Session I

Hello, I’m Leif Bergsagel from the Mayo Clinic in Arizona and I’m here in Madrid, Spain for the iwMyeloma 2023, and we’ve just finished the first session of the meeting. I’m here with Dr Francesco Maura from the University of Miami, Doctor Jill Corre from Toulouse, and Doctor Niels Weinhold from Heidelberg. The session talked about high risk myeloma and smoldering multiple myeloma and the genetic features that distinguish these things. It was a very exciting session. It started off with my talk which had a very interesting point, which was that one of the major things that distinguish the different stages of pre-malignant to malignant plasma cell disease is the level of immunoglobulin transcription. So as a cell goes from a normal plasma cell to an MGUS cell, to a smoldering myeloma, to multiple myeloma, relapse myeloma, the amount of immunoglobulin that cell transcribes goes down consistently and in the late stages, proliferation goes up. And although this seems like a relatively simple concept, it’s somewhat novel and helps us put these different phases in context. There was much more sophisticated analysis though by my partners on the stage and I’d like to ask you Francesco to say, what did you take home from this session today?

So I think that I was actually very pleased that the pioneering of FISH and a group that really made the history of FISH in myeloma and published most of the papers is transitioning to NGS, which I think is a historical sign, very welcome. It’s very hard logistically. But I think that the idea is that we’re living in a phase of transition where we used to stage patient using the FISH, which is the technology that has been around for 20 years. And now with the lower cost, more standardized computational pipeline, next generation sequencing is finally getting through, people finally see some utility in that there are prognostic model, different

different prognostic models, different factors. But the fact that the community is working on it means that we can generate more data, more data can be used for clinical trials or assess clinical trials. And we can finally get to a better understanding of a risk finally and not just on a small sample set.

Right, and you talked about sort of different features that we haven’t used in the past to stratify patients. You talked about chromothripsis, you talked about signatures induced by melphalan that occurr spontaneously induced by APOBEC. How do you see patients taking it or in their physicians taking advantage of that kind of information

So the one of the problems I think as Gareth also introduced is the fact that a lot of the species tend to co-culture together. And so for example, patients with (4;14), a lot of them in 1q and a lot of them in 13q or certain group of hyperdiploid has like all possible deletions and they have also gene expression, high risk pr or other. So the idea is how we can harmonize such complexity. We have basically every month new papers saying there is something high risk in myeloma. And so the idea is what association, what is causation – that really doesn’t matter for the patient because they want just to know what is high risk. So I think we need complex statistical modeling, more complex than cox and scoring, as the one we try to develop that is based on weight of each individual feature corrected for treatment. I think treatment is very important to correct, like one of the comments that you made about the forte and the French cohort. I think that my interpretation, even if I didn’t look in your data, but it could be that the 1q mono single gain treated with all regimens are very poor prognosis. But with the KRd transplant or KCd transplant from the FORTE are actually intermediate because these are sensitive groups. And so the difference between a single 1q and AMP is larger when you get a very sensitive group but not in the other population where, I mean, that’s just like an interpretation. But you know, I think treatment, when we look at this large cohort adjusting for treatment, age, these are very important features that for example, R-ISS2 which is extremely valuable, but they didn’t do it. So, and I think that’s a big limitation for patients because I guess ISS-3, 85 years old and ISS-3, 55 years old, a completely different outcome.

And Doctor Corre, you presented, you know, I think it was five or six questions and you addressed each of them and it was very clear and I learned something with each of those topics, but I guess maybe I’ll talk about 17p and the mutation of TP53 because that’s a controversy that’s been around for a while. And it’s much clearer to my mind. Like maybe if you’d just like to summarize the conclusions.

In fact about the deletion 17p, we have two important questions to debate. First one is the threshold to use to define the truly high risk patient with the deletion 17p. And when you look at the papers, sometimes it’s 20%, sometimes it’s 30%, sometimes it’s 50%. I already saw clinical trial showing that a drug abrogated high risk disease. And when I look at the definition of high risk, deletion 17p positive in more than 1% of plasma cells. So I think it is not acceptable anymore and we have to agree on the threshold in order to talk about the same myeloma population. So there was a meta analysis three years ago with European patient, more than 1000 with deletion 17p at different levels and the threshold of 55%, an arbitrary, was defined as the best to be clinically pertinent. And we confirm this in our own database with patients from the real-life data with all treatment. So I think this is important to have in mind that the deletion 17p is really high risk when present in the majority of plasma cells. The second question is the mutational status of TP53. Because now it is clear that when you are double hit myeloma, the deletion 17p plus TP53 mutation, this is an ultra high risk, the prognostic is very poor. But something was unclear is the deletion 17p. And this is the most frequent situation in myeloma without the TP53 mutation is associated to a poor prognosis. And yes, it is. And the other question, there is a third situation, the TP53 mutation alone without the deletion 17p and it is also associated. So we need both if we want to actually assess the risk in myeloma.

Can I ask you something? I agree, 100%. One question that I always wonder about: when you set a threshold in FISH on the percentage, you basically assume that the population is under percent two more.

But we know that even after sorting by bits. So how do you normalize?

We always, after sorting, we always check the purity and we correct.

How do you check by a microscope? Kappa lambda? Kappa know we, we uh no, we, no, we define the percentage of plasma cells but we don’t have the percentage of clonal plasma cells. So like because it’s like the 40% deletion TP53 could be 100% once corrected for purity

but in myeloma, you know that newly, newly diagnosed myeloma, that wouldn’t be an issue.

But speaking of heterogeneity Niels, you gave a fascinating talk that stimulated a lot of discussion and you showed that within an individual patient, if you biopsy the myeloma at different sites in the body, there’s there’s different genetics present and you, you even said that there was somewhere for I think was over 4000 days, there was lurking a tumor that only appeared at the final stages. How do you, how do you explain that?

So according to our experience, the situation is, in myeloma, we do the sequencing studies, we usually just see the expanded subclones or even the dominant subclones. So let’s say we detect three subclones, that doesn’t mean that there are just three subclones. It just means that these three subclones dominate at that location. And there is another point: it seems to be that there is a kind of regional evolution in myeloma. So that different subclones evolve independently from each other, different sides in this skeleton and we still don’t understand which of them contribute to the kind of diffuse pattern that you can also detect at the iliac crest and which of them are kind of locally for the whole disease course. We don’t know yet. And I guess that’s something that Irene Ghobrial is also interested in regarding with metastases in myeloma or it kind of diffuse infiltration. So that means we have a combination of dominance of subclones at sites and spatial heterogeneity that could explain that some clones are not detectable during the whole disease course. But they still, but nevertheless, they exist and can still contribute to relapse. I think it would be very important to try and identify where these cells are and what allows them to persist. So that it’s very frustrating with some of our new therapies. We can eradicate the disease completely and we can’t detect it with our most sensitive techniques. And yet still several years later, those patients may relapse and we really need to find out how we can target and eliminate that cell.

Exactly, unless, Francesco showed, so one one cell can actually drive the whole relapse. And so that kind of leads to the question: What about MRD diagnostics? If it’s just one cell that can drive relapse and you just don’t hit the location where this cell survives treatment,

it’s clear that the patient is MRD negative but there’s the relapse subclone, undetected.

Exactly. Yeah. Right. We, we also work together, we haven’t showed the data but like that the myeloma disability of seeding from one side to another, like these cells that can go from the bone marrow to the spine to the ribs. And we have like a couple of cases that are irradiated. And using the complex approach, we demonstrate that the cell seed from the radiation, like squeeze out and go through the bone marrow and repopulate the bone marrow.

So this day and anatomic distribution, I mean, you pioneered, Niels, with your paper in 2017, I think, and then now working together, I think are very fascinating and scary at the same point because it’s kind of, I can at least say how can you identify one cell and how can you identify it in the right location. It’s, you know, I think it’s possible. Well, I think with that, I’d like to thank my co speakers and thank you for paying attention today.

Session II

Hello, everyone. We are here in the 16th iwMyeloma workshop meeting in Madrid. And I’m very excited to be here with many of my colleagues who are going to talk about the tumor microenvironment but also about drug resistance, especially IMiD drug resistance. So, we’ll first start with introductions. My name is Irene Ghobrial, I’m a Professor of Medicine at Dana Farber Cancer Institute in Boston, Massachusetts. Paola?

Hi. My name is Paola Neri. I’m an Associate Professor at the University of Calgary.

Hi, I’m Larry Boise. I am a professor at the Winship Cancer Institute at Emory University.

Hi. My name is Charlotte Pawlyn, I’m a hematologist at the Royal Marsden Hospital and the Institute of Cancer Research in London.

So with that, I think we’re going to try and break it into tumor and immune microenvironment. This way, we can talk about drug resistance in both of them. And we know that truly, it’s an ecosystem, you need both of them to understand mechanisms of drug resistance. So I’ll start with Charlotte – tumour cells, and then I’ll come back to the immune cells and stromal cells, not just the immune cells and we will start by IMiD drug resistance. Can you give us a little bit of an update of what you found in your data?

So we had both from myself and then from a second talk today thinking about the mechanisms of IMiD resistant that are kind of intrinsic to the myeloma cell. So we know that IMiDs work both on the tumor cell and in the micro environment. But more of the data that we have is coming from the myeloma cells at the moment. we know that there are multiple different ways in which cells are able to generate resistance. There’s some really great work looking at sequencing studies, looking at mutations and copy loss of both cereblon, which is the key protein by which IMiDs act and also other members of the kind of pathway that controls cereblon structure and function. But really interestingly, even in data sets of patients who have become refractory to multiple IMiDs, we see these mutations and copy loss in only up to about a third of patients. So there are clearly other things going on in the tumor cell that are perhaps kind of affecting that interaction as well.

So that takes us to what else is causing drug resistance in general and especially talking about bispecifics, CAR-T. We’re in the era of immunotherapy and really understanding what is the role of the immune system in immunotherapy would be critical. And then of course, we’ll get to non-immune cells with the stroma. So maybe Paola tell us a little bit more about how we understand the immune system, especially with bispecific antibodies.

Absolutely, I think we are spoiling away because we have now new technology, new tools that we can actually investigate the single cell level. What happened to the patient in the, for example, T cell component and we can interrogate the bone marrow, we can interrogate the peripheral blood. So we’re learning a lot from investigating this component in a different level. And what we are, for example, learning that it is very important the fitness of these T-cells, because the TCE requires an engagement from T-cells and the tumor that if these T-cells are not performing well because they’re tired, we can call exhausted and they express a lot of these checkpoint inhibitors, unfortunately, they will affect how good these patients are. And I think we have now data showing that we can interrogate these T-cells before even starting therapy. And then if they are exhausting the bone marrow and the peripheral blood in a way, we say they are globally exhausted. We know the T cells were not good, they are not going to last. So they’re not going to give us the deep response we’d like. But if we have an ultra population, the peripheral blood, these patients are the ones, they respond because the TC are now engaging these cells, bringing them to the bone marrow and allow them to do their job, which is killing myeloma. So I think we are learning from, again, looking at different parts of the the immune cells where they interact with the tumor also in the peripheral blood. How important this is.

So moving from T-cells to non-T-cells and trying to understand the stroma. And I’m a big believer that the stroma is critical in multiple myeloma. Can we talk more about how the stroma can induce resistance in multiple myeloma?

Sure. I mean, I think one of the things is, as Paola points out, we have all these wonderful tools now that we can look at all these different cells and you spoke too, as well. And we’ve been thinking about the stroma involved in drug resistance for some time. And I worried now with the way that we’re looking at things that we forget about our old friend and think about and how it actually influences the therapies that we’re now moving into with the immunotherapies. These cells produce lots of cytokines and chemokines that can attract different cells into the microenvironment itself. Also, the cytokines, they have a direct effect on the myeloma cells themselves to enhance the survival of these cells. And what we talked about today was how that can even affect potentially CAR T-cells. And recent data that one of our other speakers published with Adam Cohen showed that residual cells following CAR T-cell infusion, when you look at the myeloma cells that are left, the signal that’s enriched in that is actually IL-6 and STAT3 signaling, suggesting these pathways that are activated by the stromal cells and then are influencing the response to these therapies.

Yeah, let’s talk maybe about post-therapy. Looking at, you’ve given the therapy, let’s take a look at what happened to the immune system or the tumor cells post-therapy. I think we touched a little bit about some of those in our session. One of them was our work on PIN – Post Immune Normalization, indeed showing that if you normalize the immune system post-therapy, that could be a predictor of long-term outcome. It was in one study, we’re hoping to see it in many other studies that you can be predicting long-term outcome even if you don’t have residual cells left or if you do have even small numbers of tumour cells. But your data also with bispecifics as well as the CAR-T data that was presented post-therapy, you indicated that there could be that response of now that exhausted T-cell is sort of revived a little bit. So can you give us more information about that?

Because again, even how we define exhaustion is still not perfect, is not ideal because we have some precursor, exhausted T-cells where even if they have checkpoint, even if you have the receptor inhibitor receptor can be rescued. And I’m thinking, you know, the checkpoint inhibitors should be reutilized or we have to think about again in myeloma or if they’re really terminally exhausted. So where unfortunately the cells dont even have high levels of granzymes and these are unfortunately difficult to rescue. But I will even say let’s prevent this exhaustion to happen or maybe utilize them with therapy earlier on, we cannot wait to have 10 lines of therapy and think about this approach. I think all our work seems to suggest that we have to have a healthy environment, it’s not just for T-cells, but all the other components, because they are all playing a role and allowing this therapy to be effective.

So again, going to my other favorite places, treating smoldering myeloma, treat them early before it’s too late. So maybe let’s talk about post-therapy, especially with patients not on lenalidomide, but as we get to the next generation and next generation of IMiDs, what do we want to look at post-therapy to say indeed, those patients are losing response and that will go back to some of those loss of BCMA, loss of responses to even GPRC5D. I think we saw a little bit of that tumour drug resistance.

Yes, we think similar to responses to IMiDs we’ve seen with T-cell engagers and with CAR-T cell therapy that if you lose the key mechanism by which these drugs are working. So we’ve seen data looking at loss of that cell surface receptor in the case of T-cell engagers and CAR-Ts. In IMiD response, it’s less clear maybe that that’s definitively the mechanism that’s driving resistance, but I think that’s probably also true in the CAR-T and bispecific space, we see a variety of different things that are changing in patients and perhaps for different patients, it’s different, which is the mechanism in that situation that’s really responsible for the disease coming back in that scenario.

So with that final conclusions of our session, Paola?

I think we are all learning from interrogating the tumor, the microenvironment, that we have to interrogate both because one would not give us the answer we need. And from learning from that, we can learn how to act on it and to even select the best set up for our patients. That will be my take home message.

Absolutely. And I think it also as much as we learned in and the exciting data that we saw today, there’s so much more to do, still. There’s so many, it seems like we end up creating more, you know, more questions than answers. But I think it’s definitely going to be exciting times moving forward as we now know more about what the cells are there and which ones are important in these responses.

Yeah, I can only agree, but I think it’s also important to be reminded of the stromal cells. We spent a lot of time thinking about T-cells and the immune cell compartment of the microenvironment. But actually there are many more cells and structures going on there that kind of interact. So I think it was good to be reminded of that.

Yeah, And I would say that it’s been really exciting where we see huge responses, improvement in survival of our patients with myeloma. But it’s still complex and we’re still trying to understand it more. And the more we dig, the more we understand that we barely know anything about myeloma and its complexity and we need to understand it even more. So we’re not losing our jobs anytime soon. But we’re hoping to keep understanding better who will respond to therapy and who will not, because we owe it to our patients that before they start a bispecific or a CAR-T or any therapy, we know if they will respond to this therapy and we can be more selective. We’re not treating all the patients with all the drugs, we’re treating some patients with drugs that they will respond to. And that’s our job to help our patients improve their responses and their long-term outcome. Thank you.

Session III

Hello to everyone. My name is Maria Victoria Mateos and I am here attending the International Workshop on Multiple Myeloma, the 16th edition that is taking place here in Madrid. And we are just coming from a roundtable discussion in which we have been discussing about future strategies for multiple myeloma. And the panel was composed by different speakers, Bruno Paiva. He was talking about minimal residual disease, how to incorporate the immune microenvironment in order to predict response. And we have other two relevant speakers, Marta Chesi and Jose Angel Climent talking about animal models and how can we utilize these animal models in order to translate in translational and clinical research. I was talking about smoldering myeloma, but I would like to invite you to summarize your talks during the roundtable discussion. Do you want to start, Jose Angel?

Of course, Maria. Thanks for the introduction. Yes, I have been presenting the new models of multiple myeloma that we have generated in mice. And we have tried to recapitulate all the genetic heterogeneity of the patients in the mice models and using them, we show that the genetic lesions that we induce in the mouse models can not only drive the progression of the disease but also induce immune mechanisms that are similarly seen in patients with the disease. We have the paper now published in Nature Medicine. It was released two days ago. And I’ll be happy to thank you and I’ll be happy to address all the questions that you have.

Okay, thank you, and Marta, do you want to summarize your data and how do you see it complimentary to the research that is being done?

Yeah, I think that it’s kind of like we follow two different approaches. And then you try in your approach beautifully to combine genetic lesions that we know are important for myeloma development. You combine them into unique mice to expedite the development of the disease and monitor changes in the microenvironment. I took a slightly different approach where I said, okay, let’s just introduce in the mouse one lesion and just wait and see what else is spontaneously acquired by the mice in order to develop myeloma. And it was quite gratifying to see that actually mice and human, despite the size difference are not that different in the sense that the myeloma is quite similar in the two species. And it’s characterized by similar genetic lesion, maybe not exactly the same mutation. But I like to look at pathways that are important for plasma cell transformation. And there is certainly a conservation in different pathway between mice and human.

Okay, thank you very much. And Bruno, we know that undetectable measurable residual disease is one of the most important prognostic factor in myeloma. But is it possible to predict it? How can we proceed and how the microenvironment is important or can be incorporated into the minimal residual disease evaluation.

Yes. This was a recent effort from our group, to try to anticipate what could be hopefully a scenario in the near future. That is the possibility of having different equally effective regimens for frontline therapy. And in such a scenario to offer the possibility of perhaps selecting one or the other based on the probability that a given patient would have to achieve undetectable MRD with that regimen. And the Spanish group did show that it was possible to predict MRD outcomes in approximately 70% of patients, both transplant eligible and ineligible, using data that is commonly collected at diagnosis, namely cytogenetics, tumor burden in the marrow, also in peripheral blood CTCs. And I recognize that this is not usually measured until now, maybe in the present and in the future, it will become frequently measured and also immune biomarkers. And these immune biomarkers again are usually not taken into consideration. But the information can easily be collected by flow cytometry screening of clonality that is commonly performed at the time of diagnosis. Using a simple model, it is possible to predict MRD outcomes. And later on, we also showed recently that by using the same asset that allows us to detect and quantify MRD, it is possible to perform a snapshot of the patient’s tumor immune micro environment in the marrow, and that this information can also predict progression free and overall survival. I still believe that MRD as a prognostic factor outperforms and is more relevant than immune profiling, but this may change, the equilibrium may change as more and more immunotherapies are coming into earlier lines of treatment.

Okay. Thank you very much. And just to say that I was addressing the role of different risk models for the identification of high risk smoldering myeloma. And there are many different models, the majority of them are based on clinical markers, component, plasma cell bone marrow infiltration, free light chain. We are incorporating, for example, the circulating tumor cells, imagine techniques like PET/CT. But from my personal point of interview in the future, we have to incorporate genomic characteristics because there are some mutations that can predict high risk of progression to multiple myeloma and they can optimize the clinical markers and models. So I think that we need to combine all this information. And also we were discussing about the optimal endpoint when we plan a clinical trial in smoldering myeloma. Time to progression to myeloma or maybe. And I was discussing with Marta just before this roundtable about the possibility of progression-free survival to incorporating also the second line of therapy in order maybe to evaluate the potential resistance to the treatment given as part of the first line of therapy. But anyway, I think that there are many clinical trials ongoing and all this information will clarify the situation in smoldering myeloma. Thank you very much for being here and thank you very much for your attention.

Session IV

Good afternoon. My name is Keith Stewart from Princess Margaret Cancer Centre, Toronto. I’m here in Madrid for the International Myeloma Workshop 2023 meeting. I’m joined by colleagues, Doctor Brian Walker from Indianapolis in the United States. Always sound Scottish like me. Doctor Claudia Stege from Amsterdam and Doctor Martin Kortüm from Würzburg, Germany. We’ve just finished a session looking at the future of myeloma care. And we started with an interesting discussion on some topics about where people thought that care was was going. But then we quickly gravitated to look at some of the work that’s been done in different centers around the world to try and create a path to cure for some of our myeloma patients. And I might start with Brian actually, and Brian had talked about some of the translational research that’s happened in the United States as it relates to large clinical trials. So, Brian, just summarize for the audience the sort of nature of your talk today.

Yeah, so I talked today about some of the clinical trials that are happening as part of the cooperative groups in the U.S., namely with SWOG, ECOG and Alliance. And so, the current and upcoming clinical trials involved newly diagnosed, frail patients and smoldering patients as well. And so I was talking about how those are happening and what kind of translational studies we would hope to perform in addition to those clinical trials, so that we can find out more information about the patients on those trials, from their genomics or proteomics or other cellular abnormalities and see how those associate with response to treatment, things like that.

And why has it been challenging to do those kind of studies? You made a point that a lot of the big trials have not include genomics. What do you think the challenges are to doing that?

Yes, I guess one of the big things is that these are multi center trials and a lot of the genomic

studies such as the baseline FISH is performed locally. And so you get a lot of variation in the quality of the results from local centers, especially, I guess, smaller centers which have fewer resources. And so we want to kind of change that in several ways. One is by kind of updating the technologies that are used, moving away from FISH, which has been good for the last 20 or so years, but is now looking a little outdated, giving kind of limited information about our patients, you know, we’re currently getting from FISH some translocations and some copy number changes which are prognostically important. But we’re now moving into the era where mutations and having a more rounded picture of the genomics of these patients can be of interest to identify any associations with response there as well.

Claudia, I’m going to save the best for last, I’m going to go to Martin just because it follows on more naturally. Martin, you added to the genomic discussion by talking a little bit about imaging. Do you wanna expand for the audience? Remembering there might be some lay people watching. What you were talking about with respect to scanning?

So back in 2017 at the iwMyeloma meeting, I presented data from differential PET imaging. So that was CXL4 methionine, choline FDG-PET. And what we could demonstrate is that you can display clonal heterogeneity, so a different biology of the disease. And what we then realized is that some of the traces are more sensitive. And in our German DSMM XVII trial, we have incorporated such imaging along with MRI imaging and I showed one exemplary case in which a high risk patient had already signs of progression at the end of induction therapy. It was not visible by serological markers and not visible by the PET tracers, but by the MRI. And so in this case, MRI seemed to be more sensitive. I also showed data of a patient that had progression of the CAR-T, BCMA-directed CAR-T, or suspected suspicion. That is a case that Leo Rasche from our institution very much pushed forward. And so, finally, we use the second PET tracer to differentiate the disease progression from an immune reaction, following CAR T-cell therapy. And we’ve proved that by doing biopsies and lavage of the lung to clearly demonstrate that a second PET tracer can be used for clinical purposes. It was beautiful, translational research. It made me think how much you can learn from one patient if you just go deep enough. You know, back in, a the decade ago when Jonathan Keats and I and Leif studied a single patient over serial samples, doing whole genome sequencing, I’m not sure if it still holds true what we discovered, but it was just one patient who we studied in depth and we learned a lot.

Claudia, you talked about frailty, a lot of our myeloma patients are elderly. And I think you gave a very nice description of the current state of activity of clinical research in elderly patients who are frail. Do you want to just summarize that for us?

Yeah. Yeah, exactly. As you said, because the population worldwide is aging, also the number of older and non-fit patients is increasing. And increasing evidence shows that the outcome of older patients depends largely on frailty level, more than chronological age or cytogenetic abnormalities. So we must incorporate frailty in order to evaluate treatment effects in different frail subgroups. Because if we only look at the whole picture, you cannot translate it to the clinic. So there are now a couple of trials that have published results on specific frail subgroups and showing that actually when you deintensify treatment, you can actually receive the same efficacy as compared to the standard treatment. And what we should prevent is to give patients toxicity because then it diminished treatment adherence and lowered efficacy. So I think that’s a really evolving field. Uh

I think our patients will be really delighted to know that the first thing you discovered is you can get rid of Dexamethasone.

Yes, I know, I don’t know if you have ever had dexamethasone, but I

I actually did take and I was, couldn’t understand how I felt so terrible like the next day, but I felt very sorry for my patients after two days. So, it’s a very difficult drug to take. And I think actually it has to be abandoned at some point. It doesn’t cure anybody. What I’m going to ask each of you this question. So I’ll give you a few seconds to think about what excites you the most about the future of myeloma therapy as it relates to the work that you’re doing. So, maybe it will be a little unfair to spring this on you, but Martin, what excites you?

I think it’s really exciting to see the advance of technology options. So, some years ago sequencing was so expensive and now everything becomes available. So we can much better dissect the heterogeneous patient cohorts, and then we’ll be able to really define the right treatment for the right patient. And then we will have a subset of patients that we will cure, that will be standard risk patients. We were debating whether these are 10% or 15%. We will see, but definitely there are patients that can benefit from such personalized treatment decision.

This is for the audience. We we had a discussion about people’s prediction of how many patients have been cured. Today, we’re starting therapy. There are some data, even in the old days, we were curing maybe 15%. And I think the optimistic expectations probably at least doubled that today, if you are standard risk disease.

Claudia, what’s exciting?

Yeah, I think, not to copy your words but, that it’s so important that we can treat so many patients in different ways to individualize treatment, according to risk, stratification, cytogenetic abnormalities, but also frailty. And what is actually quite funny is that even in myeloma field is not really aware of frailty and not fond of frailty. So I am very keen to increase that awareness and that frailty does matter.

Absolutely. Brian, take us home here.

Yes. So I think I probably agree with Martin as well that precision medicine is probably the most exciting thing. Like, the more we know about the genomics of these patients and the more we learn from other diseases as well. So for example, some of the rising mutations, inhibitors are coming through in the solid cancers, whether or not we can move those over to myeloma as well, and hopefully they’ll be successful. And so kind of bringing together

the things that we know about from the genomics, the advances we’ve made there and identifying what’s wrong with the cells and kind of marrying those with potential treatments that could really help the patients.

Well, thank you all of you for being with us this afternoon. We began this session actually by talking about the future of myeloma care. We talked about whether we should be treating patients earlier, whether the drugs we have today are enough to cure patients with or whether we still needed more drugs. I think the consensus was we should treat earlier. We should, we do think we have the tools today if we can figure out how to use them properly. And we also talked about whether we should be stopping treatment or continuing it. And I think that’s probably the most debatable point we came up with today. But the continuous treatment, people seem to win the vote. Anyway, tomorrow you’ll hear at the same conference about some of these exciting new drugs, T-cell engaging therapies particularly. We’ll save that for another panel. Thank you for listening.

Session V

So good morning, everyone. I’m Elena Zamagni from University of Bologna in Italy. So, I’m here with the other speakers of this very interesting session on novel targets here at the International Workshop on Multiple Myeloma in Madrid. Nizar Bahlis, Enrique Ocio and Carlos Fernandez de Larrea. So we discussed many novel targets, multiple myeloma, newer drugs, drugs that are giving the first results in multiple myeloma. And we also discussed imaging techniques in clinical trials. So let’s start with you, Carlos. You discussed a little bit about new CAR T-cells. So can you just summarize a little bit? What was the message of your presentation?

Thank you, Elena. I think that we have still a lot of field for improvement in the treatment of patients with multiple myeloma with CAR T-cells. One of the mechanism. and it was mainly the focus of my presentation, that is to try to recognize more than one antigen because we have been targeting mainly BCMA until now, that is also the main target for many of the bispecific antibodies. And I think that the combination of BCMA with another antigen, for example, GPRC5D that is already well recognized, could be very interesting to try to avoid the relapse in cells, you know, without expression of the antigen or with a low expression that can be the origin of the relapse. And I think that we have a lot of things to do. We can also try to improve the persistence but try to target more than one antigen. I think that is one of the points of the problem.

There are different ways to target different antigens. So do you think there is one which is the best one or you’re still looking for different?

Yeah, I think that there are three main different ones. The one that is single receptor, a single stock that can recognize both antigens. I think that this one is the weaker in general, the weakest in the majority of models because it depends on how is the configuration of the antigen on the surface. It’s more difficult to target both. And we have tried also, we were trying the in the Memorial and we have tried in Barcelona and it’s very difficult to an equivalence. And I think the most interesting are of either producing two CARs against one and the other antigen and to mix it – it’s something that we are doing now in a clinical trial in Spain for lymphoma.

But I think that the most interesting, because we are always aware of the price, you know, these drugs, particularly, for example, in Europe, and I think in Canada too, and I think that with a bicistronic, you are producing a CAR with a single vector, you’re transfecting the cells and the cells are expressing receptors against both antigens. And it seemed that even in vitro and in vivo, it has some advantage also like with a more powerful ability and even activity against the CAR, against the tumor cells. And I think that this could be one of the most interesting approaches for escalating that into a clinical trial.

Okay. So are there already some trials in humans? I mean in multiple myeloma ongoing regarding this new modality?

Yes, in the Memorial they are using, but they’re using two productions at the end, based on what I was discussing. But, always when you are moving from mice to human, you have all the regulatory issues and also many logistics, details. And for example, we are doing also lymphoma in Barcelona, is mixing two monospecific CAR Ts. But it’s true that probably in the future, we have to do the effort to try to also develop bicistronic ones.

Can I ask one question? Do you think that we would delay relapse or it would be also more effective from the beginning? So more responses or later relapses.

It’s difficult to say that because we don’t have result in human. But based on the results in mice, the initial response is quite the same, but the relapse are earlier when you have only one antigen. And I think that the most important thing is not to increase the response because it’s very high. Now, with CAR T-Cell, it’s 80%, even 100% with some constructs. But I think that the most important thing is even we are having this amazing response rate. We are having like 9, 12, 2 years or whatever the median progression free survival, that we have to try not to relate the deep response also in an extremely long progression free survival.

Quickly, one question also: is the CRS rate higher in mice? It’s hard to judge. Or do you infuse at the end the same dose of cells? It doesn’t matter.

It’s the same dose, we didn’t see any toxicity. You know that this model is not to see CRS in mice, but we didn’t see any general toxicity or mortality increase when using these bispecific strategies. We don’t expect more toxicity that each CAR T by itself.

Exactly.

Okay. Fantastic. So, Nizar, you focused your presentation on the CELMoDs, this newer improvement coming after immune modulatory agents. So, can you just tell us what, to your opinion, are the focus on this topic and what they can offer to the myeloma scenario, which is very full of drugs.

Thank you. And as you said, we had the IMiDs, LEN and POM for several years now and very familiar how we use them, the side effects. And the question of the CELMoD, the novel molecules have an advantage over the older generation of IMiDs or CELMoD, if you want to call them that way. Biochemically, they seem clearly more promising in vitro, for variable aspects. The more efficient in binding cereblon, we more recently learned from a new micro and structural biology data that they’re more efficient in imitating cereblon. And we’ll call the closed allosteric confirmation which allows it to better degrade the metabolite Ikaros and Aiolos. So, from the biochemistry and biochemical and structural design, the novel CELMoDs seem to be more efficient. But what I’m particularly excited about goes back to the work that Carlos is doing, that these novel CELMoDs are more important in inducing activation of T cells and NK cells even in patients who are exposed to Daratumumab, BCMA and so forth. So I think from that perspective, these molecules will be very exciting in the future, with novel combinations. So far, the clinical data, the early clinical data from these molecules in early Phase I studies also looks promising in patients who are refractory to POM and IMiD, in the sense that inducing sustained responses, I should say short-lived responses as a doublet, but nevertheless, inducing around 30%-40% response in patients refractory to LEN or POM.

So according to what you’re saying, probably instead of substituting CELMoD to LEN and POM in the already well-proven combination. We could think about CELMoD with T-cell engager or CAR T prior, after, maybe… What do you think about this?

Absolutely. There’s work, pre-clinical work from several groups, in particular here in Spain, a look at the combination of Alnuctamab, one of the BCMA T-cell engagers with one of the novel CELMoDs and they clearly show some dramatic in ex vivo and in vivo. And in mouse model synergy. So you’re absolutely right. And I think the combination with the novel immune therapy, but also some of them are a backbone therapy, need to be studies in a randomized trial to see: Is it better, like you said, than LEN or POM?

In fact, I can tell you that we are also planning a clinical trial based on that combination, using Alnuctamab plus Mezigdomide, then stopping Alnuctamab after a certain period of time, after nine cycles and then continue with Mezigdomide as maintenance, and only reintroduce Alnuctamab in case of response. So I think…

That would be a more mild way of using bispecifics.

Exactly. So I think it’s important to stop. Right. So I think it’s more, it’s an adapted strategy just to introduce and I think it would be, but I think this is the combination probably the future and even it could be interesting because we are planning, for example, to know, to rescue patients that have been highly treated. And you know, in combination with, for example, with CAR T-cells or bispecifics. But you’re thinking, for example, we are now in the era that we’re using a continuous maintenance treatment. Now the idea is forever, no? But we are exploring the idea of how to stop treatment earlier, because it’s also related to quality of life, probably. Do you see any role of these new CELMoDs instead of, for example, lenalidomide in the maintenance of patients?

Yeah, definitely there’s trials ongoing in the maintenance setting.

Unfortunately, design is still looking at continuous administration. So they’re not looking at a limited number of cycles. But as Enrique said, and as you probably hinted too as well, Carlos in the combination of immunotherapy will be interesting to see if you give them for a certain duration, even the IMiDs or the CELMoD and see whether it is efficient to induce a durable response and adjust response based on MRD. But currently the trial designed with CELMoD is still looking at it in continuous scheduling, unfortunately.

Yeah, thank you.

So, Enrique, let’s go to your presentation. You presented many, many newer targets. So quite a full scenario of newer modalities. So, what would you pick among all of them?

Now, that’s, thanks Elena. That’s a good question. So no, I think we have really been working with three main classes of drugs: PIC, …, and CD38 for the last 20 years. Now, we have all the introduction of the immunotherapy with CAR Ts, with bispecifics. But still we need drugs and novel targets for multiple myeloma. This is what they have tried to summarize. And I think there are, we have two already approved, which are the Selinexor, the exportin inhibition, and also we have, if we can say a novel target, which is the Melflufen, which is, it’s based on alkylators, but it’s maybe a novel mechanism with these peptide drug conjugates. It’s quite a specific. Yeah, exactly. So and then we have other ones that are not so approved. We have, I think we have Venetoclax with t(11;14) translocation and we have other potential pathways to be targeted, which is the Ras pathway, we have Myc and other interferon pathways. I think we have several ones, but we have to look for the best for multiple myeloma and which one would target more efficiently multiple myeloma. It was asked if we would be able to cure with these strategies. I don’t think it would be the case to cure with all these targeted strategies, maybe we are using them late in the course of the disease. Myeloma is not a monogenic disease, but I think they would help, probably would have to choose which patients would benefit from each of them.

In your opinion, because, as you correctly said, myeloma is not just one driver mutation and so on. So few patient have a single mutation. So do you see these targeted agents in addition to the rest of the treatment or as a single agent? Because until now they were tested in very late phases, single agent. So people with a RAS mutation is the standard treatment plus RAS inhibitor or…?

Maybe not upfront. I think, from my point of view, upfront we will have a very well standardized backbone.

So I think, and they are very efficient, but probably at relapse. And I said, a good example of a patient with an t(11;14) translocation at first or second relapse, I would probably go for Venetoclax in combination probably with Bortezomib or maybe with any other drug we can add to that. So I would I see them at relapse in combination with some of the standards we have.

Yeah. And you also discussed this Modakafusp alfa, this new way of restoring interferon. That was the story of all myeloma treatment when I was young. What do you think about it?

So I was striked by the results of the interferon. I heard about this when it was a Takeda compound, some time ago. And then now we had, a couple of years ago we had the first result with 40% responses. For me, the two most promising drugs now that are being developed are of course, CELMoDs that are really promising. And the other one is Modakafusp. It’s interesting, 40% responses with a good safety profile, just thrombocytopenia. And well, I think it also can be combined very nicely with other drugs. So

Elena, may I ask you a question?

Sure, I also have to reply. You talk about different modalities for imaging of multiple myeloma. I’m curious, at the end of the day, what you do practically in the clinic today, are you applying PET scan and MRI to your patients routinely? And if so which patients?

Yeah, it’s also difficult to make a worldwide recommendation because it’s really depending on the reimbursement and probably mostly on the capability of the center to be really expert in the field. So what we can say, one of the two to my opinion are really the best ones. So I clearly showed that whole body MRI is more sensitive because it’s looking at the different things. It’s looking at bone marrow infiltration of plasma cells. So by definition, even in the early phases, it’s positive while PET/CT is looking at disease metabolism, so sometimes the disease metabolism is low and so on. However, if you are not able to use a three Tesla modern MRI with expert radiologist, you’re not doing a good job. So at that point it’s good anyway to use PET/CT. The other good news is that they are systematically used now in clinical trials. So, in the next five years, we will have a lot of data and many data now are based on retrospective post hoc analysis. Now, if we will have this prospective look, we can merge what is the role of imaging versus bone marrow techniques versus peripheral blood techniques, for example, in the valuation of the response. So this is also to my opinion, important. What’s probably going to be difficult, will be to tailor treatment upon imaging exclusively, because probably this is not enough to make recommendations. So I’m seeing sort of more open vision, where there is at the same level imaging, bone morrow and peripheral techniques and this will help in the management of the patient.

And would you do that to everybody upfront and the diagnosis to all transplant candidates or also the elderly?

Yes, fit patients, of course. We are just speaking about patients where you would like to achieve MRD or highest response. So well, if you have a frail patient, you just use imaging to make a map, picture of in the old way. I mean just to map the disease that’s enough to my opinion because the frailty is overcoming the role, prognostic role of imaging. An important point. I think that this is also this is a classical question, but I think that for inclusion in trials, we are still using only serological criteria, that for measurable disease we’re using the disease in classical N protein, in serum, we have incorporated the serum free light chains. Now, 40% of for example, of patients on trial, for CAR T-cell are only included for the serum free light chain criteria. But we need criteria that for patient have only disease by imaging.

And I think that this will be very important to put up know what this your opinion of course and how we can translate that into the regulatory bodies, FDA, EMA?

That can be, you know, very difficult. Fortunately, mass spec probably will solve also another percentage of patients that will be just mass spec positive only. That has been demonstrated already. Otherwise you should recommend the standardized criteria by imaging, but not all the centers do have. So how can you run a trial where the center is not using the same exact modality? So, it’s difficult, but it can help for sure. Okay. So I think we summarized the most important topics of the day. So thank you all of you. Thank you very much. Thanks a lot. Thank you.

Session VI

Hello, my name’s Gareth Morgan. I’m a professor of hematology in New York City. I’m here today in the International Workshop on Multiple Myeloma 2023 with my good friends and colleagues, Doctor Sagar Lonial from Emory and Doctor Pieter Sonneveld from Rotterdam. Guys, we’ve just had a really good debate about the role of cure in multiple myeloma and perhaps we’ll start with you, Sagar. What do you think that the concepts we have to address to really deliver this as an idea for patients?

Well, I think one of the things we have to really embrace is the idea of not sort of doing the same old thing that we’ve done for years, which is induction, consolidation and maintenance. I think we have to think about different ways to get limited duration therapy, use all of our targets almost like they do in ALL, where they bundle a lot of therapy in a short duration, and think about stopping therapy, so that we don’t get a high risk of infections chronically over the lifetime of a given patient.

And so from your perspective, Pieter, I think you presented a sort of practical way of how we can move forward in this area. Could you just tell us about that?

Yeah, but also like Doctor Lonial is saying, we used the same concept of treatment now more or less like 10 years ago or maybe even 20 years ago. So in the meantime, we look at endpoints that reflect the whole treatment, not parts of the treatment so much, we need to know what each element in the treatment really brings to the patient. And I think we are trying to do that in EMN, European Myeloma Network, by focusing some trials on improving induction, some trials to challenge the role of autologous transplant and others to look at maintenance more specifically with the newer agents.

So what strategy should we use? I kind of noticed you made some strong analogies to alternating treatments over time to overcome resistance. What do you think of that?

Well, I think the idea of hitting the tumor pretty hard and then letting go and then hitting with a different target that, to me, is a way to potentially get around some of the things we’re seeing like BCMA receptor mutations or loss of BCMA because of continuous suppression. I think if you’re hitting with different targets in a short period of time, you never really give the tumor a chance to get a good foothold or develop resistant clones. That to me is a concept that we’ve not employed to date.

So, do you think you could achieve the same thing by having a CAR-T that recognized two epitopes instead of one epitope?

Yes, it could be. An alternative is to focus on two or more epitopes by using different drugs or if it’s exactly the same concept, the same. So using CAR-T for BCMA maybe Talquetamab or all the agents for other targets on the myeloma cell. My main point here would also be: do we know whether we can use the novel agents like CAR-T or bispecifics in the perfect way? And one eye-opener for me was a CASSIOPEIA trial where we had Daratumumab for induction, but also for maintenance. And it came out in the analysis that if patients had received DARA for induction and consolidation, giving it a maintenance, did not add any extra effect. And patients that did not have DARA front could be rescued by getting DARA during maintenance. So this tells us something about where do you position the new agents? Do you need to continue with the same treatment over and over? Like Doctor Lonial almost explained or should we, let’s say dissect the treatment in smaller parts, alternating treatments, alternating targets and carefully monitoring each part of the treatment by novel techniques. And I mean, not only response of MRD but also looking at molecular evidence of refractory cells. I think we should mention that there were some issues about the dosing used in the CASSIOPEIA during the maintenance phase. So, whether or not you can rescue people in that fashion, I think is still a little bit open to debate.

But what do you think about response adapted therapy? Because I think you both make a very strong case for that.

Yeah, I mean, I think response adapted therapy is a good way to think about, in the long term, about discontinuation and shorter durations of therapy. What makes me, and if you’re not getting a deep enough response, thinking about intensifying therapy, what makes me a little uncomfortable is, at least in and we see this in the US, people are sort of settling for a deep response early on and then discontinuing therapy without knowing whether or not that’s going to be sustained. It’s really, really important not to just stop treatment. There’s plenty of data that says you need to go, go on. Yeah. Yeah. And I think the big part of the evidence comes from the MAIA trial. I mean, this was really, like I said, an eye-opener for me, that’s by just continuing Len after the Dara-Rd you could achieve five years of PFS in these elderly patients, which was unprecedented. And no, it is unprecedented. I mean, they’re doing remarkably well.

The issue I face in the clinic is when do you stop maintenance? And how do you judge quality of life, hospital Vinit infection versus duration. So what do you think of that? What what approach do you take?

Well, it’s an important issue because we have to advise the patient and the patients maybe decide for themselves because of let’s say tolerance, side effects and so on. But in many cases, they just decide to stop because some feeling about not taking the pills anymore. And so, but for me, it’s difficult to present really great evidence, what is better. And the ongoing discussion for Len maintenance, for example, in the transplant eligible, if the DETERMINATION trial and the French trial and the EMN trial, it’s still not decided after 10 years or more, we still don’t know what’s the optimal duration of maintenance.

Yeah. You know, I think this, this is an important question and, and we certainly are on the long side of continuing Len maintenance for as long as I say, until progression or toxicity. And in year four, in year five, in year seven, I’ve got somebody who’s been on for 12 years and you know, when you see them, you say, how are you doing? Do you feel like this is limiting your quality of life? And if the answer is yes, then it’s a dose reduction or talk about discontinuation of therapy. But I think with drugs like Len and Pom, you almost do have to continue therapy in order to suppress the clone. I’m hopeful that the new CELMoDs may not be that way, that you can give limited duration because they’re cytotoxic, not cytostatic. And on the back bone of T cell-engagers where you may get much deeper responses than we get with, say, an autotransplant followed by three cycles of Dara-RVd, you might be able to discontinue sooner and I think that would be the advantage of multiple combinations. Yeah. On the other hand, if myeloma is really a chronic disease and we might not eradicate the final small number of cells, we have to continue. And then if say CELMoDs are more effective and less toxic, then I’m in favor of continuation.

So we started this debate discussing cure for patients with myeloma. I believe we’re getting to that time and I actually believe a percentage of people are cured already. So, Pieter, you describe some interesting studies. How do you think the next 10 years is going to play out in? You know, will we still be doing autologous stem cell transplant in 10 years time?

Well, our estimate is that CAR T-cells will be as effective, if not more than melphalan and autologous transplant. So I think we will not use autologous transplant in the front-line setting, but we may still use it at a relapse or later setting of the disease if needed. But I think it has been a standard for 20 years now and it’s time to reconsider.

So how do you think the next 10 years plays out?

I think we’re going to be obviously more dependent on the immune mechanisms with T-cell engagers in CAR T-cells. I think CAR T may replace transplant, but you’ve got to do something on the back end. I don’t think that induction and then a CAR is going to be sufficient to give you long-term disease control, because I do think persistence is a big issue and the persistence of a CAR in myeloma is pretty short. And so I think that’s going to be the biggest challenge.

Yeah. And of course, we need to also treat those patients with an IMiD or a CELMoD. I mean, it’s such an important element of the treatment, just leaving out maintenance, there’s no option.

So you’ve heard it here from the International Workshop, from two of the best investigators in the world. Cure is on the horizon and it’s a future that patients should look forward to, because we’re already seeing much, much better outcomes than we used to in the past. So, thank you so much for your attention and speak to you again.

Session VII

So hello to everyone. My name is Maria Victoria Mateos and I am a chair here at the roundtable discussion about T-cell engaging therapies, because we are here in Madrid at the International Myeloma Workshop. And this is the 16th edition. And Yi Lin, Adam Cohen and Nizar Bahlis are here with me. And I would like to ask first, maybe Adam and Yi about the BCMA CAR-T. Do you want to summarize your presentation about the cilta-cel and ide-cel?

Sure. You want me to go first? So I spoke about cilta-cel and first gave a little bit of an update on the original LEGEND-2 study, which was the first study with this product showing impressive four year follow-up data with median PFS about 18 months, about 20% of patients still alive and progression free at that 3.5, 4 year mark. And so we’re waiting to see if that’s going to lead to a plateau in that curve. And then I gave an update on, on the CARTITUDE-1 study, which was a US population trial heavily pretreated 97 patients and with a median 27 months follow-up. Median PFS had not been reached, 55% of patients still alive in progression free at that time. So I think looking very promising from these early studies, we have subsequent studies moving cilta-cel up earlier, in a less heavily pretreated relapse population. And we’ll have CARTITUDE-4 data coming out later this year in 1 to 3 prior lines versus standard of care therapies. And then finally, there are some trials of cilta-cel now in the upfront setting that are just getting underway. So a lot of new data.

Yeah, excellent. And what about ide-cel? Yeah. So I gave an update on ide-cel CAR-T in the US that’s been approved for after four prior lines of therapy and exposure to three major classes of drug. And we have now close to two years of experience. So, there’s an 11 center consortium that just published their data earlier this year showing that in the real world practice, 75% of those patients would not have met KarMMa-1 criteria. But overall for these patients manufacturing success rate was high, the safety and response rate was comparable to what was seeing on the KarMMa-1 study. So that’s very encouraging. We are learning some of these high risk patient profiles in terms of prior exposure to BCMA, high risk cytogenetics. Now also knowing that CAR-T manufacturing and logistics is quite complex and access had been limited, although there’s some improvement in the recent months. So trying to select for the patient that will most likely benefit from this treatment. So there’s been some data looking at the CAR-T product characteristics and some of the patient characteristics in terms of prior treatment exposures and disease burden who have been treated on KarMMa-1 and KarMMa-2 study. And of course, in recent months, the biggest excitement is the data that’s now published on the KarMMa-3 study, which is a randomized controlled study for ide-cel versus standard of care, triplet therapy for patients who are between 2 to 4 lines of treatment. So overall median lines of therapy for the patients on the studies with three other, a lot of these patients are still triple refractory. So we know biologically a high risk patient profile. And so this study met US primary endpoint with improved PFS for patients who received CAR-T. We also saw that these patients had better quality of life. So a lot of the data now currently under regulatory review in the US. And we’ve also heard from earlier in ASH this year, some of the results from ide-cel used in even earlier line setting.

Okay. So thank you very much. And Nizar, would you like to summarize the role of the BCMA bispecific monoclonal antibodies? Sure Marivi, at this session, Doctor Trudel from PMH, Princess Margaret in Toronto, she talked about teclistamab summary of the data and she summarized basically result of the MajesTEC-1 trial which is a teclistamab single agent data and overall a heavily pretreated population, median 5 prior lines of therapy, patients who have exhausted all available therapeutic options. But the triple class refractory and largely penta-class refractory, I would say. The overall response rate was around 65%. And importantly, these responses are durable, a median PFS close to 11 months in this patient population and the duration of response is even longer, close to nearly 18 months or so.

Overall these drugs are safe, except we have to be cautious about infection risk. And therefore, as we see with other bispecific antibodies, around 60%-65% of the patients do develop some sort of infection, viral infection because of infection. Hence the importance of using IVIG immunoglobulin prophylaxis. And I did present data on elranatamab, the other bispecific antibody. And also two large studies, the Phase I, first in-human MagnetisMM-1 and also the MagnetisMM-3 Phase II trial. And we do see very similar data overall response rates, 60% in heavily pretreated population with similar toxicity and safety profile.

Yeah. So thank you. And during this session, well, we heard also information about another target, GPRC5D, that we can target through our bispecific monoclonal antibodies. And Talquetamab showed to be effective in patients.

Well, with myeloma in the relapsed and or refractory situation. But for me, it’s important to see how the overall response rate in principle is maintained in patients previously exposed to the BCMA targeted therapy and more or less the same is applicable to GPRC5D CAR-T.

So I think that now we have a situation in which we can select target BCMA or GPRC5D and drugs bispecific monoclonal antibodies versus CAR-Ts.

So just a simple question before finalizing this roundtable discussion, if you have tomorrow a relapsing refractory myeloma triple class exposed and you have to select how to proceed, please tell us, to the audience, what do you plan as the two subsequent lines of therapy? So, not only the first, but the second one.

It’s clearly a philosophical answer I’ll give you, because we have no data. But I will prioritize a GPRC5D CAR T-cell first. Simply for the reason that I suspect if we use bispecific GPRC for a long time, we’re going to frequently acquire GPRC5D loss and we use BCMA bispecific as a salvage therapy.

Okay, Adam.

And I’ll take the exact opposite approach, I think, to my esteemed colleague. I think just probably go with a BCMA CAR-T first, if the patient’s stable enough to go through manufacturing, just because we have a little bit longer follow-up in terms of durability of response and then hopefully be able to rescue that patient with a GPRC5D or other non-BCMA targeted bispecific after that.

Uh Yeah, I think in the US you know, I would be more in alignment with Adam, in the sense that with BCMA CAR-T being commercially available, if a patient is fit enough for that, given it’s a single dose treatment where you can see some durability of response, I would try to get the patients to that first. Also partly because, from an insurance perspective, you only get coverage for one CAR-T. And so if there’s any consideration for GPRC5D CAR-T, then I can potentially still get patient access on trial. But in general, I think CAR-T before bispecific, just looking at some of the preliminary data in terms of the sequencing, limited data sequencing on trial and the patient profiles and biology of these classes.

Well, I would like to start maybe with the BCMA CAR-T, especially because of the durability of the response if it is available and I will go later on, maybe with the GPRC5D bispecific monoclonal antibody. We have some patients included in clinical trials in this direction. And it’s true that the outcome is quite good. But definitely, what I would like to remark is: there are no true answers, because we need to continue doing a lot of research, especially because we need to understand much more about the mechanism of resistance. And thank you very much and I hope you have enjoyed this roundtable discussion.