In this podcast, experts discuss CELMoD therapy for multiple myeloma, including mechanism of action, available clinical data and ongoing trials, and future implications.
In this episode, Jesus Berdeja, MD; Amrita Krishnan, MD, FACP; and Sagar Lonial, MD, FACP, discuss key topics with CELMoD therapy for multiple myeloma, including:
Presenters:
Jesus Berdeja, MD
Director of Myeloma Research
Greco-Hainsworth Centers for Research
Tennessee Oncology
Nashville, Tennessee
Amrita Krishnan, MD, FACP
Director, Judy and Bernard Briskin Center for Myeloma
Executive Director of Hematology
City of Hope Orange County
Professor of Hematology/HCT
City of Hope Cancer Center
Irvine, California
Sagar Lonial, MD, FACP
Chair and Professor
Department of Hematology and Medical Oncology
Anne and Bernard Gray Family Chair in Cancer
Chief Medical Officer
Winship Cancer Institute
Emory University
Atlanta, Georgia
Content based on an online CME program supported by an independent educational grant from Bristol Myers Squibb.
Link to full program:
https://bit.ly/3IwbslQ
This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
What Are the Unmet Medical Needs in 2025?
What are the unmet medical needs, however, in 2025?
And I think there still remains some. Patients who have or develop high-risk disease, patients who present with true extramedullary disease, not paramedullary disease, but true extramedullary disease of presentation, despite everything that we throw at them, do not have great long-term outcomes. I think frail patients remain a challenge, and the idea of quads or even 5 drugs as part of the combination simply is not practical or realistic, so thinking about ways to reduce the dose of many of the drugs we use and get patients into deep responses that translate into improved outcomes, I think, is an important goal.
Patients with 3 or more prior lines of therapy. We know that a number of patients early on now are receiving BCMA-directed therapy. What do we do for those patients who are progressing on those kinds of treatment options?
And finally, patients who are resistant or intolerant to major targets, IMiDs, PI, CD38, BCMA, and GPRC5D, what do we do for those patients? I think with the approval of BCMA and GPRC5D-directed therapy, we were really excited because we had things to offer, but now we have got a wave of patients that are exhausting those options, and what are new potential therapeutics that we can offer them?
What Are the New Options?
So what are the new options? Well, we have got CELMoDs, and we are going to talk about that a little bit today. We have got new CAR T-cell targets. We have got new antibody drug conjugates. We have trispecific antibodies.
CELMoDs Co-opt Cereblon via Unique Binding Features, Inducing Distinct Conformational Changes
So you are going to hear a lot about cereblon and cereblon-binding, particularly with the CELMoDs. And what I want to really focus on is the idea of how this class of agents are really different from the IMiDs, lenalidomide, pomalidomide, or even the precursor for those drugs, thalidomide.
And they really have to do with binding affinity and changes in the conformation of cereblon itself when you bind. And this closed conformation really leads to more rapid downstream degradation of those transcription factors, and actually in some cases leads to irreversible downstream targeting of some of those transcription factors as well.
Iberdomide and Mezigdomide Affect Immune Cell Populations in the Bone Marrow Microenvironment
And while I think we are really focused on killing the myeloma cell, to me, this is the real added value of the CELMoD class. It is the ability to make your immune system better. And you may hear this from me or my colleagues throughout the course of the next hour, talking about the IMiDs are effective, the CELMoDs to me are like cappuccino for T-cells. You can take an exhausted T-cell and wake it up.
And that to me really is important when we think about CAR T-cell collection, post-CAR T-cell infusion, or T-cell engagers enhancement by combining with the CELMoD class of agents. And you can see that described for both iberdomide and mezi.
Topics to Discuss Today
So what are we going to talk about in the next few moments? We are going to talk about relative additions to our treatment using the CELMoD class of data.
You are going to hear clinical data alone as well as potentially in partnership. What does this class offer over what we already have? And finally, how do we really think forward about the next 5 years about using the CELMoDs in partner with many of our existing immune targets to make all of these therapeutic options far more effective?
Just to remember, unfortunately, I got my 25-year ASCO fellowship, I have been a member. So I remember pomalidomide when it came out as a, you know, the phase I trial.
So that was a huge step forward. I have to say it actually took a long time now for us to get to these CELMoDs in terms of a newer, more potent type of immunomodulatory drug based really now on a much deeper understanding of cereblon. Because when len came out, we did not really understand why it worked. And now we really do. We can exploit that knowledge as well to develop more potent drugs.
[00:45:02]
Novel CELMoD Iberdomide
And as I said, part of that potency is in terms of its enhanced affinity to cereblon. And you can see the potency, again, 20 times higher than lenalidomide and pomalidomide, which also in a way says, okay, perhaps you do not need as high doses so you can also reduce some of the other toxicities we see with those drugs.
[00:45:23]
Iberdomide and Mezigdomide: Synergy With Other MM Treatments in Preclinical Studies
We see synergy in terms of preclinical models as well, which is important.
[00:45:30]
Iberdomide Inhibits Proliferation in POM-Resistant Cell Lines
We have seen it with iber-mezi, its activity in patients who are resistant to pomalidomide, which is a huge need for us because, again, we can talk about this. Yes, we have T-cell therapies, but there are patients who have exhausted T cells, poor T-cell function, pace of disease that makes T-cell therapy not an immediate next option for them. So, again, even for these pom-resistant patients, new options are desperately needed.
[00:46:03]
Iberdomide Associated With T-Cell Activation and NK Cell Proliferation and Activation
To me, this is probably the most interesting thing because this is where you can say, how am I going to ultimately use this drug? So we have a trial right now going at City of Hope. Dr Murali Janakiram is running it using mezigdomide as CAR T maintenance, really, again, for this idea of continuing to improve T-cell health. So I think that is a big space. I do not know who is going to touch on the maintenance post-transplant space. Again, I think there you are using it both for its direct anti-myeloma effects, but also for its T-cell effects. Again, so immune fitness being a big part of preventing myeloma relapse.
[00:46:42]
Conclusions
So, in conclusion, CELMoDs clearly lead to potent protein degradation. They can overcome len and pom resistance. They can improve T-cell fitness. So we really need to see what is their best partner. We have multiple trials right now with bispecifics and pomalidomide.
Our trials planned are in early phases using some of the CELMoDs plus these bispecifics. Clearly, studies going on with CELMoDs plus CAR T cells. So I think all of these are avenues where they can continue to improve the drugs we have now in terms of the T-cell engagers, make them better, target these high-risk populations as well.
So my job is to actually now show you some of the data that we have on these CELMoDs and maybe also touch a little bit on some of the studies that are currently occurring and that are planned as well.
CELMoDs in Development
However, I do want to state that there are currently no FDA-approved CELMoDs for multiple myeloma. So everything we are discussing is clinical trials. So just remember that.
So there are 3 CELMoDs, as you heard, in development, although 1 technically is not a true CELMoD. However, I put it in the same category. They work via cereblon modulation or inhibition as well. So we have iberdomide, mezigdomide, and cemsidomide.
Initial Proof of Activity
So we will talk about just the initial proof of activity of each 1 of these. So iberdomide was tested in the CC220-MM-001 study and mezigdomide in the 92480-MM-001 and cemsidomide in the 1101 study.
CC-220-MM-001: Iberdomide for R/R MM
So we will start with iberdomide. CC220-MM-001 is a multi-cohort study. So basically, this is in patients who are relapsed/refractory, had prior IMiDs, prior PIs, prior anti-CD38s.
And so you see that there are several cohorts, but the first 2 cohorts, cohort A and B, are iberdomide and also iberdomide with dex. And as you know, dex and myeloma is like water, right? So everything goes better with a little bit of dex.
So that is sort of almost considered like a single agent, especially with the IMiDs and now also with the CELMoDs. And so just kind of keep that in mind. And then so that was a dose escalation, but really it was the cohort D, which was the recommended phase II dose with dex, that is sort of kind of showing us the true activity of this molecule.
CC-220-MM-001: TEAEs With Iberdomide + Dex
In terms of toxicity, I think this is actually what is going to be sort of the theme of these drugs, is that as part of the mechanism of action, we expect neutropenia. That actually unfortunately comes with the way these drugs work.
So as you see here, you see neutropenia in 60% of patients, grade 3 25%, grade 4 19%. The other cytopenia is much less. However, I think what is even more interesting is that when we look at the non-hematologic toxicities, we actually are seeing much less than what we are used to with the IMiDs.
So if any of you have treated patients who are on len maintenance, for example, you know that a lot of those patients complain of fatigue, a lot of them develop diarrhea. And so you are seeing that even though those are reported here, there are very low percentages. And I think that is actually something that we would expect based on the fact that these drugs are so specific to cereblon. And it is 1 isomer only that presumably has the activity, whereas the other isomer is the 1 that often has the off-tumor or off sort of target side effects. And so we are not surprised that perhaps we are seeing that there is less toxicity with some of these drugs.
The neutropenia is common. As you can see, infections are still common in this population, as we expect. However, really the grade 3, grade 4 infections are not there, as we are seeing right now with some of the bispecifics and CAR Ts.
CC-220-MM-001: Iberdomide + Dex (Cohort D) Efficacy
So this was the data in this cohort. So our response rate of 26% with a clinical benefit rate of 36%. And if you add stable disease, you see we are going up to 79%. The PFS model is about 13.1 weeks. And I remind you that these are the numbers that we are seeing, or we saw with pomalidomide, that we saw with belantamab mafodotin as single agents when they were actually reported, including daratumumab as a single agent. And in the past, these are the kind of data that normally would get a drug approved. That is until some people started working on CAR Ts and bispecifics, which are given much higher single agent response rates. And so now this data does not look as good. However, I think this data actually looks quite good if you think about the patient population we are talking about.
CC-92480-MM-001: Mezigdomide + Dex for Patients With R/R MM
What about mezigdomide? Mezigdomide was tested in the MM-001 study as well. And again, dexamethasone, it is just part of it. However, this is basically, again, similar population, greater than 3 prior lines of therapy, prior len, pom, PI, anti-CD38 antibodies.
The patient received mezigdomide with dexamethasone. Of course, the single agent was done and eventually with combination.
CC-92480-MM-001: TEAEs (Dose Expansion)
And so when you look at the toxicities, you see very similar data, except that maybe more cytopenia, especially more neutropenia. And we would expect that. This is actually probably a little more potent drug than iberdomide. And so the neutropenia, again, 77% with a high percentage of grade 3s and grade 4s.
And again, this is expected based on the mechanism of action.
CC-92480-MM-001: Response Rates With Mezigdomide + Dex (Dose Expansion)
Now, here when we look at the actual response rates, you see the overall response rate of 40%, which is actually quite impressive, again, in this patient population. Patients achieving CRs and VGPRs, again, also impressive.
If you look at patients who have prior anti-PCMA therapy, 50% overall response rate. So, again, very active drugs in a very refractory patient population with a median PFS of about 4.4 months, duration of response of 7.6 months.
CFT7455-1101: Cemsidomide + Dex for Patients With R/R MM
Dr Lonial said we would see data on cemsidomide. So we do have a little bit of data with cemsidomide. Again, a very refractory population. Again, single agent and then with the addition of dexamethasone. I am going to show you the cemsidomide dexamethasone data.
CFT7455-1101: TEAEs With Cemsidomide + Dex
Toxicity-wise, again, back to the neutropenia as being the main toxicity.
CFT7455-1101: Efficacy With Cemsidomide + Dex
And so with this, if you go all the way to the very right, you see that for all dose levels the overall response rate is 26% and the clinical benefit rate of 40%. However, if you concentrate it on the higher dose, which is the recommended phase II dose, or at least close to the recommended phase II dose of 75 micrograms daily, you start seeing a response rate of 36%, CBR of 45%, very similar to what we have seen with the others.
Combination Data: Beyond Single-Agent Activity
As Dr Krishnan said, these drugs are not for single-agent use. They probably are going to be best in combination. So we actually do have some initial combination data as well.
CC-220-MM-001: Iberdomide for R/R MM
So we go back to iberdomide first and back to the MM-001 study, and you see the cohorts in the blue now are the combination cohorts. And so you have iberdomide-dex-dara, iberdomide-dex-bortezomib, and iberdomide-dex-carfilzomib. And so, again, these are proof-of-concept trials that may or may not lead to larger trials.
CC-220-MM-001: Responses With Iberdomide + Dex + Daratumumab (Cohort E)
Response rates are better. So, again, a very refractory population. A lot of these patients were actually dara-exposed to refractory as well, and we are seeing a real response rate of 46%. And we have been getting some patients with complete response rates.
CC-220-MM-001: Iberdomide for R/R MM
So based on this, cohort K looked at patients with iberdomide-dex-dara who were nearly diagnosed, who were transplant not eligible, or did not go through transplant. So, again, these are untreated patients.
CC-220-MM-001: Efficacy With Iberdomide + Dex + Dara for TNE NDMM (Cohort K)
However, look at these responses. So a real response rate of 95%.
And what is actually even nicer is that we are seeing a deepening of response. So from 7 months to 11 months to 14 months, you see that the green numbers or percentages are increasing. Those are the CR and SCR rates. So quite a large proportion of patients are achieving a complete response. And similar with MRD negativity, you see that patients— 38% of the patients are MRD negative. If you just look at the patients VGPR or better, we are looking at 43%.
EXCALIBER Maintenance: Iberdomide vs Lenalidomide Maintenance After Primary MM Therapy + ASCT
And then currently we also have a trial called the EXCALIBER Maintenance Trial, which is still occurring at this time. So patients who have had induction and had a stem cell transplant, and then for maintenance or before maintenance, they are randomized to either iberdomide or lenalidomide. And so this trial is ongoing, and obviously this will help us in terms of the ability for iberdomide to be useful in that setting.
Obviously, this trial has stalled a little bit because of now more data with the doublet as maintenance that has stalled some of the enrollment in the U.S., but lenalidomide still is an FDA-approved maintenance. And I think what I like about this study is that I think iberdomide, if the toxicity profile stands, I think lends itself better to a more prolonged use than lenalidomide. So we will have to see. Maybe if fewer patients come off early, we should see an improvement. So more to come.
EXCALIBER RRMM: Iberdomide + Daratumumab + Dex vs DVd for R/R MM
And then we also have the EXCALIBER relapse/refractory myeloma.
So careful there. Both are EXCALIBER, one's maintenance and one's relapsed/refractory myeloma. And this is randomizing patients to iberdomide, dara-dex vs dara-bortezomib-dex. And this study actually has now accrued completely, so we are just now waiting for the data.
And if that is a positive study, perhaps that is the study that might get this drug approved.
CC-92480-MM-002: Mezigdomide Combination Therapy R/R MM
How about mezigdomide? Mezigdomide combination data, of course, exists as well. We have these phase I dose escalation trials with mezigdomide-bortezomib-dexamethasone and mezigdomide-carfilzomib-dexamethasone, so different cohorts A and C.
CC-92480-MM-002: Dose Escalation Efficacy
And so here we see the data. I guess the response rates, if you look on the left, it is the mezi-VD and the right is mezi-KD.
You see overall response rate of 85% and median PFS of 16-20 months, depending on which one we are looking at, which dose, 0.6 vs 1.0, so both very active. And then when you look on the right, the mezi-KD, again, remember this is a more heavily pretreated population. You are seeing response rates of 85% with median PFS of 11-14 months.
So strong activity, I think, in this combination, early combination data.
CC-92480-MM-002: MeziVd Dose Expansion Efficacy
That was the phase I dose escalation. Now we have actually also the expansion.
In the expansion, you are really seeing that the overall response rate is keeping at over 80%, again, with lots of high percentage of eGPRs and CRs and ongoing on the right. You see a lot of arrows to the right, which means those patients' responses are still ongoing.
SUCCESSOR-1: Mezigdomide + Bortezomib + Dex vs Pvd for R/R MM (1-3 LOT)
We now also have phase III data from the SUCCESSOR trials.
So SUCCESSOR-1 is basically taking that combination with bortezomib-dexamethasone in patients with 1 to 3 prior lines of therapy, and patients will be randomized to mezigdomide-bortezomib-dex vs pomalidomide-bortezomib-dex, so really pinning the mezi vs pomalidomide head-to-head in patients with 1 to 3 prior lines of therapy. And this trial is ongoing. I actually do not know if this has accrued fully or not. No.
SUCCESSOR-2: Mezigdomide + Carfilzomib + Dex vs Kd for R/R MM (≥1 LOT)
And then SUCCESSOR-2 is basically the combination with carfilzomib that we showed you earlier, and that will be in patients with at least 1 prior line of therapy. Here you have to have a prior len and prior anti-CD38 as well.
So again, these are patients who have been triple-class exposed at least, and so it would be mezi-carfilzomib-dex vs carfilzomib-dex. And so this trial is actually still accruing at this time, although it is actually close to meeting its accrual.
Where Should We Use MRD in MM?
Dr Krishnan: Thank you, Dr Berdeja. And so, Dr Berdeja has talked about some of the trials he talked about use MRD as an endpoint. So in a way, I think he set the stage for, is that a valid endpoint now for us when we look at studies vs what we used to?
MRD Wish List
So first, let us take a step back and talk about if we are going to use MRD as an endpoint in our trials, what do we want from it? Well, obviously, if you are going to use MRD, you need a test that is sensitive. You need it standardized, right?
Otherwise, Dr Lonial is going to tell me that his MRD test is better than mine. So you want it widely available. Cost-efficient would be ideal, certainly, and reimbursed by payers. And ultimately, the proof in the pudding that you need it accepted by the FDA.
So as you will see, and I will show you, and we are here at this meeting, there are trials now incorporating MRD testing. In fact, most studies, including in the relapsed setting, as we will talk about, collect samples, report out MRD rates.
Most of us, certainly in the upfront setting, when we think about therapeutic decision-making and our goals for our patients, our goal is sustained MRD-negativity. Now, in the trials, and I think this is where now we finally have reached the last bullet point, which is these trials are now showing us that we can guide decision-making based on MRD-positive and -negative. And that is really ultimately where we want to be.
And so we are finally seeing some hints, and you will see 1 of those readouts on Tuesday at the myeloma oral abstract session. So I think that is very exciting for us.
Now, are we willing to take MRD and really not wait for PFS anymore? So if you look at this meta-analysis, this was from Dr Munshi that he published a few years ago of over 8,000 patients. He clearly showed both in the transplant-eligible and transplant-ineligible that MRD status correlated with PFS.
MRD in Recent Phase III Trials in Transplant-Ineligible NDMM
I am going to show you some of the data from ODAC as well. However, first of all, why is that important? Well, because we have gotten better and better at treating myeloma. So PFS used to be, it is kind of hard to imagine back in the day, PFS was 2-3 years. Now if you see the trials in terms of quad induction plus transplant, you have not reached a median PFS yet.
Many Years to Show Significant Effect of New Therapy on PFS
So if you are trying to test new treatments, how are you going to use your benchmark if it is going to take over 8 years to show a statistically significant benefit if PFS is your endpoint? And of course, no one is willing, both from a drug development standpoint, but also from a patient care standpoint. That is too long to wait in terms of evaluating new treatments for patients.
EVIDENCE Meta-analysis of MRD as an Intermediate Clinical End Point For Multiple Myeloma
Now we have the data that Dr Landgren presented at the ODAC meeting looking at MRD and presenting the case, why should MRD be FDA approved as a surrogate endpoint?
This was, again, meta-analysis using our subject-level patient data, and you can see about 8,000 patients here. I will not let us go into the details of those studies.
EVIDENCE Meta-analysis: Individual-Level Association
However, ultimately, this is probably the most important slide that I have to thank him for. At the individual subject-level association, you see that MRD correlated with progression-free survival, and for most cases also, in fact, with overall survival, both in the transplant-eligible and transplant-ineligible population.
FDA Industry Guidance on Regulatory Considerations for MRD
So the FDA, about 5 years ago, published their guidance on the consideration for use of MRD and what they would need to see to consider it a valid surrogate endpoint. And so they had to demonstrate the prognostic value of a surrogate endpoint for clinical outcome, especially in terms of long-term clinical outcomes.
So in April of last year, the ODAC had a meeting. I could say I think all the myeloma doctors watched it instead of Netflix that day. It was a very turning point, really, because it was a unanimous vote based on some of the data that I showed you from Dr Landgren's studies in favor of using MRD-CR as an early endpoint in myeloma clinical trials. So you can see here, this really moved the curve forward because now we can have a much earlier surrogate endpoint and accept that in terms of the drug development.
Did We Get Our MRD Wish List?
So let me finish by saying, so did we get our MRD wish list where we have a test next-gen sequencing or flow that is sensitive? We have standardization with next-gen sequencing. We have it now accepted by the FDA.
And now we have trials that have used it to guide clinical decision-making, the PERSEUS trial,
Dr Lonial: Thank you. So we are going to talk about a little bit in terms of future implications.
Where Do Iberdomide and Mezigdomide Fit in?
So the real question is: Where do iberdomide and mezigdomide fit in in our current treatment paradigm?
Both agents clearly have activity in exposed and IMiD-resistant patients. And 1 of the strengths that I see is the profile of adverse events and relative opportunities are slightly different. So I am going to touch on a couple of basic slides, and then I am going to turn to my co-panelists to really help us think about how we are going to think about using these down the road.
[01:23:14]
Comparing CELMoDs: Similarities vs Differences
So similarities, they are all oral. Demonstrated activity, it is being studied in earlier lines, combinations with other agents. Differences, mezi really does have greater cereblon-binding potency and actually almost induces 100% of the cells in a closed conformation, which, we think, has a better and longer effect on downstream effects.
There is also 1 difference that I am going to show you in a slide in just a moment. iberdomide, however, may be a little bit more tolerable with lower rates of severe neutropenia. And Jesus did a great job summarizing the iberdomide 001 trial.
One difference when I show the adverse events is I put a box around all the zeros, showing very few grade 3/4 adverse events, which I think really is different. Actually, we have got a smoldering trial with iberdomide as a single agent, and we have had a couple of patients say, are you sure I am getting the real drug? You told me there was no placebo here. Because they do not feel the impact of the drug on their quality of life or day-to-day living. And I think all of us that have used iber have had similar experiences with patients as well.
Potential Role of CELMoDs in the Future Treatment Landscape of MM in Earlier Lines of Therapy
What about thinking about it in the landscape of earlier lines of therapy?
So for me, the fewer non-heme adverse events really makes it a great partner for many of our induction regimens. So that KID regimen that you showed makes a lot of sense to me, thinking about how to bring it earlier and earlier. And then the maintenance setting, I think, does make a lot of sense to me.
And certainly at our center, we have not adopted dara maintenance for everybody. So that trial is enrolling like gangbusters at our place, because we are putting everybody that would normally get len. And then for mezi, the context of high-risk cytogenetics, heavily pre-treated advanced disease, is really an exciting concept where patients with extramedullary disease may get benefit from the use of mezi.
And I am going to skip through these, because Jesus already showed them.
So I am going to turn to my panel colleagues here and say, in a perfect world where FDA approvals do not get in the way, Jesus, where would you think about these new CELMoDs and sequencing them, and where would you see them fit?
Dr Berdeja: I think mezi is probably the stronger of the 2, but it definitely comes with the price, as everything we do. So I really see mezi as the 1 that is going to be in combination. When you are trying to get a patient into remission, they have folic disease, and they are progressing. I think a combination with mezi makes the most sense to me.
I like iber because it is still a very powerful drug, but it does have that improved toxicity profile. And so I think when we are looking at combinations, just like you said, so it makes it pre‑CAR T.
We know that CART Ts work really well, and we know that the toxicity with CAR Ts is less when you have good control of disease. So if you are trying to not only sort of get your disease under control, but then use a drug that also may potentiate your T-cells, I think as that holding therapy before you collect your T-cells, that would be an ideal combination for you, where iber in a combination would do that, and then also as a bridge.
Dr Krishnan: I guess my question really is more would you be willing, because you made the point much better tolerated, so did you, to throw away len and just wherever you were going to use len. I am assuming you think that phase III trial is going to be positive in favor of iber, right?
Is that going to be our biggest paradigm shift? I think possibly, yes. I agree with you, I think mezi is more potent.
I have been actually in a post-CAR T maintenance study, it is been quite well tolerated. I think we started far enough post-CAR T, and we have not had significant, obviously we do not start at full dose, so I think some dose modulation makes it fairly manageable. I would really like to use it in combination with either TALC or teclistamab.
The PFS of the T-cell therapies, 11 months or so, we really need to do better, and especially in that extramedullary disease category, so I think that is to me the most attractive place.
Dr Lonial: And it would be interesting to compare your mezi post-CAR T, I have got a cohort of I think almost 35 that I give pom to after CAR, and just see what are the differences in PFS, because I actually think this entire class is really effective. We do not have iber, mezi, so I use POM, just to give something as maintenance post-CAR.
Dr Krishnan: I do that too for the people who cannot go on the trial.
Dr Lonial: So you have got an internal cohort you could compare. I think that would be really interesting.
Dr Berdeja: And I have a few patients that were on the trial with iber with len. This is before, so this is CARMA 2. It was high-risk patients, or patients who did not have, I forget which cohort it is, but basically, who were like induction transplant and still had disease, were able to get the CAR T. And then you were allowed, as an investigator, to give maintenance or not. And every patient that is gotten maintenance on that trial has not progressed. So it is actually very interesting.
It is like an N of 8, and I think I have like 4 of those. So it is actually very intriguing, right, in that sense, that that alone was sufficient to potentially make a difference.
Dr Lonial: Yes, yes. So, Maria, I am going to come back and revisit your question by combining with T-cell engagers, because to me the question is, do you continue them both indefinitely, or does the combination allow you to get to a point where you can stop 1 or both? And how would you think about it?
Dr Krishnan: I would think about it as stop, give the T-cell engager for a fixed duration, and then continue with mezi as basic. Because all you can do is give the T-cell engager and then change the schedule, right? Because even some of these were given quarterly now.
So that would be another ideal setting, right? Continue mezi in between, and then re-boost them. So both ways, I think what you are trying to do is prevent T-cell exhaustion, right? And I think those are good ways to do it.
Dr Lonial: Yes, I mean, the trials were late relapse, so when they progressed, they did not probably stick around long enough. And they'd all had len and pom. So it is hard to do direct attribution.
Dr Berdeja: I mean, the maintenance trials and the pom-len trials.
Dr Krishnan: Yes, that is what will matter. Yes, I mean, but I do think that is the only other unresolved question, right? In terms of helping us decide as well.
Dr Lonial: Yes, I guess what I will say is, particularly in the transplant setting with len maintenance, that number is really small. It is 2.7%. And so I think a lot is said about it and a lot is made up about it, but the real data is not that high, even with the melphalan signature that is often seen in patients who get high-dose melphalan.
Dr Berdeja: Can I challenge Dr Krishnan?
Dr Lonial: Sure, please do.
Dr Berdeja: So my only concern is, so you have now a patient on a BCMA bispecific who is very immunocompromised, we know infections are very high, and now you are going to give them a drug that potentially can cause neutropenia.
Are you worried about worsening the infection potentially?
Dr Krishnan: That is fair, because I was looking at your mezi data, and you had a 33% grade 3/4, which is actually the same as what the trispecific is showing. So I do think it is fair. So I think it is not for everyone, but there are clearly even in the bispecific patients that we know signal to basically the EMD patients, right?
And with Sagar's data in terms of EMD, I think those are patients who are willing to take some degree of risk to improve that PFS.
Dr Lonial: Yes, I mean, I think part of that is why, unless they are functional high-risk, or they have extramedullary disease, I would probably favor iber over mezi in the partnership with the T-cell engager. So as we think about personalizing care, that might come into the equation a little bit.
Dr Berdeja: Again, none of this is FDA approved. We are just musing. We all do whatever we want.
Dr Lonial: So I am going to, Jesus, I am going to come back to you on the question I asked to Amrita.
If you are going to talk about combining with a T-cell engager, and it does not matter what flavor or what version you use, is your goal for the combination to do something different than the single agent or to be able to shorten duration of 1 or both?
Dr Berdeja: Well, I think the response rate of the TCE single agent is only about 60-70%, right? So there still is a large chunk of our patients that are not responding. So I think that is where I see a combination.
We know the combination data looks much better in that sense. Again, getting that initial response is very important. However, as we are seeing now with all of the TCEs, once you achieve that remission, it is very safe to start pulling back and decreasing the frequency. And I think that is where I see the potential that you can actually even stop the TCE and maybe just continue. And in my perfect world, I would do limited duration of both, where I would use the, let us say, iber to stop the TCE and then give a certain amount of time after and then stop it as well.
Dr Lonial: Yes, yes. And that is what I am thinking too. I think we as a group have used continuous therapy to do a lot of good stuff we have done in the last 15 years. However, with the agents we now have, we may be able to get to a limited-duration therapy world. And we are not going to know that until we test it. And, in fact, in the new IMWG response criteria, there is going to be a definition of cure. And it means off-therapy. And so we are going to have to get to that as we think about that more and more.