Multiple Myeloma — Year in Review Series on Relevant New Datasets and Advances

Good afternoon, everyone. I'm Neil Love from Research to Practice, and welcome back to Year in Review. Today, we focus on the management of multiple myeloma. We have a great faculty, Dr. Thanos Thamopoulos. from the National Kapistan 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. Two presentations are 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 EHAS schedule yet, but for sure, as always, there'll be plenty of great papers there as well. But Thanos, here's 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 they're actually two different papers.

Looking at so-called tri-specifics, 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 one specific agent, and we'll show you another one later. Now, Bob, you were commenting on these. I guess basically we're trying to pull together two different targets within the... the same molecule or the same bispecific. And another one, I think, combined GPRC and BCMA. Any thoughts about these, Bob?

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 tri-specific. 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. PRC5D, but lower BCMA. If your CD3 T cell engager has both, you don't have to worry about whether one target is low or high.

because the tri-specific will work whether you have one protein, the other, or both. it's a little bit easier than giving two separate bispecifics, which has already been done in the so-called redirect study. And in the redirect trial, the data looked very encouraging with what looked like a high... higher response rate than either by specific alone and really nice activity in extramedullary disease, which is one of the high risk subtypes.

So we'll talk a little bit later on about this presentation from the IRACLIA study looking at sub-Q isotuximab, something we've been looking forward to. for a while now with an on-body delivery system. And Thanos actually has it with him, is 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 tri-specific, is this bottom one looking at level of expression of GPRC5.

and benefit from, well, I guess what you see in tender heterogeneity, and I guess whether there's a correlation. of benefit. Founders, any comment about the heterogeneity that we see in terms of GPR, C5D, and BCMA for that matter? Yeah, as Bob mentioned, you know, 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 a more high-risk disease. So it would make sense. to try to combine construct monoclonal antibodies that could target two major antigens that are expressed and this is also the rationale behind using a bispecific against BCMA and also Daratumumab, which is anti-CD38.

That's a really interesting thought. We also are going to see some phase 1-2 data. This is the Ballard study of ablantamab with Len Dex. Thanos, you've been so involved with the research on Belantimab. What do we know right now about this combination? And can you talk about, I guess there's a phase three upfront trial now that's going to look at that. Right. Okay, so we were involved in developing a phase one, two study of the combination of different doses and different intervals.

of belantamomophototin with lenalidomide dexamethasone. So what we have seen from this Phase 1-2 study, which involved... non-transplant 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 dream 10 study which compares bellardy to darardy a head-to-head comparison in the frontline setting

of daratumumab versus belantamab. So, Bob, we'll get into this a little bit later when we go through some of the papers on belantamab. I really wonder whether people appreciate the fact, I guess it's been about a year, last year's ASCO and EHI meeting, we started to see data from these dream studies. But, of course, belantimab is no longer available. It was available previously.

I'm kind of curious when or if you think Belantimab 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 palantumab actually maybe has greater activity, at least in the recurrent combination setting, than daratumumab? And he answered yes. I don't know if you would agree with that. I mean, the hazard rate, we'll show later, was 0.51.

That sounds better to me, but you tell me, Bob. It's kind of strange to have a drug, the more effective and 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 agency is going to be available? going to be available, Bob. Yeah, I totally agree with that. It's interesting. The British have already re-approved Belantimab for use there. So we're waiting for the PDUFA date when the FDA will announce.

their decision here. But with two positive phase three studies showing that a belantimab-containing triplet is better than the control triplet, I think that the approval will come. As to your question... about whether belantimab is better than DARA, at least in the DREAM 7 study, which was DARA-bortezomib-dex versus belantimab-bortezomib-dex. The belantimab...

containing combination was substantially better, as Thanos will show. And I think it's probably because of two 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.

So, yeah, we'll talk more about where this is heading. I mean, 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, at least some of these phase three trials, it may replace. anti-CD38 therapy, which leads to our first topic. Please check out Bob's presentation. He goes through a whole bunch of recent trials.

on anti-CD38 therapy. You know, 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 that Thanos, that you reported in the New England Journal, looking at DARA and 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? Yeah, and actually this paper came in the printed form of the journal today, so it's a coincidence.

So, yeah, I mean, 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 ratumumab for a period of three years. One particular aspect of this study is that this study used modern imaging techniques in both control and... patients randomized treated with daratumumab, which gave the opportunity to capture so-called skeletal related events before.

they caused symptoms to the patient. So this is an important observation. And also there was a regular assessment of hemoglobin decrease of... in clearance, repeated bone marrow evaluations, which we don't do in our daily practice. So these patients were very carefully followed.

The study showed that indeed Donatumab was able to decrease to a significant extent the progression two symptomatic myeloma based on either CRAB or what we call slim criteria, meaning definition of myeloma, but without clinically evidence. symptoms and also although the data are not mature yet there is a trend for a potential survival advantage in favor of patients receiving Daratumab. 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 two of these characteristics may become a standard of care. provided, of course, we obtain regulatory approvals by FDA and DMEA.

So, Bob, I asked both of you before we start 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's PFS. Has a rate of .49. Even for survival of not mature, has a rate of .52, although the way it's plotted, it doesn't really appear that different.

Bob, pretty significant numbers. I mean, kind of surprising to me, particularly the survival, if it really plays out. Again, do you think, are you ready to do this? Would you like to do this? 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.

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 Esa. Tuximab-Lendex as the experimental arm, and the U.S. cooperative groups are doing Lendex versus Dara-Lendex. 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. 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 Darrow 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?

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 one 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 two 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. really supports the notion that 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 good.

So I put together a few questions that I had about anti-CD8 therapy in general, both related to these. but also just, I think, clinical question I hear people asking. Just to remind everybody now, at least in terms of upfront anti-CD38 therapy, both agents are approved and the patient's not eligible for a transplant.

DARA is approved with bortezomib, thalidomide, and DEX, not a very common combination, and transpound-eligible patient. Also, just to remind us, we saw the press release from the study I just showed you that's going to be... be presented at ASCO looking at the sub-Q 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 a nurse. giving it by sub-Q 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.

Yeah, indeed I was surprised to hear that they believe that this is a better way to administer the anti-CT38 monoclonal antibody because, you know, 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 state rate over five minutes.

So it is not dependent on the rapidity that the human hand can... push slower or more the you know the drag and I believe it is something that you know may be an advantage to the patient and also to the person who is infusing the drug.

And Bob, you know, 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 a third of the world, or at least the Western world, is already. injecting some kind of GPL1 drug there, so it's not totally unheard of to do self-administration. Can you see that happening sometime in the future, Bob?

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.

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.

So it'll be interesting to see how that's... All right, 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, you know, Bob presented so many great studies that had 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 a patient's transplant eligible or not. Thanos, do you agree with that?

Yes, we have just updated the EHA and EMN guidelines for treatment of myeloma. And this will hopefully will 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 in eligible 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. For the majority of the patients with myeloma, we believe that either as induction before high-dose therapy or as a continuous treatment, either daratumab or istatuximab with bortezomib. is the new standard of care So a couple of a 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?

Yeah, definitely. So we have results from a phase three trial that took patients who were MRD positive after transplant and randomized them either to Len or to Len with Dara. group that got Len and Dara did better. We also have data from a number of phase three studies where DARA was given as part of the induction and then later in combination with LEN as maintenance that show 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.

left over 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. I think that concern will be lessened. Plus, we have PFS2 data from the upfront studies, which show how people did after they progressed on treatment. If the patients who got CD38 were doing worse, then they would have a shorter PFS on their next line of therapy.

But in fact, they do better. So again, it shows that you really should include the CD38 up front. 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, or does it affect your clinical management in the maintenance setting, Thanos?

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 one MRD value is to have what we call sustained MRD negativity. meaning at least three values six months apart. We have recently published a phase two study where we took patients after transplant who had received at least three years of lenalidomide maintenance. had at least three consecutive values of MRD negativity in the marrow and the 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.

We saw that after a median of three years, 80% of MRD negative patients remained MRD negative. So, of course, we need randomized studies. Of course, this approach may not be... 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.

So, Bob, Lilium 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 MRRD, and do you use Clonaseq? Well, right now the answer is yes, that it has to be done by bone marrow. The Clonosec is more sensitive. You do need a baseline test so that they can identify the myeloma VG.

ADJ sequence, which is later followed. So if you have a patient who you haven't gotten the clonasec 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 there not quite yet at the same sensitivity as clonasec 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.

So, Thanos, I feel like every time we do a webinar, there's always an issue that we have more than one 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 two CDA38 monoclonal antibodies. And 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 advocating safety? I mean, I think up to now, people have been basically, I think, often choosing. because you can give it sub-Q, but it seems like we're going to have the option of sub-Q, maybe even with a more favorable way to give it in the near future with ESA.

Assuming you can both give both sub-Q, is there any way to differentiate them from a patient perspective or from an efficacy perspective? Are these at least indirectly too similar to try to differentiate Thanos?

Yes, I think it is, you know, more or less they have similar efficacy and, you know, 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 that there will be a possibility to use both as a sub-Q formulation provided the price also is comparable, there won't be much difficulty choosing one versus the other.

So let's talk a little bit more about polantamide. We talked about it a little bit. I mean, I don't recall many or if any situation in oncology, not just myeloma, where we've had this situation of a very effective drug. 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 are the two studies that were presented about a year ago, the DREAM-8 study, basically comparing the addition of Belantimab. 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 Belantimab. And particularly this study. Looking at Bella VD versus Dara VD. So again, basically comparing bilantumab to daratumumab. And again, here's the 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 belantimab 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?

Yeah, I believe that DREAM7 is a study that, as you mentioned before, indicated that at least in the relapse setting, belantamab is more active to doratumumab. is a very practical regimen. because we have now almost all patients with myeloma that receive 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-CT38 monoclonal antibodies as well. So this is the exact population that can be targeted. with belatamab, pomalidomide and dexamethasone, an outpatient regimen that is not associated with the high rate of infections that we see with other immune therapies. piece. 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. So, Bob, I don't know how many patients you've treated with Belantimab on or off protocol, but again, any observations in terms of the patient experience when these patients are carefully followed but 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?

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.

some of the keynote studies, even Melflufen. The reason that Belantimab 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 three studies. So I think you could put that as a result in a much better category than some of those other drugs we mentioned.

So, Thanish, you mentioned the DREAM10 study that's ongoing right now. Can you talk and 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?

Well, I believe that based on the data that we have from DREAM7 and based on the really exciting data that we're seeing in the Phase 1, 2 study with Bellardy, I expect that this trial will show that Bell 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 will have the opportunity to use MRD negativity at least as an interim endpoint that Belatimab will show.

superiority as compared to daratumab and also in this particular trial belantamab will be given every four 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.

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

Right. As Bob said, you know, there is a spectrum. Itchy eyes is the easiest thing because you can use, you know, ophthalmic drops to hydrate the eye and this will result. 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 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 my toxicity you won't lose your response so the response

will continue and sometimes be deeper despite treatment delays. And this is also something unique in the treatment of myeloma and probably based on what... mentioned earlier in the several mechanism of action of Belantamab which is beyond the antibody or complement interaction. I was just flashing on the fact, I don't remember, I guess it was a couple of years ago or maybe three years ago, just at the same time that Belantinab 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 Callender. And at the time I interviewed her, she had been on Blantamab for four years. and was doing great. I actually just heard from Dr. Callender, and now she's three years later, 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, Bobby, 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, you know, the presence or absence of BCMA? Do you think prior CAR-T therapy, BCMA therapy might affect a benefit from belantamab? Any thoughts in general about sort of losing the marker in this situation or the target?

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 by specific.

And at least in some of the work that's been already published, especially from Nazar Baylis' 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.

So Phil Brooks again wants to know what kind of follow-up do you need from the ophthalmologic point of view? Can you just follow symptoms or 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 optometrists even. I've heard that as well. Well, 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. 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 a few initial exams and then they will be clinically followed based on questionnaires that are being developed.

validated as we speak. All right, well, let's talk a little bit about CAR-T and bispecifics, and 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 is sort of things at least I hadn't heard too much about, including this CAR-T, which I had never heard of before, a NIDO cell. And Bob, you know, 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 and what you're expecting as we move forward learning more about this agent, Bob? Well, you really hit the nail on the head in terms of the toxicity profile with this, and this was also previously called DDBCMA, so you may know it by that name.

And it does look like it has efficacy comparable to Siltacel, which is the better of the two currently FDA-approved BCMA CAR-Ts, at least in terms of... of response rate and durability but unlike siltacel which does have some both acute and delayed neurotoxicity so far it looks like anita cell 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.

Yeah, I was flashing on the old light 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 siltacel, you know, this Parkinsonian syndrome? How much of a problem actually is it with cell-to-cell?

Well, I think that if we can have a product that is associated with less neurotoxicity, especially delayed neurotoxicity, is very important because we are moving the administration of this CAR T-cell. in earlier lines and even in the frontline 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 quick 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 icons 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.

Incidentally, getting back to Belandumab, Dilip in the chat room says, quote, 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, then? can do this evaluation or do you need an MD? 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 activity and an optometrist can do it perfectly well.

and give you a number, for example, 20 over 50 degrees of visual likelihood 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 period of time, they will be evaluated by questionnaires without the need of a regular ophthalmic exam. That's great.

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

Yeah, you do see some skin effects and appetite and dysgusia as you do with the T-cell engager, but you... Hopefully, we'll 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.

Interesting. So in Thanos' talk, he has a fantastic conclusion. Like in four 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 some type of maintenance.

looked at and what are your thoughts in terms of is this a direction that we may end up in? 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. 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 two different targets. and the two agents together.

Bob, of course, I guess the 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 at that point who... 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 two years. But anyhow, what about the idea of just giving the two together, Bob? Any thoughts, and what do you think about this? initial data from the redirect study. Yeah, definitely. The redirect study, as you pointed out, combined the currently two 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 T's. 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.

road, but hopefully because you're hitting two different targets, it'll be more difficult for one cell to mutate both. 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 mouthwashes or stuff. How do you deal with this?

Right. We try to do some mouthwash with soda or with steroids. And, you know, 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 they are stopped I mean 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 other hydrating creams and eventually we may have to reduce the dose or to give at longer intervals. 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. And 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 is going through the data... on buy specifics in QART was actually, when I was looking at it, it looked like the PFS advantage was pretty similar.

for the two. You know, we don't, we don't see that, you know, and like in a 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 is 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 three or four years with the two?

And if so, then how do you decide what comes first? 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.

We don't talk about this in the current presentation, but it may be with something like ibertamide or mesignamide, which may serve to reduce T-cell exhaustion down the road.

So a couple other sort of general questions about bispecifics in CAR-T. Then, as we showed earlier, a study looking at a bispecific as part of an upfront phase 1B study. Looking into your crystal ball for the future, Thanos, do you see biosphysics or CAR-T coming as upfront therapy? How do you think it's going to be utilized and in what situations, Thanos?

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 by specifics could be applied for a restricted period of time either after, let's say, an effective quadruple as a consolidation, or if they could replace high-dose therapy with melphalan in younger patients with myeloma. So I see a role.

with limited duration because still by specifics being given indefinitely or very long periods of time put the patient at a continuous risk for severe infections.

something that is a concern, especially if you have a newly diagnosed patient. 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, prophylactics, 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.

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 engagement. They all kill normal plasma cells as well, especially the BCMA-targeted therapies. You do get hypogamma globulinemia, and we have studies showing that people who get gamma globulinemia, 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. Leave 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. So, wow, I can't believe it. I'm at my last question. We actually did all the questions. Hard to believe.

Part of Bob's presentation, Thanos, you've heard about cell mods for a while. We have mesignamide as well as ibertamide 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 Mezzi. And just to sort of, again, kind of prep the docs in the community for these agents, I assume are going to end up here. Can you talk a little bit about how Mezzi and Iber compared to lenalidomide in terms of efficacy, but particularly in terms of tolerability of Thanos and where you see these cell mods fitting in.

Right. I think iberdomite may be replacing lenalidomide as a maintenance drug. There are ongoing studies. There are promising data from phase two studies. The toxicity profile...

is different. You may have a little bit more melosuppression, but the gastrointestinal toxicity is less than with lenalidomide. On the other hand, mesignomide... may be a very useful agent, especially in the era of immune therapies, because, as Bob pointed out very correctly, we need a BCMA free... intervals in order to be able to exploit the three

potentially different mechanism of anti-BCMA therapy. And I believe that drugs such as mesictamide may be combined with calfizomib, as we are seeing in the... 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 this very active immune system.

So, Thanos and Bob, thank you so much for joining us today. Audience, thank you for tuning in. Be safe. Bye-bye. Stay well. And have a great night. Thanks so much, Thanos. Thanks so much, Bob. Have a good one. Thank you. Bye-bye.