The world of immunotherapy in multiple myeloma is exploding - with new treatments being FDA-approved and others working their way through the FDA approval process. In this show, Dr. Paul Richardson focuses on the innovation in immunotherapy that we've seen in the first half of 2025. This includes a discussion about CAR T, bispecific and trispecific antibodies, and a deeper dive on a new class of drugs in myeloma called Antibody Drug Conjugates, with a drug called belantamab mafodotin going through the FDA review process, with a hopeful approval in October of this year. 

Editor's note: A drug called belantamab mafodotin is referenced in this show in multiple ways as "belantamab, bella, and blenrep." All uses refer to the same drug.  

Jenny: Welcome to today's episode of the HealthTree Podcast for Multiple Myeloma, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. Now it's mid-year and during the summer, several key hematology and oncology meetings were completed, including the Annual American Society of Clinical Oncology or the ASCO meeting and the European Hematology Associate meeting or the EHA meeting in Milan.

These two meetings showcased additional advancements in myeloma for all types of patients. We're honored to hear from Dr. Paul Richardson today about clinical research taking place that will provide patients with better options, additional options, and better quality of life. And in today's show, we'll be talking about myeloma progress and innovation. As you listen to the show, I want you to know that you can speed innovation and cures in myeloma.

So first we'll be discussing myeloma clinical trials. You can always consider clinical trials in myeloma regardless of your stage of disease. If you want to find clinical trials you're eligible to join, you can join Health Tree and connect your medical records. Now with that connection, you'll be able to see personalized trials that you are eligible to join. So instead of sorting through over 450 open trials in myeloma, you'll see a customized list based on what you've already received.

So now if I were to do that manually, it would take me about an hour per trial to do that sort of matching if I understood how to do that matching in the first place. But now you can do it in less than five minutes. It's really extraordinary what we've created for you. We have a patient navigators also that can help you through the process as well. The next way you can advance myeloma cures is by joining HealthTree and participating in surveys and studies along with establishing medical records connection in HealthTree.

Today, your data is sitting inside of your hospital's record system and may not be helping you, your doctor, or the research community. So when you join HealthTree, you put your data to work. Your data is anonymized and made available to vetted myeloma researchers so they can use that data to cure us faster. You don't have to sit and wait for cures. You can join HealthTree today to make a significant difference in the pace of recovery.

Now onto our show. Dr. Richardson, welcome to the program. 

Dr. Richardson: Thank so much, Jen. It's an absolute privilege. Honored to be with you as always and thank you for a fascinating and lovely introduction.

Jenny: Well, let me give you an introduction before we get started. Dr. Paul Richardson is clinical director of the Jerome Lippert Myeloma Center at Dana-Farber Cancer Institute. In his role, he led the development of a significant number of myeloma therapies, including bortezomib, lenalidomide, pomalidomide, ixaxomib, elotuzumab, daratumamab, isatuximab, blenrep, selinexor and CelMod therapies in addition to other immunotherapies.

Dr. Richardson has published extensively, having authored or co-authored over 400 original articles and 330 reviews, chapters, and editorials 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, Clinical Trials Corps, a position held for five 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 in 2011. And his honors include the George Canellos Award for Excellence in Clinical Research in Patient Care, the Tisch Outstanding Achievement Award for Clinical Research, as well as an honorary fellowship of the Royal College of Physicians in the UK, given in recognition for international contributions in multiple myeloma and stem cell transplantation. He was co-recipient of the prestigious Warren Alpert Foundation Prize in recognition of the successful therapy targeting of the ubiquitin proteasome pathway in 2012. He's 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 the Center of the Year in 2017. He was ranked by Thomas Reuter's Science Watch amongst the top 19 investigators at Dana-Farber for the most highly cited research in 2016.

He was a co-recipient of the ASH Ernst-Butler Prize for Clinical Science and Translational Research in the Development of Proteasome Inhibition as an Effective Treatment Strategy for Multiple Myeloma in 2015, the COMY Award for Myeloma Research in Paris, France in 2016, and the prestigious IMF Robert A. Kyle Lifetime Achievement Award in 2017, as well as the Morris Research Award in 2019.

Dr. Richardson, we're just so thrilled to have you.

Dr. Richardson: So kind of you - this all just reflects an incredible team that it's a privilege for me to work with and all the work we've done over the last 25 years together. And thank you for that introduction. It's lovely. It's really much more important that you and I are here for our patients who are listening and families and hopefully to give them a little sort of a quick review of some of the most important sort of news of the summer. And there's been a lot this summer hasn't there Jen?

It's been a very busy summer with a lot of highs and quite a few challenges too, but hopefully we can provide context for our listeners in that regard.

Jenny: Yes, I think because there was so much focus on immunotherapies at these meetings and some wonderful outcomes, let's focus our conversation today just on the world of immunotherapy, if you don't mind, because there's a lot we could talk about and it might take us forever, but let's just focus on immunotherapies and give people an update and then we'll hear more out of IMS and we'll hear the September meeting and we'll hear more at ASH of course this year.

Dr. Richardson: Well, I think in terms of immunotherapy, I think it's important for our audience to understand that in fact, pretty much every single treatment in myeloma has an immunotherapeutic construct behind it.

It's important to remember that autologous stem cell transplant using high dose melphalan was really an effort to reset autologous immunity using cytoreductive chemotherapy and then resetting autologous immunity with stem cell reinfusion and hoping for an immunogenic effect from the effects of high dose melphalan that could then engender immunogenicity from autologous reconstitution of the immune system.

And there is real truth to that. The challenge, of course are the long-term consequences of high dose melphalan, both acute toxicities long-term and otherwise. And I think with that in mind, it's important to remember that immunomodulatory therapy is truly immune treatment. We've recognized that with proteasome inhibitors,

There is immunogenicity from proteasome inhibition in itself. And so the list goes on. And of course, all our antibodies are immune therapy.

The real immune therapies of the recent era include T cell redirection and the most important ones, of course, being bispecific treatments. And then, of course, the revolution of CAR-T therapy with ex-vivo manipulation of T cells and the re-infusion of these targeted T cells to engage specific targets, be it BCMA or GPRC5D, with BCMA being approved, and obviously GPRC5D and other targets currently under study.

I think it's also important to note that some of even our most important small molecules actually engender immunogenic effects. And for example, XPO1 inhibition with selinexor - was one example - is an oral therapy that actually seems to have an effect on T cells as well as what it does directly to myeloma.

And in that same spirit, you very kindly mentioned our research in CelMods, which are distinct in my opinion to the immunomodulatory class. They fall into this broad category of degraders, which basically targets Cerebrone 3 ligase. And in that context, not only kill the myeloma directly, but engender a remarkable immune effect.

We affectionately christened mezigdomide, which is one of our most potent molecules in this space, “CAR T in a pill.” And there is some truth to that in a very kind of broad sense. So, immune therapy is an enormous subject to cover, but I think what I would like to focus on and the interests of time is really to sort of frame what immune therapy means.

I think the first thing to say is quadruplet therapy, which has been the integration of an immunomodulator, a proteasome inhibitor, and a steroid, combined with CD38 targeting with either daratumumab or isotoxamab have been revolutionary.

And really in the upfront space, we've seen first the success of powerful triplets such as RVD and KRD. Then we've seen quadruplets really take it to a new level. So the average progression free survival now derived from studies like IMROZ and of course, PERSEUS II points to patients being able to anticipate seven to eight years of disease control from upfront treatment, which without transplant is unprecedented.

The big question in the field is, does transplant add to that? Obviously, what we've seen more recently was the remarkable results of the MIDAS study from our French colleagues. And we were able to publish an editorial at the invitation of the New England Journal to try to help frame that and understand it was my privilege to write that editorial with my colleague Dr. Nikhil Munshi and of course with Dan Longo who is the senior editor at the New England Journal in the Hematology and Oncology space and a real privilege to write with him and Nikhil this editorial where we try to make sense of the MIDAS data which basically suggested that truly one size does not fit all and that in the context of quadruplet therapy in particular, first recognizing the impact of RVD and KRD previously,

Now with the quadruplets, there is a real opportunity to transplant spare in transplant eligible patients.

So we see using MRD as a tailoring tool that if you achieve very high quality response to quadruplet therapy, certainly based on the MIDAS data, recognizing there's important follow-up that will be needed, there is evidence clearly from this large and very well conducted phase three trial that actually high dose melphalan with autologous stem cell support did not move the needle compared to quadruplet therapy, which in itself is sort of a platform of immune treatment. So I think in that context, the results of the MIDAS trial and in our editorial, as we tried to help frame this for providers and patients and families alike, it's been a revolutionary step because it's really the highest level of evidence to support the fact that transplant certainly has a role and we're very clear on that in the editorial, but for an increasing number of patients, can be kept reasonably in reserve.

That's of course a huge advance because it spares patients from potentially unnecessary toxicities, both short and long term. And then it reserves the use of high dose melphalan and stem cell support for those patients who really need it, which hopefully will bring benefit across the space, not just in the United States, of course, but across the world in that regard, recognizing that in different healthcare jurisdictions, there's different access to treatments.

We have to bear that in mind because obviously, if there are limited options for patients, transplant becomes even more important in that particular setting. But certainly as far as the US is concerned, I think it helps us make sense of the upfront space. I think immunotherapy is leaping forward into that and beyond just transplant, we now have the real opportunity to deploy T cell redirecting therapy, be it T cell engagers in the form of bispecifics upfront. This is obviously a very active area.

Very excitingly, there's now CAR T studies that have been done and actually completed to enrollments such as CARTITUDE 6, where high dose chemotherapy is being directly compared to CAR T therapy to assess efficacy and to see how much of a difference CAR T therapy can make. So I think this is really very exciting. And I think this also points to the primacy of BCMA as a target (B cell maturation antigen.

This CD38 (target) has been a mainstay of therapy now for the last decade in terms of targeted treatment with antibodies led by daratumumab and isatuximab. But now, of course, we're seeing the real impact of BCMA targeting. And of course, there's GPRC5D targeting hot on its heels, which I think will bear fruit and hopefully also FCRH5. So just to share that with the group. I think that's very exciting. So CAR-T, very promising.

Will it replace stem cell transplant? Again, I'm a very strong advocate for one size does not fit all. So I suspect these will be selective tools in our armamentarium because we have to be very much aware of some of the side effects, and some of the real toxicity's can exist. Now, fortunately they're rare, but sometimes they can be very serious and even fatal. So with that in mind, I think we will always be looking to be highly selective and tailored in our approach. 0

Jenny: I know that at ASCO there was a lot of data coming out from the CARTITUDE-1 study. Do you want to mention that?

Dr. Richardson: Well, sure. Yes. No, I think that data from Pete Voorhees was fantastic. I mean, in the sense that it showed that in a subset of patients, long-term disease control over five years at high quality was maintained. I think we have to be careful, though, because obviously it was a subset and the majority of patients, unfortunately, still relapsed and faced challenges.

I had patients participate in that study as well. So it was very much aware of what the outcomes looked like, but it was still a very important presentation because it points to the real promise of CAR T.

But I do think you touched on a point here, Jen, that we need to refine CAR T. It needs to be less toxic and more, know, preserve the activity, but less toxic. And I think everyone recognizes that and that's very much work in progress.

I personally also think, Jen, that the integration of CelMods with CAR T therapy will be an incredible step forward, in my opinion. Because what that will mean is you'll be able to use cell mods, for example, to maintain remissions and allow us to be very careful with selecting active CAR Ts that are also potentially less toxic than some of the platforms that we currently have in an effort to maintain remission longer and they're very much the same way as IMiDs (immunomodulators) made such a difference to stem cell transplants. I think that's a promising new direction. But I'm also excited that there are CAR-Ts on the horizon. know, anito-cel (Kite) comes to mind as one example, which may in fact be combining the best of efficacy with less toxicity. But I really want to recognise though, that cilia-cel (J&J) clearly shows really impressive activity, recognising that there is an edge to it, which we have to be aware of, but generally speaking, it's very manageable.

In that same spirit, ide-cel (BMS) continues to perform and therein perhaps, you know, the use of CelMods to be able to maintain remissions is very promising. And it would be fascinating to learn eventually, like who are getting those severe side effects. I think studying that in more detail might be something that we look into. We really have to, Jen, because the problem is this, BCMA is not unique to the plasma cell.

BCMA is expressed in the brain. And it's also there's other areas and we've recognized some long-term toxicity such as the enterocolitis of CAR-T that fortunately is rare, but when it occurs, it can be so challenging for patients. And the long-term, the so-called late Parkinsonism, you know, we're getting better at managing it, but it nonetheless remains a much feared complication.

I think we have to be very aware of what that means because whilst it's a very small number of patients overall, particularly if you use CAR-T early, for those poor patients affected by it, of course, it's potentially devastating.

So I think we just need to be aware of how much more we need to do to refine the platform. That being said, speaking from my own patients who benefited from it, it's been, in certain it's extraordinary and nothing short of miraculous. So I think we have to realize that benefit.

I will say also for my bispecific patients, I've been so impressed with how well some of my patients have done with bispecific platforms. In that spirit, I think it would be important though, Jen, to spend a little bit of time in the immune therapy space to suggest that, know, whilst we've recognized that, for example, bispecifics can be phenomenally active and generally well tolerated.

I'm also struck even in the bi-specific space that we can see unexpected toxicities and real challenges. And I'm particularly struck by the recent experience I had in one of my patients where even with step-up dosing, targeting GPRC5D, this particular patient ran into really significant difficulties. And I'm still struck that we've got so much to learn.

In that context, Jen, I did want to spend a few minutes, if I may, in the antibody drug conjugate space, because I think for our listeners, it's probably been a little bit confusing over the last few months to understand what's gone on.

Many may know, in 2020, the antibody drug conjugate, belantamab mafodotin was approved by the FDA for accelerated approval. And this was a godsend at the time, that we were in height of the pandemic, and to have a BCMA targeting approach that did not require hospitalization that minimized exposure and made complete sense in the clutches of the pandemic. I personally thought that belantanab was a really important step forward. And for two years it was available to US patients.

Unfortunately, one of the confirmatory trials, DREAMM-3, failed to meet its primary endpoint against the pomalidomide dexamethasone control (arm). And this led to some significant regulatory challenges. There really wasn't a safety issue. I think that's important to share with the audience. But I think because it failed to meet its primary endpoint.

There was legislation at that time, unfortunately, which was I think enacted in October of 2022, which required withdrawal of drugs from accelerated approval if phase three data were in any way questionable. And the consequence of this is the belantamab mafodotin had to be withdrawn from the US market. Totally understandable in the sense that, you know, if you've got a questionable phase three, what do you do next?

Well, the really good news is DREAMM-7 and DREAMM-8 came in very recently, that last year, and showed clearly not only substantial progression free survival gain to the use of belantamab in combination with either bortezomib or pomalidomide compared to active control combinations, but at the same time what was so striking to me, in particular in the DREAMM-7 study, was a survival gain estimate in excess of three years. So really amazing results.

And with that in Europe, course, belantamab has now fully approved by the NHS even (the UK equivalent of the FDA), for example, in the United Kingdom, have it fully available and has had that since January of this year.

So I think it was a very challenging time for belantamab this summer when we had an ODAC (special FDA meeting with the company) in Maryland where the decision from the committee was five to three against the questions offered by the FDA for its efficacy in the context of understanding ocular (eye) toxicity.

And I think it's a complicated question, isn't it, Jen? You were part of that meeting, as was I.

Jenny: Right.

Dr. Richardson: And I think it's important for the audience to understand some of the context there. I think there was a very specific question for the ODAC.

I think the presentation of the data in favor of belantamab, both by patients, the company and all of us there, I think did actually fortunately have some positive effect on the decision making at the regulatory side because we've seen that the decision data around the approval of belantamab mafodotin has been moved to October, which I think is a positive sign in my opinion. I just wanted to return what you thought of that.

Jenny: Well, I think some of these committees - and patients might not know this. The committees are pulled from different diseases. you don't have a myeloma committee necessarily voting. So sometimes that committee might not see the whole context. And the way that the questions were framed, it made sense that they might vote in a certain way based on the questions that were presented. But the questions actually didn't have the whole context.

And I wrote a very extensive article that I'll link to about this. from the patient perspective, you heard over 16 patients get up and share how blenrep (belantamab mafodotin) had really benefited and even saved their lives at some point. So in my opinion, it meant the data met its primary endpoint. It did. The DREAMM-7 and DREAMM-8 results were really strong. And it didn't make sense the way the committee voted.

I think the October date is a great sign that hopefully this can get approved again. It's being used in Europe so European patients are benefiting from it and the side effects are known and manageable. So it makes sense for this to continue rolling forward. I guess I'm a very big advocate for patients having the freedom to make choices in their care, if something has a side effect that you don't like, you're going to go talk to your doctor about it and you're going to say, look, this isn't working for me. I mean, we see that with patients on Revlimid. We see that with every other myeloma drug. So this is not uncommon to just say, you know, I’m going to make that risk/benefit decision for me and my patient together with your doctor. You do that.

Dr. Richardson: Well, I that's beautifully said, Jen. I think from my point of view, I would 100% agree with you that the side effect profile from belantamab mafodotin is, in my experience, eminently manageable. I think one part of the conversation at the meeting was important. At Dana-Farber, as of that date, we had treated 166 patients with belantamab mafodotin at our center, both as standard of care, both as expanded access and as part of clinical trials.

And of 166 patients, we'd only had five hospitalizations. Of those five, four were for infectious complications related to drugs that were being used in partnership with bella. And in fact, the only case who really clearly had a bella-related issue was actually experiencing tumor lysis syndrome, which is a positive thing because the effect of the drug was so powerful on his myeloma and that patient has gone on to do very well.

So that was five out of 166. And when you look at CAR T therapy, where obviously this requires everybody to be hospitalized at some point.

And indeed bipecifics, 90% and the complications are radically different. I think you're absolutely right. And I think the myeloma committee at the ODAC didn't have a myeloma expert on it. And as a result of that, I think they didn't quite, you know, the context was not obvious to them. And I was very struck by the myeloma patient advocate who was a physician and a retired physician. And he was absolutely adamant in his support of bella.

That was not lost on me because he, in a sense, would be the most experienced on the panel and the most knowledgeable. And he was steadfast in his support. So I agree with you. I think the keratopathy (eye issues like blurry vision) is manageable. I think there was some confusion about understanding what that meant. And that was very, very obvious to me.

I think the sponsors made really amazing efforts to manage keratopathy and certainly in our own practice, it's not the issue that we were worried about that it would be. And we found that with dosing belantamab every six, 12, four, eight weeks, those kind of intervals, we just have not seen the problem be anything like, unfortunately, it was sort of portrayed to be by the FDA ophthalmologist at the panel.

I think at the end of the day, I'm very hopeful like you that the FDA will sort the wood from the trees here and we'll have an approval for the drug sooner rather than later. And I so appreciate what you said about sitting down with my patients and going over the relative risks because when you think about it, I've not had, I personally have never hospitalized a patient for bella toxicity. And I've certainly never encountered treatment related mortality, not once.

So I think it just has to provide context and yet I've seen consistent benefit from it, including one of my patients who testified where she's enjoyed complete remission for over two and a half, almost three years now, and she's MRD negative and she's never been in the hospital once, which is a remarkable result. The patient stories were very profound. it was very important actually.

I agree with you, Jen, what really struck me that I came away from the ODAP both feeling very challenged, but at the same time, very hopeful because, Jen, can I honestly say I thought patient advocacy at that meeting was extraordinary. You were one of the leaders of that process, but I thought the patient advocacy was just amazing and the patient testimonies were incredibly thoughtful and well constructed and just, know, for the myeloma patients, they're uniformly positive.

There was one patient from some policy organization -

Jenny: I don't think that was a patient.

Dr. Richardson: Well, no, not a myeloma patient. She certainly wasn't. She suggested she was a cancer survivor, but whatever that, obviously, thank goodness she's done well. But her testimony, I thought was completely, I was strangely out of context. But in any event, the patient testimonies otherwise, I would agree with you, were 100% supportive. And that was lovely to see.

Jenny: Yes, and all the advocacy organizations, IMF, MMRF, HealthTree, we were all weighing in that this should be approved. Patients need more choices and you can't deny a working product with manageable side effects if patients are still dying of myeloma. It just doesn't work.

Dr. Richardson: Right, and I especially want to acknowledge the sponsor, GlaxoSmithKline (GSK). I thought their team did an incredibly good job of addressing all the concerns and we're and speaking for myself, working with Dr. Sargalonio, we had the privilege of working with the GSK team and obviously just to be very clear with our audience, all our services were provided pro bono. There was no relationship otherwise. We were there to speak for our belief in the drug and in our patients .

Working with the GSK team was a real privilege. They were an outstanding team in my experience and I'm looking forward to full forward progress with bella, so that we will see approval. So very hopeful about that.

I think for the audience, I think it's important to understand where bella may belong. And I think, I call it bella affectionately, if I can use that term. I would just say that I think it has a role where it can be very easily integrated. I think it's important for the audience to understand it's not one drug versus the other.

The point is that bella will integrate very well in my opinion as part of therapeutic sequencing with bispecfics, with CAR-T and so on. And it wasn't lost on me, in fact, that one of our patients there who was cared for by my partner, Jacob, and his first name is David, he won't mind me sharing his name, he had received ide-cel CAR T therapy and unfortunately the CAR-T had not controlled his disease for more than six months. And then he went on to receive belantamab mafodotin—based treatment and has been in continuous remission, complete remission for over two and a half years and is MRD negative.

He was a beautiful example to me of how integrating these treatments is clearly feasible. And whilst I want to be careful about just patient examples, because sometimes people can say, well, that's just anecdotal, I would want to emphasize that we have clinical data now and science to suggest that we can rationally sequence these drugs by specifics, antibody drug conjugates, CAR-Ts, integrate the CelMods that I touched on earlier, benefit from the quadruplets upfront, limit the use of high dose melphalan so that we only use it for those patients who truly benefit and keep it away from those patients who we may actually do more harm than good.

And so in that context, really in the bigger picture, radically improve outcome.

Jenny: You talked about that in the quads at the beginning of the show. It's extraordinary what is happening. And just to see - even with the bispecifics - you see linvo (linvoseltamab) coming out and getting approved - so another bispecific antibody. You see trispecifics in progress.

I don't know if you want to touch on that. I know you have to run, but what's happening in there is amazing.

Jenny: I think you've touched on a beautiful point, Jen, that beyond bispecifics, we now have trispecifics which have the promise of triple targeting, well, or bringing the T cell in and then two targets on the tumor cell with GPRC5D and BCMA. And the goal is that by combining the two, you can achieve more with less in terms of side effects. And I'm really excited by some of the preliminary data. I think it's exciting and we're participating in clinical trials, both in the relapse setting and also funnily enough, we're also moving into the smoldering space for these platforms, trying to see if we can really leverage the immune system when it said it's healthiest as it were.

And more to follow on that. But I also think, Jen, that you touched on a very good point about the quality of the bispecifics. I do want to say that, you know, obviously teclistamab approved, elranatamab approved, it's very exciting.

And I want to applaud FDA here, of course, because I must always say FDA has been a fabulous partner in moving drugs forward and approvals in every way, recognizing the recent challenges that we saw, at the same time, linvo’s approval, I'm sorry, I apologize, we've struggled to pronounce the full name, but linvo has been a really, really nice addition. I personally, for my patients who've received linvo on clinical study, they've done extremely well, both from the point of view of benefit and side effects. So I'm really excited to see linvo approved. was, I think, very, that was a highlight of the summer for me. Yes, I would a hundred percent agree.

Jenny: A lot happened this summer in the immunotherapy realm. And I know that will continue. Well, Dr. Richardson, we're so thrilled to have you. We know how hard you're working to help get all these drugs in trial and approved. And again, we encourage patients to consider joining clinical trials because many times you will get early access to some of these newer therapies that are really extending life.

And until we have a myeloma cure, we will keep going. And I'm sure you will keep going. Thank you.

Dr. Richardson: Thank you so much, Thank you, everyone. It's an absolute pleasure to be on the show today. And Jen, look forward to seeing you soon. Well, thank you so much.

Jenny: And thank you 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.