So I am going to spend the next few moments really talking about the need for new treatments in relapsed and refractory myeloma, and I am going to start off with what I call the current state of the art.

 

[00:36:14]

 

Current State of the Art

 

Randomized trials have demonstrated benefit for early intervention among the highest risk group of patients, whether that is len or len-X from older studies, or more recently single agent daratumumab that was favorably reviewed in the U.S. by the FDA, ODAC. These are certainly things that, I think, are coming to be in the next 6-12 months. We will see, I hope, at least 1 drug approved in this context that will allow us to begin to treat the highest risk group of smoldering patients.

 

Induction therapy with 4 drugs, including an IMiD, PPI and anti-CD38 for all except the frail, and that may be a discussion question amongst the 3 of us. I am not sure that for the truly frail we have changed the standard of care. I think DOD is still pretty good for those patients. For the fit, not frail, I would argue that transplant still offers significant benefit, and so I am still doing that in the right people.

 

Transplant, again, continues to offer significant benefit for the fit patients, and immunotherapies are clearly active, but I think we need to get to a point where we can limit duration or figure out ways to enhance their long-term efficacy by reducing the duration of therapy, particularly in the context of T-cell engagers.

 

[00:37:35]

 

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?

 

[00:38:58]

 

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 that are going to be reported on at this meeting, and then combination strategies for immune therapy.

 

I always like putting this editorial that Jonathan Kaufman and I wrote in JCO, I think it was in 2013 or 2014, in response actually to a French study looking at VTD vs VD in newly diagnosed, it was Professor Gaudreau's trial. It was a great editorial if you have not read it, and we call it the era of combination therapy. And the reason that I think that is so important is combination therapy is what has moved the field forward, and I think we have great immune targets. The question is, how do we put these drugs together to make them more effective?

 

[00:39:48]

 

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.

 

[00:40:30]

 

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.

 

[00:41:11]

 

Cemsidomide (CFT7455) Binds Cereblon, Facilitating Ubiquitination and Degradation of Key Proteins

 

Now there is another class of drugs that is in a similar family called cemsidomide or CFT7455. Many of us on the stage have actually used this drug. I have got several patients on it right now at my center. And this also has very high cereblon-binding affinity and does have preclinical activity.

 

And I can tell you it has clinical activity even in len- and pom-resistant patients. So, certainly, a very exciting class of drugs. It is oral, and I think does also make a potential good partner. And you will see some data in the next 3 months on the phase I trial of cemsidomide as well.

 

[00:41:49]

 

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?

 

So with that, I will turn things over to Amrita, who is going to talk to us about novel approaches to protein degradation in multiple myeloma.

 

Novel Approaches to Protein Degradation Pathways in Myeloma

 

[00:42:20]

 

Dr Amrita Krishnan (City of Hope Cancer Center): Thank you, sir. Thank you. Thanks for the opportunity to speak a little. This has been homework for me too, to go back to the beginning of just what is cereblon. We talk about it all the time. And I actually had not realized this. It is a cerebral protein.

 

And actually, when you look at the literature, there is a lot of research using it binding to cereblon for psychiatric drugs. I think that was a big learning curve of just how widely expressed this is. And it also kind of raised my interest in the question, which we have not talked about.

 

However, maybe we will solve those points on met needs. The 1 he did not mention was CNS involvement with myeloma. So I think something we also need to think about.

 

[00:43:19]

 

Cereblon E3 Ligase Modulators: Next-Generation Immunomodulatory Agents

 

However, he kind of already went through this, you know, his beautiful pictures in terms of understanding what it does in terms of binding to cereblon, changing the confirmation of cereblon from an open to close confirmation, which then enhances. So those are your answers to that question. The degradation of those transcription factors, Ikaros and Aiolos, and leading ultimately down to increased apoptosis.

 

However, also the effects, as he alluded to, and I will talk a little bit about this in terms of the T-cell effects and immune activation, which, I think, is a big area where we can exploit these drugs even more, quite frankly, because I think the future of these drugs is really not as a single agent. It is really what are you going to partner them with?

 

[00:44:08]

 

Protein Degradation in MM

 

This is basically just a beautiful cartoon, again, just showing cereblon, the CELMoD binding, the Ikaros/Aiolos pathway leading to this protein degradation and ultimately cell death.

 

[00:44:18]

 

Novel CELMoDs in Development

 

Here you can see, 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

 

Sagar touched upon this with cemsidomide, but we have seen it also 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.

 

Let’s Return to an Earlier Question

 

[00:47:28]

 

Posttest 1: Which of the following best describes differences between novel CELMoDs and approved IMiDs in regulating myeloma cell proliferation and modulating immune responses?

 

And with that, we will go back to our earlier question. Which of the following best describes the difference between novel CELMoDs and approved IMiDs? So I would expect a 100% answer on this one.

 

All right. We got 100% now. Wonderful.

 

My work is done here. Thank you.

 

And then I will turn this over now to my friend and colleague, Dr Jesus Berdeja.

 

CELMoD Clinical Trial Data

 

[00:48:30]

 

Dr Jesus Berdeja (Greco-Hainsworth Centers for Research Tennessee Oncology): Thank you, Dr Krishnan. All right. So these guys have talked a lot, but they have not showed you a single piece of data. I mean, it is ridiculous. I can see you are waiting. 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.

 

[00:48:54]

 

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.

 

[00:49:22]

 

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.

 

[00:49:38]

 

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.

 

And so in this cohort specifically, patients had to have at least 3 prior lines of therapy, including lenalidomide, pomalidomide, PI, and anti-CD38 antibodies.

 

[00:50:44]

 

CC-220-MM-001: Baseline Characteristics and Prior Therapy With Iberdomide + Dex

 

So 107 patients treated, you see the median age there. These are patients who had on average 6 prior lines of therapy, 100% IMiD refractory, you see 95% POM refractory, 85% LEN refractory, almost all PI refractory, either bortezomib or carfilzomib, 100% anti-CD38 refractory, almost 100%, 97% triple-class refractory. So, a very refractory patient population.

 

[00:51:23]

 

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.

 

[00:52:49]

 

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.

 

[00:53:35]

 

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.

 

[00:54:00]

 

CC-92480-MM-001: Baseline Characteristics and Prior Treatments (Dose Expansion)

 

However, I just want to show you sort of the dose expansion data. And so, 101 patients treated. Again, very heavily pretreated. You see a lot of 100 percents there on the right, which tell us these patients basically exposed to all these agents and refractory.

 

[00:54:16]

 

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. And I think we have to get used to that. We have to expect that. And we have to start learning to use growth factors with these drugs to really keep that potency going. And that will be sort of a theme of all these drugs and something maybe we can discuss as well.

 

Again, in terms of the other toxicities on the right, you see that, again, there is some diarrhea, there is fatigue. However, for the most part, these are pretty low-grade, very rarely high-grade, and less percentage than we are used to seeing with the IMiDs.

 

[00:55:12]

 

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.

 

[00:55:45]

 

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.

 

[00:56:12]

 

CFT7455-1101: Baseline Characteristics and Prior Therapies With Cemsidomide + Dex

 

So 47 patients, 6 prior lines of therapy. Again, very refractory on the right.

 

You actually see that here we are looking at patients who had prior CAR T, prior bispecifics, and sometimes both. So a very refractory population.

 

[00:56:30]

 

CFT7455-1101: TEAEs With Cemsidomide + Dex

 

Toxicity-wise, again, back to the neutropenia as being the main toxicity, maybe a little more like iberdomide. However, it is hard to say. These are phase I trials, different populations. It is hard to say which one we have.

 

However, all of them are expected to have some neutropenia. Infections are seen. But, again, grade 4 or higher infections were almost unheard of. And, again, the non-hematologic toxicities were pretty mild.

 

[00:56:58]

 

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

 

[00:57:26]

 

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.

 

[00:57:38]

 

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.

 

[00:56:03]

 

CC-220-MM-001: TEAEs With Iberdomide Combinations

 

I know this is hard to read, but it is all the toxicities put together. And the bottom line is that we are seeing, again, neutropenia as the main toxicity, but really no other significant additive or additive toxicity in the combinations as we have come to expect with these drugs.

 

[00:58:21]

 

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.

 

[00:58:38]

 

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.

 

[00:58:54]

 

CC-220-MM-001: TEAEs With Iberdomide + Dex + Dara (Cohort K)

 

And so when we look at this data that has been recently presented of 75 patients – this was just presented at IMS last year – we see, again, toxicity-wise, you are seeing more neutropenia, which would be expected with the addition of daratumumab, and you see some infections, again, not unexpected. And then the other toxicity is pretty mild still, so the combination did not seem to make that worse.

 

[00:59:21]

 

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%.

 

[00:59:56]

 

GEM21menos65: Iberdomide + Isa-Vd for Patients With Transplant-Eligible NDMM

 

This study is ongoing. This is from the Spanish group, Gen21menos65. So it is iberdomide with isatuximab + bortezomib + dex, or quadruplit. So similar to the quadruplits we are doing, of course, but instead of lenalidomide, we are putting in iberdomide. We think of it that way. These are patients transplant-eligible, and they'll be randomized to 3 groups.

 

The iber-ISA-VD vs ISA-ISA-RVD, which is the current quadruplit, vs just RVD, followed by transplant, and then maintenance. So I think this would be a very interesting trial to help us. What is the added effect of substituting iberdomide for current IMiDs.

 

[01:00:45]

 

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.

 

[01:01:51]

 

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.

 

[01:02:24]

 

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.

 

[01:02:40]

 

CC-92480-MM-002: Baseline Characteristics and Prior Therapies

 

And so we have seen some data from both of these cohorts. You see 49 patients in the mezi-VD and 27 patients in the mezi-KD arms.

 

These are different patient populations, so just kind of keep that in mind. In terms of the prior lines of therapy, you see that the bortezomib combination is only 1 median prior line vs 2 in the carfilzomib.

 

And then in terms of the prior anti-CD38 use, 40% in the bortezomib arm vs 81% in the carfilzomib arm, so a more heavily pretreated population in the mezi-KD population or cohort.

 

[01:03:20]

 

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.

 

[01:03:59]

 

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.

 

[01:04:25]

 

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.

 

[01:05:01]

 

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.

 

[01:05:46]

 

Notable ASCO 2025 Abstracts

 

So here at ASCO there are 2 posters updating some of this data. This poster, Abstract 7532, it is updating the results from the CC220-MM-001 trial, which is in the cohort with iberdomide, bortezomib, dexamethasone, in transplant-ineligible patients that I showed you earlier. So if you are able to, I think that is Monday morning, please go see that.

 

And then there is also Abstract 7553, which is actually an interesting combination called KID, which is the carfilzomib, iberdomide, dexamethasone in transplant-eligible newly diagnosed myeloma. And this actually looks very interesting. And they are showing very deep responses and also no adverse effects on stem cell collection, which I think is a good thing, because there is a concern about maybe the anti-CD38 antibodies in some of this.

 

So I think that is why this, I think, looked very interesting. So anyway, stop by if you can.

 

Let’s Return to an Earlier Question

 

[01:07:00]

 

Posttest 3: Which investigational CELMoD is currently being evaluated in phase III trials enrolling patients with multiple myeloma in the post-ASCT maintenance and relapsed/refractory settings?

 

So with that, we will return to some questions.

 

So posttest 3: Which investigational CELMoD is currently being evaluated in phase III trials enrolling patients with multiple myeloma in the post-transplant maintenance and relapsed/refractory settings? Is it:

 

1. Cemsidomide;
2. Iberdomide;
3. Mezigdomide; or
4. No CELMoD is currently being assessed in a phase III trial.

 

[01:07:51]

 

I guess we got 0.1% better. Most of you knew it already, so I confused one of you, maybe.

 

The answer is iberdomide, which is being tested. Remember, it is being tested as a maintenance in EXCALIBER maintenance trial, and it is being tested in relapsed/refractory one to 3 priors in the EXCALIBER relapsed/refractory trial. So there is the rationale of the answer.

 

And mezigdomide is only being tested right now in the relapsed/refractory setting in the phase III trials.

 

And with that, I will turn it over back to Dr Krishnan.

 

Where Should We Use MRD in MM?

 

[01:08:36]

 

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?

 

[01:09:00]

 

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.

 

[01:10:33]

 

Myeloma Response Criteria

 

So if you think about myeloma response criteria, it has really evolved. And it went through these various iterations and to even beyond stringent CR. In fact, maybe I am going to be controversial. These guys can jump in. I think stringent CR is kind of useless now, in the face of MRD. I am not even sure why we still have it listed because really MRD has become more of our gold standard.

 

[01:11:02]

 

IMWG Criteria for MRD in Multiple Myeloma

 

Having said that, though, I think the challenges we have is MRD or method, and you also need to remember imaging as well, right?

 

So, you know, we have flow-based MRD, sequencing MRD, and I think we can have a discussion later, but most of us would be happy with either method as long as with flow you have a certain degree of sensitivity, i.e., 10^-5. And we will talk about the pros and cons of each method.

 

[01:11:32]

 

Dr Fonseca lent me this slide, and it really just is a way to say we need to sort of move even our own mindsets ahead. And so his tweet was basically that, you know, why would you talk about chest X-rays when you can go to a high-resolution chest CT? So maybe you think about MRD in the same way. Why are we still talking about stringent CR when we can talk about MRD instead?

 

[01:11:57]

 

Immunoglobulin Loci Can Be Used to Quantify and Track Immune Cells Over Time

 

So when we think about MRD, we think about it in 1 of 2 ways. One is by a PCR-based next-gen sequencing assay. And what that does is it uses immunosequencing to look at unique sequences in each individual patient's myeloma. And then so you need a baseline sample to detect those sequences that then you can then follow up.

 

[01:12:29]

 

Monitoring Technique for Myeloma

 

So when we look at MRD, so there are 2. And just myeloma in general, how do we monitor patients with myeloma? So we have imaging. We talked about PET really is kind of our gold standard or whole-body MRI. Blood-based, right now, it is serum protein electrophoresis. I would say probably in the next few years, that is also going to change to some more sensitive blood-based assays, including mass spec, as well as some other sort of more assays based on PCR clonotypic, again, looking for circulating DNA.

 

We are not there yet, but we need to get to the same sensitivity that we do in the bone marrow. And then in the bone marrow, we obviously look at immunohistochemistry, pretty insensitive, but we still do that. And then we look at either flow-based MRD assessment or sequencing-based MRD assessment.

 

[01:13:25]

 

Flow Cytometry

 

So flow, the good news is you do not need that baseline sample. You can do it on any marrow sample you have. You send it to your own lab, so the turnaround is quick.

 

You need a pathologist who is trained, and you need a highly sensitive flow panel to do that. I do not know if you guys can tell me now, do you do flow or NGS? NGS. NGS for us, too. So the con is you do need a fairly large volume, and in a way, sometimes that fresh sample can be problematic, depending on when you do your marrows. And certainly for large trials, very hard to do a large trial with flow-based assays.

 

[01:14:02]

 

Next-Generation Sequencing

 

Vs next-gen sequencing, smaller volume, you can do it on stored samples. You do need that baseline sample to detect that original sequence, but it is something that you can do because it is standardized. You do not have to train your own pathologist.

 

For very large trials, at least in the U.S., this has been the way we have done this. And certainly in the trial that I am going to reference that we did for SWAR with 1400 patients, we used next-gen sequencing for all these reasons.

 

[01:14:41]

 

Evaluation of MRD as Surrogate Marker for PFS

 

So now getting to the next point, which is what we asked about.

 

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.

 

[01:15:09]

 

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.

 

[01:15:36]

 

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.

 

[01:16:03]

 

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.

 

[01:16:32]

 

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.

 

[01:16:58]

 

MRD in Patients With R/R MM Treated With CAR T-Cell Therapy

 

I just threw this in here for Dr Berdeja. Also, in terms of for CAR T, you can see, again, MRD is very meaningful as an endpoint and outcome in terms of progression-free survival here as well. So both in the newly diagnosed setting, in the relapsed setting, in the cellular therapy space, all these places, MRD has really now become our big marker.

 

[01:17:21]

 

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.

 

[01:18:25]

 

MIDAS: MRD-Adapted Therapy After Induction IsaKRD for Transplant-Eligible NDMM

 

However, even more so, I think this is where, for us as clinicians, it will be very important. So this is going to be presented on Tuesday. And this is a really important study because you see quadruplet induction. And then you see patients randomized based on MRD status to various risk-adapted consolidation and maintenance. And I will not spoil the thunder in terms of the outcomes, but you will see in terms of they used MRD pre-maintenance as basically an outcome from arm A compared to arm B and arm C compared to arm D.

 

So I think this is a really important study for us because it gave us a much earlier marker of trying to answer the question, do you need to do tandem transplant in high-risk MRD-positive patients rather than having to wait 5-6 years and looking at PFS?

 

[01:19:30]

 

PERSEUS: VRd ± Daratumumab in Transplant-Eligible NDMM

 

And then we have the PERSEUS study. This also is a really nice study in the sense, again, here we are seeing this idea that we are using MRD to guide clinical decision-making.

 

And so I will just focus on the maintenance part of Perseus where patients who were MRD-negative discontinued daratumumab after 2 years. And I would say at least for me, this was very impactful and something that I have started to do in our own clinical practice as well, based on this data.

 

[01:20:01]

 

DRAMMATIC: MRD-Guided Maintenance Therapy

 

And then the trial that I led, again, shows you how much I do believe in MRD.

 

This is a huge trial, 1,400 patients. Patients are randomized to, now we are really putting our money where our mouth is, stopping maintenance based on their MRD status at 2 years. So again, same theme, using MRD to make a clinical decision, which is ultimately really what we want and what patients want us to really onset when we keep saying we want to check MRD.

 

[01:20:31]

 

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, the MIDAS trial, and hopefully in the future, the DRAMMATIC study as well.

 

Let’s Return to an Earlier Question

 

[01:20:59]

 

Posttest 2: Now, how likely would you be to consider a treatment for multiple myeloma that was FDA-approved based on MRD-negative CR data?

 

So let us go now to our earlier question. How likely would you consider a treatment for myeloma that was FDA-approved based on MRD-negative CR data?

 

We stayed at 100%. Thank you.

 

And now I think I will turn it back to Dr Lonial.

 

Future Implications for Selecting and Individualizing Treatment for R/R MM

 

[01:21:45]

 

Dr Lonial: Thank you. So we are going to talk about a little bit in terms of future implications. And Jesus already showed a few of the slides in terms of trial design that I was going to touch on.

 

And I want to get some feedback from our colleagues here during the course of this one. And then we have already got a good selection of questions for us to handle in the Q&A afterward as well. However, this is really meant to be sort of interactive. And the good news is you cannot be wrong because there is no right answer to many of the questions I am going to ask you guys.

 

[01:22:16]

 

Topics to Discuss Today

 

So what, again, we are going to talk a little bit about is the same topics that we started with, but we are going to wrap up a little bit.

 

[01:22:24]

 

Novel CELMoDs in Development

 

And as you all know, obviously, the CELMoD agents are a continued evolution in terms of how things go.

 

[01:22:30]

 

CELMoDs Co-opt Cereblon via Unique Binding Features, Inducing Distinct Conformational Changes

 

And there are clear differences in how these drugs bind, what their affinity is, and what their efficacy is. And that leads to potential new opportunities for utilization as we think about it.

 

[01:22:41]

 

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.

 

[01:24:27]

 

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.

 

[01:25:20]

 

Responses in Patients With Extramedullary Plasmacytoma

 

However, I do want to show this slide, which I think really speaks to some of the efficacy of mezi in a truly unique way for this class of drugs. The IMiDs, particularly len and pom, and I think Joan Bladet has published on this data multiple times, really do not have significant activity in extramedullary disease.

 

That is what differentiates the IMiDs from the proteasome inhibitors, which do have some activity, but unfortunately, it is not terribly durable. Iber has not been looked at in the detail to which mezi has. However, you can see here, in terms of response rates for patients with extramedullary disease, and these PET scans of patients with a large liver plasma cytoma that basically melted with mezi, really demonstrates something unique about mezigdomide, which is, unlike the others in this class, it does penetrate into tissue better.

 

And in fact, if you biopsy plasmacytomas, you see a higher level of mezi than you do with the other IMiD class of drugs. This, again, this plus its binding affinity really does make it really exciting in the high-risk cohort of patients, which is a clear unmet medical need, as I demonstrated earlier on.

 

[01:26:34]

 

Emerging Strategies

 

So what are the emerging strategies that we all think about?

 

Well, I think iberdomide plus T-cell engagers makes a lot of sense. That was 1 of the questions that was brought up for us already. There are trials already doing this, looking at iber.

 

I do not know if there are mezi trials looking at this in terms of partnership together. And then, as you mentioned, the mezi maintenance after CAR T-cell therapy, iberdomide maintenance after CAR T-cell therapy. One of my longest responders on a CAR was on the trial where they got a CAR and then followed by iber maintenance.

 

And then, to me, the idea of using it before you collect the product actually makes a lot of sense. It is not dissimilar from the BTK inhibitors in CLL or other diseases, where it seems to activate T cells. For me, if you can think about using iber or mezi for 2 weeks before you put them on apheresis, I wonder what you do to the T-cell compartment in order to really be able to do that most effectively.

 

[01:27:33]

 

Discussion Questions

 

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. I was going to actually ask you a question, which neither of you I heard say. They just presented all the trials.

 

I never saw on any slide SPMs.

 

Dr Lonial: You never saw what?

 

Dr Krishnan: SPMs.

 

Dr Lonial: In iber and mezi?

 

Dr Krishnan: Yes.

 

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.

 

All right. Let us do a few more polling questions, and then we are going to do some questions from the audience.

 

A Few Final Polling Questions

 

[01:36:35]

 

Poll 3: Do you plan to make any changes in your clinical practice based on what you learned in today’s program?

 

Do you plan to make changes in your clinical practice based on what you learned today in today's program?

 

1. Yes;
2. No; or
3. Uncertain.

 

[01:37:05]

 

Poll 4: Please take a moment to text in 1 key change that you plan to make in your clinical practice based on this education.

 

Okay. Please take a moment to text in 1 key change that you are going to make in your clinical practice based on this education. So that is part of the learning cycle that I showed you, I think, in slide 5 or something early on.

 

So I do not know that that will be shared here. I do not think it will. No, it will not. So it is really just for the organizers to get a sense on what to do overall. So please take a moment to type that in.

 

Q&A

 

Dr Lonial: So we do have a few questions. And I have a few questions and actually, I will do them up here. Yes, that is okay.

 

I will stay up here. So let us start off. There is a question about CELMoD's effect on stromal compartment. For instance, the ability to reduce the microenvironment's ability to promote tumorgenesis. Anybody want to talk about that?

 

And I think what we know is that it does change the cytokine milieu in the microenvironment. Similar to the IMiDs that have an effect on downregulating TNF and IL-6 expression, that is probably the greatest effect on the microenvironment, unless you think about the tumor microenvironment including immune cells, in which case you probably do get more NK cells and more activated T cells than you would get with the other classes of drugs as well.

 

I am going to ask Jesus this one. Why is there a better response in the post-BCMA patient population than in cohort D?

 

Dr Berdeja: I do not think there is a better response. I think it is just smaller numbers. However, I think it is maintained. And that is the important thing. It does not seem to affect the efficacy, which I think is important as we talk about unmet needs for these drugs. However, I would not consider that an improvement. I just think it is just it did not show a decrement.

 

Dr Lonial: Yes, that is right, with one more line of therapy.

 

Okay, there is a question about combining BCMAs or bispecifics with CELMoDs. I think we touched on that one already, so I will not make you do that one again.

 

There is also a question on might CELMoDs be approved or not based on MRD findings? So, Amrita, do you want to touch on that one?

 

Dr Krishnan: Yes, I do not remember this trial you showed, Jesus, the one that was going to be EXCALIBER 2, right? I do not remember the endpoint.

 

Dr Lonial: EXCALIBER relapsed/refractory.

 

Dr Krishnan: Yes, what was the endpoint of that, though?

 

Dr Berdeja: PFS.

 

Dr Lonial: PFS is the primary, but they are going to go perhaps for accelerated based on MRD.

 

Dr Berdeja: With the plan that PFS should read out as well.

 

Dr Lonial: That is right, that is right. And then there is a question on MRD-based decisions for allo transplant.

 

Dr Krishnan: Meaning would we do allo if you are MRD-positive?

 

Dr Lonial: I am reading you what I have here.

 

Dr Krishnan: I mean, even coming from a big allo transplant center leading that trial on allo, we do not do allo anymore for myeloma.

 

So MRD would factor more into doing CAR T for us as a decision, but not in terms of allo.

 

Dr Lonial: And this is, I will just say, is a question that comes up a fair amount, particularly from Asia, where access to the drugs is not quite the same. And I have had patients that have progressed on a CAR and are on TALC and are being urged by their docs to have an allo transplant in fifth-line therapy. And my advice, despite the fact that you can do it, is I do not know that you should do it. Because the benefit in that setting is pretty small, if any. So, okay.

 

Any other comments? I will give you guys the moment for the last comments, unless there are other questions from the audience. No other questions? There is nothing here.

 

So, Jesus, I will let you get your final word in.

 

Dr Berdeja: Yes, no, I think something to what Dr Krishnan said before, remember when we got the lenalidomide, we had no idea how they worked. And so then once the cereblon sort of story unfolded, it is allowing for these very specific drugs now to target and really go after the target and minimize anything beyond that. And I think that is what we are seeing translated as these excellent response rates and also the decreased toxicity.

 

So I think it is a great story from the development of the class of drugs. So I am very excited about these classes of drugs.

 

Dr Krishnan: I guess my take-home is the initial thing, unmet needs. You know, there is a trial, Karina Patel's, there is a poster here, quintessential, right, looking a quad-exposed patients now. So it is really the post-BCMA space is where, is a huge unmet need for us.

 

And so potential for this drug and also, to be honest, for other classes of drugs, clearly, there is much more work that we need to do.

 

Dr Lonial: Okay. And I remembered one question I wrote down that I forgot to bring up. So when you referenced Rafael's slide, one of the sticking points in the IMWG response criteria is that in order for MRD to be a valuable, you have to be in CR. And I think there is a lot of back and forth on that definition.

 

From my perspective, if sustained MRD is really what is important, and it takes 2 more months to get there, then that is a marker of sustained. And so I do not have a problem with CR continuing to need be necessary for patients to be declared MRD-negative.

 

Like if you are not CR-negative, but you are MRD-negative, that does not count, actually, technically. It gets reported all the time. However, it technically does not count. I like the durability aspect of having to have CR before you can call it MRD, because I think it gives me more confidence in that data point. However, tell me you are all disagreeing.

 

Dr Berdeja: I agree to an extent, except for the modality of therapy. So, you know, like if you are looking at a CAR T, for example, that is such a quick kill of the myeloma cells that oftentimes the kinetics of the heavy chains can lag behind. And so in that setting, I feel like, you know, you may eventually get there.

 

However, I think having that MRD early point, I think, is important. However, again, I think eventually you do have to get to that CR because we know those patients who do not get to CR who are MRD negative do not do as well.

 

Dr Lonial: That is right.

 

Dr Krishnan: So, I mean, I agree with both of you in the sense of what you are doing with an individual patient in terms of clinical decision-making is important. However, if you are trying to do a trial, and we had to do this in DRAMMATIC because of Jesus's point in terms of the kinetics of heavy chain too, we allow patients who are VGPR as well to have that MRD assessment and then be randomized. Because there are patients to your point who are going to get to that CR. However, for a trial, you cannot do it 2 months. You cannot wait.

 

Dr Lonial: That I think makes sense. I think, and what I will say is in the new response criteria, it is not changing. So you still have to have a CR technically to be MRD-negative.

 

What I would push back a little, Jesus, is that we learned that at day 30, people could be MRD-negative, but it does not mean anything because they are not in CR, right? Many of them will come right back out. So what is the true value of that early endpoint? Maybe a later end point you can argue.

 

Dr Berdeja: I would say if you are MRD-positive at day 30.