to maximize T cell health from a physical activity and diet perspective, although probably some of the same concepts that we've talked about earlier, including plant-based diets, staying healthy overall, exercise, being mindful and using mindfulness techniques, these are probably all things that certainly have a chance of benefiting. It may be, as I mentioned earlier, with combinations like pomalidomide as well as mezigdomide, that we will have actual drug therapies that may improve T cell health.

There's also a little bit of published data about Selinexor potentially improving T cell health. Of course, the main things that you want to try to avoid are corticosteroids because steroids kill lymphocytes, and also alkylating agents, in particular, bendamustine, because you have a really long-lasting decline in lymphocyte levels, and it can be very difficult to collect good T cells from patients that have had bendamustine or that have recently had melphalan. So those are all things you want to try to be careful about using. 

Jenny: Okay, wonderful to know. I think everybody would love to get off steroids. It's their least favorite drug. Okay, should we talk about quickly new testing methods? Like you hear a lot about MRD testing and then all these new methods coming out, like circulating tumor cells or single cell sequencing. What do patients really need to know about this or to ask their doctor about, and then how useful are they? Are they just using research? Are they coming to the clinic? Just kind of what's your overall opinion about some of these options? 

Dr. Orlowski: Yes, great questions. I did want to follow up and make one comment about your corticosteroid concern, which is definitely valid, but Rahul Banerjee had an oral presentation at ASH where he analyzed SWOG clinical trial data for patients with newly diagnosed myeloma, and what he actually found is the patients who had dose reductions of dexamethasone during their initial therapy had no difference in outcome compared to patients who did not have dose reductions. So that doesn't necessarily mean that everybody should have a dose reduction, but I think it does suggest the possibility that if you're not tolerating it well, don't be worried that a reduction will compromise the benefit, which often is the case. So that's something to really consider. Keep that in mind. 

Jenny: Yes, or talk to your doctor about it. 

Dr. Orlowski: Yes, definitely. Now going back to the testing, I think first of all, there were quite a few abstracts around two broad concepts, and I know we're kind of running out of time, so I'm not going to quote specific data, but we see more and more information about the value of circulating myeloma cell assays in both predicting outcome and in predicting the biology because, first of all, we've known for a while that more myeloma cells in the blood, as you would imagine, is associated with a worse prognosis than patients who have less myeloma cells in the blood, but now the sequencing techniques are getting so good that many of the assays can even do sequencing and look for mutations. 

The second category I wanted to briefly mention are what's called mass spectroscopy or spectrometry assays, which are able to look for the myeloma-derived protein in the blood, and some of these now appear to be able to get down to the level of sensitivity of some of the bone marrow assays. So that would be just incredibly wonderful if we had that available because, first of all, we could look at the biology of your disease and do MRD testing potentially only from blood tests and not have to do bone marrows. Because of the convenience of the blood tests, we would be able to examine the biology and the disease burden more frequently. We know that if we monitor the myeloma better and react more quickly, the outcomes will be better, but we certainly don't want to be doing bone marrows on people every three months. But if these blood tests could hopefully soon replace the bone marrow, then we'll be able to have more accurate and better information in a real-time fashion. So those are the quick little things to say about the new ways to measure myeloma levels. 

Jenny: Yes, it'll be interesting to see those evolve, because that would be fantastic, and yes, it'd be amazing and much less painful for everyone. I don't know. I've had like 20 biopsies now. I think I've been counting, and they're not that great or fun. Well, we all enjoy going through that. 

Are there any clinical trials that -- you mentioned a few as we went along through this show, but are there any other clinical trials that you'd like to bring up or highlight? 

Dr. Orlowski: Well, one study that I would mention briefly, and this is, again, a little bit of a shameless plug, but we've mentioned this compound before. The HDP-101, which is a BCMA antibody drug conjugate, which we previously showed in laboratory models, is more active against deletion 17p myeloma than against standard myeloma, and of course, deletion 17p is a high-risk feature. So this drug is now in phase one trials, and there was an abstract at the meeting showing that there was so far good safety and emerging evidence of activity. By the way, at least so far, there was no ocular toxicity. Those of you that have read up or maybe even had belantamab know that one of the more significant side effects can be blurry eyes or dry eyes and visual changes, and at least so far with the HDP-101, that has not been seen. So that's one for those of you, especially with deletion 17p, but even with just relapsed refractory myeloma, that's a good one to watch out for. (Click this link to find the trial)

Jenny: Is that only open for patients with deletion 17p, or is it just including patients with 17p? 

Dr. Orlowski: It's open for all patients. It does include deletion 17p, but you don't have to have that to be eligible because the drug works really well even in what's called wild-type 17p, which means patients without that deletion. Again, in the laboratory, what we found is that that molecule works better than belantamab. We don't know if that will be the case in patients. It's still too early to tell, but at least in the laboratory, it looked better. 

Jenny: Okay, well, that's fantastic. I think having an option for, especially for deletion 17p patients, is wonderful. I know those antibody drug conjugates kind of work differently than the bispecifics. They kind of drop a toxic payload on those cells, so it's wonderful that you're not seeing the ocular issues, the blurriness and things like that that people experience with belantamab. So that's wonderful, and that's open at MD Anderson, correct? 

Dr. Orlowski: And a number of other places, including Emory, which is a big myeloma center, and others, and if you want to look it up, just go to clinicaltrials.gov, or there are many wonderful trial navigator portals, including one that you and HealthTree have. 

Jenny: Yes, so we will put a link to those trials that you mentioned when we do the final transcript of the show, and that should be out within a week or so. So just kind of watch for that, and you'll be able to find those links after the show. 

I want to open it up just for a few minutes for caller questions. I know we're at the end of our show, so it might only be one or two. But if you have a question for Dr. Orlowski, you can call 347-637-2631 and press 1 on your keypad. Go ahead with your question. 

Caller: Thanks, Dr. Orlowski. This has been very interesting. You mentioned CELMoDs. Will those replace Revlimid and Pomalyst, in your opinion, as treatment and maintenance? 

Dr. Orlowski: Yes, great question. Right now, we don't yet have FDA approvals for CELMoDs. One of the nice things about the CELMoDs is that they seem to be active in patients with myeloma that is either sensitive or resistant to IMiDs, and we don't know if the opposite is true. For example, if somebody had iberdomide first, would their myeloma then respond to pomalidomide? Until we know that, I think still the sequence would be best for IMiD followed by CELMoD. But if the CELMoD, let's say, is twice as good and you can still have better responses afterwards to pomalidomide, then reversing the sequence may be reasonable. So that's a long-winded way of saying I don't think we know the answer yet. 

Caller: Okay, great. 

Jenny: Thank you for the question. Caller, go ahead with your question. 

Caller: All right. Thank you so much, Dr. Orlowski. You're just amazing. Post-stem cell transplant, first refractory to Revlimid maintenance, what determines whether you favor DKd or DPomd? which I think right now that's your only choice. 

Dr. Orlowski: Those are certainly very good options. I tend to decide based on the molecular features, and if somebody has high-risk molecular features, I tend to go to DKd, whereas if somebody has standard-risk molecular features, I tend to go to DPd. 

Caller: Got it, got it. Thank you. 

Jenny: Thanks for the question. Caller, go ahead with your question.

Caller: Yes, thank you very much. I have a molecular feature of 1q, and I'm high-risk smoldering, and my M protein is at 2.6 at the latest. I'm looking at the clinical trials. I'm looking at the CAR T cell, the CAR T trial at Dana-Farber. I just get -- right at this stage, I'm very confused with all of the information, and I don't want to do a clinical trial that is not the best. I mean, I could use some advice, I guess. 

Dr. Orlowski: Thanks for the question. It's, of course, difficult in the context of a very short discussion over a radio program like this to give you optimal guidance. One thing you can look at, I don't know when you were diagnosed, but we do know that so-called smoldering myeloma in evolution, meaning people who have disease where the M protein or the free light chains are rising over time have a higher risk of progression than people whose M protein or free light chains are stable over time. So even if you're in the high risk category, you can consider that, and maybe that will give you an idea of whether you need to decide now or whether you can take a little bit of time and look into the future and do more research while you wait. So that's one consideration. 

You know, depending on what the additional molecular aspects of your disease are, certainly the CAR T cells are one of the best therapies that we have in the relapsed refractory setting. I mentioned some of the data in newly diagnosed disease, and one of the advantages that they have is that unlike some of the immune and chemotherapy combinations where you're on some kind of treatment for up to two years for many of the smoldering studies, the CAR T cell approach is a one and done, if you will, because you're going to get your T cells collected, you're going to get lymphodepletion, then you're going to get reinfusion. Once you get past that first month where there's a higher risk of the cytokine release and the eye cancer neurotoxicity, after that, you're going to be off of any treatment, and that's when people feel the best. So it really depends on your individual preferences. 

I would definitely suggest also that you get a second or even a third opinion, and maybe that will help you in deciding further. But definitely if you're high risk with 1q, considering a CAR T cell study for smoldering is very reasonable. 

Caller: And if I do happen to flip over to active and I'm no longer eligible for the CAR T trial, that's newly diagnosed from what I understand, and then I'm limited to whatever is available for newly diagnosed patients. 

Dr. Orlowski: Correct, but there are trials looking at incorporating CAR T cell therapies into frontline treatment, so the fact that you would progress, which hopefully wouldn't happen. But even if it does, that doesn't mean that you're automatically excluded from CAR T cell therapy. 

Caller: Okay, great. All right, thank you very much. You guys are doing good work. Thank you. 

Dr. Orlowski: I was just going to say, for those of you that have questions that we can't get to, my email address is rorlowski@mdanderson.org. So feel free to shoot me a question that way. 

Jenny: Okay, wonderful.  Are you okay on time for a couple more questions? 

Dr. Orlowski: Yes, I'm okay. 

Jenny: Caller, go ahead with your question. 

Caller: Yes, thank you. I'm asymptomatic. I was diagnosed by my primary. I didn't believe him. He sent me to an oncologist. I ultimately ended up with a specialist at U of Miami. This summer, in August, was when I started treatment. My doctor said I should have four months. Since I had no adverse effects, he kept it for two more. Since then, I have been on Revlimid maintenance. Again, I hear so much from these people that are suffering so. My real suffering is my mental health and not realizing, can I be maintained at this level indefinitely? I don't know if I'm cured, but I'm certainly stabilized. I see my physician every three months, and they just smile. They said everything's wonderful. Is it a certainty that I will eventually progress? 

And my other question is, even though he said no, when a family member thought about a stem cell transplant, he said not for me. I also read what you didn't mention is that there's a risk after a period of time of secondary cancers developed from the treatment for myeloma. I appreciate you taking my call because when I go online, I only see terribly sick people. I can't find anyone like myself that's just hanging in there. I don't even feel bad for taking up your time. I appreciate your response.

Dr. Orlowski: Well, thank you for your call, and by no means should you feel sad for taking up time. The good news is that there are a lot more people who are doing really well than it sounds like you've been able to connect with. A couple of things, there were a few different questions that were in there. First of all, you're at a great place. University of Miami has a wonderful myeloma program. In terms of stem cell transplant source, it is true that the vast majority of the transplants that are done in myeloma are autologous using your own stem cells and not from a donor, which would be allogeneic. Family members may be matches for you, but at least in the past when studies were done comparing, for example, two autologous transplants versus one autologous and then an allogeneic, the results were not substantially different, which is why autologous is still the standard of care. You don't have to worry about graft-versus-host disease if you do an auto. Graft-versus-host is where the donor stem cells attack your normal tissues because their job is to attack anything that looks foreign.

You're also on Revlimid, and you wanted to know about second cancers. That's a complicated question because we know that myeloma patients who get no treatment are at increased risk of second cancers. Definitely, there are a number of studies that show a small increased risk of second cancers with Revlimid. But overall, the benefit of the maintenance is still felt to substantially far outweigh the risk. There's no way on an individual basis that we can predict whether you will progress or will not, although if you have standard risk of disease, the chances are that you will have a lower risk of progression and that if you do progress, it will happen later than if you have high-risk disease.

Then finally, you wanted to know if there's a chance that you will never progress, and the answer is that yes, there is a chance you will never progress. Probably somewhere in the 10 to 20 percent range of patients can stay on maintenance therapy and may never relapse. Here's hoping that you fall into that group. Definitely, if you think that things like support groups or other interventions may help you to feel better about the situation, please avail yourself of whatever resources you want. Again, if you think that a second or third opinion would help you feel better, definitely go for that as well. 

I hope I've covered everything that you wanted to know. 

Caller: Can I ask one other quick question? I was going to ask my doctor when I see him in a couple of months, can I go and try to skip a month? I see him every three months. I'll take it for two months and skip it for one month and then resume it, just to see how that works. Again, just to not give myself so much Revlimid if it doesn't make much of a change. 

Dr. Orlowski: There haven't been studies that have looked at what I would call from your description, that would be a discontinuous maintenance schedule where you do a month off and a month on. I can tell you, if a patient of mine asked me that question, I would probably say, since we don't have a lot of data, my preference would be to recommend that you stay on a continuous schedule. 

Caller: Okay. 

Jenny: Okay, wonderful.

Caller: I appreciate your response because I will ask my doctor when I see him in a couple of months.

Dr. Orlowski: Very good. 

Jenny: Okay, thank you. HealthTree has a lot of resources too that could help. We have a HealthTree Connect social media groups. We have Coaches. We have a whole university, so you can learn more about myeloma.

With that, Dr. Orlowski, I know we've gone far over what we had. We still have caller questions, but I would encourage you to email Dr. Orlowski. If you need his email, just email me, jenny@healthtree.org again. Do you want to mention your email one more time? 

Dr. Orlowski: Sure. It's rorlowski@mdanderson.org. Again, thanks for having me on the show and best wishes to everybody. Stay warm in the cold weather. 

Jenny: Oh, thank you so much, Dr. Orlowski. It's been a privilege to have you on.

Thank you to our listeners for listening to the HealthTree Podcast for Multiple Myeloma. We invite you to join us next time to learn more about what's happening in myeloma research and what it means for you.