Introduction: ASCO 2025 Preview

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome back to Year in Review, as today we focus on the management of multiple myeloma.

We have a great faculty: Dr Thanos Dimopoulos from the National and Kapodistrian University of Athens Alexandra Hospital in Athens, Greece, and Dr Bob Orlowski from the University of Texas MD Anderson Cancer Center in Houston.

Today, we’re here to talk about multiple myeloma and particularly what’s been happening over the past year. As with all of our programs, we will be discussing the use of unapproved agents and regimens. So please consult the package insert for more information on approved indications.

All of our Year in Review series, I meet with the faculty separately to record a presentation. I met with both of the faculty in the past week. Both of their presentations are available now in the chat room for you to check out after this webinar. And when the webinar is ready, we’ll send that out along again with these 2 presentations. They’re really great. They go through a lot of papers.

Here are the papers that they went through in detail. We’re not going to go back through these, but I picked out some of the key papers and some themes. And more importantly, some of the questions I had in my own mind that came out because of these presentations. And really, that’s what we’re going to focus on here today and really kind of get an update of what’s going on with myeloma.

But before we get into what happened over the past year, we thought it would also be helpful to provide sort of a brief overview of what to expect from ASCO. We don’t know the EHA schedule yet but for sure, as always, there’ll be plenty of great papers there as well.

But Thanos, here is the actual schedule for the oral presentations. I’m curious what are some of these that maybe we should be looking forward to receive. One that kind of caught my eye and there are actually 2 different papers looking at so-called trispecifics. Of course, we’ll talk a lot about bispecifics. But we have a couple of papers now looking at bispecifics. You’ll notice this lower one there, which is 1 specific agent, and we’ll show you another one later. Bob, you were commenting on these. I guess basically, we’re trying to pull together 2 different targets within the same molecule or the same bispecific. And another one I think combined GPRC and BCMA. Any thoughts about these, Bob?

DR ORLOWSKI: Yeah. I think these are really interesting molecules. The one you’ve got here on the bottom of the screen is a BCMA and GPRC5D and CD3 trispecific. The advantage is that some patients have myeloma cells with high BCMA but low GPRC5D, and other people can have the opposite where you can have higher GPRC5D but lower BCMA. If your CD3 T-cell engager has both, you don’t have to worry about whether 1 target is low or high because the trispecific will work whether you have 1 protein, the other or both. It’s a little bit easier than giving 2 separate bispecifics, which has already been done in the so-called RedirecTT study. And in the RedirecTT trial, the data looked very encouraging with what looked like a higher response rate than either bispecific alone and really nice activity in extramedullary disease, which is one of the high-risk subtypes.

DR LOVE: So we’ll talk a little bit later on about this presentation from the IRAKLIA study looking at subQ isatuximab, something we’ve been looking forward to for a while now with an on-body delivery system. And Thanos actually has it with him. He’s going to show it to us and talk about it. We’ll get to that in a second. Also, the interesting one here, kind of getting back to this idea of a trispecific, is this bottom one looking at level of expression of GPRC5D and benefit from — well I guess what you see in terms of heterogeneity and I guess whether there’s a correlation of benefit. Thanos, any comment about the heterogeneity that we see in terms of GPRC5D, and BCMA for that matter?

PROF DIMOPOULOS: Yeah. As Bob mentioned, there are patients that express these antigens at different levels, and especially those that have been previously treated. However, there is no direct correlation between response and the levels expressed. There may be a correlation with circulating levels, higher circulating levels being associated with BCMA with more high-risk disease. So it would make sense to try to combine, you know, construct monoclonal antibodies that could target 2 major antigens that are expressed. And this is also the rationale behind using a bispecific against BCMA and also daratumumab, which is on CD38.

DR LOVE: That’s a really interesting thought. We also are going to see some Phase I/II data. This is the BELARD study of belantamab with len/dex. Thanos, you’ve been so involved with the research on belantamab. What do we know right now about this combination? And can you talk about I guess there’s a Phase III up-front trial now that’s going to look at that?

PROF DIMOPOULOS: Right. Okay. So we were involved in developing a Phase I/II study of the combination of different doses and different intervals of belantamab mafodotin with lenalidomide/dexamethasone. So what we have seen from this Phase I/II study, which involved nontransplant eligible patients and most of them had some degree of impaired fitness, we saw a very high percentage of response and a very long progression-free survival. And this formed the basis for the ongoing DREAMM-10 study, which compared bela/Rd to dara/Rd, a head-to-head comparison in the frontline setting of daratumumab versus belantamab.

DR LOVE: So Bob, we’ll get into this a little bit later when we go through some of the papers on belantamab. But I really wonder whether people appreciate the fact, I think this has been about a year, at last year’s ASCO and EHA meeting, we started to see data from these DREAMM studies. But, of course, belantamab is no longer available. It was available previously. I’m kind of curious when or if you think belantamab might become approved again, both in the United States and EHA. And also, after seeing Thanos go through the data, I turned to him and said, would I be correct in saying that right now it looks like belantamab actually maybe has greater activity, at least in the recurrent combination setting, than daratumumab?

DR ORLOWSKI: Yeah.

DR LOVE: And he answered yes. I don’t know if you would agree with that. The hazard rate we’ll show later was 0.51. That sounds better to me. But you tell me, Bob. And it’s kind of strange to have a drug that more effective than one of the most effective drugs we have and have it not available. Do you agree with that general assessment of efficacy? And when do you think this agent is going to be available, Bob?

DR ORLOWSKI: Yeah, I totally agree with that. It’s interesting. The British have already reapproved belantamab for use there. So we’re waiting for the PDUFA date when the FDA will announce their decision here. But with 2 positive Phase III studies showing that a belantamab-containing triplet is better than the control triplet, I think that the approval will come. As to your question about whether belantamab is better than dara, at least in the DREAMM-7 study, which was dara/bortezomib/dex versus belantamab/bortezomib/dex, the belantamab-containing combination was substantially better as Thanos will show. And I think it’s probably because of 2 things. First of all, there is a direct cytotoxic effect of belantamab, which also daratumumab has. But belantamab can also induce what’s called immunogenic cell death, which is a different immune mechanism of action that dara doesn’t have. And so that may be why it certainly looked better in that study.

DR LOVE: Yeah, we’ll talk more about where this is heading. Oncologists always like to add things, so maybe we’re going to end up with a quintuplet someday. But as Thanos was just saying, right now, it looks like in some of these Phase III trials, it may replace anti-CD38 therapy.

Anti-CD38 Antibodies

DR LOVE: Which leads to our first topic. And please check out Bob’s presentation. He goes through a whole bunch of recent trials on anti-CD38 therapy. We always try to sort of get to the bottom line of what we think docs in practice want to know about. So I have some general questions that came out of Bob’s talk that I want to run by you. But first, I want to talk about this study, Thanos, that you reported in the New England Journal looking at dara in smoldering myeloma. Of course, we’ve had a number of attempts to look at treating high-risk smoldering. I don’t know to what extent it actually has been embraced up to this point. But I’m kind of thinking based on this data that was just presented that this is maybe going to become standard of care quickly. Thanos, can you kind of summarize what was looked at there and what was seen and what your take is on it?

PROF DIMOPOULOS: Yeah. And actually, this paper came in the printed form of the journal today, so it’s a coincidence. So yeah. In this trial, patients who were considered high risk based on definitions made about 10 years ago, they were randomized to either observation or to receive single-agent daratumumab for a period of 3 years. One particular aspect of this study is that this study used modern imaging techniques in both control and patients randomized to be treated with daratumumab, which gave the opportunity to capture so-called skeletal-related events before they caused symptoms to the patients. So this is an important observation. And also, there was a regular assessment of hemoglobin, decrease of creatine clearance, repeated bone marrow evaluations, which we don’t do in our daily practice. So these patients were very carefully followed. And the study showed that indeed daratumumab was able to decrease to a significant extent the progression to symptomatic myeloma based on either CRAB or what we call SLiM criteria, meaning definition of myeloma but without clinically evident symptoms. And also, although the data are not mature yet, there is a trend for a potential survival advantage in favor of patients receiving daratumumab. I believe that at least for what we consider today as high-risk patients, meaning patients who have more than 20% bone marrow infiltration or more than 2 grams of monoclonal protein or a free light chain ratio more than 20, at least 2 of these characteristics, daratumumab may become a standard of care provided, of course, we obtain regulatory approvals by the FDA and DMEA.

DR LOVE: Bob, I asked both of you before we started here whether you’re ready to use it, you like to use it, whether it’s practice-changing. I’ll point out there that even though the curves look different, both of those curves on the right, so the top one is PFS, hazard rate of 0.49. Even though survival is not mature, hazard rate of 0.52 although the way it’s plotted, it doesn’t really appear that different. Bob, pretty significant numbers. It’s kind of surprising to me, particularly the survival, if it really plays out. Again, do you think that you’re ready to do this? Would you like to do this?

DR ORLOWSKI: I’m definitely ready to do it. The hazard ratio you quoted is a very common number in other studies looking at adding a CD38 onto a different platform. So it’s not actually a surprising number. I think also, there will be additional studies coming. There’s the so-called ITHACA trial that looked at len/dex as the control arm and then isatuximab/len/dex as the experimental arm. And the US cooperative groups are doing len/dex versus dara/len/dex. So I think down the road, we’re probably going to be doing the triplets in these high-risk smoldering patients, especially if you monitor them and their free light chains or M-protein are going up over time.

DR LOVE: Yeah, that’s a great practical point. In our astute chat room, Hassan brings up the issue of lead time bias with trials like this and also I guess whether the progressors actually got dara on progression. Another person in the chat room, Swati, says she actually offered it to a patient today although it’s not approved. I don’t know if you can actually get it done. But somehow, she actually offered it. I also wanted to ask you, Bob. This is another paper that you talked about looking at MRD in patients who had transplant. Can you comment on what was seen here and whether you think this data suggests that maybe it’s worth doing MRD for practical purposes clinically or even from a research basis doing it and the idea of maybe thinking about how it might affect your future therapy? Bob, what did they look at here?

DR ORLOWSKI: Yeah. I think it actually makes the argument to do it for clinical purposes, not just research. But across the top, you can see a comparison. These are people who were 1 year out from transplant who had MRD done. And both the PFS and the OS were better if patients were MRD-negative. That’s not shocking because less cancer is always going to be better than more cancer. But the really interesting thing is in the bottom 2 panels where they compared patients who were sustained MRD-negative versus patients who started MRD-positive but then converted to MRD-negative. And it really shows that the people who converted to MRD-negative did as well as the people who had sustained MRD negativity from the get-go. And that really supports the notion to do the MRD. If they’re MRD-positive, think about additional treatment that maybe could convert them to MRD-negative because it looks like that’s really going to make a difference in their outcomes.

DR LOVE: So I put together a few questions that I had about anti-CD38 therapy in general, both related to these papers but also just I think clinical questions I hear people asking. Just to remind everybody, now, at least in terms of upfront anti-CD38 therapy, both agents are approved, and if the patient is not eligible for a transplant, dara is approved with bortezomib/thalidomide and dex, not a very common combination, in transplant eligible patients. Also, just to remind us, we saw the press release from the study I just showed you that’s going to be presented at ASCO looking at the subQ formulation. And we’re going to talk about that in a second. This is actually what it looks like. Thanos actually brought one with him. I was curious, Thanos. One of the questions I had about this is, I know you’ve had experience with it. Very few people including Bob have. I asked you to talk to your infusion nurses and get a little more input on this because, of course, everybody wants to know how is the patient experience going to compare using this approach compared to the way it’s used right now with the nurse giving it by subQ infusion. Can you show us what it looks like? It looks like it’s smaller than your, you can see, it’s smaller than your hand there, Thanos. And what the nurses are telling you about what it’s like to use this.

PROF DIMOPOULOS: Yeah. Indeed, I was surprised to hear that they believe that this is a better way to administer the anti-CD38 monoclonal antibody because you place it, as you can see here in the slide, in the patient’s abdomen. And then, there is a little hole here that you can put your isatuximab. And then, you set the pump and it will inject it automatically at a steady rate over 5 minutes. So it is, you know, it is not dependent on the rapidity that the human hand can push slower or more, you know, the drug. And I believe it is something that may be an advantage to the patient and also to the person who is infusing the drug.

DR LOVE: And Bob, I wonder too whether or not maybe in the future, we could be thinking about administration at home maybe with a visiting nurse or maybe even by the patient themselves. I feel like probably one third of the world, or at least the Western world, is already injecting some kind of GLP-1 drug there, so it’s not totally unheard of to do self-administration. Can you see that happening sometime in the future, Bob?

DR ORLOWSKI: I definitely think so. What will probably happen is the first couple of doses when there’s a little bit of a higher risk of an injection reaction will probably be done at the center or clinic or office. And if people tolerate that, I could definitely see this either being applied by a home nurse or maybe even self-administered by the patient. We do have some precedent. Ofatumumab is approved for multiple sclerosis and is a CD20 antibody that can be given at home. So there are already people who have blazed that trail for us.

DR LOVE: It’ll be interesting to see how this — alright, so these are my top 20 questions. We’ll see if we can get through most of these. We already dealt with the first one. We already heard about smoldering. But this may be sort of a general simple question, but I’m a simple person sometimes, Thanos. And Bob presented so many great studies that have been done. We could spend the whole hour just talking about them. But the bottom line is it kind of seems to me that anti-CD38 monoclonal antibody in general is becoming a standard part of induction treatment whether the patient is transplant eligible or not. Thanos, do you agree with that?

PROF DIMOPOULOS: Yes. We have just updated the EHA and EMN guidelines for treatment of myeloma. And this will hopefully be published soon. And as you said, we recommend that anti-CD38 containing quadruplets are considered as the standard primary therapy for both transplant eligible and ineligible patients provided they are not unfit. Because we know that the elderly population is quite heterogeneous with many patients being fit, some unfit, and several being frail because of comorbidities associated with age and other diseases. So for the majority of the patients with myeloma, we believe that either as induction before high-dose therapy or as a continuous treatment, either daratumumab or isatuximab with bortezomib, lenalidomide and dexamethasone is the new standard of care.

DR LOVE: So a couple little more specific, more controversial questions, Bob. What about in the maintenance setting? What role do these agents have? And does MRD get factored in?

DR ORLOWSKI: Definitely. So we have results from a Phase III trial that took patients who were MRD-positive after transplant and randomized them either to len or to len with dara. And the group that got len and dara did better. We also have data from a number of Phase III studies where dara was given as part of the induction and then later in combination with len as maintenance that showed that that is superior. And we just earlier this year finished enrollment to the SWOG study that compares len to len/dara as a maintenance irrespective of whether dara was given during induction. I think that dara does add to len in terms of outcomes in maintenance. And I think one of the concerns in the past is, gosh, if you burn your anti-CD38, you’re not going to have anything leftover in second-line. Now, we have BCMA antibody-drug conjugates coming. We’ve got CAR T-cells approved in second line. The bispecifics are coming second-line. So I think that concern will be lessened. Plus, we have PFS2 data from the up-front studies, which show how people did after they progressed on treatment. And if the patients who got CD38 were doing worse, then they would have a shorter PFS on the next line of therapy. But in fact, they do better. So again, it shows that you really should include the CD38 up front.

DR LOVE: I see Dr Philip Brooks. Good to see you, Phil. I haven’t seen you in the chat room recently. He brought back up this issue of MRD, Thanos, in the maintenance setting, whether that’s something that’s worth doing. Does it affect your clinical management in the maintenance setting, Thanos?

PROF DIMOPOULOS: Yeah. I believe that it is and it will affect it more in the future. And as Bob pointed out, even more important than having 1 MRD value is to have what we call sustained MRD negativity, meaning at least 3 values 6 months apart. We have recently published a Phase II study where we took patients after transplant who had received at least 3 years of lenalidomide maintenance and had at least 3 consecutive values of MRD negativity in the marrow and a negative PET CT. And we discussed with the patient the possibility of discontinuing lenalidomide. We then followed the patients with not only blood and urine studies, but with sequential MRD evaluation. And we saw that after a median of 3 years, 80% of MRD-negative patients remained MRD-negative. So, of course, we need randomized studies. Of course, this approach may not be applicable for high-risk myeloma patients. But definitely, in the future, MRD-guided therapy will be of value. And we already have the MIDAS trial from France, which is evaluating prospectively this approach.

DR LOVE: So Bob, Lilliam in the chat room wants to know the optimal way to do MRD testing in the community. And Phil Brooks, who I just mentioned, said do you need to do a bone marrow every time for MRD? And do you use clonoSEQ?

DR ORLOWSKI: Well, right now, the answer is yes, that it has to be done by bone marrow. The clonoSEQ is more sensitive. You do need a baseline test so that they can identify the myeloma VDJ sequence, which is later followed. So if you have a patient who you haven’t gotten the clonoSEQ on at baseline when disease was present, then you have to do it with next-generation flow on the marrow. But I will say there are a lot of coming blood-based assays including by mass spectrometry, circulating myeloma cells and other techniques, which I think they’re not quite yet at the same sensitivity as clonoSEQ on the marrow, but I think that time is coming. And then, it’ll be a lot easier for everybody to just look at peripheral blood.

DR LOVE: So, Thanos, I feel like every time we do a webinar, there’s always an issue that we have more than 1 agent in a class that we have to compare indirectly. This happens all the time in oncology. CDK inhibitors in breast cancer, PARP inhibitors, et cetera, et cetera. Here, we have 2 CD38 monoclonal antibodies. This is kind of a basic question, but how do you decide or how will we decide which one to use? And do you think there’s any difference in efficacy and safety? I think up to now, people have been basically, I think, often choosing dara because you can give it subQ. But it seems like we’re going to have the option of subQ maybe even with a more favorable way to give it in the near future with isa.

PROF DIMOPOULOS: Yes.

DR LOVE: Assuming you can give both subQ, is there any way to differentiate them from a patient perspective or from an efficacy perspective? Or are these at least indirectly too similar to try to differentiate, Thanos?

PROF DIMOPOULOS: Yes, I think it is more or less they have similar efficacy and we have seen studies in the past try to use one after progression on the other and despite the small number of patients these were not positive. So to make a long story short, now with the possibility to use both as a subQ formulation, provided the price also is comparable, there won't be much difficulty choosing one versus the other.

Belantamab Mafodotin

DR LOVE: So let's talk a little bit more about belantamab. We talked about it a little bit. I mean, I don't recall many, if any, situation in oncology, not just myeloma, where we've had this situation of a very effective drug that was available then became not available, still is not available. Looking at that data it seems like the patients are losing out a little bit in this situation. So these were the 2 studies that were presented about a year ago, the DREAMM-8 study basically comparing the addition of belantamab to pom and dex versus bortezomib. We saw a marked advantage there. You can see the difference here with again a hazard rate of 0.52 by using the belantamab. And particularly this study looking at bela-Vd versus dara-Vd, so again basically comparing belantamab to daratumumab. And again here's a hazard rate of 0.52. Thanos, anything you want to say about these studies? And also the issue that everybody asks about, which is ophthalmic toxicity. You've done a lot of work showing that by decreasing the interval between the belantamab that it can be very effectively managed without losing anything in terms of toxicity. How do you see the clinical use of this agent right now and what's the patient experience, Thanos?

PROF DIMOPOULOS: Yeah, I believe that DREAMM-7 is a study that, as you mentioned before, indicated that at least in the relapsed setting belantamab is more active to daratumumab. DREAMM-8 is a very practical regimen because we have now almost all patients with myeloma that received lenalidomide maintenance. So at the time of progression most of them, if not all of them, will be lenalidomide resistant. And we will be having an increasing number of patients who will be progressing on anti-CD38 monoclonal antibodies as well. So this is the exact population that can be targeted with belantamab, pomalidomide and dexamethasone. An outpatient regimen that is not associated with the high rate of infections that we see with other immune therapies. And also as you said that by adjusting the interval of administration of belantamab and waiting for the ophthalmic toxicity to resolve, clinically this can be given to the patients without many concerns.

DR LOVE: So Bob, I don't know how many patients you've treated with belantamab on or off protocol. But again, any observations in terms of the patient experience? When these patients are carefully followed with good ophthalmic follow-up are they generally able to avoid clinically symptomatic issues? And what kind of issues do you see? Is it more acuity? Do they have discomfort in their eyes? What do you see, Bob?

DR ORLOWSKI: You can see a spectrum. Sometimes they have dry eyes or blurry vision. They need to use eye drops. On occasion you will have compromise in terms of being able to read or drive. I did want to say though that in myeloma we've had a history of previous drugs that were maybe initially approved or looked good and then didn't make it because of poor survival, venetoclax, for example, in the BELLINI trial or pembrolizumab in some of the KEYNOTE studies, even melflufen. The reason that belantamab did not continue its approval was simply because the right trials were not designed. It wasn't because the efficacy or toxicity was not there in the Phase III studies. So I think you could put that as a result in a much better category than some of those other drugs we mentioned.

DR LOVE: So Thanos, you mentioned the DREAMM-10 study that's ongoing right now. Can you review again what that's going to look at? And I'm curious what you think it's going to show and if it shows what you think it's going to show, how do you think it's going to affect clinical practice?

PROF DIMOPOULOS: Well, I believe that based on the data that we have from DREAMM-7 and based on the really exciting data that we're seeing in the Phase I/II study with bela-Rd, I expect that this trial will show that bela-Rd will be associated with longer remissions, deeper responses, more MRD negativity and hopefully a survival advantage. So I believe that, of course, it will take years. However, now we have the opportunity to use MRD negativity at least as an interim endpoint that belantamab will show superiority as compared to daratumumab. And also in this particular trial, belantamab will be given every 4 months. So it will be given at a very convenient interval for the patient and possibly this will be associated with reduced rates of high toxicity.

DR LOVE: Wow, that's really amazing. Again, I can't think of too many treatments in oncology that are given every 4 months but that's really exciting. Thanos, again, you've had so much experience with this agent. What do the patients actually experience? Do they have discomfort in their eyes? Is it more acuity? How much of an issue actually is it if they're carefully managed?

PROF DIMOPOULOS: Right, as Bob said, there is a spectrum. Itchy eyes is the easiest thing because you can use ophthalmic drops to hydrate the eye and this will resolve. In about one-third of the patients in these belantamab studies, you can see decrease of visual acuity, which may be clinically significant meaning patients may have issues with daily activities but this will resolve, almost always I will say, more than 95% by holding the dose and giving it later and maybe also at a reduced dose depending on the severity of the toxicity. And one interesting thing about belantamab is that if you have a patient who is responding and you have to hold the drug because of eye toxicity, you won't lose your response. So the response will continue and sometimes be deeper despite treatment delays. And this shows something unique in the treatment of myeloma and probably based on what Bob mentioned earlier in the several mechanisms of action of belantamab, which is beyond the antibody or complement interaction.

DR LOVE: I was just flashing on the fact — I don't even remember, I guess it was a couple of years ago or maybe 3 years ago. Just at the same time that belantamab was taken off the market, we were doing a program where I was doing video interviews with patients with myeloma. And one of the patients I interviewed for that program was a patient of Dr Natalie Callander. And at the time I interviewed her, she had been on belantamab for 4 years and was doing great. I actually just heard from Dr Callander. Now it's 3 years later and she's still doing well. I'm not saying that's a typical patient, but it was kind of strange to be talking to her just as the drug was getting pulled off the market. Well, we'll see where this interesting story continues.

One more question, Bob, and this comes up all the time in terms of targets and losing the target and whether you lose efficacy. Any thoughts about belantamab as it relates to the presence or absence of BCMA? Whether you think prior CAR-T therapy or BCMA therapy might affect benefit from belantamab? Any thoughts in general about sort of losing the marker in this situation or the target?

DR ORLOWSKI: Yeah, in part, as Thanos mentioned earlier, the correlation between the level of expression and efficacy is not one that is as strong as we would probably like, but there are assays available for BCMA expression level. And I would say if somebody is negative for BCMA on those, then I would definitely think about not giving belantamab after prior CAR or bispecific. And at least in some of the work that's been already published, especially from Nizar Bahlis' group, it looks like antigen loss or mutation is more common among the T-cell engager treated patients than among the CAR T-cell patients.

DR LOVE: So Phil Brooks again wants to know, what kind of follow-up do you need from an ophthalmologic point of view? Can you just follow symptoms or do you need to send them to the ophthalmologist? And I guess we can say we know from the prior approval that they're probably going to be required to see an ophthalmologist or maybe even optometrist even. I've heard that as well.

PROF DIMOPOULOS: Well, —

DR LOVE: Go ahead, Thanos.

PROF DIMOPOULOS: We try to establish a protocol where patients will have a baseline evaluation because we have been surprised that several of our patients may have cataracts or other unrecognized issues that could be dealt with. And then to have a few visits and then to establish a clinically useful questionnaire that could be done at the clinic and really avoid the regular examinations by an ophthalmologist or an optometrist unless the patient develops new symptoms. So I believe that in the future we will be dealing with these patients with few initial exams and then they will be clinically followed based on questionaries that are being developed and validated as we speak.

CAR T-Cell Therapy

DR LOVE: Alright, well, let's talk a little bit about CAR-T and bispecifics. We've spent entire programs on this topic, but we're going to pull out some of the things that Thanos went through in his discussion and things that stuck out to me or sort of things at least I hadn't heard too much about including this CAR-T, which I had never heard of before, anito-cel. And, Bob, it's interesting, it appears like this is an agent where there's less toxicity particularly neurologic toxicity. Any comments about this agent? Also in terms of efficacy what we know about it and what you're expecting as we move forward learning more about this agent, Bob?

DR ORLOWSKI: Well, you really hit the nail on the head in terms of the toxicity profile with this. This was also previously called ddBCMA so you may know it by that name. And it does look like it has efficacy comparable to cilta-cel, which is the better of the two currently FDA approved BCMA CAR-Ts at least in terms of response rate and durability. But unlike cilta-cel, which does have some both acute and delayed neurotoxicity, so far it looks like anito-cel does not, which would be really very much welcome. And most of the cytokine release syndrome is mild as well. So those are additional positives.

DR LOVE: I was flashing on the old lite beer commercial, Great Taste, Less Filling. It seems like this has both. Thanos, any comment on this agent? Where you see it heading? And how much of an issue right now are the neurologic issues with cilta-cel, you know, this parkinsonian's syndrome? How much of a problem actually is it with cilta-cel?

PROF DIMOPOULOS: Well, I think that if we could have a product that is associated with less neurotoxicity, especially delayed neurotoxicity, is very important because we are moving the administration of these CAR T-cells in earlier lines and even in the front-line setting. So I don't want a newly diagnosed patient with myeloma to develop a potentially irreversible neurotoxicity because of the treatment. So based on the construct of this product, it appears that there is a quicker release from the BCMA target and this could help the product to eliminate myeloma cells without the severe immunotoxicity and the potential of neurotoxicity. So yes, I believe that ICANS is not a common problem but for patients, especially when treated early in the course of the disease, this is something that we should try to decrease its severity and avoid it.

DR LOVE: Incidentally getting back to belantamab, Dilip in the chat room says, "In the community, quick and reliable ophthalmic evaluation is nearly impossible." So it may be not the same as in an academic center. Do you think that optometrists, Thanos, can do this evaluation? Or do you need an MD?

PROF DIMOPOULOS: No, I think, the thing that you need is not to have a detailed assessment of the cornea, it is to be able to evaluate visual acuity and an optometrist can do it perfectly well and give you a number. For example, 20/50 degrees of visual acuity is usually associated with impairment of daily activities. So I think this could be done in real life and I believe that in the future most of the patients for extended periods of time they will be evaluated by questionnaires without the need of a regular ophthalmic exam.

DR LOVE: That's great. So Bob, any comments? We're talking about targets here. Obviously with bispecifics we have a GPRC5D there in terms of talquetamab. But now we see this report of a CAR-T product that's going to have the same target looking pretty encouraging. I've never thought to ask, I wonder do they see like the taste stuff there with the CAR-T? Or I don't know if I see it there on the list. But Bob, any thoughts about this?

DR ORLOWSKI: Yeah, you do see some skin effects and appetite and dysgeusia as you do with the T-cell engager but you hopefully will have less of it because with the T-cell engager, you're giving continuous therapy whereas with the CAR-T, the T-cells are not around as long. So hopefully there will be less of each of those.

DR LOVE: Interesting. So in Thanos' talk, he has a fantastic conclusion. Like in 4 minutes, if you watch that last part of his talk, you get so many great points. And Thanos, I just picked out a couple of things that you brought up there in your conclusion about CAR-T. And one is this issue of whether or not we ought to be thinking about sort of a second dose of CAR-T either as consolidation or as some type of maintenance. Is this being looked at and what are your thoughts, Thanos, in terms of is this a direction that we may end up in?

PROF DIMOPOULOS: Yes, I believe that especially in heavily pretreated patients where we know that the expected benefit is a year or a year and a half it would make sense to repeat it after several months, especially if we see that we can monitor the expression of the antigen. For example, if we see that there is a significant reappearance of BCMA, if the patient tolerated the first procedure well, I think that this is something that could be repeated in order to extend the period of benefit.

Bispecific Antibodies

DR LOVE: So let's talk a little bit about bispecific antibodies. There's a lot there to talk about but just particularly in terms of what's new. And this is pretty interesting. I think Bob referred to it before. We were talking about a bispecific with 2 different targets. But here is just giving the 2 agents together. Bob, of course, I guess quality-of-life issues with talquetamab make it a little bit different than teclistamab. I was just flashing incidentally. When we did that program where I interviewed patients, I interviewed a patient that at that point who'd been on teclistamab for a year and a half, doing great, in remission, felt great. And that was about the exact same time it was approved, kind of emphasizing the potential role of being in a trial. But just as it was coming on for everybody else, he'd already been on it for almost 2 years. But anyhow, what about the idea of just giving the 2 together, Bob? Any thoughts and what do you think about this initial data from the RedirecTT study?

DR ORLOWSKI: Yeah, definitely the RedirecTT study as you pointed out combined the currently 2 bispecifics, which are from Janssen, one against BCMA, one against GPRC5D. And the results looked very encouraging, particularly this is being directed at patients with extramedullary disease who don't respond as well to single-agent T-cell engagers or to CAR-Ts. And I think there's a good possibility that it ultimately will get a regulatory approval in that space. I think the only potential downside is that if myeloma cells can either mutate or downregulate both targets, you're eliminating one option for therapy down the road. But hopefully because you're hitting 2 different targets, it'll be more difficult for one cell to mutate both.

DR LOVE: And as you see here these patients did, more than two thirds of them or about two thirds of them, did have taste changes. Thanos, from a practical point of view, how do you manage these patients with taste changes? What do they report to you? I've heard about like mouthwashes and stuff. How do you deal with this?

PROF DIMOPOULOS: Right. We try to do some mouthwash with soda or with steroids and we ask the patient, for example, to see whether some kind of more acid foods or more salty foods taste better. It is a significant problem to the patients that needs to be addressed because if they stop taking adequate calories, they start losing weight, they start losing muscle mass. And the other issue also is the nail changes that again we try to apply topical steroids or rather hydrating creams. And eventually we may have to reduce the dose or to give longer intervals.

DR LOVE: So, Thanos, also talked about another bispecific, linvoseltamab. It seems to also have very good efficacy. We'll sort of see where this heads. But I wanted to get into more general issues. Bob, one of the things I was noticing, again sometimes I see stuff like so many different times but then finally I see it sort of. And one of the things I noticed when Thanos was going through the data on bispecifics in CAR-T was actually when I was looking at it it looked like the PFS advantage was pretty similar for the two. We don't see like in CAR-T with diffuse large B-cell this plateau and a lot of people being cured. And you do see a pretty prolonged PFS with bispecifics, which leads into the question that we also have in lymphoma but again in a different context as there we're looking at maybe curing at least in diffuse large B-cell. But from your point of view, Bob, indirectly looking at the effect on PFS, does it seem like you have similar median PFS at 3 or 4 years with the two? And if so, then how do you decide what comes first?

DR ORLOWSKI: Well definitely the duration of response for patients who have good responses to bispecifics those are definitely very impressive. I still think that the overall PFS is better with the CAR-T and the complete response and MRD negativity are better. So for patients that have both as an option, I would still recommend the CAR-T first and then if they relapse to think about the T-cell engager afterwards. The reason is that first of all you get a nice treatment-free interval from the CAR-T. You'll get a longer duration of benefit. It looks like the risk of mutation or deletion of the target is lower with a CAR-T than with a bispecific. And also immediately after a bispecific, it can be tough to collect enough T cells to be able to manufacture CAR-T. And usually the feeling is that we need to do something in between there, and we don't talk about this in the current presentation, but it may be with something like iberdomide or mezigdomide, which may serve to reduce T cell exhaustion down the road.

DR LOVE: So a couple of other sort of general questions about bispecifics in CAR-T. Thanos, we showed earlier a study looking at a bispecific as part of an up-front Phase IB study. Anyhow looking into your crystal ball for the future, Thanos, do you see bispecifics or CAR-T coming as up-front therapy? How do you think it's going to be utilized and in what situations, Thanos?

PROF DIMOPOULOS: Yeah, I think there are ongoing studies that likely will be positive. The question is in order to reduce the infections complications whether this especially for bispecifics could be applied for a restricted period of time, either after let's say an effective quadruplet as consolidation or if they could replace high-dose therapy with melphalan in younger patients with myeloma. So I see a role but with limited duration because still bispecifics have been given indefinitely or for very long periods of time put the patient at continuous risk for severe infections. This is something that is a concern especially if you have a newly diagnosed patient.

DR LOVE: You actually anticipated my next question. So Bob, can you give us more of a qualitative view of how much of a problem infections are with bispecifics? What type of infections? How do you approach immunization, prophylaxis anti-infectives, the use of immunoglobulins? And do you see bispecifics being given for a fixed duration in the future to try to limit these issues?

DR ORLOWSKI: Yeah definitely infections are a concern. The targets that are being gone after on the myeloma cell are also expressed on normal plasma cells. So CAR-T, T-cell engagers, they all kill normal plasma cells as well especially the BCMA targeted therapies. You do get hypogammaglobulinemia and we have studies showing that people who get gamma globulin replacement have lower risks of infection and some also support that there may be a better survival. Infections can be a little bit different than what we're used to seeing. You have to monitor for CMV. You can get fungal infections, adenoviral infections. It's often helpful to have an infectious disease expert readily at your beck and call to consult with if you need. So definitely it's something to watch for. In terms of fixed duration, right now the therapies are given until progression, but I do think that there is a rationale to consider, for example, treatment to MRD negativity, and then maybe give a period off of treatment with maybe restarting therapy at the time of MRD conversion from negative to positive. And studies like that are currently underway.

Other Novel Agents

DR LOVE: So wow, I can't believe it. I'm at my last question. We actually did all the questions. Hard to believe.

So part of Bob's presentation, Thanos, you've heard about CELMoDs for a while. We have mezigdomide as well as iberdomide that we've been hearing about forever but they're not available. Bob showed some pretty encouraging data as we've been seeing with these agents. One so called mezi. And just to sort of again prep docs in the community for these agents, that I assume are going to end up here. Can you talk a little bit about how mezi and iber compare to lenalidomide in terms of efficacy but particularly in terms of tolerability, Thanos? And where you see these CELMoDs fitting in?

PROF DIMOPOULOS: Right. I think iberdomide may be replacing lenalidomide as a maintenance drug. There are ongoing studies. There are promising data from Phase II studies. The toxicity profile is different. You may have a little bit more myelosuppression but the gastrointestinal toxicity is less than with lenalidomide. On the other hand, mezigdomide may be a very useful agent especially in the era of immune therapies. Because, as Bob pointed out very correctly, we need BCMA-free intervals in order to be able to exploit the 3 potentially different mechanisms of anti-BCMA therapy. And I believe that drugs such as mezigdomide may be combined with carfilzomib, as we're seeing in the ongoing SUCCESSOR-1 and SUCCESSOR-2 studies, will provide such an opportunity. And also we definitely need active combinations of drugs with different mechanisms of action because we know that unfortunately many of our patients will continue to relapse despite all these very active immune therapies.

DR LOVE: So, Thanos and Bob, thank you so much for joining us today. Audience, thank you for tuning in. Be safe, stay well and have a great night.

Thanks so much, Thanos. Thanks so much, Bob. Have a good one.

DR ORLOWSKI: Thank you.

PROF DIMOPOULOS: Thank you. Bye-bye.