Episode 153: Myeloma Capstone, Pt 2 - MRD-Guided Therapy, Maintenance, and Relapsed/Refractory Sequencing

Summary

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The Fellow on Call: The Heme/Onc Podcast

Episode 153: Myeloma Capstone, Pt 2 – MRD-Guided Therapy, Maintenance, and Relapsed/Refractory Sequencing
Guests: Dr. Mani Moyuddin (Huntsville Cancer Institute/University of Utah) & Dr. Adeel Khan (UT Southwestern)
Release Date: April 22, 2026

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Episode Overview

This episode dives deep into current approaches to multiple myeloma management, focusing on:

• The role and application of minimal residual disease (MRD) testing
• Individualized strategies for maintenance therapy
• Sequencing of therapies in relapsed/refractory disease, with a keen look at integrating new cell therapies and bispecifics

Throughout, the experienced roundtable—hosted by Ronak, Vivek, and Sean—offers practical, evidence-driven perspectives, referencing relevant trials and sharing pearls for adapting approaches to the rapidly evolving landscape.

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Key Discussion Points & Insights

1. MRD Testing: Real-World Utility and Implementation

(01:06–08:18)

• Clinical Integration
  Dr. Khan notes MRD has become a top patient question:

  “I check it really at every opportunity I have for a bone marrow biopsy.” (01:36, Dr. Khan)
  Most commonly after induction, post–transplant/CAR-T, and during maintenance:

  • Induction: Decide on transplant/CAR-T candidacy
  • Maintenance: Assessing sustained MRD negativity or progression

• Depth of MRD Assessment

  • Acknowledgement that clinical practice commonly uses higher sensitivity (10^-6), compared to some older trials (10^-5), leading to apparent discrepancies in MRD negativity rates.
  • “You might look MRD negative with a less resolution look, but you won’t be once we have our conventional tests.” (03:00, Dr. Khan)

• Guiding De-escalation
  For patients with sustained MRD negativity (standard risk), therapy can often be reduced—on a case-by-case basis, balancing treatment intensity and patient quality of life.

Timing and Sustained MRD

(04:00–08:18, Dr. Moyuddin & Dr. Khan)

• Induction Duration:
  Dr. Moyuddin suggests MRD assessment after 6–8 cycles if induction is to guide transplant, echoing the MIDAS trial approach.
• Stopping Maintenance:
  Spanish Ixazomib + Revlimid trial offers a data-guided point:
  • MRD-negative after 2 years? Stopping therapy yields ~83% 4-year PFS.
  • MRD-positive patients continued on Revlimid, with 4-year PFS ~50%.
• Applicability Limits:
  For high-risk patients, there is hesitance to stop maintenance; personal anecdotes support caution.

Notable Quote:

“For standard risk disease, the outcomes are excellent and it is our duty now to design trials where we stop treatment even earlier because we know that the outcomes for these patients are really good once they achieve MRD negativity.”
(07:31, Dr. Moyuddin)

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2. Maintenance Therapy: One Size Fits … Whom?

(08:18–13:37)

• Doublet Maintenance
  Dr. Khan favors DARA-Len (Daratumumab + Lenalidomide), often prioritizing DARA when long-term Len is not well-tolerated due to SPM risk and patient symptoms.

  “The DARA-Len just works very well … I tend to do is push for DARA-Len doublet maintenance for most patients.” (08:49, Dr. Khan)

• Re-examining Revlimid’s Place

  • Dr. Moyuddin challenges the assumption that Revlimid maintenance offers OS benefit in the modern, post-transplant, post-novel agent landscape.
  • Notes the foundational Revlimid maintenance data is now outdated, as regimen backbones and salvage treatments have evolved:

    “Maintenance works best when pre-maintenance therapy is … bad and when post-maintenance therapy is bad, that’s when maintenance is going to shine, right?”
    (11:10, Dr. Moyuddin)

  • High-risk patients: No approach (stop, continue, combine) seems to substantially change 3-year relapse rates.

• Emerging Drugs—Cell Mods

  • Anticipation for iberdomide’s approval; ongoing studies will clarify its maintenance role.
  • Both guests agree: Without trial data, expanding maintenance options risks being guided by habit rather than evidence.

• Cost & Access Considerations

  • Acknowledgement of the substantial, often prohibitive, cost of lenalidomide—even post-generic status (13:37, Dr. Khan).

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3. Sequencing Therapy in Relapsed/Refractory Myeloma

(14:42–27:07)

Modern Second-line Choices: CAR T, Bispecifics, & More

• Case Presentation & Decision Algorithm
  Given new lytic lesions and relapsed myeloma (post VRD, auto transplant, Revlimid maintenance):

  • BCMA-Directed Therapy:
    • Three RCTs (Belantamab, Teclistamab [TEC], Cilta-cel) support BCMA-therapy superiority over standard triplets
    • Preference for Teclistamab (“Teclistamab will probably give better efficacy results and it’s a more predictable safety profile.” (17:33, Dr. Moyuddin)
    • Cilta-cel reserved for higher-risk, refractory cases due to toxicity unpredictability.

  Quote:

  “There is no clear right answer, therefore there’s no clear wrong answer … we can accept that it’s gray and that it’s constantly evolving.”
  (19:50, Dr. Khan)

  • Trial Differences:

    • Teclistamab trial population: less heavily pretreated, less DARA-exposed/refractory.
    • Cilta-cel: more high-risk, len/data-refractory patients.

  • Patient Preference & Logistics Play a Role

    • Center location, willingness for frequent appointments, side effect profiles, and access inform therapy selection.

Bridging Therapy Before CAR T

• Standard Bridging:

  • Carfilzomib/Pomalidomide/Dex (KPD) still widely used as effective bridging.
  • For urgent, high-risk, or extramedullary disease, may need cytotoxic chemo or fast-acting bispecific like talquetamab.

• Timing/Sequencing with Bridging & Pheresis:

  • Avoid bispecifics or cytotoxic chemo before T-cell collection if possible. If bispecifics (talquetamab) must be given, hold them at least 4 weeks before apheresis.

  • “If at all possible, I try to get the apheresis done before giving talquetamab or before giving cytotoxic chemo. If you give talquetamab before you do apheresis, there’s a much higher likelihood of getting an out-of-spec product.”
    (25:02, Dr. Moyuddin)

  • Too cytotoxic a bridging regimen (i.e., classic salvage PACE) can damage T-cells needed for CAR T manufacturing.

  • Sometimes "line of therapy" definitions require creative structuring to access desired agents.

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Notable Quotes & Memorable Moments

• On the Future of Maintenance:

  “I hate to burst BMS’s bubble, but their golden age of long-term maintenance and their drugs being used forever is over.” (13:13, Dr. Moyuddin)

• Rapid Change in Myeloma:

  “This seems to change about every six months. At every American Society Hematology meeting in December, every ASCO and European Hematology associated meetings in June, and then our September International Myeloma Society meetings, the game changes.” (21:45, Dr. Khan)

• On Individualization:

  “Even with sequencing therapy decision making, it is not one size fits all … there are so many nuances and a lot of it is dictated by the individual patient, their biology, and also their preferences, the logistics of getting to clinic, et cetera.” (27:07, Ronak)

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Key Timestamps

| Timestamp | Topic | |-----------|-------| | 01:06 | Start of MRD discussion; practical use cases (Dr. Khan) | | 04:00 | Timing and duration for MRD assessment (Dr. Moyuddin) | | 07:31 | Validating MRD-guided therapy discontinuation | | 08:18 | Approaches to maintenance (DARA-Len, Revlimid, high-risk nuances) | | 11:10 | Revisiting the basis for maintenance therapy | | 12:33 | Anticipation for cell mods in maintenance | | 13:37 | Cost/access realities | | 14:42 | Transition to relapse/refractory sequencing | | 15:49 | When and how to use CAR T, bispecifics, and triplets in relapse | | 17:33 | Teclistamab vs. Cilta-cel comparison | | 19:50 | Patient-centered, individualized approach in relapse decision | | 22:09 | Bridging therapy before CAR T, cytotoxicity and sequencing | | 25:02 | Timing of T-cell apheresis around bridging therapies | | 27:07 | Episode wrap-up and individualization as a recurring theme |

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Episode Tone, Style, and Utility

The episode maintains a conversational, approachable yet data-driven tone, mixing trial data with real-world stories, humility, and candor about uncertainty. Both guest experts exude practicality, make complex points accessible, and stress patient-centered care—while never shying away from acknowledging the limits of current data or the speed at which practice is changing.

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In summary:
This episode provides an invaluable, up-to-date guide for any myeloma provider or trainee seeking to navigate the maze of MRD-driven decision-making, maintenance strategies, and the integration of cutting-edge therapies in relapsed/refractory disease. The take-home: Stay flexible, stay patient-focused, and keep an eye on new data—because the landscape will change again, and soon.

Transcript

[A]

Hey, friends. This episode of the Fellow on Call is not meant to be used for medical advice and is intended for educational purposes only. Patient information has been modified to ensure privacy. The views expressed in this episode do not necessarily reflect the views of our employers. Enjoy.

[B]

You don't have to know everything, just where to ask. On Premium Fellows get fast one on one answers from top oncologists. So you show up prepared and confident. And it's free. Sign up now at Premium Co.

[A]

Welcome to another episode of the Fellow on Call, the hemonc podcast. We're coming at you from Merlot University Medical Center. I'm Ronak.

[C]

I'm Vivek.

[D]

And I'm Sean.

[A]

And in today's episode, we continue on our Myeloma roundtable capstone discussion with our guests, Dr. Mani Moyuddin, coming from Huntsville Cancer Institute at the University of Utah, and Dr. Adeel Khan, who's coming to us from UT Southwestern in Dallas, Texas. We started a great conversation with them last week. Make sure you check out that episode first and then we pick up today.

[D]

So for our next question, we want to ask a little bit about MRD testing. So in some of our previous episodes we've talked about the increasing role of MRD testing, but we wanted to see how each of you use MRD testing in clinical practice, and particularly for patients, for example, who might have been treated previously with a triplet like vrd, eventually got an auto transplant and now they've been on revlimid maintenance for years. So in those situations, would you ever consider stopping using MrD if you're already using it at the moment, or how do you incorporate into your practice?

[B]

Yeah. So, you know, MRD testing has been really all the rage in pretty much every trial, and it's very much gotten around to the patient advocacy groups as well. So patients want to know what their MRD status is. Very, very much so. And so I check it really at every opportunity I have for a bone marrow biopsy. Unless there's really a reason that they have obvious over disease, there's no point in doing that. But that typically then ends up being like right after induction, if you're making the decision of transplant or some sort of car T therapy and then thereafter to see what damage you did. And then for those who are negative to then see at least one year later what might be going on. Have they maintained MRD negativity or have they not? And in terms of like, how to apply some of the trial data in practice, one thing that I like to note is that a Lot of the trial data has still used 10 to the minus fifth versus conventionally in practice we're using 10 to the minus sixth. And so we're using a deeper look. And so the MRD negative rates that we get in real practice compared to what was seen in some of these trials, particularly now some of the older ones, that's just not the same. And you know, there has to be some recognition of that, that you might look MRD negative with a less resolution look, but you won't be once we have our conventional tests in ways that I've used it very specifically. So acknowledging like the Midus data and the ongoing MRD to stop data, what I've tend to do is for instance, if someone's getting induction, like at very reasonable time points, if someone is MRD negative and this was someone who is transplantable, I discuss with them what the role of a transplant would even be in someone who has such a deep remission, is it going to then offer them anything meaningful once they have achieved our deepest known response? Beyond that, then at other time points where we're making critical decision making, if someone is MRD negative, I say listen, I don't know that we need a whole lot of treatment here because if the goal is to reduce the myeloma burden as much as possible, we have already achieved that. And on the flip side I try to then alleviate treatment. So if someone is then MRD negative and they've been getting let's say doublet maintenance with daratumumab, lenalidomide, it's an opportunity to actually alleviate that, particularly per their symptoms and their preferences. A lot of people want to be on in the maintenance phase as minimal treatment as possible. And so someone who has MRD negativity at 10 to the 9 6, that's a great candid to say, hey, let's peel this back and give you just as high of a quality of life as we could achieve.

[C]

Before I throw it out to Mani and maybe Mani, you can answer the question here. How many cycles of a quad induction do you give before you check your first MRD assessment? And then do you look for sustained mrd? And at what time point are you looking at sustained MRD to maybe deescalate maintenance? If you were giving somebody a DARA R maintenance?

[E]

Yes, those are great questions. So as far as the first question is concerned, the longer you give induction, the more time you've had to see a full effect of your induction therapy. And I personally think that if you are deciding whether or not to do a Transplant, it makes sense to give more induction cycles. So you've allowed the induction to do what it needs to do and then you make a decision. So the MIDAS trial used six cycles of ward therapy before bone marrow biopsy was used to make MRD guided decisions on whether to transplant or not. I would say that the kind of MRD negativity rates we saw in the MIDAS study, we just don't see that with data vrd. And I know there's multiple explanations as to why that's the case. I'm not out there claiming that ISA or carfilzinev are necessarily more important. There might be something to that. But. So, long story short is, if I am to make a bone marrow biopsy, to use a decision for transplant, I want at least six cycles of four, perhaps even eight, recognizing that the kind of induction we're using doesn't give the same results. So 6 to 8, I would say, is the answer. Now, as far as your second question is concerned, the most mature data that I routinely use in clinic comes from the Spanish group. So they did a randomized trial of Ixazomib plus revlimid versus Revlimid alone as maintenance. The primary endpoint of the trial was to see if Ixasomib and Revlimid was better than Revlimid. And that trial was unsuccessful at showing that izomib was any better than just giving Revlimid alone. But the interesting thing, what they did, and I think that's the actual enduring legacy of this trial, is that for people who are MRD negative at two years, so this is 10 raised to power minus 6, and they have to have been MRD negative two years after completion of maintenance. So two full years of maintenance. If they were MRD negative, then there was no further randomization, but they just stopped treatment and then they were followed for another four years. So this is a good number that I can use. I can give them a 4 year PFS from the time point at which maintenance therapy was stopped, and that was about 83%. So that's pretty good. Those are really, really good odds. Now you'd wonder, what did they do for the MRD positive patients? They just kept them on revlimid and the four year PFS for that cohort was 50%. So that's still not holidays. Right. But what we don't know is how they would have done if Revlimid was stopped or if other approaches were done. So I routinely stop maintenance at the two year mark. Now, anecdotally, and again, these are Anecdotes. But the last several people who had high risk disease and I actually took them to the three year mark because I was just uncomfortable. They unfortunately, anecdotally I can think of like three patients they did relapse within like one year of stopping treatment. So I think that, you know, the jury is still out on how much this data truly applies to like the highest risk disease and whether it's truly safe to discontinue treatment. I think all the patients who have stopped treatment on have never regretted it that they got a year or two off treatment even if they relapsed. But I think the jury's out on that. But for standard risk disease the outcomes are excellent and it is our duty now to design trials where we stop treatment even earlier because we know that the outcomes for these patients are really good once they achieve MRD negativity. And if they don't have high risk features, they are more likely to also sustain MRD negativity. So maybe even six months of treatment once MRD negativity has been reached is enough. Maybe you don't need several years. But that's how I approach MRD guided discontinuation and escalation.

[B]

On the note of the cycle length, Cassiopeno is our first quadruplet trial. But really what started the trend was Griffin and Griffin was really a randomized phase two. But there they did the four cycles transplant, then two consolidated cycles thereafter. And the American style of adopting that data has really been moving the two cycles up front to make it then six. So people do kind of the either the four or the six and six has really then become our standard. And so that is what I myself do as well.

[C]

And the last question that I have with this, when you have these patients sounds like mani, you're giving these patients single agent revlimid. You got the overall survival benefit from the meta analysis. And so it sounds like that's what you're doing, not necessarily the DARA revlimid approach. Adeel maybe doing it the DARA revlimid approach. I'm just curious what for Adeel, you know, if you're doing DARA R maintenance and I don't want to speak for Moni too, I'll let you chime in here. But for Adil, if you're doing Dara R maintenance after dara rvd for the perseus stage data, are you looking at mrd at 2 years and using that to drop the dare or how do you use that data?

[B]

I would love to say that I'm very protocolized. The reality is I'm not. So it sort of depends on circumstance and patient preference. I will say in general for all comers, I have very much favored though the doublet maintenance with the DARA Len. I think it just works very well. And between the two, while I acknowledge the time and cost toxicity of the dara, the Len has more concerns that I attach with it from the secondary primary malignancy risk and the fact that people just tend not to feel great on Lenalidomide for the long run. And so I tend to be more leery of that. And with the Auriga trial, we had support for DARA in the maintenance space. And so what I tend to do is push for DARA Len doublet maintenance for most patients, again, whether standard risk or high risk there and then depending upon circumstances of the patient, the preference to try to whittle things down, how treatment is ultimately going for them, and if their disease is very well controlled with MRD negativity to then drop it back. And so that ends up being more of a conversation with the patient rather than a this is what I do. If this, then that.

[E]

So, you know, it's like an hour long conversation in itself, right? Like maintenance and how do you individualize it? I would say that one size maintenance approach does not work, unfortunately. That's what's done in trials. And I think that we must acknowledge that maintenance comes from an era where we were using two drugs, occasionally, three drugs, where we didn't have all the amazing treatments that we have now at relapse, where people didn't even necessarily get revlimid at either induction or at relapse. So like, the data has clearly expired. And I don't personally believe that revlimid maintenance improves overall survival in 2026. I don't think it does. It was a completely different era at that time. There are some people where the data is clear that they probably need more than revlimid. And then there's some people who need perhaps revlimid or something along those lines. And then there's some people who need like nothing. But we need good trials to actually like validate all of these approaches. So acknowledging that, I would say that. And the one more important point is that there's nothing magical about revlimid. Revlimid just happened to be the right drug that was studied in those circumstances that were favorable for maintenance. Maintenance works best when pre maintenance therapy is, I was about to use the S word, when pre maintenance therapy is bad and when post maintenance therapy is bad, that's when maintenance is going to shine, right? And that's when Revlimid was plugged into that landscape. And when you try to plug newer drugs, they're not going to show the same benefit because pre maintenance therapy is improved and post maintenance therapy has improved. So it's going to be very hard to show an overall survival benefit today. So acknowledging all of that, I'd say that from a regulatory perspective and then all just in terms of what's approved and what's easy to use. And then also there's something to be said about maintaining data sensitivity at the time of relapse with all the amazing regimens that we have like data tech, et cetera, and we're going to get more. So my practice case is that for, you know, most patients with standard risk disease, especially if they've achieved a really good response to treatment, the maintenance and they got a stem cell transplant, the maintenance is usually just revlimid. If they didn't get a stem cell transplant, then it's usually data and Revlimid for high risk disease. I will acknowledge that a lot of what we do for maintenance is treating ourselves. The data would show that for the highest risk disease, the two plus cytogenetic abnormalities, whatever approach you do, your three year risk of relapse is about 50%. Whether that's the master approach where you stop treatment altogether, or whether it's the Griffin approach where you kept data and Revlimid altogether like you've kept them going. So acknowledging that and acknowledging that a lot of it is like us wanting to do something because we hate to see these people progress early. My approach is data and land maintenance for those with high risk disease.

[B]

It's going to get even more complicated as soon as the cell mods come onto the scene. So we're expecting iberdomide to be approved based on the Excalibur data, maybe even later this potentially in the fall. And cell mods are sort of like the daughter of the IMids of thalidomide, lenalidomide and pomalidomide. And there is actually an ongoing trial looking at iberdamide in the maintenance space. And there's similar studies on mezigdamide as well. And so as the options also become More numerous, I 100% agree we need trial data, otherwise this becomes more of a convention and a cherry picking of I have done this, therefore I continue to do this. Rather than we know by data that this is actually offering something and this is something that we should continue.

[E]

I mean, I hate to burst BMS's bubble, but they their golden age of long term maintenance and their drugs being used forever is over. And I think even though the Iberdomide trial is going to be positive, I just don't see it having the same future where the future that Revlimid previously enjoyed, like give this one drug forever mint $20,000 a month in cash and like make billions of dollars overall. That's just not going to happen in my opinion.

[B]

Sorry bhp, with so many, with so many other drugs. Yeah, for sure. And that also speaks to the other side of the coin where there are some people who really don't want to do maintenance for various reasons. And part of that can actually be financial because as Manny alluded to, despite being generic, Lenalidomide is still very expensive, needlessly and almost horrifically expensive for those patients. You know, while it's detached from our guidelines, we say, hey, it's okay, you know, we can defer and then we will watch and we have plenty of other options for treatment. Should that be the fourth situation on a patient? So yeah, it's a very different space in the modern era. Let's take a moment to learn more about the sponsor for today's episode.

[A]

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[C]

Alright, so let's move on to our final discussion point. And this is the relapse refractory patient. How do we sequence our new cellular therapy agents? What do we do for bridging therapy? Do you ever just do KPD in a patient? You know, I think all these questions are percolating through everybody's heads when we have all this new stuff on the block. So let's say we have a patient, a younger patient, say 55 years old, standard risk, IgG Kappa myeloma, got Dara VRD auto transplant, let's say about three years ago, had been on Revlimid maintenance, 10 milligrams daily. Had not continued the daratumumab maintenance because let's say they were MRD negative. And so the provider decided, hey, I'm just gonna do revlimid alone. And now they have a biochemical recurrence of their disease. And the astute oncologist got a PET CT which showed new lytic lesions. The patient's otherwise asymptomatic and excellent performance status. What are you recommending for a second line therapy? And I'll switch the case a little bit. Let's say they got a triplet induction. Hadn't seen DARA before. Does that change your mind? So this is the million dollar question. How are we sequencing now? CAR T versus bispecific DARA combination therapies.

[E]

I guess I can go first here. So we now have three randomized trials where BCMA directed therapy has shown an overall survival advantage compared to database triplets. And that's for Belantamab, that is for tech data, and that is for CILTA Cell. Now you can argue that the best database triplet may not have been chosen as the control arm. And you know, are these truly better than data cart fills and webdex? I don't think we're going to get a clean answer to that question. But what we do have is compelling, that BCMA directed therapy should generally be the standard for first relapse. So the fundamental question then boils down to which BCMA directed therapy. Personally, I find Belantamab inconvenient and I think it's toxic. And we don't know what downstream effects it's gonna have on other therapies. So I'm not a big fan of using Belantamab. So then it boils down to CILTA cell and tech data. Now, at face value, if you just were to loosely compare the PFSs of these two trials, the PFS for tech data at three years was around 83%, whereas the PFS for Cilta cell at about three years, sorry, at about 30 months, so that's actually less than three years, was around 59%. So at face value, if you were committing the sin of cross trial comparison, tech data appears better than CILTA Cell. But there's more to the story because the tech data patient population was less heavily pretreated, right? So you had zero percent of people that were data refractory. You only had about 5% of people that were data exposed. Whereas with the CILTA Cell study, you had about 23% of people that were data refractory. You had more, you had universal lens refractoriness, you had higher rates of PI refractoriness. So it's not a clean comparison for the patient in practice, who is completely data sensitive and completely data naive, has never gotten any data at all. I personally think that tech data will probably give better efficacy results and it's a more predictable safety profile. Cilta cell is very, very unpredictably toxic. Right. Like, I just think that the current trials that we have, they don't show the full picture of Cilta cell toxicity. So Cilta cell is a big, big, big gamble for somebody who has a lot of other really good options. Cilta cell is amazing if that was the only thing we had. But it's not for somebody at first relapse that's data naive. They're going to have great results, protect data. I'd rather just do that rather than go the Cilta cell route. I would ideally want to use tech data for a finite duration of time, not continue it forever. And I hope that future studies will guide the way to that. So that's the approach. Now, for somebody who is both data and len refractory at the time of relapse, that's a more difficult decision. And I think that especially if their relapse happened fairly quickly into treatment, maybe just a year into transplant, and let's say they had high risk disease or even if they didn't, the disease has now shown to you that it's high risk for such a patient. I think that currently, today, so March 2026, I would narrowly lean towards Cilta CEL over tech data for such a patient, recognizing that the cartitude data probably better fits such a patient. Now this might change come June 2026 where we get data about tech monotherapy. The Majestic 9 trial, which will include such patients, and apparently from what I've heard, the results are really good and perhaps even comparable to Cilta cell. But as of today, for such a patient, I would lean towards Cilta cel. So I think it really has to be individualized based on what they're exposed to. I will always, every time I talk about relapse myeloma, I always put a plug in for continued observation. If this was a truly biochemical progression and it was happening many, many years after a stem cell transplant, I would say you can watch. But in somebody with lytic lesions, I think the answer is clear. You should treat. And this is how I would approach treatment.

[C]

Adeel, same question to you. So you have your patient in front of you. How are you approaching the sequencing strategies? And if you do choose car T cell therapy, how are you choosing bridging options? What are you using for your bridge?

[B]

So with subsequent lines of therapy discussion, what I like to say first to patients, because this tends to offer them comfort in a space that's very messy, is that There is no clear right answer, therefore there's no clear wrong answer. We can accept that it's gray and that it's constantly evolving. And you know, as Manny alluded to the Cartitude 4 data which supported second line Cilta CEL versus the Majestic 3 data which supported Daratech, they are very different populations. So while we have been making a cross trial comparison, it's really hard to say that that's the right thing to do here. Massaging that into what to then offer people though is if someone has not had DARA and if someone is relapsing, then the daratech combo, it has a great deal of potency, it is well tolerated and thus that becomes something that I would favor with someone who's, let's say young, high risk and they really have, you know, a very brisk type of disease. Someone who blasted through induction, blasted after an auto. That's where the extra potency of Cilta CEL is more meaningful potentially. And we know that based on some of the Cartitude 1 data that for some of these long term MRD negative individuals, whether they were truly high risk, quote unquote, by that definition or not didn't seem to matter. It really worked well for them. But I acknowledge that was also a small subset of the study that was only patients looked at one center. But there is, I think some potency there that I would acknowledge and use in those circumstances. But the final piece is, you know, really patient preference counts a lot. You know, some people are not coming to a center with a great deal of easy access or they have other situations that come up that make them want to do more one thing or another. And I acknowledge that again, if there's not a clear right answer, we're not making a wrong decision here. If that's in line with your goals of treatment. I think beyond that we should acknowledge, as Manny also said, that this is going to change very fast. You know, like we have Majestic 7 in the works, looking at frontline tech. And then that's going to change the calculus as well because then how do you use Majestic 3 data once that one reads out? So this seems to change about every six months. At every American Society Hematology meeting in December, every American Society of Clinical Oncology and European Hematology associated meetings in June, and then our September International Myeloma Society meetings, the game changes. And so this content only becomes relevant for the interregnum periods between those major conferences.

[E]

And then I guess to your point about bridging, I'd say that Carfilzomib Palmdex is still an appropriate bridging. And I do have people sometimes who are progressing biochemically on data len and they're biochemically progressing fairly quickly after transplant. My intent is clearly to move them to Cilta cell and I think that carfuls and a pondex can be used. Now, there are occasionally people who, for whom you need stronger things, right? So there's people who are progressing with like extramedullary disease. And for those you need cytotoxic chemo, preferably after you've collected the car T cells. And then there are people for whom I want to use tarquitamab. And I do have to sort of play around the lines of therapy to get talcuramab to them. And I often am able to do that, use a steroid pulse, you know, count previous radiation, etc. To get them to four lines of treatment and perhaps use talcoramab to get them to Cilta cell. So it is again, highly individualized. I would say that after a few horror stories and also looking at all the data, I'd say that Cilta cell is unequivocally safer if you do it when the disease burden is minimal. Is Cilta cell more effective? I think that the data is very confounded, right? Because retrospective data, people who've already responded, their biology is different, they're going to do well whatever you do compared to people whose cancer didn't respond. So I don't know if it's necessarily more effective, but it definitely appears to be safer if you do it at a time when disease burden is minimal. So you got to factor that in, right? It's not just in like what you do, but it's also like, how effective is it? How much of what you need to do there, like dalcotimab, for what it's worth, is, you know, within one to two cycles it will dramatically lower the disease burden. And for some people, I think that is like the best approach. And I also think that talcomab is a very toxic drug with really bad like mouth, skin and nail side effects. And perhaps it's best used in such a context. You use it for like two months before a lot of the horrible skin, mouth, nail, weight loss toxicities set in and you get them to something else definitively.

[B]

Yeah. The challenging with the early Cilta cell use is the bridging therapy. And so not having the available bispecifics, then talc really in particular ends up being the challenge. But in those rare cases where you do Want to push for early cilta cell again using the CARB2.4 data? You do have many more options of what you can give to someone, which usually buys in the time for their T cells to be manufactured into CAR T cells and then the time for lymphoid pleading chemo.

[C]

So one other question that I have. Let's say you have this patient and you're planning to give them car T cell therapy. They have some rapidly progressive disease. You think about using kpd, but you think you need something better. You need that talquetamab. When are you starting the talquetamab? Is it after apheresis? Do you ever start it before apheresis or do you worry those T cells are going to be exhausted? How do you determine when to do that? And are you doing something like a high dose of cytoxan to cool them off? How do you think about that type of patient?

[E]

If at all possible? I try to get the apheresis done before giving talcotumab or before giving cytotoxic chemo. If you give talqueramab before you do apheresis, there's a much higher likelihood of getting an out of spec product. Now I recognize that we live in a very imperfect world and there are times where you just have to treat the myeloma right away. So in those situations, if I have given talqueramab, I usually will give talquetamab for a few months, get them into a deeper response and then hold treatment, hold for at least four weeks and then I'll try to collect them again. And I would say that if you were to use chemotherapy like sort of similar rules apply, it would be. But I guess it's with chemotherapy like sometimes you just like you, you give it and then you collect the CAR T cells around the time their blood counts recover. Right. It's not again, not ideal, but sometimes it's just. It is what it is. But with chemotherapy perhaps like you don't have to wait, you know, that long. So that's how I do it. But I'd be curious to see how Adeel does this.

[B]

Yeah, actually very similarly. You know, I agree you really want to push for phoresis as rapidly as possible because as soon as you give something that is using that CD3T cell cascade, you're compromising it. And so you're not going to get necessarily as potent of a product as you would if you didn't have to do that. And the other piece to it is if you give something too cytotoxic you can also wipe out that CD3 cascade for what you want because you need an intact or relatively intact immune system for an immunotherapy to take hold. And so while we don't have good data on it, giving something like a PACE style regimen, which was an old salvage that we used to use, probably is not the greatest approach in this day and age where you would potentially compromise your T cell redirecting therapy afterwards. So talquetamab, again, works really well typically. And so that ends up being my favorite choice if I can get it. And if not, you know, again, we have more conventional options that I can try to, to sort of cycle through. And sometimes a little bit of finagling and redefinition of what a line of therapy is will get you to that magical number of fourth line to where you can get the true drug that you're aiming for.

[A]

Thank you both. This was so incredibly insightful and it's so nice to hear. I think the big takeaway for me from this conversation is that even with sequencing therapy decision making, it is not a one size fits all, as you guys have alluded, There are so many nuances and a lot of it is dictated by the individual patient, their biology and also their preferences, the logistics of getting to clinic, et cetera. And so really, I think trying to come up with a standard approach to how we manage patients in the second line and beyond is clearly very, very difficult. From what you have outlined, I think that this was a phenomenal discussion over the last couple of episodes with you guys. So thank you so much for your time. I think this is a great place to stop. I know there's going to be a lot more questions that I'm sure are going to be answered at upcoming meetings, and I wouldn't be surprised if people reach out to the two of you to also pick your brains about these things now that you guys have been on the show. So thank you in advance on behalf of our listeners. So I think though, that wraps up another fantastic episode of the fellow on call. So until next time, we'll see you all later.

[C]

See you later.

[D]

See you later.

[B]

This podcast was edited by Resonate Recordings.