Dr. Paul Richardson of the Dana Farber Cancer Institute shares a mid-year myeloma review of ASCO, EHA and upcoming International Myeloma Society findings of the fast-moving research being performed in myeloma. Updates include the expanding world of bispecific antibodies that include one FDA-approved drug and anticipated approvals for two new bispecific antibodies. He will also discuss exciting results from CAR T cinical trials,  CAR T newcomers, sequencing preferences, BCMA targeted therapies, new therapy targets in myeloma, cellmods, MRD advances, blood-based testing, clinical trial end points and more. 

Thanks to our episode sponsor, Karyopharm.

 

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. We’d like to thank our episode sponsor, Karyopharm, for their support of this program. 

Now before our show this morning, I'd like to let you know that we will be launching what we call HealthTree 2.0 On October 23rd. When we started this and this podcast is actually exactly 10 years old, I wondered how can patients help accelerate a myeloma cure? How can we contribute for these amazing researchers? one of which you will hear from today. Over the last 10 years, we've built over 14 software tools to do precisely that. So we have an education pillar of tools that include this podcast and our news website, our HealthTree University, our Round Tables. We have a pillar, our second pillar of programs is community building, so we connect you to each other, so you can use our Health Tree Connect social media network or find a myeloma coach, or we'll have a growing number of regional communities that you can help volunteer for in the future. And then the third pillar is our Healthtree Cure Hub Data Portal, and that's really where we want to invite you to help participate and help these researchers accelerate a cure faster, because when we share our myeloma stories and the investigators are able to do surveys and studies and data research using our real-world evidence, we get closer to that cure. So we are super excited to be able to share that with you. Look for that live and virtual event, mostly virtual event, on October 23r. Please go ahead and register for that. 

Now on to our show. Dr. Paul Richardson, you have been so kind to participate in his mid-year review. We're a little past the mid-year review because we had technical challenges last time. But to help us understand the many advances that are being made in myeloma, and we do this type of review twice a year because there's so much happening. So Dr. Richardson, welcome to the program. 

Dr. Richardson: Jennifer, it's an absolute pleasure and always wonderful to connect with you and have the opportunity to share some of the excitement around important recent advances over the last six months or so in myeloma, which as you point out, Jen, they just keep coming, which is so wonderful to see but also tempered by the reality that we've got lots of work to do. And whilst progress is made, again, the challenges, as you and I discussed before, remain very real. 

Jenny: Very much so. Well, let me give a short introduction for you before we get started, because we have a lot to talk about, and be thinking of questions that you want to ask at the end and we will open it up for caller questions at the end. 

So Dr. Paul Richardson is RJ Corman Professor of Medicine at Harvard Medical School and the attending physician at the Division of Hematologic Oncology and the Multiple Myeloma and Bone Marrow Transplant Service at the Dana-Farber Cancer Institute. Dr. Richardson is a Clinical Program Leader and Director of Clinical Research for the Jerome Lipper Multiple Myeloma Center at Dana-Farber. He's also the chairman of the Multiple Myeloma Committee for the Alliance and Alliance Foundation for clinical trials and a Myeloma Steering Committee member of the National Cancer Institute. He is editorial board member for publications like Clinical Cancer Research, Journal of Clinical Oncology, Journal of Oncology, and many, many others, and is a distinguished myeloma specialist who is highly influential in the new drug approval process. Having led many phase three clinical trial efforts to get many of the drugs that you're familiar with, bortezomib and many immunotherapies, daratumumab, carfilzomib, so on, you've heard of these drugs and maybe use them, to markets. So we're so appreciative for his efforts there. 

He has received the Ernest Bulow lecture and prize from the American Society of Hematology for his translational advances and achievements in enabling clinical science in myeloma. And he's also recognized and appreciated by the patient advocacy community as a recipient of the Robert E. Kyle Lifetime Achievement Award by the International Myeloma Foundation for his work that's resulted in significant advances in research treatment and the care of myeloma patients around the world. 

Dr. Richardson, thanks again, and we will just jump in. Maybe we just want to start in kind of how a patient moves through their myeloma journey because there's a lot to keep updated. So in the newly diagnosed myeloma setting, what are the changes that you're seeing? Are we going from triplets to quad therapies for newly diagnosed patients? 

Dr. Richardson: Well, Jennifer, thank you for that lovely introduction. Just one little quick, if I may, I finished my 10-year term as the Alliance Chair. I just want to acknowledge the new chairman, Dr. Saad Usmani.

Jenny: Oh, wonderful. 

Dr. Richardson: He took over in that important role about a year ago or so. And so having done, you know, and obviously doing great things. During that time, actually, obviously, during my 10 years there, we obviously saw the DETERMINATION trial come through the CALGB 100104, lenalidomide maintenance trial, which to many of our listeners was actually the platform for the FDA approval of lenalidomide maintenance. So I'm very kind of grateful to my Alliance colleagues for that and in particular Dr. Phil McCarthy because we ran that trial, started that trial way back in around 2005. And what's so beautiful is that I have patients still on that study, and we're now -- where are we? 2023 phasing. So it points to the real progress being made. 

And in addition to DETERMINATION, which we can touch on in a minute, with the leadership of people and the Alliance team during, you know, now about eight years ago, nine years ago, we started the GRIFFIN study. It's so relevant to just what you asked because the GRIFFIN study, which we were very grateful to be partnered with a fantastic team at Janssen, we were able to do a large randomized phase two trial to document clearly the addition of daratumumab to RVd, which is our workhorse, as you know, really was amazing in terms of results. So the GRIFFIN study laid the stage for now quadruplets with a combination of RVd plus daratumumab. And for a randomized phase two run from a intergroup study, the Alliance with AFT support and Janssen partnership, which was absolutely key to be very clear, we were able to generate so much information. So RVd-dara has become a gold standard, if you will, in the upfront setting, recognizing that phase three trials are still cooking with this large phase to provide a breakthrough to insurers and to provide access for our patients to the importance of a quadruplet therapy. 

So to kind of share for the patients on the call today the sort of rationale, the idea is that obviously if lenalidomide, which is a fabulous drug we worked over the last 20 plus years is our Navy and bortezomib is our Air Force and dexamethasone is our army, daratumumab becomes the Marines. The addition of the Army, Navy and Air Force with the Marines has been a game changer. And of course, we mustn't forget the Coast Guard of zoledronic acid and drugs like it, but nonetheless, sort of quadruplet approach plus this drug of antiresorptive therapy upfront treatments for patients has been transformed. 

The big question is how much does transplant add to this? I think that that in the transplant eligible group has been very important. One of the most interesting aspects of all of this is the evolving space. I want to especially acknowledge my colleague, Dr. Hani Hassoun, who presented again from the Alliance platform our results from DETERMINATION in subgroups at the European Bone Marrow Transplant Meeting in Paris earlier this year. What Hani showed, which was quite remarkable, is that whilst transplant in younger eligible patients clearly results in progression-free survival benefit, we don't see with longer term follow-up overall survival benefit yet. We may but not yet. But most importantly, what we see as subgroup benefits and specific subgroups do particularly well. And most importantly, some groups actually don't benefit from early transplant. 

So this was really very important data. What Hani showed was the fact that certain high-risk patients, particularly those who may have 4;14 as a cytogenetic abnormality may benefit from early transplant in terms of progression-free survival gain. But interestingly, patients with standard risk and/or, for example, a higher body mass index may get less benefit from early transplant. What was so interesting, Jen is that he's sort of drill down deeper on our work regarding ethnicity and race. What we've identified in our African American patients is that actually for African American patients who are actually reasons of pathobiology, the access to free medicines, everything was equal in DETERMINATION. So we were able to ensure excellent access, and we had 20% participation or close to it. It was actually 18%, 19% participation from African American patients. And because of that wonderful participation, we're able to ascertain that, in fact, in the African American population, early transplant, particularly for people who have higher BMI, may actually be not associated with the benefit that we would have expected. It points, I think, to a passive biologic mechanism that we're hoping to better understand. 

My colleague, Jeff Saunder, and other colleagues from the DETERMINATION team are hopefully going to be presenting, we hope, breakthrough data on this at the ASH meeting coming up in San Diego in December. So more to follow but real excitement about choices for patients that you don't necessarily have to have one size fits all and that quadruplets are really making a difference. I would be remiss in not acknowledging the incredibly good work of investigators such as Ola Lundgren who have looked at carfilzomib-based strategies combined with lenalidomide, dexamethasone and daratumumab, KRd-Dara. Ola has specifically identified the success of KRd-Dara as an upfront approach. 

Similarly, Luciano Costa has led the MASTER trial where we've combined KRd-Dara with transplant and seen that equally to be very promising. But I think what's so exciting about Ola's data is his very high rates of MRD negativity as a research clue pointing to clinical benefit without having to go to transplant, which I think for patients is a wonderful choice to potentially consider, recognizing that clearly high-dose therapy remains a standard of care for the younger patient with myeloma, but the point is that you have choices. I think for patients going forward, that's absolutely key. 

Jenny: Well, absolutely. I love what you're saying about personalizing care also from the beginning, because what you're saying is we can subgroup patients and not everybody has to be treated in the same way. Personalized medicine doesn't necessarily need to be all genetic space. We can look at other things like race or body weight or things like that and decide. I think that's so fascinating. Can I ask a further question about just -- oh, go ahead. 

Dr. Richardson: Jen, I was just going to say before we dive into that, I think you've raised such an important point because multiple myeloma is truly multiple myeloma. I think you're so right, Jen. Subgroups really matter. What we're learning is that these have real pathobiologic correlates. So one obvious example is age. As we talk about upfront therapy, I think it's important just to acknowledge, incredibly important advances for older patients do, because what we've realized is that you've got three drug platforms like lenalidomide, dexamethasone, and daratumumab, the so-called Rd-Dara, that performs extremely well in older patients. But what's also equally important is that we're also looking at the quadruplet of, for example, RVd plus dara but with the RVd adjusted for the older patients so that it's better tolerated. Exploring that as an exciting option for patients is really very interesting because there are a number of trials that are looking to sort of tease this out better. 

But my point simply is that in the old days you must be thinking, as you say, of one size fits all. If you're transplant eligible, that's the way to go. If you're not, we look at other things. We're getting much more sophisticated in our approach, and I think age is an important part of that. I simply emphasize it because it's not just frailty or perhaps inability to tolerate treatments that are so intensive, but it also points to immune exhaustion or absence thereof and how that may be very important for tailoring treatments to improve outcome. 

Thank you, Jen. I'm sorry.

Jenny: No, no, no, it's such an important point. And this goes to something that I always say in every show almost is this is why you need a myeloma specialist on your team, because if you are making therapy decisions at the beginning of your treatment or at relapse and the person treating you does not understand all these different nuances or how things could be adjusted, you are just not going to do as well and you won't have a higher quality of life. So I always suggest the patients try to consult with a myeloma specialist as they're making treatment decisions and then fine, get your infusion at home. But that's such an important point that I want to make. 

Okay, let's talk about personalizing care a little bit more. You mentioned in the transplant idea about high-risk patients with maybe 4;14 patients doing better with transplant. But for other higher risk patients, are there other approaches that you're seeing either in clinical trials or just right off the bat? If you see a high-risk patient younger, older, what's your go-to strategy in trying to manage that? 

Dr. Richardson: I'm so sorry, Jen. So in terms of, are you speaking of high risk, you mean, correct?

Jenny: Yes. Are there other approaches beyond that transplant approach that that you would look out for high-risk patients? 

Dr. Richardson: Yes, absolutely. Well, I think importantly, the thing about risk is to under understand its complexity, Jen. We're realizing, again from DETERMINATION, we learned that there's many nuances to what high risk means and this field is constantly evolving. For example, 1q amplification or significant gain is now recognized as a higher risk factor. We've also recognized that there are differences between the implications of 17p deletion and actually partner abnormalities with it. As well as say, for example, translocation 4;14. 

So I think there are a lot of nuances to interpreting risk because first important point to share with our audience, I think what we've learned from recent data in terms of high risk is that we have in our armamentarium some very exciting drugs. Obviously, we've had the revolution of immune therapy with, of course, CAR  T transplants dramatically impressive in the relapse setting. We also have bispecifics making a tremendous splash in the relapsed place as well. I think what's important to recognize, though, is that there are other small molecules not in the cellular or T cell redirection space, which may be very valid in the high-risk setting. For example, Selinexor, which is an XPO1 inhibitor, an oral agent, is one very good example of that which targets 17p deletion quite specifically in the way that it works. The clinical data support that as well as the laboratory studies that have been done.

I think beyond that we also, of course, have our currently available agents with different aspects to their activity. But carfilzomib is a very potent high-risk adapted proteasome inhibitor and so is bortezomib in its own right too, but ixazomib also seems to target 17p in the frailer patient for whom an oral approach may be preferable. In the same token, in the space of antibodies, it's very clear that the monoclonal antibody isatuximab, for example, is particularly useful at targeting 1q amplification really breakthrough data from the IKEMA trial led by Dr. Phillip Morrow establishing that. So I think there's a variety of options that we have to take on high risk. 

Again, Jen, this sort of pivots back to our previous point that we're able to tailor to patient need. Certainly, from the point of view of a younger patient who's transplant eligible, clearly in a variety of trials, not just DETERMINATION but another's, we've shown that higher risk patients do benefit, it appears, from early intensification. I think what's important, though, is to note that much of this data doesn't necessarily reflect the impact of quadruplet therapies and what they may be doing. So we just have to bear that in mind. But having said all of that, we've got good options for our patients. I think the promise of the cellular therapies in particular being used early, to my mind anyway, is a very attractive and exciting new avenue of research. 

Jenny: Yes, we're definitely going to talk about that in a little bit. I want to ask you a couple more questions before we get to that. So minimal residual disease testing is kind of gaining in popularity to potentially even become a new clinical trial endpoint. How are you using MRD testing to manage treatment after first set of therapies or your first line therapies and then at relapse? 

Dr. Richardson: It's a super question. I think that MRD clearly is such a useful tool in the setting of research. I think, Jen, what we have to be a little bit careful about is how we interpret its use in the clinical space's standard of care. I think there's definitely a role, in my opinion, for its use in adjudicating decisions around particular approaches. For example, again, just pivoting back to the DETERMINATION trial, we showed that MRD negativity was associated with better outcome regardless of what you did. Whether you had a full induction mission strategy with early transplant, or you delayed it, if you're MRD negative, patients appear to do really well regardless. So this is an important principle that MRD may help guide treatment choices.

I want to emphasize other trials led by really outstanding investigators have shown similar outcomes as well. I think MRD, therefore, has great utility in the research space, no question. In the clinical standard of care space, I think the one caution I would have about it, is the importance of being sustained. In other words, just one MRD measurement alone, be it positive or negative, needs to be taken in context. I think the question of whether or not it's a sustained result, be it positive or negative, is relevant to making treatment choices. Above all, the [0:19:38] [Indiscernible] has to be taken into account. But I think the role of MRD continues to grow. I personally see it as a remarkable step forward and a very important tool in our armamentarium to tailor therapy. So more to follow but certainly something that may help guide treatment choices. 

One thing I would say Jen is it's very useful, in my opinion, after induction emission therapy in newly diagnosed patients is value later when we're dealing with relapse and a slightly more unstable situation in terms of clonal evolution and so on of the disease. Then one has to perhaps use it a little bit more judiciously because as you and I have talked about before, Jen, you can see MRD negativity after CAR T, for example, that can be very reassuring initially but then actually, unfortunately, not be associated with, you know, may not be that stable. It may actually not last very long. Whereas in other settings, MRD positivity and negativity can be much more sustained. I think it's a complex equation but one that is very exciting to have the ability to use in the appropriate setting. 

Jenny: Wonderful. And for people who aren't aware, MRD testing is just a more sensitive way of testing the monoclonal protein after treatment. 
Well, let's talk about also personalizing care when it comes to 11:14 myeloma because that's the only type of myeloma that has a specific drug. Do you think about using Venetoclax early on, or do you have patients with 11:14 go through their first therapy and then use it later? What's your strategy there? 

Dr. Richardson: That's a super question. Jen, I just want to clarify one thing on MRD, just to realize that it is also a look at the level of the cell. That's the key, right? It's not just to look at the monoclonal protein. It's to look at the level of the cellular activity of the disease. So we have currently complete response, stringent complete response. And then when we drill down to MRD negativity is times 10 to the minus five times 10 to the minus six our ability to detect disease at a cellular level. We used to use this highly sophisticated flow cytometric method, Euro flow, or next generation sequencing, which is built by adaptive technologies. I think they both have great value, but certainly in the US adaptive technologies is a very strong -- it has a very strong presence in this area and has proven to be very helpful certainly in our clinical trials. But just to clarify that for the audience because, again, it complements the assessment of protein. But you're quite right, there is another entity, which is called heavy chain assay, which actually is a very tight to drill down on protein. That's a research tool that's developing very quickly or heavy light it's called for short. 

In any event, pivoting back to your other question, which is absolutely spot on, about whether or not to use Venetoclax in translocation 11:14. I would agree with you very much about the role of Venetoclax in this setting. You raised it so nicely before, Jen. It's all about subgroups. And the point is that this particular genetic subgroup of myeloma 11:14, for patients, it means that in your disease, you have the translocation. It's not obviously in you as a person but it's in your myeloma that you have this translocation of these chromosomes. What that means is it translates to a particular series of events within the tumor cell that can be interfered with by this remarkable oral agent Venetoclax. What's so interesting is that in 11:14 disease, particularly in relapse, it's particularly helpful. Unfortunately, it's not yet FDA approved, although I'm hopeful that may change relatively soon, but it is FDA approved for other cancers, so we're able to use it off label. What's so interesting, Jen, is that if you use it, if you use Venetoclax, in a non 11:14 translocated patient, i.e. their disease does not have it, the outcomes can actually be not nearly as good and, in fact, deleterious, which is why I think, in fairness to FDA, they've been very careful with the approval here because, obviously, we've got to be very clear, it belongs to the 11:14 patients. 

You asked, I think, a key question. Should we be using it earlier? I think certainly in first relapse, it's justified upfront is probably still around with protocol directed treatment at the moment because, obviously, upfront studies to date have not been deployed and all read out, although I do think in early relapse, it makes sense to deploy. Very straightforward, works really well, in my experience, although one does have to be careful about infections and blood counts when you're administering the therapy. 

Jenny: Okay, wonderful. Well, you mentioned first relapse, and so let's talk about that a little bit. What strategies do you look to for first relapse? And then we'll maybe talk about earlier use of CAR T.

Dr. Richardson: Yes. Well, I think in early relapse - it's a lovely question, Jen. I think in early relapse, obviously, what's so interesting and it's an evolving treatment landscape, as the quadruplets have become so effective in the early treatment setting, when we now look to first relapse and second line therapy, we're having to think in terms of treatments that our patients previously would have embarked upon much later in their natural course of their disease. Now, the good news here is that if you've had upfront treatment, especially with either a triplet or quadruplet, the likelihood is, with or without transplant, your disease control will be a number of years, hopefully many years. Then when you relapse, the question will be what do you deploy? Typically, what we use are a variety of drugs that may recapitulate some of what you've had in terms of drug class, but importantly, be different. So for example, if bortezomib has been used up front, the use of carfilzomib in first relapse makes sense and vice versa. If carfilzomib has been used early, the use of a proteasome inhibitor like bortezomib but rationally combined with something else which enhances response. 

So one thing that's clearly happening is that we are using proteasome inhibitors immunomodulators and next generation approaches in early relapse. But what has arrived that's made such a difference in this first relapse space has been the impact of BCMA-targeting therapy. Of course, in that regard, probably the news is since our last podcast together, Jen, has been excitement around CAR T therapy as exemplified by CARTITUDE-4, which was presented as a plenary session at ASCO in June and then published in the New England Journal almost simultaneously and showed that the use of CAR T in first relapse for younger fit patients who were eligible for this approach really resulted in unprecedented disease control compared to standard approaches that were used for the control group. Recognizing for those patients who participate in the control group, they could obviously have access to CAR T at a later date. So really exciting data, but I think it's heralds really a new way of thinking about early relapse, which is how do we integrate BCMA adaptive strategies or targeted strategies in those patients. 

Jenny: I had an opportunity to sit in that ASCO session, and it was incredible. The data was really so impressive, really unbelievable. So when you look at -- I know that these companies, Bristol Myers Squibb and Janssen Oncology, are looking for earlier approval in these one to three lines based on some of this data. Do you think it's more effective because the patient's T cells are fitter? Or what do you think is the reason for, or the disease is just not as sophisticated by that point because you're using it earlier lines? What do you think is the reason for the better impact? 

Dr. Richardson: Well, I think all of the above. I think that, you know, as you've so nicely framed it, Jen, I think patients are better able to tolerate the platform, which is important. I think also their immune exhaustion may be that much less and, therefore, this may be very powerful. But I think there are some important caveats. I think, obviously, we know that targeting BCMA with CAR T therapy is highly effective in the majority of patients. But we also have to be aware that there is a side effect profile, and sometimes, rarely fortunately, but sometimes it can be really quite serious. So I think there there's a lot of work to do to continue to sort of show the reproducibility of this approach in earlier disease. But I think you're absolutely right, Jen. This heralds a new era. I think that as we make CAR T therapy more available, which I think is another key point, more accessible, and at the same time, that much safer, it will, I think, hopefully bear tremendous fruit going forward. But I think we would be mistaken in saying, you know, it's the only thing because at the end of the day, obviously CAR T, it isn't right. I mean, there are many other options for patients. 

Jenny: Right, patients relapse. 

Dr. Richardson: Well, not just that.  We have to remember the median age of myeloma is 70 in terms of its onset. My practice has many patients in their 80s and early 90s. You know, clearly an intensive approach such as cell to cell may really be not wise in such an older frailer population until we know much more particularly about the central nervous system toxicity and at the same time, the ability to use other approaches because as you and I have said before, Jen together, treating multiple myeloma is truly a marathon. It is not a sprint. What we may really impact on what we do late. So I think we need to be careful. 

But I also think, having said that, you're quite right, that this obviously -- the other exciting thing, in my view, in early relapse is going to be bispecifics. We have the fantastic approvals of elranatamab this summer as a new BCMA targeted bispecific T cell engager with this T cell redirection quality. What I liked about the elranatamab data was the subcutaneous approach. It may be that much easier to, therefore, give as an outpatient, which is critical for accessibility. At the same time, it's got every two weeks injection times, and these make life for patients so much better. At the same time, there may be some differences in infection profiles and complication rates, although I think one has to be careful with that. Having said that, the activity's 60% to 70% response rate, which is very much along the lines of what we're seeing with teclistamab and which is the other big bispecific that's approved for BCMA. 

And then, of course, to add on to that, we have the approval of talquetamab, which is another bispecific T cell engager. But importantly, for our audience, it targets GPRC5D. Now, please don't worry about the long name, but that is a different target than BCMA. It isn't associated with the same BCMA-related toxicities, although it does, unfortunately, cause skin changes and changes to nails and some epithelial mucosal surfaces. But I think what's most important is that it is a new target. Again, the data there look very promising, again around a 70% response rate. 

So these are really remarkable agents. But again, I want to stress I think we've got lots of other ones, right, Jen, we can talk about? I'm looking to you to guide me there because obviously we could spend the whole conversation on bispecifics and CAR T, but if you'd like to touch elsewhere, I'm very happy to so do. 

Jenny: Well, I want to focus on just a few follow-up questions, if you don't mind, because it's a very big discussion point. So first, why is BCMA such a great target for multiple myeloma? 

Dr. Richardson: Well, because B cell maturation antigen, as the name sounds, is expressed in myeloma almost universally, but it's important to realize that it's a downstream marker in the ontogeny of myeloma. So we would be remiss if we said that if you target BCMA, you don't have to worry again. Unfortunately, it's not true. BCMA targeting is highly successful. And despite the success of the CARTITUDE-4 patients, we do know from earliest studies in such as CARTITUDE-2 with updated data, we were shown great results. But at the end of the day, patients still, unfortunately, are relapsing. And speaking from my own patients who've been through various BCMA CAR T's, one of my patients very recently, she had a wonderful experience in terms of tolerability with a different platform. It was a caused, Jen, CAR T again targeting BCMA. But she enjoyed three years of remission with it, but then, unfortunately, is relapsed. But nonetheless, it's been well worth that three years because he's had an excellent quality of life. The important point is what do we do now? So we have to realize, you know that these relapses occur. 

But anyway, pivoting back to your key question, BCMA matters because it's ubiquitous and because it's such a marker that we realize, like CD38, we can exploit accordingly. There are other ways of targeting BCMA not just bispecifics from CAR T but also antibody drug conjugates. And in particular, the example here is belantamab mafodotin, which provides a very different approach, which we can perhaps talk about in a moment. But I think it's important to note that BCMA is not only expressed by plasma cells, and that's the problem. It is expressed in the central nervous system and that is very relevant because some of the toxicities that we see, particularly the fortunately very rare but very real entity of late Parkinson's, which unfortunately to date hasn't been manageable. When it occurs, it's proven generally incurable. These are the kinds of things you have to look out for. But I want to stress, fortunately, these types of serious toxicities are very rare now, especially if we use the platform earlier. So I think this bodes well. Of course, I would stress, these late onset CNS phenomena are not seen with bispecifics. One of the downsides of the bispecifics in the BCMA space is infection, and that's one of the things we have to be a bit careful about as well. 

Jenny: And going back to the neurological issues with some of the BCMA direct to CAR T therapies, is there a way of telling it ahead of time? Like maybe is it family history, or is it that somebody already has a toxicity issue? Is it because patients have high tumor burden, or what do you think is causing, or do we know enough about that yet or have enough data about that? 

Dr. Richardson: Yes, it's a super question, Jen. And I would say to you, definitely we know that higher tumor burden can be an issue, that's for sure. So the lower the tumor burden are going into CAR T therapy, the less likelihood of serious side effects. I think also, you're right, that there may be vulnerabilities related to underlying medical issues that may steer us away from necessarily targeting BCMA in that way, perhaps looking at GPRC5D or FcRH5 is another receptor target that one might pursue. So I do agree with you. There are opportunities to be more tailored in that regard. But I think we're learning a lot and I think the great news, what I'm so impressed by is the whole enormous effort being put behind cellular therapy and the remarkable energy and scope of all the studies that have been done. So I think that we'll learn a lot relatively quickly about this as we go forward. 

But I think, to your point, we do have to be very thoughtful about patient selection. Certainly, in my own experience, serious toxicities have been usually in my older patients. Having said that, I have seen some surprises in my younger patients. So I think one has to be careful. But I think at the same time, one cannot argue was what you saw at ASCO in June, which was so remarkable from the CARTITUDE-14. 

Jenny: It would be so amazing to know that ahead of time, and then you could give someone a BCMA bispecific antibody, and then follow it up with a different CAR T with a different target. I mean, this goes back to what we talked about at the beginning with more personalized approaches and that would be incredible if you have that information ahead of time. And probably you don't right now, but we just need more data. 

Dr. Richardson: Yes. I think I can help a little bit here. I think in the field, the data that we've seen more recently suggest going for BCMA first and then going for GPRC5D afterwards is an algorithm that people are following. But you're quite right, Jen, is that based upon a really strong scientific rationale? Perhaps. Not quite yet. I think there are some clues, extramedullary disease and so forth, other features, which may be guiding those sequences. But I do think that the success of the antibody proteasome inhibitor, immunomodulator, small molecule platforms, provides us with an ability to be very kind of strategic. I think going to target BCMA and then weaving in next generation targets makes great sense. But I think what's important for patients to hear is that, you know, as we said a little bit earlier, it's very important to take the long and strategic view. I think that there are some patients in whom you have to pull the big guns early because their disease is so aggressive and so difficult to treat. There are other patients who can enjoy success for years and keep these more sophisticated and complicated approaches in reserve and use them when they need them.

Jenny: You talked about accessibility, that they're more accessible. Can you speak to that? Because I know that a lot of academic center facilities, they were getting one or two slots for some of these CAR T's. I think that's changed, right? 

Dr. Richardson: Oh, it most certainly has, particularly in the area of clinical research. That for sure, for protocols, and also for on the commercial platforms as well. I think that this has all gotten much better. I think having said that, and the bispecifics have helped tremendously because they've taken a lot of pressure off the system so that we don't have the waiting list that we had to deal with, which was so troublesome and so complicated to navigate. I think having said that, the off-the-shelf construct is really important to embrace. For the majority of my patients, they do not want to come in the hospital. They do not want to face complicated regimens. And if at all possible, they would much prefer everything outpatient. I think this is incredibly important when one thinks of access to communities and particularly vulnerable communities. 

So I think the strength of some of the recent research as well has been in the availability of, you know, of not just infusional strategies or hospitalization requiring strategies but strategies that can be deployed in the outpatient setting. And obviously, I think the bispecifics will increasingly move into that area where we don't have to hospitalize patients for step-up dosing. We'll be able to do this as an outpatient. But equally, I think, and CAR T may get there too as well with a strong outpatient component, but I think what's important, Jen, is really to emphasize the value of some of the true outpatient strategies that are, you know, I can see a patient in the clinic one day and start their treatment either that same day or the very next day. I think those are very important to have in the toolbox as well. 

Jenny: Right. That's the difference between -- so maybe one want to talk a little bit about sequencing and also different strategies. So fixed or continuous duration of these bispecific antibodies, especially with what you're talking about, like the infections being an issue, or other reduction strategies. So do you want to address like, what what's happening on the research side to determine like, do we do bispecific antibodies on a continual basis? There were other studies that we're doing to bispecifics together. And another one that I think you had mentioned, the ALNUC. I wasn't familiar with that one, so let's dive into bispecifics a little bit more.

Dr. Richardson: Yes, of course, Jen. I think, obviously, the continuous administration of these drugs in a relapsed refractory patient in which other options have become exhausted makes sense complete sense to do in case they're in relapse. But earlier, you're absolutely right that situations do. I appreciate you mentioning and beyond, obviously, the success of teclistamab, the impact of elranatamab now emerging. And then, of course, we have alnuctamab, ALNUC as we call it for short, alnuctamab, which is coming shortly on the heels of all of these antibodies as well as other ones. There's a phenomenal [0:41:20] [Indiscernible] platform as well, that is showing great promise in clinical trials. So I think there are lots of these agents coming. 

I think the important point is you're right, there needs to be convenience and fixed duration potentially adding to the benefits. I think, as we think more about BCMA targeting, this issue of infection is very real. Everyone needs intravenous immunoglobulin (IVIG). Some real-world experiences in Europe from expanded access programs were particularly sobering and showed some of the challenges and when you don't have highly sophisticated prevention strategies for minimizing infection. There was particularly striking data from some groups in Eastern Europe, which were really sobering and then told us you've got to be so careful about infection. 

So I think we need to be aware of how we best integrate that into our treatment paradigm. So yes, you're quite right, Jen. Lots of research looking at this. I suspect we'll be looking at fixed durations, because patients would love that anyway. And then perhaps conversion to oral therapies that can maintain remission in a rational fashion. 

Jenny: It will be so exciting to see what happens. I know, there are, I don't know, like six or seven bispecific antibodies. I know Regeneron has one. AbbVie has one. It's just expanding exponentially, so it's amazing. Do you want to circle back and talk a little bit about belantamab mafodotin and just provide a little update about that? Because I don't know, when we talk about sequencing strategies, if a CAR T stops working or something like that, can you take a break, do a different type of therapy, and then go back to BCMA target, maybe like that, or just provide an update on where they're at with their data also.

Dr. Richardson: Well, I think belantamab mafodotin as an antibody drug conjugate exploits BCMA but then delivers a warhead, which then triggers immunogenic effects within the disease that then enhances the body's immune system to destroy the myeloma. It doesn't carry with it the risks of either cytokine release syndrome, which can be really challenging for patients, particularly with cardiovascular issues and so forth. And it doesn't carry with it the risks of central nervous system injury which, of course, can be fortunately rare, but can be really serious when they occur. So I think there's real hope for this approach, in my opinion, because again I think it's a matter of all hands to the pumps. It's never been one versus the other. You know, we'll need all of these agents. 

The biggest challenge for belantamab was the ocular toxicity. The really good news there is that we've really figured this out. Dose and schedule really matters. You can dose belantamab mafodotin every six to 12 weeks now and see efficacy, particularly in combination, and lower the dose. This also has implications because you can imagine here, Jen, a patient can come to the clinic once every six to 12 weeks even for their infusion. Obviously, we monitor them in the interim, but nonetheless, beyond an oral agent partnered with this, in a way, that could be highly convenient and also effective. 

So these are exciting approaches that have been refined as we've tried to better figure out how best to use belantamab. But I think we would be remiss in suggesting that it has the same sort of power in terms of response rates that say, for example, teclistamab has with a 60% to 70% response rate. That's not what we see with belantamab as a monotherapy. It's about half that. But when we combine it with other drugs, that's where we see it show its promise. So when you combine belantamab mafodotin with oral agents like pomalidomide, important to remember in the [0:45:01] [Indiscernible] study in Canada showed a median progression-free survival to belantamab combined with pomalidomide for 24 months, which is remarkable. If you think about, it's two years, right? So this approach really has promise. 

Now, the challenge has been really more of a regulatory one, that the accelerated approval for belantamab mafodotin had to be withdrawn because of the failure of DREAMM-3 to meet its primary endpoint. The study was a head-to-head comparison of belantamab mafodotin versus pomalidomide and dex. And someone had the privilege to develop a pomalidomide and dex, which I love as a drug. It's a very good platform, and it's great combined with other agents to see pom-dex perform better than we expected was great. But, obviously, unfortunately, belantamab did not meet its primary endpoint in that particular phase three.

But you know, Jen, we've been here before. Carfilzomib, in its first trial, randomized trial, after the accelerated approval, actually didn't meet its primary endpoint. Fortunately, a spire came in shortly afterwards and led to its full approval. Look at carfilzomib, recognizing its cardiac. It, nonetheless, is a game changer. I mean, it's improved survival. It's at high-risk disease. It's incredibly important. So we've been here before. I think the next set of generation of studies from for belantamab coming through include DREAMM-8 between studies are the acronym for the studies that belantamab mafodotin users as their global effort continues. I'm hoping that studies like DREAMM-8 and there's another one called DREAMM-7, as those come in, they will help be kind of spire like and bring the belantamab back to access and approval to patients so that we've got access for patients to it. Because certainly, in our own practice, and we're leading trials of belantamab combined with other novel agents, as well as our own expanded access program, we clearly see a role for it. And to your point is, where is it? Well, it can be used -- I mean, ideally, if you're going to go for BCMA, early, go probably in the appropriate patient for either CAR T first or bispecific in a young, healthy well, otherwise fit patient. But in a frailer patient for whom CAR T or bispecific is really problematic for a variety of reasons, the appropriate use of bela with careful ocular care and monitoring, as well as rational combination partner, in our experience, we've seen some remarkably good results. So I think, you know, again, it's an example why we need all of these Asians, not just a select few. 

Jenny: I agree. I agree. Every myeloma patient might use every drug at some point. 

Dr. Richardson: Absolutely. 

Jenny: And let's talk about others in the pipeline. And I know this time goes by so fast, and we have to talk about so much because this is a review. But do you want to talk about the CELMoDs like mezigdomide and iberdomide?

Dr. Richardson: Absolutely. I'd be delighted, because again this boils down to oral agents that are truly off the shelf and above all, then provide access and particularly to vulnerable communities be there rural, frail, older patients, minority communities who do not want to come into hospital, for example, for logistic and socioeconomic reasons. So this is, to my mind, a priority. And we're so pleased with how the CELMoDs have performed. Iberdomide is one to touch on first, but it's important to remember these are not, as one colleague said to me, are they glorified IMiDs?  They're really not. They are in that sort of broad spectrum of drugs that are immune active, and immune modulators in a broad sense. But if you look at them at a molecular level, they're bigger molecules than the classic thalidomide and lenalidomide and pomalidomide. They are actually bigger in their size and they engage the whole of the cereblon E3 ligase complex, so they literally lock in in the way that the immunomodulatory drugs classically don't. And they've been specifically designed to do this, which I think is an enormous acknowledgment of the skill of the medicinal chemists that originally Celgene, who put this together, is now obviously under the umbrella of Celgene BMS. 

Essentially, mezigdomide and iberdomide engage the cereblon E3 ligase complex do so powerfully and trigger what I think is really the key of their activity. They are powerful degraders. They degrade Aiolos and Ikaros, which are two key transcription proteins that are fundamental switchboards in B cell pathobiology and they not only kill myeloma cells, but they also activate the immune system. You know, in our team, we have mezigdomide, CAR T in a pill because you can give it and it's so powerful that it actually can engender dramatic responses in both the tumor and at the same time in the cellular components of the immune system. And by doing that, you get, just in an oral therapy, really encouraging results. So it's a privilege to be part of the mezigdomide phase one, two teams. We published our data in New England Journal, actually in hardcopy, just a week ago. So the timing of this podcast actually, Jennifer, in some way, is its birthday. We got a nice editorial with it from the New England Journal and written by a super scientist in Australia. Dr. Schwartz really did nail it. I mean, he nailed some beautiful diagrams for anyone who can have access to it. I'm happy to send it to you if you'd like to have them to share. 

Jenny: I would love to.

Dr. Richardson: I'll happily send those to you, Jen, just because Dr. Schwartz's editorial is really very thoughtful. The diagrams are lovely. The important point is that, the light humor aside, the important point is mezigdomide as an oral therapy worked in triple class refractory patients and not only in those in whom all of the major drug classes have failed them but also in patients who have BCMA exposure, and indeed, their BCMA therapies also went out of steam. So we were dealing with an oral agent where you do three weeks on, one week off. The response rate overall was around 41%. And everyone would say, well, [0:51:10] [Audio Glitch] 60% or 70%? Well, it does actually because you can just take it as a pill. And above all, we're going to be combining it with other agents in the future. 

And then when we looked at particular subgroups like the BCMA-exposed patients and those patients in whom either belantamab had failed them or bispecific had failed them or actually even a CAR T had failed, we were very impressed that the response rate was 50% Jennifer. So that was really [0:51:36] [Audio Glitch] to us because it almost suggests that a reset has happened. And in the context of -- I want to be careful about that because I'm not sure we know that. But because of the immune activation, such all market as drug, it does seem a reasonable hypothesis that in the BCMA-exposed patients, mezigdomide may be even more powerful. 

Now, iberdomide has also done great things. It's not as potent as mezigdomide, but it's moving earlier. And I want to especially acknowledge my colleague, Sagar Lonial, whose lead that work, and all of the team involved. With iberdomide, what's happened is we've gone earlier, and it's got none of the side effect profile that can be sometimes a bit of a problem with lenalidomide, which is exciting. And what's really interesting as well in terms of iberdomide and mezigdomide is that they don't seem to have the same risk of second cancers, which is extremely important. So that, I think, is very relevant because becomes particularly relevant for iberdomide being used early and as a maintenance drug in the future, we hope. 

Jenny: Absolutely. And maybe one more and then we'll go to questions if that's okay. I know Takeda is working on a drug called Tak-573. Do you want to share what that is and how it works? 

Dr. Richardson: Yes, Tak-573 is an immunoconjugate, so it works by targeting CD38 and then bringing in interferon warhead along with it. So a little bit like belantamab mafodotin but a different target CD38. So it's a good drug, and it's showing promise. I think there's targeted sort of approach, Jen, is really important because there are studies ongoing in that. And then, as you and I've talked about before, there are other targeted approaches which deliver cytotoxic warheads to where they're supposed to go. And of course, we have in Europe, it's not unfortunately, hopefully back on the research table soon in the US, we have, of course, melflufen, which is the targeted way of delivering a cytotoxic warhead. So there are lots of excitement there. 

But pivoting back to Tak-573, it's highly immunogenic. It appears to work very well with gamma interferon, and in the same way as belantamab mafodotin maybe immunogenic, I think belantamab is Tak-573 is very promising and well tolerated as well, in my experience, and also for that matter melflufen is also immunogenic. We've learned that and I think that's really important to know. 

So these approaches all have an immune basis as part of what they may do, but some, to varying degrees, may be less dependent on the immune repertoire of each patient, which I think, again, pivots back to this key point, Jen, that we're able to offer different options to different patients in different settings. 

Jenny: Right, and it's different stages. I know like for the melflufen example, it worked quite well on patients who had not had a prior transplant or recent transplant. Before going there, maybe that's one.

Dr. Richardson: Jen, one of the most important things to melflufen, to be honest with you, is the elderly, the frail and elderly. I mean, it's a very well-tolerated drug. I think patients don't lose their hair, so once a month infusion. I don't know if you saw this but in Europe, it was approved for peripheral infusion now. So it's got even, because previously we had to give it by central line. 

So I totally agree with you, I think, in an older, frailer patient, it has promise as shown in the clinical trials that led to its full approval in Europe. But I think, obviously, we were very hopeful we can get it back on the research agenda here in the US and then move forward. But I really wanted to emphasize, to your point, though, Jen, that with drugs like Tak-573 and belantamab, where they are so useful, in my opinion, is that they can be sandwiched into the sequence of treatments that we have. And we've got to think about how we use our treatments strategically to improve outcomes. So you can think about, you know, if you've done a CAR T and the patient, unfortunately, the CAR T runs out of steam, do you go straight to a bispecific, or can you give them a little bit of a break, give a patient a break to let their T cells reboot? What can you plop into that therapeutic sequence that will be effective, but at the same time, not exhaust T cells? So one example might be Tak-573 or actually, for that matter, depending on your healthcare jurisdiction, melflufen or belantamab mafodotin. So you see how these things can be reasonably used. 

Jenny: Yes, absolutely. I think that's where it's such a blessing to have all of this in myeloma. It's incredible what's happening. Thank you for doing the whole description because it is so much to cover in one hour.

I'm just going to open it up for a few minutes of caller questions. So if you have a question for Dr. Richardson, please press 1 on your keypad. We have our first caller question will be 6251. Go ahead with your question. Hello. Go ahead and ask your question. 

Dr. Richardson: Hello, Jen? 

Jenny: I'm here. I think they might have hit the button on accident. Okay, what I just like to ask is, as we move forward, what are you the most hopeful about in multiple myeloma in the next, I would say, two years? 

Dr. Richardson: Well, I think, obviously, what I think we're seeing is that across the spectrum of disease, we're seeing an increasing proportion of patients enjoy excellent disease control for prolonged periods of time. What I'm very hopeful for is that the promise of the bispecifics and the CAR T treatments will lead to a subgroup of patients being functionally cured, essentially, by these approaches. I also think, by the same token and it's my strong research focus, that we can complement the success of the CAR T and bispecific space by rationally building powerful oral agents, mezigdomide being one example, that can enhance our therapeutic armamentarium to further extend disease control in a way in which quality of life above all is also conserved or enhanced. And then at the same time, recognize that all of the various drugs that we have we need. So again, small molecules, to my mind matter, we touched on Selinexor earlier and that may be a very – I should have mentioned that actually as a potential sandwich for some of the strategies we just talked about without T cell exhausting, so that's very real. 

I think, Jen, other aspects of this are the ability to have all the available agents to rationally combine and use in select settings, because frailer, older patients, to my mind, are an area we need to focus on actually, because I think whilst these exciting new advances really have promised for the majority of patients, there are a significant number of patients who remain perhaps less able to safely receive some of these more intensive treatments and to be able to offer those patients very safe, reasonable, non-toxic approaches that are convenient, to my mind, is very exciting. 

So I'm really excited for myeloma. It's been a privilege to be part of the research community for the last 25 years or more. I think at the same time, I'm so excited to see such incredible, exciting younger investigators really leading the charge with cellular therapy, with bispecifics and so on, and really making a difference for our patients. It's also wonderful, frankly, Jen, to have such great advocacy from organizations such as yours and your own leadership of your team as a patient who really knows what all this means, providing such service to our patients because that to me is incredibly important too. 

Jenny: Oh, well, thank you so much. For one minute, let's just go back to Selinexor, because you mentioned it for deletion 17 patients earlier in the show, but are there other instances or sequencing that you typically use that? 

Dr. Richardson: Well, I think the important point to realize is that, again, some of the data are emerging, for example, at this year's IMS, which is next week in Greece, where we're talking about a subset from the BOSTON trial who are bortezomib naive, and they received bortezomib and Selinexor in first relapse and enjoyed an amazingly long PFI. I mean, it's approaching 30 months, which I think is amazing. So these weren't necessarily 17p selected patients. Again, if you said 30 months in CAR T, they'd all say, Oh, yeah. Well, that's all we see anyway, isn't it? But Selinexor, bortezomib in the first relapse 28 months medium PFI, it's not bad.

I think what's most important about Seli is we've learned to give it in a way that is much more tolerable. Selinexor is a tough drug orally if it's given according to the label of twice a week and just for steroids. If you combine it with other drugs and give it once a week and go low and slow, as I like to say, it really, in my experience, can be very beneficial. In fact, I have a wonderful patient of mine with 17p disease and he relapsed, unfortunately, after a platform of carfilzomib, isatuximab, lenalidomide and dexamethasone. So he got excellent therapy up front. He got stem cell harvested. He wanted to keep transplant and reserve. He's a young family, and he's a very busy executive, so he has a lot on his plate. And we got a wonderful result using Selinexor, bortezomib, pom and dex for him because he's 17p deleted, I should emphasize, and so that is irrelevant. But we were able to onramp him successfully to a CAR T, which we're hoping to pursue next month for him, to give you a real example. Lovely guy, lovely family. Oh, my goodness, five years in with bad high-risk disease at the beginning, hasn't needed a transplant. He doesn't want it because he wants to be fully functional and not have time away from his family. We're very hopeful that the cilta-cel platform he'll be getting next month will take him to the next step. 

Jenny: Well, that's a perfect example for all patients. All of us will have to consider a lot of these therapies as we have our life with myeloma. And hopefully, one of these combinations and sequences will ultimately relate to a cure. 

So thank you so much, Dr. Richardson, for everything you are doing in development in clinical trials on all platforms. It's just unbelievable. I really look forward to hearing from you and many others many others at IMS next week.

Dr. Richardson: My pleasure, Jen. Thank you for all you do. And above all, a huge thank you to our audience for taking time out on their Friday afternoon and just wish everyone a lovely weekend. Thanks so much, Jen. 

Jenny: Yes, thank you so much. And thank you to 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.