Learn about the progress made in multiple myeloma during 2023 in this important podcast with expert Paul Richardson, MD of Dana Farber Cancer Institute. As a global leader in myeloma research, Dr. Richardson shares updates on many strategies for newly diagnosed myeloma patients and many treatment options in development for relapsed and refractory multiple myeloma. He gives a preview of what to watch for in the coming ASH meeting and the great progress that has been made with the most recent treatments discussed in this summary show. 

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. The pace of innovation continues in myeloma with a wide variety of developments in the first portion of this year, and we're now into the fall, if you can believe it. We wanted to provide a review because there were shared developments in multiple myeloma, both at the American Society of Clinical Oncology Conference or the ASCO meeting, the European Hematology Association (EHA) meeting in Madrid and the International Myeloma Society meeting in Rio. 

These three meetings really showcased additional advancements in myeloma for all types of patients. We're very honored to hear from Dr. Paul Richardson today about clinical research taking place that will provide patients with better options, more options and options with better quality of life. Now, HealthTree is committed to providing programs like this for you to better learn about these innovations that you can help speed along by joining clinical trials. 

Patients should always consider joining a clinical trial at every stage of their treatment journey. Clinical trials are how the experts advance myeloma care and how new treatment options become approved by the FDA. And HealthTree is also committed to helping advance research using the HealthTree Cure Hub Registry. This is a data registry that you can join to help contribute to research, even if you're not able to join a clinical trial today.

And before we get started with our program, I just want to highlight one particular project that we're working on. Let me just give you this example of a type of research that you can join because we'll be discussing this drug class today. And this is a project that we're doing in partnership with over 10 myeloma researchers and the International Myeloma Society to better understand how bi-specific antibodies are being used in the real world. The researchers want to know what your experience was like, how heavy the caregiver burden was, your step-up dosing experience, what worked best and for whom, and the subgroup analysis will be key to what we'll be talking about today. So this is a study, HealthTree is inviting patients to over a three-year time period. So if you are on a bispecific antibody within the next three years, we invite you to join. And you can find this study here.

So now, Dr. Richardson, welcome to the program.

Paul Richardson: Thank you very much Jenny. As always, absolute pleasure to join you and I wanted just to acknowledge the incredible work you do and your foundation does. It's extraordinary and my patients increasingly have such lovely things to say about HealthTreat. And so again, it's privilege to be with you today.

Jenny: That's great. We're so happy to hear that. Let me give you an introduction for you before we get started because we have a lot to talk about. 

Dr. Paul Richardson is clinical director of the Jerome Lipper Myeloma center at Dana Farber Cancer Institute.

In his role he has led the development of a significant number of myeloma therapies including bortezomib, lenalidomide, pomalidomide, ixazomib, elotuzumab, daratumumab, isatuximab, blenrep, Selinexor, CELMoD therapies and additional immunotherapies.

Dr. Richardson has published extensively, having authored or co-authored hundreds of articles and hundreds of reviews in peer-reviewed journals. In addition to holding positions on the Editorial Boards of leading journals, he is prior Chairman of the Multiple Myeloma Research Consortium (MMRC), Clinical Trials Core, a position held for 5 years as part of a rotating tenure, and for which he continues as a member of the Steering and Project Review Committee. 

He was appointed Chair of the Alliance Myeloma Committee from 2011 to 2021. Honors include the George Canellos Award for Excellence in Clinical Research and Patient Care, and The Tisch Outstanding Achievement Award for Clinical Research, as well as an honorary Fellowship of the Royal College of Physicians (UK), given in recognition for international contributions in multiple Myeloma and stem cell transplantation. He was a co-recipient of the prestigious Warren Alpert Foundation Prize in recognition of the successful therapeutic targeting of the ubiquitin-proteasome pathway in 2012. He was also a co-recipient of the Accelerator Award for contributions to clinical research and patient enrollment in MMRC studies, as well as for the Research Center of the Year Award in 2009, followed by the second award for Center of the Year in 2017. He was ranked by Thomson Reuters Science Watch amongst the top 19 investigators at DFCI for the most highly cited research in 2016. He was the co-recipient of the ASH Ernest Beutler Prize for clinical science and translational research in the development of proteasome inhibition as an effective treatment strategy for multiple myeloma in 2015; and the prestigious IMF Robert A. Kyle Lifetime Achievement Award in 2017, and the Morse Research Award in 2019.

So you are just one of the top myeloma experts globally and we're so thrilled to talk to you today.

Paul Richardson: Jenny, thank you very much for that absolutely lovely introduction. It's so kind of you and it reflects obviously what I think is so important in the myeloma research community, which is amazing teamwork. It's been my privilege to work with a phenomenal team at Dame and Farber. And I especially want to acknowledge my clinical research colleagues who have made all of those advances possible. And also most importantly, the remarkable bench to bedside model that we have developed in our laboratory colleagues who've provided such an information data to help us advance next steps, recognizing that the whole process is both complex and involves so many moving parts. 

It's difficult to acknowledge everyone in just a few minutes, but just to say it's been such an incredible experience in the last 20 years to be part of a myeloma research community that's moved the needle so far. But I also want to above all, especially acknowledge organizations like your own and above all our patients and families because without their participation in clinical trials and their commitment to helping us in that and their trust in us to put their welfare first is so important. 

And I think as we think about clinical research in our group, our philosophy is the best research is the best care and vice versa. And we really strive to do that, recognizing that in the phase one setting there are elements of uncertainty, in the phase two setting it's less so. And in the setting of randomized control trials, it's so important that there's true equipoise (or good options in both trial arms) and so that we use best therapies in every aspect of phase 3s in as much as we possibly can, recognizing some of the regulatory challenges that we have to navigate. 

But generally speaking, equipoise is absolutely required for phase 3s, and that's something in our program we embrace. 

So anyway, with that in mind, Jen, I wanted to share with the audience that I think 2024 has been one of the most remarkable years, and I think in the context of the focus of our conversation today, I really wanted to start with some of the summer papers that were presented at ASCO and EHA, and in particular acknowledge in the upfront space, the success of the quadruplet therapies. We really had the most important randomized phase three information coming in from the IMROS trial, which was the combination of RVD plus isatuximab, an international study led by my colleague Dr. Thierry Facon also was the very deserving awardee of the Waldron-Strauss Award at the IMS in September in Rio. 

But very importantly, Thierry and his team showed that when you combined RVD plus isatuximab without transplant, the response rates were dramatic. The MRD rates were extraordinary. And what to me really caught my eye with this work was the quality of progression free survival that patients were able to achieve. What that meant was that with RVD alone, we got great results, exceeding actually 50 months as a medium, which is terrific. I mean, that's again, as people get more familiar with using RVD, the results improve and we've seen that consistently. And then what was particularly amazing is that the RVD isatuximab combination with the use of isatuximab exceeded everyone's expectations. 

The median PFS (progression free survival) estimate is somewhere between 80 and 90 months, which if you told me a few years ago that a quadruplet therapy would be able to offer a patient without transplant a 80 to 90 month PFS, I would have said that seems very hopeful. And to actually see it is so good. And then of course we had a great presentation at IMS of the Cepheus data led by Dr. Saad Usmani, where Saad showed the same thing essentially with RVD-Dara. 

I mean, we don't quite have the same degree of estimate on the median PFS yet for the RVD plus Dara arm, but the RVD arm performed very similarly and the RVD Dara arm seems to be performing very well at least based on the hazard ratios and the estimates so far. So we've now got two randomized phase three trials, state of the art studies, which show that the addition of the CD38 antibody is absolutely game changing in terms of the outcome. So with that in mind, I think quadruplets have become now an established standard of care, both for the transplant eligible and the transplant ineligible. 

I want to especially acknowledge my colleagues in the GRIFFIN study led by Peter Voorhees and obviously it was an Alliance study led by actually the Alliance committee and of course the Alliance group, but then added to by the support of Janssen in the context of the clinical trials mechanism that we have in the Alliance. 

The GRIFFIN study was really game changing in that it established the role of RVD plus daratumumab in that particular setting. And then basically to then see the randomized phase two data almost be perfectly reproduced by PERSEUS on the one hand, which was presented at ASH last year. And then of course published in the New England Journal, but then to also see now that RVD plus Dara in CEPHEUS and RVD plus isatuximab performed extremely well is sort of a validation of all of this that we're seeing the highest levels of evidence support the use of quadruplets. Now, obviously there is the combination of KRD plus isatuximab and of course already well established the role of KRD plus daratumumab. So I think there is now a number of quadruplet combinations that have transformed the upfront landscape in newly diagnosed myeloma and generated outcomes that are, I think it's fair to say, unprecedented. 

And a key question this then raises is, you know, how much does transplant add in the newly diagnosed patient?

Jenny: That's a lingering question for lots of patients.

Dr. Richardson:  I think it's crucial. And I think what it establishes, because obviously, what we learned in DETERMINATION was and studies like it, including our French partners, IFM, DFCR 2009, or the IFM 2009 studies, as it's more simply known, is that you can keep transplant in reserve and not necessarily lose survival benefit. In the French case, that was because you could use transplant late. And in DETERMINATION, so far at least, we've seen that only about a third of our patients have been transplanted in a delayed fashion, and with about 70% not being so. And even with that, we're seeing no difference in overall survival despite a substantial PFS gain. And this raises the fascinating question is can you reasonably keep transplants in reserve? 

Can you collect and wait so that you avoid some of the downsides of high dose melphalan, which we've recognized are very real. They include obviously the second cancer issue, in particular AML/MDS, albeit rare but important. And at the same time, also this other challenge that if you've got such PFS gain to your randomized trial in favor of early transplant, why do you not see a substantial overall survival benefit at least yet?

Now that may be because we need longer follow up and that's coming, but the follow up is pretty mature actually. And if one thinks about this, other studies have shown very similar things. 

So it suggests that maybe what we call an element of competing risk. In other words, some patients clearly benefit from high dose melphalan, others may not. And that being the case, the opportunity to keep transplant in reserve and use it when you need to has a lot of appeal, I think especially for patients because of side effects, quality of life and so forth. 

And this data with the quadruplets, I think really helps make sense of this because what it says is you can use your four drug combination, you can establish a very high quality response, you can harvest stem cells. And you know what, you can sort of think a little bit about the transplant, should you do it or maybe should you keep it in reserve? 

And obviously, MRD has really helped that process. If you're MRD negative on assessment, It gives us a greater degree of confidence that you may do just as well with keeping transplant in reserve. 

Now, the MRD data has been shown in a number of trials and just to focus on DETERMINATION, we showed that if you're MRD negative, however you got there, be it with RVD early transplant or with RVD and transplant kept in reserve, you did just as well. If you were MRD positive, well, that's where transplant could really potentially help. 

So with that as a backdrop, we now have the quadruplet platforms with the GRIFFIN study in the Alliance Foundation for clinical trials being its major backer with Janssen in the Alliance study I mentioned. What we did with GRIFFIN was to establish the role of MRD and show that MRD negativity translated into excellent outcome and clearly showed the benefit of the quadruplet with the transplant. And obviously PERSEUS validated that.

Now what's interesting is to see CEPHEUS and IMROZ with the potential value add of isatuximab really generating MRD rates that are comparable but in those populations didn't have transplant as they were not a transplant eligible population. So as you think about it, I think this has been an absolutely astounding time for myeloma in the upfront space because 2024 has established the value of quadruplet therapy.

Jenny: Absolutely. And this is a theme that I'd like us to weave throughout this show, is this idea of more personalized medicine or looking at different subgroups of patients because we know that there might not be a singular myeloma cure, but myeloma cures in place. So as you talk about different strategies and different clinical trial, trial designs and things like that, maybe you can help us understand how the field is advancing to incorporate those types of views into these different strategies. Because what you're saying is, you know, for some patients who might not be higher risk or whatnot, they might want to defer transplant and some patients who might be higher risk might want to use that upfront. You know, similarly, if we go a little bit backwards, are there other MGUS or smoldering myeloma types of approaches that have stood out to you in the first part of this year at all? Or should we move forward?

And then I do have actually one more question about the differences between isatuximab and daratumumab, because patients might be a little more familiar with daratumumab because it was available for a longer period of time. Both, as you mentioned in these studies, are having really incredible outcomes.

Paul Richardson: Well, let's start with that last question first, if I may, Jennifer, because I think you're absolutely right, Jenny, that the issue of the isatuximab/daratumumab debate is a fascinating one. 

It's a very good one. I think there was a view in some quarters that isatuxamab and daratumumab were essentially the same thing. I must say, having had the privilege of developing daratumumab in the first place and then also being involved in the development of  isatuxamab and working with some great colleagues in that regard,

I would say that I think they are different, but I think the differences are not huge. They are subtle and nuanced. And I think that the science kind of guides us a little. Daratumumab, for example, relies on complement mediated killing as one of its primary mechanisms. Interestingly enough, in 1q amplified myeloma, which is a particular high risk feature in about 40% of patients who newly diagnose nowadays, the mechanism for complement mediated killing is blunted by a pathobiological mechanism within the disease process itself. 

Now this is early data and it's predominantly preclinical, but it's intriguing. And of course, isatuximab doesn't rely on complement mediated killing as its major thing because that's why you can more safely give it to people with COPD and asthma and so on because it doesn't actually activate the complement cascade to the same extent that Dara does, though that complemented mediated killing was absolutely vital if you didn't have it. 

You wasn't you weren't going to get off the ground. Well, isatuximab does have it, but to a lesser degree and relies on other mechanisms. Interestingly enough, in the clinical trials with isatuximab, the signal in 1q amplified disease has been very impressive. 

Now for daratumumab, yes, clearly it works in 1q amplified disease, so it's not an all or nothing phenomenon, but it may be that it's a little bit less powerful in 1q amplified disease, we don't know yet, but it's an interesting example of the subtleties. 

And then I think there's other aspects which rely on the effects on what's called the immune  milieu, where essentially there may be differences in the antibodies in that regard. I think when you drill down to it, isatuximab binds to a different part of the epitope of the CD38 target than does Dara. So you can see why there may be subtle differences, but I think it would be wrong to say there's major differences. That would not be correct.

But are there subtleties that can be tailored to a patient? Absolutely. And I think the other thing that becomes very relevant is sequence, right? Because if you've used Dara early and your patient relapses and it's five or six years later, and perhaps BCMA isn't the best go-to target in that particular patient's case, and they don't particularly want to necessarily get a bispecific or a CAR T, and an antibody drug conjugate may be attractive, but obviously not currently yet approved.

So with that in mind, could you revisit isatuximab? You probably could in the right combination. Obviously putting something else together with it. great question about isa versus dara. I would say great to have both subtle differences, not huge ones. 

I personally like to use isatuximab particularly in high risk disease. And I like to think of it in patients who, for example, may have a history of asthma, chronic obstructive pulmonary disease or otherwise, well that's surely a minority. Oddly enough actually it isn't. You know there are significant numbers of patients in our frailer populations in particular who may have some degree of adult onset, restrictive airway disease and in that context you know isotuximab may be more attractive.

Jenny: And this is one of the things that I want to highlight too, is the importance of seeing a myeloma specialist because as you're discussing, there are a lot of nuances where you do and don't favor particular drugs. So we always suggest the patients add a myeloma specialist onto their care team, particularly when they are trying to make treatment decisions. 

Just a little clarification too, the 1Q gain is a genetic feature and that's found in quite a few patients, right?

Paul Richardson: Yes, about 40%. So I think, but I do want to emphasize though that, you know, and this is where the value of the CEPHEUS trial is so important to my mind, that showed that there is activity from dara in the 1q amplified population. Clearly, I don't think it's one works and the other fails. I think it's actually more complicated. I think that there may be aspects to the cytogenetic picture in a particular patient that may make one antibody particularly attractive. And what I mean by that is that isatuximab can be very effective through a mechanism, apoptotic killing, which is more direct. there's lovely data, primarily from the German group, looking at the use of isatuximab as a platform in high risk disease, where they actually combined it with KRD and showed really remarkable activity in high risk patients. So I think as we think about the tailoring of treatment, it does make sense. Now, of course, dara has the enormous advantage, with sub-q (a shot vs. an IV) in the FASPRO preparation. The good news is that isatuximab now is catching up with that. It has its own sub-q platform which is currently being developed and I believe will be approved fairly soon.

Jenny: And an on-body system too. (a device that sticks on your skin and delivers the injection).

Paul Richardson: It's very kind of clever. I think the important point is that, to be frank with you, my patients who've been getting isatuximab IV, I've actually never had really much of a complaint. I mean, it's not a long infusion. And I think with both antibodies, however they're given, sub-Q and FASPRO case, IV and isatuximab case, and with a conversion to sub-Q presumably happening soon, I've really been struck that there are huge differences between CD38 antibodies and other antibodies. 

I mean if you take a different hat on and think about rituximab for example, you know there are lots of reactions to rituximab. Rituximab is a great antibody if you've got lymphoma and it really works but reactions occur. What I'm so struck by with both of these antibodies is how well tolerated they generally are. One important caveat, not to infusion-related reactions but more to toxicities is that in both isatuximab and daratumumab's case we have to be vigilant about chest infections.

Those are real and people need to be very proactive and the second piece is that hypogammagobulinemia (low infection-fighting antibody levels) can occur with both It possibly may be a little more common with dara than isa, that's possible and there are some data to suggest that, but regardless, IVIG is very important. So these are sort of important caveats to how we use these antibodies but overall the message in 2024 is CD38 has really continued to be the gift that never stops giving and that targeting has been great.

Jenny: These quad therapies, are changing completely the upfront landscape for newly diagnosed patients. It's amazing.

Paul Richardson: Yes, I completely agree. And as part of maintenance too, which I think is an important emphasis for our audience as well.

Jenny: Great. Is there anything that you wanted to mention about the precursor conditions before we either continue talking about newly diagnosed or relapsed?

Paul Richardson: Right, yes, I think in the precursor space, there's a lot of excitement and I particularly have the privilege of working with my colleagues, Irene Ghobrial and with Betsy O'Donnell and Omar Nadeem. And in our group, we've been really with Irene's leadership on the sort of forefront of newer ideas in this space. Omar's leading an effort in which looking at CAR T therapy in high risk smoldering disease and also at bispecific therapy in particular teclistamab. 

And I think what I can speak to with some authority is the teclistamab study, I would just simply say that there we've been very pleased by the lack of severe complications seen with the approach and the tolerability has been favorable and the remarkable results. 

I would say that some of our patients have, and it was very relevant to your study Jenny, there's a quality of life aspect to this that is relevant. So that's important to share with patients. The CAR T space I think is very, very courageous. And I think so far, at least so good, but it's such early days, I would be careful there. 

I think frankly, the data that that I've worked closely with and most of my patients have chosen have been quadruplet therapies in high risk smoldering disease. And the safety signal there is very reassuring and the results are phenomenal. So I think if one thinks kind of logically, think teclistamab, CAR T, immunotherapy in ultra high risk smoldering that to my mind has merit. 

And I applaud the studies that are being done for high risk smoldering only under the setting of clinical trials, of course, because it wasimportant area that we have studies rather than just loosey goosey care because otherwise we'll never know what we're doing. 

I think the quadruplet therapies are looking particularly exciting because you're minimizing the toxicity and the quads have already clearly established in the upfront space now standards of care in my opinion. So with that being the case, using the quadruplet strategy in high risk modeling the approach to the appropriate patient who would like to participate in the trial and is happy to make that commitment, think certainly speaking from my own practice and my own patients who participated in Omar’s RVD-Dara study, for example, the results have been outstanding. So I think we're very happy with that field. It's evolving quickly. 

But I also think we need to be very clear that there are significant numbers of smoldering patients in whom observation, periodic infusion of an anti-resorptive therapy if there's osteopenia, care regarding infections and a careful holistic approach is very interesting and very helpful. 

I'm especially impressed frankly by the more holistic work that for example Betsy O'Donnell is part of and other colleagues around the country, particularly the group at Memorial where they're looking I think very thoughtfully at subtle changes in the mean milieu, work on gut microbiome homeostasis and holistic approaches and lifestyle choices that I think really makes sense to me and a number of my patients have been participating in this work and it's fascinating and I think really encouraging because it's essentially holistic and above all non-toxic and it involves rational changes in lifestyle so we think about weight reduction, think about exercise, we think about reducing inflammation, we think about how to optimize immune function by optimizing the microbiome - a revolutionary concept some years ago now clearly established in the world of allogeneic transplant, you know, clearly makes sense to explore in our world. And I think to my mind, is part of a holistic approach in the small ring and precursor space, which is where I personally think the biggest, the greatest benefits lie.

Jenny: It's fantastic. And it's something patients can do too. So they're very excited. We are helping facilitate the Nutrivention Study in smoldering myeloma. So if someone is interested in that, that's just a plant-based diet for two weeks just to test what happened to your microbiome before and after. So those types of things are so, they're very empowering for patients. (Join the NUTRIVENTION 2 Study here) https://healthtree.org/myeloma/curehub/public/research/5jLN2I1z8ORyETSwrhNY

Paul Richardson: Exactly.I think so and I think one of the most obvious things to share with patients is weight reduction. We've realized for some time that body mass index is associated with risk in myeloma. Obesity is a risk factor in women and in men for myeloma and I think that this for its etiology. 

It's based on this whole construct of an an inflammasome and an inflammatory milieu and in that inflammatory milieu if you can reduce inflammation you can impact favorably on your disease process and weight reduction is such an important part of that. So I think these are all incredibly as you say empowering things to do and not to put pressure on people because I mean I know with my patients you know telling someone that they have to lose 10 pounds in six months is not trivial. That's a hard hard ask, so it has to be very encouraging and positive and constructive but it's so worth it because all of all a lot of health things a lot of health related outcomes improve with weight reduction

Jenny: It's a great point. Okay, before we move on out of the newly diagnosed setting, can we talk about maintenance? Because you mentioned that. Where are the trends heading in maintenance therapy for someone who has just begun and completed their initial therapy?

Paul Richardson: Well, I think maintenance is a standard of care in the disease. I think there is a necessity for keeping disease control optimized after successful intensification and induction of remission treatment. Now, obviously if you've been consolidated, as we call it with a high dose melphalan and stem cell support, the data absolutely show benefit to the approach.

An important point, though, is that the number of agents that can be safely used in maintenance after high dose therapy may be curtailed frankly because of the effects on bone marrow reserve and so on. So we typically use an immunomodulator like lenalidomide as our backbone.

We can successfully add to it with a proteasome inhibitor if there's a need to cover high risk. And clearly the PERSEUS, GRIFFIN and other study data support the value of the monoclonal antibodies in this setting. 

However, I think what we're learning is again, just as you said so nicely at the beginning, Jenny, one size does not fit all. We're learning to adapt our maintenance to reflect both tolerability and side effects as well as the need for benefit really being a more part of that, but the need for disease control, I guess, is what I meant. 

So I think as you think about this, we need to be tailored. And I think what's particularly exciting is in the absence of transplant and high dose melphalan, we've really recognized there too, the maintenance matters. So it can be an immunomodulator, it can be a proteosome inhibitor, and it can be an antibody (monoclonal antibody).

And the upside there is if the patient has not had exposure to high dose chemotherapy, the marrow reserve may be a little more robust.

And on the other side of things, also some of the non-hematologic toxicities, in particular neuropathy, may be less amplified. So it gives you a little bit more flexibility. 

And funny enough, Jenny, we showed this in the DETERMINATION trial, we showed that the ability to tolerate lenalidomide after high dose of melphalan, generating a fantastic PFS benefit in almost two years, which was great. 

But what we showed was that the lenalidomide dosing had to be reduced more, and there were more infections, interestingly enough. So it does tell you that just throwing everything at the patient and maximizing their maintenance may not be actually the way to go, but a more tailored approach with a less kitchen sink type approach may make sense in particular settings.

Jenny: And do you use minimal residual disease or MRD testing as part of that decision making process after someone's completed therapy?

Paul Richardson: Thanks - super question and as a matter of fact in clinical trials absolutely as a tool in clinical practice increasingly using MRD to assess whether or not intensifying with high dose melphalan is appropriate or keeping it in reserve maybe wiser that's absolutely something in our group that we like to use in terms of maintenance a little bit more cautious here because the data isn't clear because at end of the day if your MRD negative after three years of maintenance can you stop?

Well we'd like to think so, but do we know? Well ,we don't so perhaps it's wiser to enroll in clinical trials that address that question and my colleague, my partner, Dr. Clifton Moe who's leading our DETERMINATION 2 study which is currently being built and and it will be a big national trial we'll keep you fully appraised and involved Jenny if we may as an organization you know basically it's it's it's hopefully going to answer questions like that.

Jenny: Fantastic. Well, there's so much happening in the relapsed setting that we have a lot to talk about. So how do you want to start? We know that we have some FDA approved options, CAR-Ts, bispecifics, but we also have some up and coming new approaches like CELMoD therapies or even having blenrep come back (an antibody drug conjugate). So I'll let you drive the order because you'll make it all make sense.

Paul Richardson: Well, thank you, Jenny. Well, I think the good news here is that the relapsed/ refractory space has continued to really gather momentum. And obviously we had the really dramatic results of CARTITUDE-4 study, which showed the value of cellular therapy of the use of CAR-T in early relapse outperforming control therapies, which in fairness were obviously standards of care at that time. 

But really, some of us might suggest, yes, but there are more powerful other combination strategies and drugs that we now use. The simple message being that CAR-T has made a real difference and I think for those who are eligible and for those who it’s an appropriate, it’s wonderful and clearly dramatic. 

I think however where we've come with CAR-T is to realize that the approved platforms that we currently have be it ide-cel, cilia-cel, with more coming, we've realized that cilia-cel clearly generates the most dramatic long progression free survival intervals and high rates of MRD that appear more stable. 

The cilia-cel story, however, has been tempered little bit by the realization in real world practice of some of the toxicities. And I think this is what I really want to share with the audience is the clinical trials were pristine. They were very well conducted. They were rigorous. They were really from a regulatory point of view, examples of teamwork and collaboration with the regulators and the establishment of these very important treatment platforms for the appropriate patient. 

I think real-world practice has brought to sharp relief that there are substantial challenges with some of these approaches in a minority of patients, but when they occur, they're really challenging. I think the other thing I've learned from my real-world use of platforms like cilia-cel is, you know, dramatic responses, MRD negativity, but just as one of my patients showed, months after his cilia-cel MRD negative complete response, know, a PET CT without a smidgen of disease, then within 10 months, very unfortunately, he relapsed. And that was he was the perfect CAR T candidate, if I may just be bold with this. 

And I was so surprised. And so was he obviously. And so we're now pulling this together to what do do next. And I think therein lies the rest of the stories that essentially, bispecifics have become really important, I think. Certainly, in my experience, I've had some great results. 

We've also seen plenty of patients in whom unfortunately the bispecific platforms have failed them. 

The good news is that we have multiple targets and multiple antibodies so we have multiple approaches to the bi-specifics going for BCMA. We have most importantly talquetamab for GPRC5D and hopefully cevostamab for FCRH5. The need for these targets is really clear though because BCMA targeting therapy unfortunately can sometimes run out of steam, can fail and if that's the case our patients need salvage strategies that make sense. 

Another thing that we've learned in the last year or two is really the importance of immune exhaustion and the importance of sequencing and I think there's been great data looking at trying to combine bispecifics with other drugs such as pomalidomide really showing the value of that approach.

I think also in the CAR T space, there are some fantastic new trials and new agents coming through very close now. think I'm hoping for approvals in certain settings as well of better CAR T platforms as it were, recognizing that both cilia-cel and ide-cel have been phenomenal. 

I think on the CAR T side, one other thing we've talked about before, Jenny, which is relevant is that vast majority of patients do have some issues with CRS and so on, but do very well. We do also realize, however, that the hyper inflammatory signals that are being generated in certain settings can be very challenging. 

So in our own program, for example, we've recently had some significant challenges with an HLH-like syndrome, which has been very difficult to manage. This was a little unexpected, to be honest. And so we're realizing there are lots of things to learn. 

The last part of it is the late neurological toxicities, which can be quite, quite difficult to say the least and having very sadly lost one of my own patients to Parkinsons, so I can speak very directly to it. 

I would simply say that it's an important challenge. It's fortunately rare, but it is, and certainly in my poor patient's case, it proved lethal for her. So I think we have to be very thoughtful about this. does, when people say late Parkinson's, well, does that mean it's just like late Parkinson's and you get better over time, it may be a bit disabling, but it's not the end of the world. That's not what we're seeing. We're seeing an autoimmune type of phenomenon in the and midbrain where there does appear to be what we call gliosis, which is this destruction of central nervous system tissue by the immune system. And fortunately, this is very rare and it seems to be rarer the earlier you use the platform. So that's good news. But, know, in my opinion, once is too many. So, you know, how do we minimize this so that isn't a barrier to cure?

Jenny: Is there a way of identifying patients that might be more susceptible to that going in? And then as you look at the two CAR-T options, do you favor one over the other with age or frailty or things like that in your strategy?

Paul Richardson: That's a super question. I personally think ide-cel is less toxicity-prone in my own experience with it. I think a cilia-cel is very powerful and in some patients it can be quite challenging, but fortunately that's a minority. I think the late Parkinson's thing is not necessarily one CAR T over the other. I think it's a class effect of the platform because BCMA may in fact be expressed in the brain.

It is a function of BCMA cellular therapy. Fortunately, it appears to be less associated with earlier use of CAR T and above all, some of the newer CARs that are coming through are being very designed to minimize some of the toxicities. Your question is such a good one. Who gets it and why? 

It may be related to tumor burden. It may be related to endothelial activation and injury. In other words, the blood brain barrier becomes breached and in that setting the central nervous system toxicity becomes more of a worry. There are a variety of factors but I think in essence this is an evolving field. What is good news is there is work being done to try and stop this in its tracks and I was privileged to be part of a special clinical pathologic conference at the Mass General in which we actually discussed specifically my patient who very sadly passed and it was very clear in our discussion there that there are some very important advances being made so I think minimizing the risk on the one hand, and then if it occurs having some strategies that make sense is a very active area of research.

Jenny: Are you seeing that more in men versus women or do you know?

Paul Richardson: I can't comment to that. I can say is that in my particular patient's case, she was a lady. I would say that generally speaking, I mean, I really want to emphasize for our audience, this is rare. It is not a common issue. 

But if you look at real world experiences for CAR T, and you and I discussed this before, Jenny, the real world data are showing up to 10% treatment related mortality from real world studies. This is recently published. We have to be very cognizant. 

That reminds me of early days of transplant and fortunately we are able to get that right down with advances in supported care to less than 2% as people may know in the sense of transplant. Interestingly enough in the context of the work at Mass General there's been some hint that if you've had prior high dose melphalan some of your toxicities from CAR T may actually be a little bit greater. Now this is very preliminary so I don’t want people to take away the idea that high dose melphalan makes your CAR T more likely to be difficult. 

But it recognizes something that was presented and is being published should be out in full manuscripts soon, where the Mount Sinai group looked at their real-world experience of 70 CAR T patients at the time and showed that if you had had prior chemotherapy with high dose melphalan, your risk of second cancers went up. And in that context, it was higher than what you would expect, probably is the better way of saying it. 

So I think this is all the sort of strategic thinking we have to now have in our mind's eye. How can we spare people late toxicities that could be life threatening by being strategic with the uses of these exciting new modalities earlier?

Jenny: And it's this chess game for patients too. So the shared decision making is real and you need to be educated as a patient as much as you can. 

HealthTree is working on now a three year CAR T study too, and we'll probably have that out within the next three months. So if you have had CAR T, we can aggregate some of that real world data because we really need to see and answer questions like this.

Paul Richardson: Right.

Jenny: And then, know, sequencing, like what do you do first? Do you do CAR T first? Do you do a bispecific first? All these different questions need to be answered.

Paul Richardson: Well, I think you're absolutely spot on Jenny and I again want to applaud you and your team for being engaged in these specific trials because it is so interesting this construct around what we call Real World Data because obviously to get any kind of therapy to get full approval by the FDA rightly requires an extremely careful approach. 

And I think the CAR T world is to be applauded for the care and fastidiousness with which these studies were approached and how they were executed. 

Of course, these strategies because they're complicated, they're sophisticated, require hospitalization, they require expert nursing, expert physician care. When they go into real world practice, there's a steep learning curve and that is just a reality. Bispecifics, perhaps less so, but still inpatient step up dosing, tolerability questions, management, all of this makes it much more absolutely and to my mind, you for many of our patients, just having to be admitted to the hospital is always a challenge and then - 

Jenny: Prophylactic (or preventative) tociluzumab (to prevent cytokine release syndrome) or something like that.

Paul Richardson: What is really a challenge for both CAR T and bispecifics is that whilst we're in, we're no longer pandemic with SARS-CoV-2, the reality is it is endemic. So SARS-CoV-2 is here to stay and in the CRS and in endothelialopathies of bispecifics and CAR T, this may be a factor. We've certainly had experiences where CAR T has been challenged by persistent COV-2 infection and bispecifics as well.

The good news is with all those advances that we've had in Covid-2 therapy or SARS-CoV-2 therapy, things, thank God, are so much better. But it doesn't change the fact that these are challenges and we still are losing patients to Covid-2, SARS-CoV-2, to COVID-19 because, you know, they've unfortunately had profound challenges with a variety of immunosuppressive issues and chronic infections, CRS and so forth. Thankfully, it's truly a minority, but it points to the fact that we need what I consider real world options for our patients. 

And what I mean by that is real world means not just efficacy as in high response rate, phenomenal PFS, it's also what I call this PFS toxicity assessment, you know, what does the event-free survivor look like? What does toxicity mean? Because if you're one of those patients in whom you have a lethal toxicity, I mean, my God, that's it, it's done. You're done. It's a catastrophe by anybody's measure. If you're one of those patients who's had some sort of toxicity that then sets you up for lethality later, that's just as important in a sense. 

So when you think about all of these strategies, I think it's really important that what you're doing with real world assessment is brought to bear because it tells you what you're really doing in terms of the field. And I think it's an incredibly important initiative that you're doing, Jenny.

Jenny: Well, it's so important and you all want answers to these questions so we're always doing this in partnership with investigators because they're the ones, you you are the ones asking these important questions. We need to figure it out. Do we want to talk a little bit more about bispecifics before we jump to other drug classes?

Paul Richardson: I think we can simply say that the bispecific space is an incredibly important addition to the armamentarium. There are real efforts to make them safer, more convenient, more patient friendly to your point. And then I think what's exciting in the bispecific world is combining bispecifics with CELMoDs, with other drugs. And by doing that, being in a position to really improve the therapeutic index. And I think exactly the same principles apply to CAR T as well.

Jenny: Can you explain a little bit more about cell mods?

Paul Richardson: It’s obviously been a focus of research for me since really the last seven or eight years. They are distinct from immunomodulators. And obviously we were very fortunate in seeing the success of iberdomide work led by my colleague, Dr. Sagar Lonial and others, and which was a privilege to be part of where we showed that iberdomide was well tolerated and very active, even in the face of IMiD resistance and, you know, triple class refractory disease, and even when BCMA strategies had failed our patients. So we saw a nice solid signal from iberdomide. 

To my mind, the impact of mezigdomide has been even more striking. Mezigdomide is a classic degrader. It is a molecular glue. It targets the cerebronethri ligase complex and closes it 100%, whereas, for example, pomalidomide in the IMiD class only manages 20%. And for that matter, iberdomide is actually 50%. So this 100% closure by mezigdomide preclinically is translated to what we see in the clinic. We were very fortunate last year that we were able to publish some of our early work in the New England Journal and it got a very nice editorial with it from the journal, which I think is always very encouraging because it tells you that's how the editorial board of the New England Journal view the quality of the work and its potential impact. 

So I think mezigdomide has barrelled forward as an oral approach combined with other strategies that's particularly exciting.

I like it because it can be used after BCMA has failed a patient and after other strategies including teclistamab failed patients. And so with that in mind, it becomes a very important next step in therapy. 

My colleague Dr. Luciano Costa has led our trial of what we call NOVEL/NOVEL. And NOVEL/NOVEL is quite amazing. It combines mezidgdomide and dexamethasone as the backbone with other very rational oral therapies that are biologically targeted.

We have looked at very exciting MEK inhibitor, trimetinib, you may be familiar with. Trimetinib is a very interesting drug. As a monotherapy in myeloma, not so encouraging. But in combination, the results have been remarkable. Luciano will be presenting at ASH next month, fact. Some of our early data with trimetinib. I wish I could tell you at Jenny because it is embargoed until it presented. I can only say the results are quite remarkable.

This is such a it's just a remarkable advance so the construct that you can use mezigdomide after cellular therapy has failed a patient, after a bispecific has failed a patient is one thing. Te idea that you can then use mezigdomide in combination with other strategies that actually haven't been terribly effective on their own, yet generate results that my goodness, we've never seen anything like this before, is particularly exciting. 

And then of course we use mezigdomide bortezomib, with carfilzomib, with daratumumab, and we've used it with elotuzumab as well, and these results have been phenomenal. So I think, you there are now studies of iberdomide, for example, with isatuximab, to give you an example. Mezigdomide obviously is more in the relapsed setting, iberdomide is going more up front. 

I think the CELMoDs have been really, to my mind, one of the most rewarding research areas for some for our group in particular, Dana Farber, for the last several years, because it's been great to have the advances in immune therapy, Jenny, but then to have the CELMoDs be able to deliver for us has been has provided our patients with very important options. 

And a couple of additional points, oral therapy, use in the community, easy for patients, easy for providers. 

Jenny: It's all about access and accessibility. 

Dr. Richardson: Exactly. And then I think the other piece that's so important is the complication rates. So we christened mezigdomide as “CAR T in a pill”. Obviously, we're being a little bit cheeky because it's not CAR T, and these are phenomenal platforms, but mezigdomide can actually achieve remarkable responses, especially in combination, and very durable ones, too. I think it was very important to share with the audience though is the tolerability profile. 

We've seen significant myelo suppression but it's manageable. This is what's so interesting. No weird neurotoxicity, no thromboembolic signal, no cardiac signal, no renal signal and this is I think key - the infection signal is low and that I think is vital for our patients and as we think about it in the pivotal 001 trial that we published in the journal we had only one COVID related mortality in this total study size of over 170 plus patients. was 178 patients. 

Now remember, in the same time period, the teclistamab study was enrolling right in the same time period, we were in the middle of the teeth of the pandemic. Very sadly, there were 23 COVID deaths in that trial. So you can see the what I'm going with this that the value of oral therapies really has to be seen as a net effect. 

We’ve got a response rate of 41% in that study, 30% activity and extra medullary disease, which was particularly gratifying to see the drugs uniquely designed for that. And then in the post BCMA space, we have 50% response rate. Now, these are great. 

Now, obviously, they're not 65% that are bispecifics, or 80 to 90% of the CAR-T,  but my argument is, but that shouldn't dismiss the value of the mezigdomide. You know, it clearly has a role in the strategic sense.

Jenny: And just historically, just if patients don't understand, so the whole thalidomide, Revlimid, pomalidomide, all those drugs, those immunomodulatory drugs, people really didn't know how they worked. And then they found that this cereblon pathway was important. These new drugs are kind of an extension of that, but hailed from that background.

Do you see those replacing the Revlimids and pomalidomides of the world over time?

Paul Richardson: Super question. I think the immunomodulators have to be seen as where they originally came from. The thalidomide story obviously is well known and this was a the palamida ring was the key to it. It was built from some brilliant medicinal chemists in Germany. And obviously, unfortunately, the tragedy of its development was its approach, more than its tragic deployment in exactly the wrong population for morning sickness. It could not have been a worse decision. 

The thing is that the silver lining to that very dark cloud was that it's antineoplastic, that it has these remarkable effects on tumor growth, and survival that became very obvious with myeloma, with some pivotal but essentially empiric work, as well as obviously its very interesting effects. 

And this I think is sometimes underappreciated, its effects in leprosy where you had this fungating form of leprosy that was so deadly that thalidomide worked for it. It was actually its first FDA approval. So I think it's an incredibly interesting class of drugs, but the image are quite different in my opinion to CELMoDs. 

CELMoDs were purpose built to engage this cerebral nephrely gaze complex, and they were molecular glues, essentially, that's what they were designed to do to trigger degradation. So the degraders that are molecular glues, the innards, smaller molecules, actually, in terms of the actual size, some similarities, but tremendous differences in the cell mode. 

So it's important to understand that. To your question, it therefore means we really need them all, right? Because there'll be healthcare jurisdictions where lenalidomide is a great drug, it really works well. 

There's still some countries believe it or not who don't have access to upfront lenalidomide and that is true. We need the IMiDs available to those health care jurisdictions where there may be limited availability of the CELMoDs conversely in the US.  

I still think we'll need all of them for the right patient.  And I think it would be a strategic mistake to say well, we don't need a Revlimid anymore because clearly that's a drug that has literally improved survival globally for myeloma by by many, many milestones. 

So I think we'll need them all. The one other point I would make, which is really important for people to hear, is that there is an intrinsic second cancer risk to lenalidomide driven from the Revlimid's mechanism. It's magnified if you have melphalan. It's much less if you just use Revlimid without melphalan. But I think what's really important to share with the group is that both iberdomide and mezigdomide do not have this property, it seems, preclinically.

Now clinically we've seen no evidence to suggest it does. So this second cancer risk may be absent or less in CELMoDs. And if that's the case, that's another very important value add.

Jenny: That’s good to hear.

Jenny: Myeloma patients will use most likely every tool in the toolbox. So we need more tools. We don't have a cure yet. You know, at IMS, I was listening to a presentation and it was about high-risk myeloma and they were saying a quarter of patients are still dying in under three years. And according to the SEER data, you know, we have 40% of patients still dying in under five years. So we need all these new tools and we can't stop innovating. So it's very exciting to hear about what's happening.

Paul Richardson: Well, I agree, Jen, if I may, you touch on something that's so important. And I use this slightly simpler term, we need all hands to the pumps. You know, fortunately, the ship is sailing. And we're not we're not sinking. That's for darn sure. But the fact of the matter is that the ship is sailing, but we've got a long way to go. 

And I'd like to say that we're kind of mid-Atlantic right now, whereas unfortunately, before we were barely out of the English Channel. Now over the last 20 years, we're, almost there, you know, almost made it to New England. But the point is to get to New England, we still have a lot of work to do. 

And I would say to you that in terms of all hands to the pumps, we really should mention the antibody drug conjugate story because belantamab mafodotin targets BCMA. 

There are other antibody drug conjugates coming that target GPRC5D, for example. And this is a really interesting concept because essentially you're targeting the delivery of your warhead. So in belantamab mafodotin's case, you're targeting BCMA and you're bringing in the mafodotin and you're triggering what we call an immunogenic signal, which is really important mechanistically. And obviously there are other drugs that are trying to do this. 

The real excitement was after the disappointment of the DREAMM-3 study where it didn't meet its primary endpoint, unfortunately, suggesting that pomalidomide could perform very well, particularly in younger patients. But the bela plus dexamethasone, it was active, but it didn't meet its primary endpoint. That led to the withdrawal of the belantamab. 

But then, two studies, DREAMM-7 and DREAMM-8 came in. And these obviously have been the other headline news of the year, where DREAMM-7 combined with bortezomib and DREAMM-8 combined with pomalidomide, the PFSs were dramatic. And why I really want to share them with the audience is because it's worth mentioning that the median PFSs for bela plus Velcade/dex were around three to four years. And the median PFS for bela/pom/dex were similar, approaching four years. This is huge. 

And so the question really is, wow, wasn't that unexpected? And two, this means seriously that bela, in my opinion, needs to be back. Now, obviously, the ocular toxicities are concerning, but it's very manageable. And it's reversible in almost all cases. And I'm not aware of one case in our practice where it hasn't been reversible. 

The other thing is I've not seen, and I say this very carefully with lots of touching of wood, I've not seen a single toxicity in my practice from Bella and we've been involved in DREAMM-1,  DREAMM-2, we were involved in DREAMM-8 actually and we led DREAMM-5 which has been a very exciting kind of novel type approach and we've also got a very busy expanded access program for bela, which is going very well.

We have not seen lethality from the use of the drug. It doesn't do the same stuff as the BCMA targeting approaches might do from CAR T, for example, because there isn't this breaching of the blood-brain barrier. So I think at the same time, we need to recognize its value and say, look, this is a very important drug to have on the playing field. 

And in the same space, of course, Jenny, as you and I know, fully approved in Europe, but not unfortunately in the US, is melflufen, which is a peptide drug conjugate. So same kind of idea, kind of a guided missile, if you will, designed to deliver. The good news there is that it's doing very well in the ex-US setting, and at the same time, we are looking to next generation peptide drug conjugates, which may further help with the efficacy of these approaches. to your point, Jenny, all hands to the pumps, and we're just excited to see a host of different options beyond just the current immunotherapies.

And then I want to touch on one last drug if I may. And this is the targeting of P300. There's a drug called Inobradib. I call it Inobradib. Ino for short. It's been led by British colleagues who have done an amazing job in putting it together. It's an oral therapy which synergizes with immunomodulatory drugs in the preclinical setting. And it appears to be performing very well in the clinic. This is work led by Emma Searle, who's actually from Manchester in the United Kingdom and others and it's made a real impact in early phase studies and it's arriving, well, it's already arrived, it's been presented. 

The data are quite encouraging from a safety point of view and Emma will be presenting at ASH some very nice work in combination and in great credit to the FDA, it's my understanding that they are very interested in this oral agent and there's ongoing discussions about where it may potentially help. So, you know, again, there's just one more example and I could go on for another hour about more.

Jenny: Very nice.

Paul Richardson: There's another lovely, very interesting degrader from the C4 company, which is in a different category to CELMoDs, which is also very interesting and we'll be presenting the data at that at ASH. But they give you two simple oral examples of exciting new stuff that's coming. So I would just say the good news is like this.

Challenges exist, right, we know those, Jenny. The good news is we've got an array of new options to help us meet those challenges.

Jenny: This is amazing progress. When I was diagnosed in 2010, there was nothing like this. It was like transplant or very little to offer. So in just a few years, you can see the amount of significant progress that's been made. It's really incredible. Now I know we're at time, but I do want to ask a few questions if you have time.

And some of these have been covered already, so we can just say they've been covered and move on. But Heidi was asking for ways to prevent progression in smoldering myeloma. You kind of talked about this holistic model. Are there any other thoughts that you have on that topic?

Paul Richardson: Well, I think only other than the new strategies that are immunotherapeutically based, you you have the RVD-Dara combination strategy, maximum response, and then maintenance for them. It's essentially bringing the frontline paradigm into the smoldering paradigm, but in high risk so that patients who are going to convert to active disease, it's kind of stitch in time saves nine. I guess that's where I would land with that. And I think, however, you're right, Jenny, that the holistic approaches to immune millieu really make sense to me and I love those. It's great idea.

Jenny: Daniel was asking how long on maintenance?

Paul Richardson: I think until progression and or intolerance is the current standard care, going forward, we'll see where that lands. But hopefully that will continue to be an important area.

Jenny: Heather's asking, can high-risk myeloma patients go off maintenance or go from double maintenance to single maintenance to protect kidneys or what strategies do you suggest for high-risk patients?

Paul Richardson: Wow. Well, that's a big question. I think high risk therapy involves best therapies. And to your point earlier, Jenny, definitely sitting down with a myeloma expert to get an understanding of the nuances. I think the good news is we have drugs like, one drug that's actually important to mention that targets del17p is selinexor. And as an oral therapy, it can be challenging, but in combination it can actually be much more manageable and very easy to use in combination with other drugs. 

So selinexor, for example, and high risk myeloma relapsed/refractory in particular, but also there are studies now going up front could be really interesting to explore. This targets a mechanism called XPO1. And I think in that setting, selinexor or base therapy can be very useful.

The BOSTON trial validated that in a randomized clinical study. I think also we are actually studying mezigdomide combined with selinexor and dexamethasone in the STOMP study led by my colleague Clifton Moe. We're very excited about that.

Jenny: Great. Linda's question, we covered a little bit because her question is the one everybody asks, will transplant be phased out?

Paul Richardson: No, no, I think transplant continues to have a role. The question is, in whom does it serve best? And we have really interesting data from DETERMINATION, which you'll be hearing more about, in which we've identified that African American patients seem to get remarkable benefit from RVD alone and keeping transplant in reserve. 

They get great benefit from early transplant too, but to our surprise, there was much greater benefit from RVD alone with transplant being kept in reserve. Now we have to be very careful because the numbers are relatively small and so these are subgroup analyses and hypothesis generating but a working hypothesis we have is that there's this pathobiological phenomenon in African Americans called Duffy Null that maybe it's enough over 70% of African Americans or up to 70% of African Americans this may actually tell us more about who benefits from what why so I use this as an example to simply illustrate that transplant I think remains a standard of care question is do you have to use it everyone and may be actually specific subgroups in whom keeping it at reserve may be wiser. But lots of work still to do in that regard.

Jenny: Okay, we had a lot of CAR T questions. how Alex was asking, how long is the immune system recovery post CAR T?

Paul Richardson: Very long. I think we're learning, right? There are some people who recover faster, some takes years.

Jenny; Joan was asking, can patients get two CAR T therapies?

Paul Richardson: Yes, absolutely. I've seen that and one of my patients is exploring that, a very option having originally done well with BCMA targeted CAR T and is now thinking about another, but again, in the context of clinical trials, this is where these kinds of questions probably are best asked.

Jenny: Terry was asking about the status of fast CAR-Ts or just more rapid development. I know there’s anito-cel coming up and you know lots of...

Paul Richardson: Yes, again, lots of work there. And Jenny, you may already have this, but I could certainly recommend one of my colleagues who's a particularly good CAR T person to chat with. He's wonderful gentleman. His name is Adam Sperling. He's particularly expert in our group on CAR T therapy. I'm sure he would be very happy to talk to you about this.

Jenny: Okay, maybe we'll do another show just on that topic. And then Karen's asking, if you relapse after CAR T, what are some of your best options?

Paul Richardson: Well, this is a great question and a difficult one. Obviously revisiting other drugs, the use of selinexor around CAR T has been quite rewarding anecdotally and also in studies that have been worked particularly in Europe exploring this. I think the CELMoDs obviously come straight to mind. Immune exhaustion is the issue. Using bispecifics after CAR T, the results have not been as good as if the patients are just getting bispecifics alone and vice versa. If you have a CAR T first and then a bispecific later, it seems to be better than having a bispecific first followed by a CAR T.

The one subgroup of patients where I think it may not be the case that prior BCMA targeting is adverse is with antibody drug conjugates. In other words, if you've had belantamab earlier in your course, getting a CAR T later may actually not be the drop off that you see with the bispecific because the mechanisms are different. So I think there lots of questions there, but in short, it's a complex answer that requires sitting down with your team. But the good news is you can clearly swap in and swap out. So that I think is good news.

Jenny: Impactful.

Paul Richardson: The other thing is in Europe, know of this, use of the drug melflufen, which we touched on earlier, as a relatively non toxic approach because you don't lose your hair, no mouth, sores, infection rates are very low. They're using in Germany, example, melflufen based combinations in between to sort of provide a totally different approach.

Jenny: That might not be a bad idea (particularly for patients who haven’t undergone transplant).

Paul Richardson: It targets extramedullary disease, you know, it's a different mechanism of action, all of these things may be what you need between two immunotherapeutic approaches. So the idea is that a drug like melflufen, a peptide drug conjugate, provides you with a cytotoxic that's mechanism of action is different that can overcome a thing like immune exhaustion or rather can work despite immune exhaustion.

Jenny: Last question. John is just asking about best approaches for high-risk relapse patients. You kind of talked about this and the need for specialists is critical here.

Paul Richardson: Yes, I think for a high-risk newly diagnosed patient, quadruplet is a must. The question of transplant needs to be carefully considered. And at the same time, protocol (clinical trial) participation makes sense. I mentioned earlier, selinexor, or particularly because it targets del17p disease, is always a thought in my mind when it comes to high-risk disease.

Jenny:  Dr. Richardson, we've covered a lot of ground. You gave us a great heads up for the upcoming ASH meeting, which is going to happen in the blink of an eye, really. And we'll be excited to hear all the data that reads out there. But thank you so much for taking time with us today. Thank you for your work and all you do for myeloma patients and everything that's happening at your institution in the myeloma community as a whole. It's extraordinary.

Paul Richardson: And thank you Jenny, and it's really a privilege. It's great, and I so enjoy our conversations Jenny, thank you.

Jenny: Well, thank you. And we thank 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.