Patient and Physician Perspectives on Multiple Myeloma Data Presented at ASCO and EHA 2025: A Podcast

00:00:00: You are listening to an ADIS Journal podcast.

00:00:05: Welcome to this ADIS podcast in oncology and therapy.

00:00:09: The podcast will focus on data presented at the twenty twenty five American Society of Clinical Oncology or the ASCO meeting with additional highlights from the twenty twenty five European Hematology Association or EHA Congress.

00:00:22: The podcast is aimed at everyone interested in the latest research in multiple myeloma presented at these scientific congresses.

00:00:30: For our listeners, you do not need to be an expert as we will keep this conversation very simple and understandable even for technical terms.

00:00:38: Today, we are joined by myself.

00:00:40: I'm Jenny Alstrom, founder and chief executive officer of the Heltry Foundation and Dr.

00:00:45: Luciano Costa, Mary and Bill Battle Professor of multiple myeloma at the University of Alabama in Birmingham.

00:00:52: The views expressed in this podcast are solely those of the authors and do not necessarily reflect those of their employers, the podcast sponsor, ASCO, EHA, or any of their affiliates, and this podcast was sponsored by Johnson & Johnson.

00:01:06: The authors have received no honoraria related to the development of this podcast, and medical writing support was provided by Amica Scientific and funded by Johnson & Johnson.

00:01:16: Now, Dr.

00:01:17: Costa, maybe you want to introduce yourself before we get started, and then after you, I'll just give a little bit of background about myself as well.

00:01:23: Sure.

00:01:24: Thank you very much, Jenny, for having me.

00:01:26: I always enjoy chatting with you.

00:01:29: And of course, particularly fun to hear each other's perspective on the new data in mutual myeloma.

00:01:36: As I said, I'm a direct the mutual myeloma program at the University of Alabama at Birmingham.

00:01:41: And I also serve as the chair of the Scientific Steering Committee for Commit Multiple Myeloma Trials Innovated.

00:01:49: Thanks for having me.

00:01:49: Wonderful.

00:01:50: Thank you so much for joining.

00:01:52: And my name is Jenny Alstrom.

00:01:53: I'm a Multiple Myeloma patient.

00:01:55: I was diagnosed in two thousand ten and in two thousand twelve.

00:01:58: we launched the Heltree Foundation with the idea that patients aggregating their data together could provide researchers with greater insights.

00:02:07: Now, today we will be talking about multiple topics from the ASCO in the IHA meetings, including emerging measurable residual disease or MRD negative-driven strategies, new immunotherapies, including extramedulary disease, toxicity management and supportive care, and precision medicine and future directions.

00:02:26: So Dr.

00:02:27: Costa, let's just get started with MRD testing because we know MRD status is this growing area of interest in the treatment landscape for multiple myeloma.

00:02:37: MRD testing could help physicians and patients with newly diagnosed myeloma decide whether to increase or reduce treatment based on how well it works.

00:02:47: Do you want to elaborate about what you learned from these different meetings about MRD testing?

00:02:53: I think you would agree with me that we really have seen MRD going from a remote concept to something that people start embracing as a potential prognostic factor, but also trials that directly answer how to use MRD to adjust therapy for somebody.

00:03:16: So the evolution this last ten, fifteen years has been absolutely fantastic.

00:03:21: As you pointed out, even though a single-time MRD has been shown to be prognostic at a different milestone of treatment, there is no doubt that there is abundant data to show that the sustainability of that MRD negativity carries a lot more weight.

00:03:40: What we learn at ASCO is an update from the ISCIA trial.

00:03:45: This study has been reported before as showing more complete responses with MRD negativity on the experimental arm, the quadrupled arm.

00:03:55: And now we also saw greater proportion of patients achieving sustained MRD negativity.

00:04:01: So MRD becoming below ten to minus five and staying dead for at least one year.

00:04:08: And that is particularly important among patients with high cytogenetic risk.

00:04:13: which is, of course, a more challenging population.

00:04:16: And that was a higher proportion of patients sustaining midi-negativity with carfusel mid-base.

00:04:22: but triplet was also demonstrated on the Ischia trial.

00:04:27: We also saw some M.I.D.

00:04:29: spings, so to speak, on the Purcells trial, which is a global registrational trial that demonstrated in a definitive manner that Daratumumab when added to the standard of care of VRD, transplant, VRD, and land maintenance, greatly improve the depth of response and progression for its revival.

00:04:51: And not surprisingly, also increases the proportion of patients with sustained MRD negativity.

00:04:58: Another portion of that as well, actually is being done right now, is to use MRD to recognize early patients who are doing extremely well, that perhaps can continue to do well with less therapy.

00:05:13: And conversely, patients who are not doing so well and perhaps need more intensification of therapy.

00:05:20: And we saw a very bright glimpse of that at ASCO with the initial results of the MEDA study.

00:05:28: So that study took patients with newly diagnosed myeloma, young patients, you're going to have sixty-five, mostly in Europe.

00:05:36: and gave those patients six cycles of quadruple therapy and then asked different questions according to MRD status.

00:05:43: If patients are MRD negative, it asks whether you can forgo transplant or defer a transplant and have those patients instead having additional cycles of EZKRD.

00:05:57: And interesting enough, that so far does not seem to be any difference between single and tandem transplant.

00:06:03: And of course, it's going to be a few years before we learn the definitive answer.

00:06:08: This answers such an important question about how to personalize treatment, how not to under-treat a patient, how not to over-treat a patient.

00:06:16: And you don't have that without this early data.

00:06:20: So having this MRD technology is truly, truly amazing.

00:06:25: Now one of the other topics that we want to talk about are bispecific antibodies or trispecific antibodies and some long-term follow-up of CAR T cell therapies.

00:06:36: We know that this whole body of research on immunotherapies is becoming so big.

00:06:43: We're so appreciative as patients that we have these new targets, whether it's BCMA or GPRC-VD or other things like that.

00:06:51: These products are providing really deep response rates, longer-term remissions, even in heavily pretreated relapsed myeloma patients, which is truly astounding.

00:07:01: You're seeing these response rates that are very high that you never really saw before in the myeloma toolbox.

00:07:07: And some of these new treatments are tackling this antigen escape idea where cancer cells are changing or they lose antigens on their surface and they may shift immunotherapy from a salvage to a frontline treatment.

00:07:20: And as we know, you know, you test these things out in highly relapsed patients and you kind of bring them up in earlier lines of treatment once you have determined how effective they are.

00:07:30: And obviously everything's been through safety before, but it's very nice for a more newly diagnosed patient or first or second line patient to be able to take advantage of some of this newer technology because it's so much more effective.

00:07:43: So maybe we'll want to talk about that.

00:07:45: and then the prognosis and unmet need for people who have extramingular disease.

00:07:51: Those are of course two very hot topics and they kind of intersect.

00:07:56: We're seeing something that was never seen before.

00:07:59: You have drugs that by themselves are giving better, deeper and sometimes longer responses in patients with multi-relapses.

00:08:10: that you can achieve with combination in newly diagnosed disease.

00:08:15: I think it's going to be a very short period of time before those therapies come into earlier use.

00:08:21: We're going to see the trials mature in the upcoming months to a few years using bi-specific T-cell engagers in earlier lines.

00:08:30: We already have data for BCMA-directed CAR-T-cell therapy as early as in second-line therapy.

00:08:37: with improvement in progression for survival and overall survival.

00:08:41: And we're starting to see now data pop up with those therapies used in newly diagnosed setting.

00:08:47: So there's two particular studies worth mentioning.

00:08:51: One, it was actually from last ASH with the initial part of Majestic V. So that was the Bispacific T-cell Engager.

00:08:59: The ClistaMab combined either with Linnolidomide and Dartumomab or Linnolidomide, Brutismib and Dartumomab.

00:09:07: In long story short, everybody respond and everybody who had enough therapy to be re-evaluated had MID negative response.

00:09:16: And we saw something similar at ASCO with the Magnetism VI tribe.

00:09:21: So this is an older population, not eligible for transplant.

00:09:26: And the default in those patients can be assumed to be linalidomide and dartumomab.

00:09:32: And now they combine EuronataMab, which is a BCMA directed by specific T-cell engager.

00:09:39: And we don't have MRD data yet, but long story short, everybody responded, and most of the responses are deep response.

00:09:48: So I think to see the current by specific T-cell engager as being certainly transformative, but this is just version one point all, right?

00:09:58: We are starting to see the evolution of those therapies, not only in terms of finding better safer combinations, finding better safer schedule of administration, but also developing new T-cell engagers altogether that could come with a better efficacy or even a better toxicity.

00:10:23: We did see the first glimpse of that at ASCO.

00:10:27: with the first disclosure of the data for a tri-specific T-cell engager called JNJ- five-three-two-two.

00:10:36: So that is an antibody that binds the T-cell, like the ClistaMab or the QuettaMab does, binds BCMA, like the ClistaMab, and binds GPRC- five-two, like the QuettaMab, with a different site, with a different affinity.

00:10:52: But on developing this therapy, the investigators took the opportunity and addressed all the elements that have been a concern for the implementation of the ClistaMap, TuquetaMapo, and EuronataMap.

00:11:07: So they develop a therapy that is a single flat dose, giving once every four weeks outpatient with one step up dose.

00:11:16: And by giving prophylaxis, they essentially eliminate the risk of a higher grade CRS.

00:11:22: So now, you know, we're getting to a regimen or to a therapy that is no longer super sophisticated, needs a specialized center, but something that in the future, I believe most pileable patients could receive at their doctor's office, even if that's outside the hospital setting.

00:11:41: Just needing to go to an academic center from a patient standpoint is sometimes very difficult.

00:11:46: We're learning so much after these come out and they become FDA approved, and then you get to use them in your practice.

00:11:52: And maybe you want to explain step-up dosing.

00:11:55: I don't know how many patients know what that is.

00:11:57: Yes, so that's a great point.

00:11:59: For device specifics that we have currently approved, the ClistaMap, the QuetaMap, and IrannataMap.

00:12:06: the main immediate toxicity, something that's called cytokine release syndrome.

00:12:12: And the way I explain to patients is cytokines are substances that our body produce or immune system produce to orchestrate an immune response, right?

00:12:24: Our immune system is extremely complicated, different cell types, they need to communicate with one another in order to coordinate that attack, so to speak.

00:12:34: And the way they communicate with one another is by releasing those substances called cytokines.

00:12:41: Well, when we give somebody car T cell, or in this case, a bi-specific T cell engager, we essentially overwrite all the physiologic mechanisms and induce a very robust activation of the T cells and immune response.

00:12:58: So that releases cytokines, a bunch of them, some are more important than others, that make people have a fever.

00:13:07: And in more extreme cases, can make people have a lowering of the blood pressure, problems oxygenating their blood, or even needing intensive care.

00:13:19: Well, in the early days of developing those therapies, we learn a few tricks.

00:13:25: You don't give the intended dose on the first day.

00:13:29: You give a fraction of a dose and then you can have another three steps or two steps or depends on the drug we're using until you reach the intended dose and surprisingly as you do that the reaction goes down.

00:13:46: So we learn a lot about how to manage this but at the present time those drugs are still recommended to be followed with initial hospital observation for those first two or three doses, right?

00:13:59: And beyond that is not an issue anymore.

00:14:02: Once you kind of a break in, the CRS essentially does not occur.

00:14:06: So in developing this therapy, the investigators address that had on by giving preventively this medication called Tocillizumab that blocks one of the main cytokines that drive their reactions, called interleukin-six.

00:14:24: And by doing so, you know, this became essentially a known issue.

00:14:29: Patients had essentially grade one CRS, which is fever, and nobody had the bad type that required hospitalization and ICU care, which becomes a much more predictable profile for a therapy that is intended to be given in the office.

00:14:46: not necessarily the hospital setting.

00:14:49: You have now two ClistaMab, Talcatamab, Linvoseltamab got approved this year, and OrangeMab.

00:14:56: So you have four of these bi-specific antibodies, and then you just had mentioned the trispecific antibody.

00:15:02: And so learning how to administer this in better ways, and then having the proactive Tosalusamab plus just one step up dose, it's just getting better and better how you administer this.

00:15:14: It's great.

00:15:15: Now we see that second devolution, right?

00:15:17: Now try specifics.

00:15:18: So you mentioned the G&J five three two two product, but there's an additional one as well.

00:15:24: Now the ISP two one.

00:15:27: well one targets BCMA, CD-E thirty eight and CD three.

00:15:33: So it doesn't have the GPRC five D it has CD-E thirty eight.

00:15:36: The first thing that everybody asks is Well, but, you know, aren't we already using CD-Thirty-Eight when we use drugs like Isatuximab or Eratumumab?

00:15:46: Yes, indeed we are, but here's a different site of binding to CD-Thirty-Eight.

00:15:52: And despite the vast majority of the patients in that study had already received therapy with an anti-CD-Thirty-Eight, And a lot of those patients have received other T-cell redirecting therapy.

00:16:05: They still show a response rate of seventy-nine percent, which is of course very encouraging.

00:16:11: And I'm pretty sure we're going to see development of this trispecific in the upcoming years for the benefit of our patients, of course.

00:16:19: Well, it's fascinating to see two different approaches with a trispecific antibody.

00:16:23: We know that GPRC-VD and BCMA are great targets.

00:16:26: And we also know that BCMA and CD-III are great targets.

00:16:30: So that's fascinating.

00:16:32: And then CAR-T is coming along as well.

00:16:34: We're learning on still a lot, a lot, even though that started before by specifics.

00:16:38: Absolutely.

00:16:39: And I think this meeting was a little bit surprising, in a way.

00:16:44: By now, we all have learned about CAR-T-V-I.

00:16:48: This was a trial that support the initial approval for seal to sell.

00:16:53: very high response rate, durable responses.

00:16:57: Then we had Cardytid IV with early lines of therapy, improvement in progression for free survival and overall survival, supportings of the cell in second line therapy and so forth.

00:17:08: So what we saw in this meeting, perhaps one of the most celebrated findings that was disclosed in this meeting is the very long term, five years.

00:17:18: off-patients treated with cartitute.

00:17:20: So those are patients who all had the three main classes of therapies.

00:17:24: They either de-aid, immunomotority aids, exporters of inhibitors.

00:17:29: They all had disease progressing in their last line of therapy.

00:17:32: So if you go back in time, ten years ago, or eight years ago, when Nicola and Chibata entered the myeloma landscape, A patient like that would have, in average, a thirty percent chance of responding to whatever you try.

00:17:45: And those responses tend to be very short-lasting, and the average survival for those patients was less than a year.

00:17:52: And now you have a therapy that is a one-time treatment.

00:17:56: And now, at five years later, one of every three patients is alive, disease-free, and a subset of those patients who had had one particular institution being very regimental in terms of assessing MRD, doing PET scans eerily, near all those patients remain MRD negative and PET negative.

00:18:20: So when I saw the data, my first thought was fantastic for those patients.

00:18:25: If you can do that in disease that is already highly refracted, right?

00:18:29: It's almost ironic that the population that is first bringing the word cure into the mainstream of myeloma is people with refractory disease, not the newly diagnosed, right?

00:18:42: So it gives you an idea of how much we can be able to cover in the upcoming years as we bring this auto-directing therapy into early lines.

00:18:52: Of course, there are challenges that are much more acceptable when you're dealing with a more desperate situation than there are newly diagnosed patients.

00:19:01: For example, our tolerance or willingness to accept a risk of second malignments or a risk of delayed neurotoxicity or risk of infection might be quite different in the upfront setting that it is in the relapse refractory setting.

00:19:17: And I think learning more about the patients who experience that and who don't will give you a better idea because then you feel safer about doing it in an earlier setting and you have confidence.

00:19:29: So you can have that risk benefit discussion with your patient in a really informed type of ways.

00:19:34: And then you saw a CAR T brought up in earlier lines of therapy, right?

00:19:38: This point is very well taken.

00:19:40: I think some of the, not the nature of the problems, but the magnitude of the problems that we have learned with CAR T, you know, the neuro toxicity, the high-grade CRS and the second malignal and so forth, they are likely to be minimized when you move to earlier lines because you're infusing on patients who have a disease that is less proliferative, right?

00:20:09: I tell patients the disease is the fuel to the fire, right?

00:20:13: So when you infuse, when you're unleashing this very powerful drug or cell drug that is able to proliferate and engage with more target in somebody who has a lot of disease, you're adding a lot of fuel to the fire.

00:20:28: Now, if you're doing that in a setting where the disease is more constrained, the disease is another downward trajectory.

00:20:35: And you have less of that, you have less of that toxicity.

00:20:40: So a lot has been said about the importance of bridging, which is essentially the therapy that you give between collecting the cells and the four or five weeks that it takes to manufacture those cells.

00:20:55: But the reality is when you're doing this for patients with six, seven, ninths of therapy, whose disease is reflected to anything for everything, you don't have a lot of safe options, right?

00:21:05: Or options at all.

00:21:07: Now, as you move, as you learn evidence in earlier lines, and we saw that we carted to four, now you take patients who had LAN refractory disease, not necessarily TIPR class refractory, the majority were not, and you had proper bridging, which in this trial was DARA-POM-D for the majority of patients, and you have a disease.

00:21:28: on the downward trajectory that therapy becomes a lot safer, with very few, if in any cases, of serous grade three or higher, much less of the delayed neurotoxicity, and essentially much less of the eye cans.

00:21:43: So some of those problems are going to improve biting cells as we redefine the population.

00:21:51: that can best utilize that therapy.

00:21:54: GPRC-VD as well is becoming a target in CAR-T, which is so fascinating to see.

00:21:59: Yes, indeed.

00:22:01: We are seeing, of course, GPRC-VD is a very well clinically validated target.

00:22:08: We learn with TokwetaMab how relevant that can be.

00:22:11: You have responses in close to seventy percent of the patients.

00:22:15: The challenge with GPRC-VD, as you know, The expression of that protein is not unique to myeloma cells or even plasma cells.

00:22:26: It's expressing other tissues such as skin, nail bed, taste buds.

00:22:31: So the initial exposure to that therapy can lead to skin changes, can lead to rash and changing taste.

00:22:38: that ultimately leads patients to... have some weight loss, which can be very disturbing to patients.

00:22:44: We certainly have learned a lot about how to use the drug.

00:22:49: with less frequent dosing, and with more time, those symptoms tend to get better, people regain their weight, and actually can be a very reliable long-term strategy for disease control.

00:23:00: But we also learned that, unlike BCMA, the myeloma cells very quickly can drop GPRC-V-D.

00:23:07: So losing GPRC-V-D for the cell does not seem to affect its ability.

00:23:13: And the risk of infection seems to be quite less than what you see with BCMA directed therapy.

00:23:18: But the fascinating picture that is formed in gene is both for Tuquetamab and for GPRC-V-D directed CAR-T cell, the prior therapy with a BCMA CAR-T does not seem to affect or in much or not effect at all the responses down the road for those GPRC-FID directed therapy, really telling us

00:23:43: or

00:23:44: reminding us those are really different targets, independent targets.

00:23:48: And even if that disease has become resistant to BCMA directed therapies, GPRC-FID directed therapy, I still like it to work perhaps to the same rate and to the same depth that in those naive patients.

00:24:02: Well, the meetings also talked about four drug therapies, right?

00:24:05: So combining, so going from really a triplet combination therapy idea to a quad therapy idea.

00:24:11: Quads have been developed now for near a decade, but mostly as a therapy for younger, more fit patients who we generally regard as transplant eligible.

00:24:23: But now we have two large trials with one cause to fuse with DARA VRD.

00:24:31: And the other cow in rust with isotuximab VRD.

00:24:35: So two different CELi-TERD-EIII monoclonal antibodies.

00:24:38: And in both shows, there are similar things that when you add this therapy to a backbone of VRD, you have a huge improvement in progression for survival.

00:24:50: Well, that'll be interesting to learn.

00:24:51: And I know the meetings talked about extra medullary disease, which is myeloma that has escaped outside of the bone marrow and lodged itself somewhere else in the body.

00:25:01: And that's typically harder to treat myeloma.

00:25:04: But maybe you want to share what was found in the meetings for extra medullary patients because they have a distinct need.

00:25:12: Absolutely.

00:25:12: And I would say EMD, or extra medullary disease, became a buzzword lately.

00:25:18: So, extramedular disease is something uncommon at a time of diagnosis, not impossible but uncommon, but becomes more frequent, more common as patients go through multiple lines of therapy.

00:25:31: And we don't have any therapies that work extremely well for those patients.

00:25:35: And when by specifics were first tested, the patients with extramedular disease tend to have less frequent response.

00:25:43: So it was actually very surprising when the first study was reported, combining two by specifics.

00:25:51: And we see that two therapies that give party percent response, when they got combined, they had close to eighty percent response in this study that called redirect one, that first work up the optimal dose and schedule for those drugs to be given together.

00:26:10: So some maybe look at this and say the numbers actually might look better than it does with CAR-T cell, single target CAR-T cell.

00:26:18: Not to mention the fact that bispecifics are off the shelf.

00:26:22: So if you have a patient in front of you with extra medullary disease, fastly growing disease, the earliest that CAR-T is going to be infused are six to eight weeks down the road.

00:26:32: While bispecifics in theory could start within a few days.

00:26:36: It's of course an expensive combination, a combination that requires a lot of supportive care because of the risk of infections that come with it and the GPRC-V directed toxicity, but a combination that might be very appropriate for those patients with EMD.

00:26:52: Now we have all these questions as patients and you as a physician, how do you use these in the real world?

00:26:59: What are you learning about using these new immunotherapies earlier versus later?

00:27:05: Or how are patients getting to know the management of some of the side effects?

00:27:09: And when you think about academic center products being used versus community providers using some of these new tools, because sometimes when we're out in the community, Patients have not even heard of CAR-T or by specifics before and to me that's just shocking.

00:27:26: That's one of the reasons we're trying to run some of these programs is to educate patients on that, that they have these new therapies available.

00:27:33: To me it seems like a big shame that that therapies are FDA approved and have been tested and you can get these and they have these incredible seventy, eighty, ninety, hundred percent response rates and they're not being used sometimes.

00:27:47: How do you think about that in your practice?

00:27:50: Ultimately the patient is the decision maker.

00:27:53: You give the information, you give your perspective, you even give your opinion, but then is that the patient to make the decision.

00:28:01: How are patients perceiving this?

00:28:03: Are people rushing to see those therapies available early, expecting that?

00:28:10: Or do you think patients are more reluctant to embrace therapies that are so new and have some toxicities that are not totally well understood yet?

00:28:19: I think patients, if they know about these newer therapies, they want them.

00:28:24: And so it's a matter of getting to the patient and saying, look, he was a patient, you need to advocate for yourself.

00:28:29: You need to be informed enough to know what's out there and available.

00:28:33: You need to be asking your doctor about it.

00:28:35: Sometimes they don't get it mentioned because sometimes the doctor doesn't feel comfortable administering it or whatnot.

00:28:42: And in that case, you probably need a specialist on your team.

00:28:45: That's why we always advocate that a patient has a specialist on their team.

00:28:50: They don't have to go to that doctor all the time, but it's important to be aware of these newer therapies so you can ask your doctor about when they're right for you.

00:28:59: So to me this is just a whole lesson in patient education, patient advocacy, teaching patients how to become self-advocates so they bring this up with their doctor.

00:29:09: Well, let's talk about side effects for a little bit.

00:29:11: So some of these drugs have newer side effects that we didn't have before.

00:29:16: Like in myeloma, you didn't really deal with nausea or things like that or other types of things.

00:29:21: And some of these drugs introduce new concepts that the myeloma providers are now really well able to manage.

00:29:30: But making sure that everybody knows how to manage them, the caregiver, the patient, the community provider, and everything is important.

00:29:37: So maybe you just want to talk about some of those findings and side effects and how you manage them.

00:29:42: So I think that's very important and if you look at the by specifics today, you know, we're in middle of twenty-twenty-five and compared to two years ago, it feels like it's almost like a different drug.

00:29:57: Of course the drug didn't change.

00:29:58: What changed was how we deal with it and how we manage the therapy and also the better job that we are doing at matching the right therapy to the right patient.

00:30:09: And I think that the toxicities are, you know, they fall into a few categories.

00:30:14: One is the immune mediated toxicity.

00:30:17: They're talking about a cytokine release syndrome that I discussed earlier and something called ICANS, which is the immune effector cell associated neurotoxicity syndrome, which for those who haven't heard of that before, it's better described in the context of CAR-T.

00:30:33: It's very rare, if ever, by specific cell engagers.

00:30:37: It's believed to be related to some cytokines going into the brain tissue.

00:30:43: And the manifestation can be changes in handwriting, changes in ability to name objects, do quick math or even articulate words.

00:30:56: Does toxicity happen at a very specific time, as far as two, three weeks of therapy?

00:31:02: In the case of bi-specific, when it ever happens, usually the first week, they are not permanent and they are usually promptly reversible with steroids.

00:31:10: So I think that and Sierra asks, are the ones who we hear first, we hear the most?

00:31:17: We have to do training on those topics to be able to prescribe those drugs.

00:31:22: But honestly, nowadays they are not very relevant element on decision making because it's uncommon or very rare for somebody to have a life-threatening... CRS or ICANS with existing therapies and because we have better ways to recognize and manage and so forth and those patients are under direct observation anyways.

00:31:43: Now the problems that I think are disturbing to patients and intriguing to us are the rare but serious late-term complications.

00:31:53: you know in the case of CAR T cell we're talking about, you know, Bell's palsy that seems to occur in about, you know, one to three percent of the patients usually take some steroids and get better.

00:32:05: We don't fully understand the mechanism.

00:32:07: There is some inflammation around the facial nerve.

00:32:09: The other toxicity is the movement disorders, Parkinson's-like symptoms.

00:32:16: They're describing about one percent of the patients.

00:32:19: Fortunately, it's rare.

00:32:20: It seems to be more common in patients that are treated with a high disease burden.

00:32:23: We're starting to develop some early attempts to intervene on patients who might be at risk of those toxicities.

00:32:32: A lot of our patients will have a very rapid expansion of the cartils.

00:32:36: The number of cartils in the blood rises very quickly in the second, third week after a cartil.

00:32:41: And those are not toxins that we have seen with bi-specific disengaged.

00:32:46: Let's be clear.

00:32:47: The other problem that I think is less of a challenge now that it was four or five years ago, but it's still a challenge, And that's the one that every physician, three-dimensional patient needs to be aware of.

00:32:58: Because that does not happen in the, you know, it's not limited to the expertise of the treatment center during those first two or three weeks.

00:33:07: It's the risk of infection.

00:33:09: So that is very high for BCMA directed therapies.

00:33:13: And part of how that works, that kills everything that has BCMA, including mature B cells and mature plasma cells.

00:33:21: So if the treatment works and you want the treatment to work, that patient is not going to be producing monoglobulins for the entire duration of the bispecific therapy, or for at least six months after CAR T. So there is now several guidelines.

00:33:37: They are very similar.

00:33:38: They essentially say, get all your vaccines, get IVIG when your monoglobulins are low and your monogamous will be low.

00:33:46: essentially for the entire duration of biospecific therapy or for at least six months after CAR-T.

00:33:52: Ever patients should be forever on encyclovir or valocyclovir.

00:33:57: Prevent pneumocystis pneumonia with bactrine three times a week for the first three months after CAR-T or for at least the duration of therapy for those on biospecific.

00:34:08: And important is any early signs of infection need to be addressed aggressively.

00:34:15: So if you have a fever in the first two or three weeks, most likely CRS, you're going to be under direct observation of a specialized team.

00:34:23: But if you're having fevers a month later, two months later, it's not CRS, it's the infection that you're proving otherwise.

00:34:29: The other part is the GPRC-VT direct therapies, calcium GPRC-VT related toxicity.

00:34:37: That is something very tricky because we don't have yet high level data randomized trials that teach us how to improve on those boxes.

00:34:50: For the most part they are not life-threatening.

00:34:52: We talk about.

00:34:53: our nails look funny, they look split easily, they look weak.

00:34:58: You can have a skin rash.

00:35:00: that's usually in the first you know, a few weeks that tend to get better over time.

00:35:04: And I think that bothers people the most is that things don't taste right and people can often lose their body weight.

00:35:10: So there's a lot of remedies.

00:35:13: One of them, particularly for the taste issue, is You know, use foods or food additives that can kind of spice up the taste.

00:35:24: Sometimes acids, lemon drops to preempt your your taste buds before a meal.

00:35:30: Sometimes patients describe a change in the perception of texture.

00:35:34: It's like, you know, things feel dry and don't go down easily.

00:35:38: So it's not the best time to explore the new bread that the new bakery around the corner start making.

00:35:46: It's time to go more for the soft foods, have a bite and have a sip of this, you know, back to back, go for the milkshake, goes for the things that have nutritional value and then go down more easily.

00:35:58: for the skin, you know, moisturizers, things that don't have a lot of additives, sometimes nail polishers to give some protection to the nails are not splitting, you know, our team has developed and every institution has developed a series of package of recommendations to give to patients.

00:36:15: What we often do as physicians is reduce the frequency of a demonstration.

00:36:21: after a certain number of doses.

00:36:23: that varies by the patient, by the judgment of the doctor.

00:36:26: And that has been shown to reduce the frequency and severity of some of those toxicities.

00:36:32: And then in the meetings, I noticed that Bellantima and Maffidotin might be making a comeback and has some eye-related issues.

00:36:40: Do you want to just briefly cover that?

00:36:42: So, Valentin Mabma, for those who don't know, it's a drug that was briefly available in the United States for, I think, a little bit over a year and was voluntarily removed, waiting for more definitive data.

00:36:58: And now my comeback, now that we have a couple of trials that have been performed and resulted showing improvement in disease control, and one of those trials also improving overall survival.

00:37:09: But the biggest challenge with this medication has been that the byproduct of that drug that is delivering high concentration in the cell can cause some transient toxicity to the corneal tissue so they can lead to blurry vision.

00:37:23: And most patients will have some and a few patients will have a lot of it.

00:37:29: And the timing is very variable.

00:37:32: Sometimes you can be on the drug for months and then develop it slowly.

00:37:35: It can be very sudden on the first few doses.

00:37:38: It seems to be reversible in near all cases, but the reversibility can take quite a bit of time.

00:37:46: One of the hindrances of this drug is the trials in the initial approving of the United States require an ophthalmologic exam before each dose.

00:37:55: So I think this therapy is likely to come back because there's more and more trials.

00:38:00: I think that a lot of the success or lack thereof of this drug is really going to depend on how the practices evolve around this drug.

00:38:09: I think it's being perceived as very promising, particularly for patients who are not in academic medical center getting CAR-T or by specifics.

00:38:20: But our patients who perhaps are more frail, not willing, not willing or able to travel, who don't want to have to spend time in the hospital or even receive a therapy that has a reasonable chance of a taxis that may land in the hospital.

00:38:35: For that, patients at the LentaMab offer a new mechanism of action with a new target that's otherwise being explored that clearly can advance their control of their disease, particularly when given in combinations.

00:38:49: This continues with that shared decision-making, improved communication that you need to have, and that communication that needs to happen between a community provider and an academic center specialist too.

00:39:00: because in the meeting there was some data that came out about the veteran population that certain certain things like chronic kidney disease or maybe older patients or black patients or things like that people weren't getting referred out so much.

00:39:16: So we need to think about how does everybody get access to the same types of treatment so everybody can benefit from these good results.

00:39:27: Absolutely.

00:39:28: I think two things that are crucial, Jenny.

00:39:31: One is, as you pointed out, is access, right?

00:39:34: I mean, if you have all those wonderful therapies approved, but they are of no good if people cannot get them.

00:39:40: But also patients, and I totally echo what you said earlier, the patient needs to be their number one advocate.

00:39:47: They need to feel in power to seek out information and question.

00:39:53: the recommendations in a good way, the recommendations that are being made.

00:39:57: And of course, there's some room in the upcoming years to better understand the toxicity and as you said, develop models that we can take to the clinic to help ascertain the risk for that individual patient and then having an informed discussion with the patient of the pros and cons of pursuing such therapy.

00:40:18: And the second point that I think is very important, and I love seeing how re-award evidence is being elevated in its respectability as we look at evidence for cancer treatment, particularly myeloma.

00:40:31: And of course, you and the Health Tree have really accelerated that by hearing the voice that matters, which is the patient voice, but also learning how therapies perform in people who are not necessarily the ones in clinical trial.

00:40:46: that tends to be a population that's more standardized with fewer comorbidities and less racial diverse.

00:40:52: And the tremendous work has been done on generating that data, for example, for CAR-T cell advice specifics.

00:40:58: And we learned something very valuable that some therapies can be given safely for patients with chronic kidney disease, even dialysis, even though there was never tested that way in clinical trials.

00:41:10: But when you start treating hundreds of patients, you can collect the data, learn something.

00:41:15: Absolutely.

00:41:15: and that brings us to our last topic which is precision medicine and what health trees doing is inviting patients to collect their records into a single place so that patient becomes their own data aggregator.

00:41:26: and then we want to open that data up to the research community.

00:41:29: and then once you do that we go through multiple steps.

00:41:32: We're aggregating the data, but then we're cleaning it, and then we're validating it against AI models.

00:41:38: And what we're finding is that AI can be very helpful to do certain things.

00:41:42: For example, you could take MRD results, and you could see who's more likely to progress.

00:41:48: Same thing in smoldering myeloma.

00:41:50: You can do an immunoprofile of a smoldering myeloma patient, or do deeper genetic testing like a whole genome sequencing.

00:41:58: and really identify who is going to progress to active myeloma.

00:42:02: I think, you know, tools like AI give the perspective of understanding, for example, you know, finding patterns, right?

00:42:12: This could be expression of clusters of differentiation in a subset of T cells, but also could be symptoms, right?

00:42:20: You might have a symptom.

00:42:21: that seems weird.

00:42:23: Nobody picked that up on a clinical trial with a hundred patients, but now we need to treat a thousand.

00:42:28: and everybody's inputting data, that becomes a discernible pattern.

00:42:32: And that can help us identify blind spots on our therapies, oppositions that have not been reported before, things that are important for patients that we have not paid attention to.

00:42:45: So the value of that is really hard to even understand fully.

00:42:51: And I think what you are doing with the Health Tree is fascinating.

00:42:56: by taking the perspective of the patient and essentially acknowledging the fact that the data is zoned by the patient because it's their data and taking the patient's willingness to share that information with identified way for the sake of the greater good is brilliant.

00:43:15: Patients have a superpower that they have access to all of their data and they can share it with anyone that they want to make research go faster.

00:43:24: Okay.

00:43:24: It's time to wrap up.

00:43:25: I think we'll just kind of cover the points that we made earlier.

00:43:30: We talked about MRD negativity that it's becoming more of a therapeutic goal and a monitoring benchmark.

00:43:36: It's becoming really standard of care and I think any patient should be asking their doctor about MRD testing when and how to do that.

00:43:44: We know that new immunotherapies can achieve long-term disease control and remission that was previously really unheard of.

00:43:51: We talked about the results that we're seeing from by specific antibodies, CAR T, all these different new therapies and looking forward to the future for trispecifics and things.

00:44:01: We're looking at supportive care, being essential to maximizing treatment benefit and limiting treatment toxicities, and how there is a good handoff that can happen between community provider and academic center, and then how personalized treatments could reshape outcomes for patients, including those with high-risk smoldering meloma.

00:44:20: Is there anything else you want to share for the wrap up?

00:44:23: I just want to thank you for giving this stage for us to learn from each other and I'm doing so also share some new directions that the treatment for this annoying disease is going with the therapies that we now have.

00:44:38: So thank you again.

00:44:40: Well, thank you for being an expert in myeloma, for caring for myeloma patients every day and for everything you're doing in research.

00:44:47: Really what you're doing is extraordinary.

00:44:49: So patients, thank you very much for that.

00:44:52: And we thank our listeners for

00:45:22: listening.