Webcast

Video clip 1

[MOHAMAD MOHTY: 00:00.4]

You can see we have one of the probably hottest and most exciting topics to be discussed during this congress, but also starting with a symposium. And this is namely about the emerging role of B-cell maturation antigen directed strategies in newly diagnosed multiple myeloma.

[MOHAMAD MOHTY: 00:25.1]

The symposium, of course is being broadcasted live, so hello to our virtual audience wherever you are. And it is an interactive sympo, so please don’t hesitate to share, your questions, comments, et cetera.

[MOHAMAD MOHTY: 00:44.7]

And today, this morning, I’m joined by a very highly distinguished faculty of top experts, but most importantly friends, namely, the co-chair of this COMy meeting, Professor Mariví Mateos.

[MOHAMAD MOHTY: 01:10.5]

I’m also very pleased having my friend and colleague from Saint Antoine, Professor Malard. We have also the famous Professor Terpos from Greece. And last but not least, we’re very pleased that Wendy Bursey, who is a specialized nurse in Hamilton, from Canada, has kindly accepted to join us.

[MOHAMAD MOHTY: 01:39.9]

The usual disclosures. Obviously, it’s a CME symposium and we do have some important learning objectives. And hopefully after this sympo, you will be able to define and refine strategies to more effectively assess risk and frailty in newly diagnosed multiple myeloma, to critically appraise the biological and translational rationale for introducing these BCMA-directed therapies and of course, to interpret the efficacy, safety, and future implementation challenges of these treatments.

[MOHAMAD MOHTY: 02:28.0]

This is the program, summarized here. We’ll start with Dr. Mateos giving you a broad overview about the landscape of newly diagnosed multiple myeloma. Florent will give you a few biological hints on why actually targeting BCMA is really worth it and probably should be a priority.

[MOHAMAD MOHTY: 02:56.7]

And Evangelos will walk you through some of the clinical data. And we will have the important part of the sympo, which is the roundtable discussion at the end. It’s a CME-certified activity, so you will be able after the event to collect your CME EBAH point.

Video clip 2

[MOHAMAD MOHTY: 00:00.1]

So now, it is my great pleasure and honor to introduce Professor Mariví Mateos, who will give you an overview about the treatment landscape of newly diagnosed multiple myeloma. Mariví, the floor is yours. Thank you very much.

[MARÍA VICTORIA MATEOS: 00:22.5]

Thank you very much, Mohamad, for the invitation to participate in this symposium. Although the title of the symposium is to redefine the treatment of newly diagnosed myeloma. My presentation will be basically focused on what we are doing right now and I will review the current treatment landscape for newly diagnosed patients with multiple myeloma.

[MARÍA VICTORIA MATEOS: 00:49.7]

We should start with an adequate stratification for every newly diagnosed patient with multiple myeloma. Probably you remember that at the beginning we considered just albumin and beta-2 microglobulin to define ISS.

[MARÍA VICTORIA MATEOS: 01:07.8]

We incorporated later on LDH and some cytogenetic abnormalities, and we had the revised ISS. Now we have other novel cytogenetic abnormalities: TP53 mutation, circulating tumor cells, plasma cells in peripheral blood, extramedullary disease, and with this what we are going to do is to refine much more the risk stratification at the moment of new diagnosis.

[MARÍA VICTORIA MATEOS: 01:36.8]

But, of course, we have also to consider some patient-based factors and I do refer not only to the chronological age but to the biological age, frailty, as well as organ function, and comorbidities. And the final result of this is if we evaluate the disease risk, we evaluate the frailty throughout the use of potential frailty scores.

[MARÍA VICTORIA MATEOS: 02:02.0]

In the end, the treatment selection is going to be much more precise. And today, and especially in terms of the future, we have to integrate and to combine the biological risk and the physiological reserve in order to select the most appropriate therapy for newly diagnosed myeloma patients.

[MARÍA VICTORIA MATEOS: 02:24.4]

In 2026, the treatment recommendations basically are based on transplant eligible and transplant ineligible. And in the transplant ineligible we usually consider the fit population and the frail population.

[MARÍA VICTORIA MATEOS: 02:41.0]

And how important is it today to distinguish between transplant eligible and transplant ineligible? We are going to see the efficacy of the different combinations for these two groups of patients. During the COMy [congress], I am completely sure that we are going to discuss a lot about one of the new objectives we are going to have in patients with multiple myeloma, that is the cure.

[MARÍA VICTORIA MATEOS: 03:05.0]

We know that the cure is basically driven by surrogate markers based on minimal residual disease. This is one of the reasons why distinguishing between transplant eligible and transplant ineligible is important. This is going to be driven by the treatment goal.

[MARÍA VICTORIA MATEOS: 03:21.2]

Here, you can see what we established as a surrogate marker or definition for cure. And patients have to stop treatment, we have to monitor the serological, and, of course, the minimal residual disease negative and if it is maintained for five years, once the patient stop therapy, this is going to be what we consider as a potential cure.

[MARÍA VICTORIA MATEOS: 03:46.1]

If we focus on the transplant eligible population, the quadruplets are the standards of care. One possibility and one standard of care we use right now is the PERSEUS regimen with quadruplet Dara-VRd, transplant, Dara-VRd, Dara-Len maintenance.

[MARÍA VICTORIA MATEOS: 04:04.3]

Here you can see the significant benefit in progression free survival in comparison with the triplet. I previously alluded to the importance of the minimal residual disease and with PERSEUS, 75% of the patients achieved overall minimal residual disease negative and the projected median progression-free survival for a young patient with newly diagnosed myeloma receiving the PERSEUS regimen can be up to 17 years.

[MARÍA VICTORIA MATEOS: 04:36.5]

Together with Dara-VRd, Isa-VRd is another potential quadruplet and we will see maybe similar results with this German study. We have, today, information about the first part of this study. Isa-RVd followed by autologous stem cell transplantation versus RVd followed by autologous stem cell transplantation.

[MARÍA VICTORIA MATEOS: 04:59.0]

And here you can see how after transplant, the minimum residual disease negativity rate is over 60%. So, the maintenance part is pending but in principle, from the first randomization we see also a benefit in progression-free survival indicating that in the transplant eligible population, the quadruplets followed by transplant is the standard of care.

[MARÍA VICTORIA MATEOS: 05:24.9]

If we focus on the transplant ineligible population, and we establish first the priority for the fit populations, you know that the quadruplets are also the new standard of care. One is based on Isa-VRd followed by isa, len, dex.

[MARÍA VICTORIA MATEOS: 05:42.8]

And here you can see how overall the minimal residual disease negativity rate is approximately 58% with significant benefit in PFS in comparison with the triplet. And the median progression- free survival expected for this quadruplet is approximately 90 months.

[MARÍA VICTORIA MATEOS: 06:02.9]

And the same is with CEPHEUS, similar quadruplet but with daratumumab instead of isatuximab. MRD negativity rate 60%, benefiting PFS and median progression-free survival estimated of approximately 100 months.

[MARÍA VICTORIA MATEOS: 06:20.2]

So, at the beginning I showed you how it is different to establish between transplant eligible and transplant ineligible. And, in principle, the MRD negativity rate is higher when we incorporate autologous stem cell transplantation.

[MARÍA VICTORIA MATEOS: 06:38.7]

This is the first summary slide just in order to conclude. Should transplant eligibility be redefined based on risk adapted treatment strategies? And maybe this is something that we are going to do in the future.

[MARÍA VICTORIA MATEOS: 06:55.8]

Point number one, patients with high risk. This slide includes two triplets: VRd or KRd. But you can see here how when patients presented with high-risk cytogenetic abnormalities, transplant clearly benefited these patients.

[MARÍA VICTORIA MATEOS: 07:13.6]

In line with this, when we go to the quadruplets, here you can see the forest plot for PFS for quadruplets in fit, newly diagnosed myeloma but the hazard ratio for patients with high-risk biology is not as good as in the overall population.

[MARÍA VICTORIA MATEOS: 07:31.3]

This is the reason why maybe for these fit, newly diagnosed myeloma patients that, in principle, we consider transplant ineligible, if they present a high-risk cytogenetic abnormalities, we can potentially push them to go to autologous stem cell transplantation.

[MARÍA VICTORIA MATEOS: 07:49.1]

Or maybe we are going to see in the subsequent presentations new strategies that will be available in the future in order to overcome the poor prognosis in this specific population. Can we utilize the minimal residual disease also as risk factors for transplant eligibility?

[MARÍA VICTORIA MATEOS: 08:10.2]

You know that the MIDAS study evaluated this concept and, in principle, after Isa-KRd minimal residual disease negative, transplant and no transplant resulted in almost identical MRD negativity rate 10 to the minus 6 over 80%.

[MARÍA VICTORIA MATEOS: 08:29.0]

But this information is preliminary at the moment and I think that we need to wait in order to see how this MRD negativity rate is sustained over time and how this will evolve in terms of progression- free survival. What about the frail population?

[MARÍA VICTORIA MATEOS: 08:47.0]

You know that it is critical to identify what is the frail population and definitely the modifications needed in order to deliver optimal strategies for this population with an acceptable safety profile.

[MARÍA VICTORIA MATEOS: 09:05.5]

We will see also in the subsequent presentations how maybe new strategies are going to be very useful for these frail population. Today the standard of care is basically MAIA, with excellent data. But it’s true that not all patients included in the MAIA were frail.

[MARÍA VICTORIA MATEOS: 09:23.8]

The median age was 72. According to the modified International Myeloma Working Group Frailty score, frail patients had excellent outcomes also with the MAIA but it is possible even to modify. And the French group conducted this study in which Dara-Len-Dex was basically based on the modification, based on stopping dexamethasone from cycle three.

[MARÍA VICTORIA MATEOS: 09:51.0]

With this very simple approach we see in the green line, how the PFS and the overall survival remained quite well and especially the safety profile for this population is better. We will see how the new combinations will be incorporated also in this frail population for improving outcomes.

Video clip 3

[MARÍA VICTORIA MATEOS: 00:00.4]

Do we still need new approaches in newly diagnosed myeloma patients? We’ve seen how with the current strategies we have for newly diagnosed myeloma patients, outcomes are excellent and indeed we can offer minimal residual disease negativity rates very high for this population and as we’ve seen with excellent outcomes.

[MARÍA VICTORIA MATEOS: 00:25.1]

But what challenges remain? Residual disease persists in some patients or minimal residual disease can reappear because relapse still occurs in a significant fraction of patients. Continuous therapy is an issue and we are moving towards a fixed duration of therapy.

[MARÍA VICTORIA MATEOS: 00:45.6]

And especially if we wanted to evaluate the proportion of patients cured according to the definition, we have to move towards a fixed duration of therapy strategies. And, of course, the frailty sometimes limits treatment intensity.

[MARÍA VICTORIA MATEOS: 01:02.3]

And maybe with the new approaches we are going to resolve this situation. Can earlier use of immune-based therapies such as BCMA-directed approaches help achieve deeper and more durable responses?

[MARÍA VICTORIA MATEOS: 01:17.8]

And maybe this is applicable to all newly diagnosed myeloma patients? Maybe, adding in 20XX, for sure we will discuss what will be the most appropriate BCMA-targeted therapy for each newly diagnosed myeloma patient.

[MARÍA VICTORIA MATEOS: 01:36.2]

So, these are my conclusions. I think that today we have a well-established standard of care but the work is in progress. We needed to continue improving. I think that we are moving towards risk-adapted therapy, response-adapted therapy, and frailty-adapted therapy.

[MARÍA VICTORIA MATEOS: 01:54.5]

And I stop here. Thank you very much for your attention.

[MOHAMAD MOHTY: 02:03.2]

Thank you very much Mariví for a very beautiful and elegant talk to set the stage. Now it’s my- So, please don’t hesitate to send your questions. We’ll have some Q&A at the end.

Video clip 4

[MOHAMAD MOHTY: 00:00.4]

It’s my pleasure to welcome Professor Florent Malard, from the Sorbonne University here in Paris. And Florent will walk us through some of the biological arguments why BCMA is an important target and why it should be a priority when it comes to selecting the right treatment.

[FLORENT MALARD: 00:25.5]

Thank you Mohamad for the invitation. It’s truly a pleasure to be here at COMy. It’s very important to understand why it’s highly relevant to move this BCMA-targeting treatment in the front line, and I will try in the next couple of minutes to convince you why this is very relevant for our patients.

Video clip 5

[FLORENT MALARD: 00:00.3]

So why is this important? And why did we decide to target BCMA when we start developing these drugs. So, we know that BCMA is expressed on the B cells but mainly it’s expressed on the plasmacyte. As you can see here, the expressions of the BCMA will increase when the B cell differentiate toward the antibody-secreting cells on the plasmacytes.

[FLORENT MALARD: 00:30.3]

What is very important also is that it’s uniformly expressed on malignant plasma cells, has a higher density compared to normal plasma cells, making BCMA a near universal and selective expression, and this is truly an ideal therapeutic target with very few off targets.

[FLORENT MALARD: 00:50.7]

It’s mainly on the normal plasma cell that we target, with a well known hypogammaglobulinemia that is a side effect. How does BCMA work? So, we know that BCMA is expressed on a multiple myeloma cell.

[FLORENT MALARD: 01:08.5]

We have the expression of the BCMA, in fact the stromal cells, bone marrow stromal cells, but also the osteoclast and the macrophages in the microenvironment are going to secrete some APRIL and BAFF that are some growth factors for the B cells, but also for the plasmacytes.

[FLORENT MALARD: 01:27.3]

When it will go on the BCMA, it will activate different pathways. We have the MEK pathway, we also have the PI3K/AKT pathway and the NFκB pathway that mediate survival signaling.

[FLORENT MALARD: 01:43.4]

So BCMA will target the survival of the plasmacyte. It will also lead to some angiogenesis and some osteoclast activations, and it will also have some immunosuppressive effects on the bone marrow microenvironment.

[FLORENT MALARD: 02:00.4]

And it explains why the expression of the BCMA, and the high expression of the BCMA on the tumoral plasmacyte is associated with some survival of the tumoral cell. The angiogenesis effect and also the activation of the osteoclast, and the deleterious effect on the bone of the patients.

[FLORENT MALARD: 02:20.0]

As you can see here, also, we can have some expression of some secretase at the surface of the cells that lead to the presence of soluble BCMA that may be very important as a resistance effect to the anti-BCMA in some patients.

[FLORENT MALARD: 02:37.7]

So, what do we have so far when we speak about BCMA-directed treatment? So we have the antibody-drug conjugate so it targets the BCMA and we have the drugs on the antibody that is delivered directly next to the myeloma cells and it induces cell death.

[FLORENT MALARD: 02:56.1]

We have the CAR T-cells, we are very familiar with them that will also target the BCMA and directly kill the plasmacytes. We have bispecific monoclonal antibodies where the bispecific is mainly here to take the CD3-positive T cells, to bring the CD3-positive T cells next to the plasmacyte.

[FLORENT MALARD: 03:21.3]

This is a CD3-positive T cell that mediates the cytotoxicity and kills the cells. It seems that those CD3 cells are very important when we go to the BCMA-directed treatment, mainly for the bispecific and CAR T-cells.

[FLORENT MALARD: 03:39.3]

In fact, when we look at the number of CD3 and CD8 positive T cells at the time we start the treatment with bispecifics, we find that in patients with higher numbers of CD3 and CD8 T cells in the blood have higher response rates.

[FLORENT MALARD: 03:58.9]

In this study that was presented at the IMS last year but that have not been published yet, they look more closely at the CD8 level and also at the absolute lymphocyte count.

[FLORENT MALARD: 04:14.1]

So, it’s very basic, you just look at the lymphocyte on your cell count, and they find that in some patients that have some baseline so at the time we start the bispecific antibody low we have a very short PFS around seven months compared to 22 months in patients with baseline absolute lymphocyte counts above the threshold they defined, and it was really highly significant.

[FLORENT MALARD: 04:41.2]

They also look at the absolute lymphocyte trajectory over the course of the treatment with the bispecific. They find that in patients, when they have the rising in the lymphocyte count so an improvement in the lymphocyte count level, they find a higher PFS of 23 months.

[FLORENT MALARD: 04:59.4]

While in patients that have some stable, low but stable, it was six months, and in patients that remain with very severe lymphopenia, a PFS of one month. So, it’s truly the patient when we have some primary failure of the bispecific antibodies.

[FLORENT MALARD: 05:17.9]

Beyond the number of CD8 and CD3 T cells, it seems also that the functionality of the T cell matters. In this study, they look at the granzyme B and perforin expression. So granzyme B and perforin are some hallmarks of the cytotoxicity of the CD8 T cells and they find that in patients that have a higher expression of granzyme B and perforin, they have a better response compared to patients that did not achieve a response with lower levels of granzyme B and perforin.

[FLORENT MALARD: 05:55.5]

Clearly establishing that we need the CD8 positive T cells that are functional that are able to mediate cytotoxicity to achieve a response. Last but not least, it seems also that we can have some T cell exhaustion and some dysfunction that is clearly correlated with achievement of a response.

[FLORENT MALARD: 06:17.6]

When we look in the cohort of patients treated with teclistamab and expression of PD-1, that is an hallmark of T cell exhaustion, they find that in patients that have expression of PD-1 on the CD8 T cells have less response, a higher expression of PD-1 in non responding.

[FLORENT MALARD: 06:37.0]

In the elranatamab cohorts, there are some similar results. They also look at the phenotype of the CD8 positive T cells and the exhausted phenotypes were associated with a lower progression-free survival compared to patients that had CD8 positive T cells with no exhaustion markers.

[FLORENT MALARD: 06:59.4]

So clearly T cell fitness matters, number matters, functionality matters, and the fitness matters to achieve the response with bispecifics. So, when we look at the mechanism of resistance to bispecifics in multiple myeloma.

[FLORENT MALARD: 07:18.1]

In the primary refractory resistance, so a patient that will fail on the bispecific and did not achieve any responses, it seems that T cells are a key player and patients with exhausted T cells will not achieve response.

[FLORENT MALARD: 07:36.5]

And we also have some factors that are related to the multiple myeloma features, in particular with aggressive disease. And also, when we have some high soluble BCMA that can mediate the resistance. But it’s not only about that, it’s also about T cells.

[FLORENT MALARD: 07:54.4]

When we look at the CAR-T. So, CAR-T, of course this is a treatment we give to the patient. But with myeloma, we use only autologous CAR-T cell and we take the T cells to make the CAR from the patient. So, it’s also important to have some fit T cells to make some good CAR-T cells.

[FLORENT MALARD: 08:14.6]

In fact, when we look at the profiles of the T cells in this setting, we find that when you have some CAR T cells that express more exhaustion markers, we have a decreased efficacy and a decrease cytotoxicity of the CAR-T cells.

[FLORENT MALARD: 08:34.1]

Beyond the fitness of the CAR T cells, it will depend also on the type of T cells we collected from the patients. In particular, if you have live T cell, central memory T cell, effector memory T cell or effector T cells.

[FLORENT MALARD: 08:49.4]

In fact, we have the better persistence on proliferative capacity when you have more naive T cell subsets. The ratio of the CD4 to CD8 T cell is also important. So far, in myeloma we just take bulk CD8 to make the CAR-T cells.

[FLORENT MALARD: 09:08.5]

But we know that in lymphoma, for example, there are some products with some very strict and chosen ratio of CD4 to CD8 T cells. Clearly this is associated with a better response and decreased toxicity.

[FLORENT MALARD: 09:23.6]

So, this is truly something we need to investigate in the field of CAR-T for myeloma. Last but not least, we have also some markers of senescence beyond the exhaustion of CAR-T cells. When you have some immunosenescence T cells, you have a decreased cytotoxicity or decreased proliferative capacity.

[FLORENT MALARD: 09:42.0]

That may explain why making some CAR-T cell in very old patients may not be the best strategy because of this immunosenescence. But we know that also some old patients really achieved some good responses. So, we may in the future be able to assess the immunosenescence of T cells in old patients to see if they are fit or not to make some good CAR-T.

[FLORENT MALARD: 10:04.3]

So why move the BCMA directed treatment earlier? So, I just show you that the T cell fitness is key in the achievement of the responses. In fact, earlier treatment and in particular repeated treatment with alkylating, in particular, high-dose melphalan but also proteasome inhibitors will lead to some decrease in naive or stem cell like T cells.

[FLORENT MALARD: 10:28.1]

It will lead to an increase in the exhaustion marker of the T cells and to a decreased efficacy of the CAR T or the bispecific antibodies given this previous exposure to alkylating treatments.

[FLORENT MALARD: 10:44.0]

So, it may be good in fact to move them frontline before you use high dose melphalan, before you use all other alkylating or proteasome inhibitors. Should we combine them? On the opposite, some other drugs seems to enhance the effect of CAR-T cells.

[FLORENT MALARD: 11:02.6]

But rather than giving them before doing the CAR T or doing the bispecific, we may give them, the patient, as a combination strategy. Mainly this is IMID, lenalidomide, pomalidomide, and so on that increase the T cell proliferation, increase the ratio of central memory and effector memory and decrease regulatory T cells on PD-1 expression.

[FLORENT MALARD: 11:31.3]

So clearly if you associate some IMID with some bispecific antibody it may increase their efficacy. Anti-CD38s such as isatuximab and daratumumab, also may be some good treatment to be combined with the bispecific, since it decreased Tregs and Bregs, increased the CD8 positive T cell cytotoxicity, and this is a truly strong candidate for combination treatment with BCMA treatment.

[FLORENT MALARD: 11:59.5]

And I think it will be shown in the next presentations. So, to conclude, BCMA is highly effective and a validated target in multiple myeloma. The efficacy of BCMA-directed treatment is critically dependent of the T cell fitness.

[FLORENT MALARD: 12:18.6]

Disease progression on prior treatment will drive progressive T cell exhaustions and this directly limits the efficacy of the CAR T or the bispecific antibodies, and earlier use may preserve the immune competence and improve the outcome in particular if you combine them with the right treatment.

[FLORENT MALARD: 12:36.8]

So, thank you again for your attention.

[MOHAMAD MOHTY: 12:44.5]

Thank you very much Florent for a beautiful summary. So, you managed to make something simple while it is extremely complex, and I’m sure we’ll have lots of questions about this.

Video clip 6

[MOHAMAD MOHTY: 00:00.6]

Now, it’s my pleasure to welcome Professor Evangelos Terpos from Greece and he has led some of the very innovative, I would say, and brave approaches on introducing BCMA-directed therapies in early disease settings.

[MOHAMAD MOHTY: 00:18.6]

Thank you Evangelos.

[EVANGELOS TERPOS: 00:19.6]

Thank you so much Mohamad. Thank you to all of you, that you are in the first session of the day, Mariví mentioned several times that in this conference and in the next conferences of multiple myeloma we are going to discuss more and more the word “cure”.

[EVANGELOS TERPOS: 00:38.1]

And I think that we are having fascinating days, for all myeloma physicians, that we are going to talk about cure and when we say cure for a disease, it is that we need to have equivalent life expectancy to individuals without the disease, without myeloma.

[EVANGELOS TERPOS: 00:55.8]

So as Mariví mentioned, in order to say that to have cured a patient definitely we need to have no myeloma-related mortality, PFS after first-line therapy for 10 years or even more, MRD negativity 10 to the minus 6 for 5 years, for example.

[EVANGELOS TERPOS: 01:15.6]

We don’t know exactly the date, but this is what we have defined. And no M-protein by mass spectrometry or no circulating tumor cells. So, all these are very important. We need data to support that. But I think that we have the right treatment to achieve cure now.

[EVANGELOS TERPOS: 01:34.8]

Mariví also mentioned that for patients who are eligible for transplant, the PERSEUS study showed an expected median PFS of around 17 years. But on the other hand, the sustained MRD negativity as you can see at two years, the level of 10 to the minus 5 is 56% suggesting that we have another 44% who cannot achieve a sustained MRD negativity for two years.

[EVANGELOS TERPOS: 02:05.6]

And definitely they will not do it for five years, which is the cure definition. So, for these patients we need something more. And this something more comes from the anti-BCMA directed therapies that in the late phases of multiple myeloma, have shown fantastic results.

[EVANGELOS TERPOS: 02:24.4]

And that’s why the CAR-T products like cilta-cel, ide-cel, the bispecifics, teclistamab, elranatamab, linvoseltamab and also talquetamab, which is not directed, which does not target the BCMA, have been licensed. But all these agents coming earlier, and cilta-cel has been licensed at second line now in Europe.

[EVANGELOS TERPOS: 02:44.9]

But we have the fantastic results of the MajesTEC-3 trial that has just been published in New England Journal of Medicine by Luciano Costa and Mariví Mateos. And you can see the three-year probability of PFS with the combination of teclistamab with daratumumab and Florent, I think, showed you why daratumumab can accommodate and enhance the action of teclistamab or other anti-BCMA bispecific antibodies 83% versus 30% with the standard of care that was used in this study.

[EVANGELOS TERPOS: 03:19.7]

So, I think that we have all the rational, the preclinical but also the clinical, that the anti-BCMA therapies will come earlier and why not in the first-line therapies? And when we talk about frontline treatment, the anti-BCMA agents can substitute or can be added in the treatments that we have, they can replace transplant, and of course we can optimize their administration based on specific patient characteristics like those who are MRD negative or they are frail.

[EVANGELOS TERPOS: 03:55.3]

And we come in the first part of what I suggested previously, the introduction to the induction treatment of the bispecific, either adding a bispecific antibody to what is given now or substitute some of those drugs.

[EVANGELOS TERPOS: 04:13.4]

And in the MajesTEC-5 as you can see in the induction we have the combination of teclistamab with daratumumab plus lenalidomide either given weekly or monthly or with daratumumab, bortezomib, and lenalidomide. So, you can see that we have only the disappearance of dexamethasone in this arm.

[EVANGELOS TERPOS: 04:33.9]

And the first data that we have from last year’s IMS by Mark Rabb, you can see that the MRD negativity rate for these combos, of course not big numbers of patients yet but it is 100%. How about using belantamab mafodotin in the same induction treatment?

[EVANGELOS TERPOS: 04:56.4]

And you can see here the Spanish trial which included belantamab with bortezomib, lenalidomide, and dexamethasone. So instead of Dara-VRd we have Bela-VRd. And you can see how belantamab is given with different doses. And the results were fantastic with MRD negativity rates up to almost 100% PFS at 3 years of 78% overall survival at 3 years of 82% and especially the addition of belantamab benefited patients with high-risk cytogenetics as you can see here in the curves.

[EVANGELOS TERPOS: 05:34.1]

I think that we have several data suggesting that the BCMA-targeted agents come to first line, and all these data give the rationale to have big phase three trials. But it’s not only the induction treatment that the anti-BCMA can be used but also the consolidation.

[EVANGELOS TERPOS: 05:55.5]

And you can see here the linvoseltamab study, the IMMUNOPLANT, that was presented as a normal presentation in the last ASH meeting. While linvoseltamab was given in patients after induction having not achieved MRD negativity.

[EVANGELOS TERPOS: 06:11.5]

And in all patients who linvoseltamab was given for a fixed duration as you can see here, not a big number of patients of course, got 19 patients, but all of them became MRD negative. And the bispecific antibodies comes also to the maintenance phase.

[EVANGELOS TERPOS: 06:30.3]

And we have two big studies randomized the MajesTEC-4 and the MagnetisMM-7 studies where, in the first one, teclistamab was combined with lenalidomide either given every four weeks, lenalidomide alone or teclistamab alone in order to know if the MRD negativity and the possibility of cure for a fraction of patient is increased.

[EVANGELOS TERPOS: 06:54.9]

And similar design but not in combination is lenalidomide, elranatamab against lenalidomide in the MagnetisMM-7 study. The MajesTEC-4 that I previously showed to you has given us some results and Elena Zamagni presented in the ASH 2024 that, in low numbers of patients between 25 and 30, but you can see the addition of teclistamab to lenalidomide here or teclistamab alone offers at 6 months, very high MRD negativity rate of almost 100%.

[EVANGELOS TERPOS: 07:33.3]

So, I think that all these data suggest that the addition of bispecific antibodies in induction or maintenance phases probably will give us very high MRD negativity rates. The question is if this is going to be seen in a high number of patients and for how long this will remain.

[EVANGELOS TERPOS: 07:54.6]

Other strategies to substitute and to substitute autologous transplantation with anti-BCMA targeted immunotherapy. And this comes from the EMN-28, the CARTITUDE-6 study where autologous transplantation is directly compared to the cilta-cel and then lenalidomide for two years in order to see if, with a CAR-T product, we are able to increase the MRD negativity rate.

[EVANGELOS TERPOS: 08:23.4]

And at least in some of these patients go to cure. How about the transplant ineligible patients? We do know that at least for the fit or intermediate fit patients, the quadruplets are the standard of care, as Mariví mentioned. And the CEPHEUS study gives a median of 8.3 years.

[EVANGELOS TERPOS: 08:42.6]

Can we make it better for these patients? Or how about the frail patients that they cannot easily tolerate these drugs? First of all, in the MajesTEC-7 study, we have the introduction of teclistamab or talquetamab in combination with daratumumab and lenalidomide versus Dara-Rd.

[EVANGELOS TERPOS: 09:03.6]

And the first results that were presented by Niels van de Donk in the ASH meeting, showed an overall response rate of almost 90%. The impressive TecLille of the IFM study which included teclistamab plus daratumumab versus teclistamab plus lenalidomide offered fantastic results in this study that was presented as an oral presentation by Salomon Manier in the last ASH meeting.

[EVANGELOS TERPOS: 09:32.9]

And you can see overall response rate of 100% with teclistamab plus daratumumab also supporting what it was said before, and an MRD negativity rate of 100% in the 27 patients that were available, suggesting that possibly this combination may come forward in the first-line treatment of these patients.

[EVANGELOS TERPOS: 09:58.8]

How about the ADCs? Our group scheduled this study that for the first time we have given belantamab every eight weeks. And in the first part of the study we had different schedules: 1.4, 1.9, or 2.5 milligrams per kilogram given every eight weeks.

[EVANGELOS TERPOS: 10:18.2]

And then the dose to go for the second part of the study was 1.9 milligrams per kilogram every eight weeks. This was published in Blood a few months before and at the second part of the study also we had a randomization between the hematology driven decision of how we are going to manage the ocular problems or an ophthalmology-based decision for the dose modification of belantamab.

[EVANGELOS TERPOS: 10:44.7]

And what we’ve seen first is that we have dramatic increase in the response rate of almost 100%. We have fantastic PFS with an 18-month PFS of 83% and 24 months of 77%.

[EVANGELOS TERPOS: 11:02.3]

But more importantly, and this was reported in the last EMN meeting and it’s a poster presentation at the next EHA meeting, that the predicted PFS for the combined cohort range from 86 to 115 months and, especially for the 1.9 mg per kg, 84 to 102 months which is very similar to what has been presented for the quadruplets.

[EVANGELOS TERPOS: 11:28.9]

More importantly, regarding ocular events we have seen that if the ophthalmology uses the VRA questionnaire, which is very simple regarding everyday clinical activities, you can see that we’ve seen similar frequency of adverse events when the dosing was defined by the hematology or by the ophthalmology ocular assessments.

[EVANGELOS TERPOS: 11:51.7]

And I think this is critical. I wanted also to mention that from this 100% of the patients who responded to treatment, 50% of the patients had MRD negativity. For the whole population it was 83% for the evaluable patients.

[EVANGELOS TERPOS: 12:11.3]

Belantamab was given in combination with bortezomib, lenalidomide, and dexamethasone in the DREAMM-9 study. And you can see here that the MRD negativity rates were even more, going up to 90 and 100% in the subset of the study.

[EVANGELOS TERPOS: 12:28.1]

And these results led to the DREAMM-10 randomized study where the patients, newly diagnosed, non-eligible for transplant were randomized to receive either belantamab with lenalidomide and dexamethasone or daratumumab with lenalidomide and dexamethasone.

[EVANGELOS TERPOS: 12:45.1]

How about the frail patients? Sonja Zweegman designed I think a very interesting study, the EMN 37, we call it FITFIX study, where tec-data or tal-dara was given for a fixed duration of treatment and then there was a free interval and if the patient relapsed we had a restart for the frail population, in order to check if these very efficient drugs can be given in the frail population, but of course we cannot give them continuously.

[EVANGELOS TERPOS: 13:22.1]

So, where it seems that the guidelines are going from the 2027 and after? Probably we are going to see teclistamab, daratumumab, and lenalidomide or quadruplet with teclistamab, daratumumab, bortezomib, and lenalidomide in induction treatment before transplantation or other bispecific-based combinations with elranatamab, for example.

[EVANGELOS TERPOS: 13:47.2]

We may see cilta-cel to substitute autologous transplantation or based on the results that Mariví showed by the MIDAS study. Probably we may not see autologous transplantation anymore in standard risk patients who achieve MRD negativity.

[EVANGELOS TERPOS: 14:04.5]

Definitely the tandem transplantation based on the MIDAS trial seems not to be an option anymore. While the bispecific plus minus lenalidomide going also to maintenance for patients who are not eligible for transplant.

[EVANGELOS TERPOS: 14:19.9]

The bispecific with daratumumab with or without lenalidomide seems also to go to first-line therapy. And also, belantamab in combination with lenalidomide and dexamethasone based on the DREAMM-10 study. But even with bortezomib, lenalidomide, and dexamethasone seems also to go to first-line treatment.

[EVANGELOS TERPOS: 14:38.8]

And you can understand that with all these new data that are coming with the new years, our work is extremely fascinating but also very difficult, because if this goes to first line then you can see what’s going to happen afterwards and the sequencing is going to be a question that of course I have no answer to that.

[EVANGELOS TERPOS: 14:58.4]

So, thank you for your attention. I think it’s my last slide.

Video clip 7

[MOHAMAD MOHTY: 00:00.0]

Before going into the discussion, it’s my great pleasure to introduce, Dr. Wendy Bursey from Hamilton in Canada. And she’s a nurse specialist and she will share her experience with BCMA-directed therapies in relapsed refractory multiple myeloma.

[WENDY BURSEY: 00:21.1]

Thank you Dr. Mohty. And thank you everyone for having me here in this panel to discuss the nursing perspective of moving BCMA therapies to earlier lines. As BCMA-directed therapies move to earlier lines of treatment, the nursing role becomes even more important in supporting safe patient-centered care.

[WENDY BURSEY: 00:41.1]

Nurses are often the consistent point of contact for patients and caregivers, helping them understand what to expect, recognize symptoms early and know when to call for help. While safe delivery depends on a multidisciplinary team, nurses are central to translating the treatment plan into practical education, monitoring, escalation and day-to-day patient support.

[WENDY BURSEY: 01:07.3]

From a nursing perspective, one of the biggest changes in earlier line BCMA therapy is the type of patient we may be supporting. These patients may be less heavily pre-treated than those in the relapsed/refractory setting. Some may be fitter, more independent, and still active in their daily lives.

[WENDY BURSEY: 01:28.0]

At the same time, earlier line treatment may also include frail or transplant-ineligible patients, older adults and patients with comorbidities who need additional support. This broader population changes the nursing approach to education, monitoring, and care planning.

[WENDY BURSEY: 01:46.7]

In earlier lines, the patient may not anticipate the intensity of monitoring, infection prevention, and symptom reporting expectations that can accompany BCMA-directed therapy. Nurses play a key role in preparing patients and caregivers for what to expect, reinforcing safety messages and ensuring concerns are escalated early.

[WENDY BURSEY: 02:11.8]

Nursing education starts before treatment begins. Nursing help explain what toxicities can occur, when they are likely to happen, what symptoms should be reported, and how to accept, how to access help after hours. Standardized pathways are essential so patients, caregivers, and health care teams know when and how to escalate concerns.

[WENDY BURSEY: 02:35.9]

This education is most effective when it’s reinforced consistently and supported by clear toxicity management pathways. A major nursing priority is early recognition and escalation of toxicity. Nurses are often the first point of contact when patients report fever, confusion, weakness, infectious symptoms and other changes.

[WENDY BURSEY: 02:59.0]

For BCMA-directed therapies, this means maintaining a high level of awareness of CRS, ICANS, infections, cytopenias, fatigue, and treatment-related complications. Clear nursing assessment processes and escalation pathways help ensure patients are assessed quickly and managed appropriately.

[WENDY BURSEY: 03:22.1]

Nursing prevention is another important area where nurses have a- sorry, infection prevention is another important area where nurses have a major role. BCMA-directed therapies can increase infection risk and when used earlier, patients remain on therapy or under monitoring for a longer period.

[WENDY BURSEY: 03:40.9]

Nurses reinforce fever reporting, infection precautions, adherence to prophylaxis, and the importance of attending monitoring appointments. The broader team may help coordinate antimicrobial prophylaxis, immunoglobulin replacement, vaccination planning, monitoring for viral reactivation, and management of recurrent infections.

[WENDY BURSEY: 04:03.1]

From a nursing perspective, our role is to make sure patients understand why these measures matter and when they need to alert the team. We often reinforce the same key messages at multiple touch points, report fever promptly, do not wait overnight, call with new respiratory or infectious symptoms, and continue prescribed prophylaxis unless advised otherwise.

[WENDY BURSEY: 04:27.7]

Therapy-specific monitoring also requires strong nursing coordination. For bispecific antibodies, nurses help support step-up dosing, workflows, observation periods, symptom checks, and patient education around CRS and neurotoxicity for CAR-T therapy.

[WENDY BURSEY: 04:46.6]

Nursing involvement includes caregiver education, monitoring expectations, and reinforcing emergency instructions for antibody drug conjugates. Nurses may help coordinate and reinforce ocular monitoring requirements. The key message is that moving BCMA therapy early is not simply about giving treatment sooner.

[WENDY BURSEY: 05:08.0]

It means preparing patients earlier, educating more proactively, and ensuring that monitoring and escalation pathways are clear from the beginning. Nurses are central to this process because we help connect the clinical plan with the patient’s lived experience.

[MOHAMAD MOHTY: 05:29.7]

Thank you very much Dr. Bursey.

[MOHAMAD MOHTY: 05:36.7]

And definitely, our nursing colleagues are playing a key role in the delivery of these sophisticated and very complex treatments to myeloma patients.

Video clip 8

[MOHAMAD MOHTY: 00:00.1]

Now, time for some discussion. So, my first question to all of you guys and this is the spirit of the sympo, BCMA to be used first.

[MOHAMAD MOHTY: 00:15.8]

But actually when I listen to you, it has to be combined with anti CD38. It’s not one against another. How do you feel about it?

[EVANGELOS TERPOS: 00:30.8]

I think, Florent mentioned very nicely why they can be combined with either IMIDs, CELMoDs probably, or with daratumumab or anti-CD38. I think that the first step that all the studies are going to, that is not to go against daratumumab but to be added to daratumumab or isatuximab in order to have, according to the preclinical data, more MRD.

[EVANGELOS TERPOS: 00:59.7]

I think with the definition of cure that Mariví presented, I believe that it is so important to have this five years of MRD negativity and we need to do our best and to give all the best drugs that we have upfront in order to achieve that.

[EVANGELOS TERPOS: 01:14.9]

That’s why I believe that they are going to be combined.

[MARÍA VICTORIA MATEOS: 01:18.4]

Yes. And on top of that. So, at the same time I think that the combination is perfect. We have to try to select the optimal partner and maybe not to go to the quadruplets that we are using right now.

[MARÍA VICTORIA MATEOS: 01:34.4]

So, I think that what we should know, what we should not do is Dara-VRd and going to add the BCMA bispecific monoclonal antibody because personally I consider that it is too much. It’s true that we have the preliminary data from MajesTEC-5 with teclistamab plus daratumumab, bortezomib, and lenalidomide.

[MARÍA VICTORIA MATEOS: 01:59.6]

And maybe it is not necessary. And we’ve seen based on MajesTEC-3 that there is a clear synergistic effect with anti-CD38. And do we need the IMID in this double combination, especially for going to the first line of therapy?

[MARÍA VICTORIA MATEOS: 02:16.4]

Maybe the answer is no. Can we combine BCMA bispecific with IMIDs, with CELMoDs? As you said, there are several trials planned to evaluate this combination. Why not? Maybe. So I think that we are now in a process of I would say de-escalation in order to move to optimal strategies, combining maybe no more than two compounds.

[MOHAMAD MOHTY: 02:44.3]

Excellent. And this is actually something completely new in myeloma where usually we were always, we’ve been always criticized by adding drugs. 1, 2, 3, 4. And now we’re trying to de-escalate. So Florent, you alluded to an important aspect of the treatment that CAR-T cells or T cell engagers, you definitely need fit T cells.

[MOHAMAD MOHTY: 03:13.0]

While for the same target, namely BCMA, with antibody drug conjugates actually can circumvent the immune status. Although we always love to have a good immune system. So, why is this important actually?

[FLORENT MALARD: 03:32.5]

So, yeah, this is important because the T cells directly act in a way the drug is acting either with the CAR-T or bispecific. When you go to belantamab, of course this is a drug that is combined with the antibody and goes into the cell.

[FLORENT MALARD: 03:51.4]

So, the T cell doesn’t act here. So, this is where we should think differently. And this is why this is very relevant to have the bispecific and the CAR-T in the first line, and if patients fail, we can have the antibody drug conjugate that may work after because-

[MOHAMAD MOHTY: 04:09.5]

Or the other way around.

[FLORENT MALARD: 04:10.4]

Or the other way around. If you have a patient and if you have some biomarker that we don’t have a good T cell fitness, you know, it is not going to work there. So, this is where we should go for the antibody drug conjugate treatments. So, we maybe need also to have some more biomarker-guided treatment.

[FLORENT MALARD: 04:27.0]

Well, we are now going to use some drugs that truly work with each patient’s human body and immune system.

[EVANGELOS TERPOS: 04:36.2]

And in order to support that for the belantamab mafodotin, we have seen that its action is also not dependent so much with the, let’s say, the help of daratumumab, for example. We had the BelaRd study that I showed you, with an MRD negativity rate of 50% and 83% in evaluable patients.

[EVANGELOS TERPOS: 04:57.9]

With the addition of dara, this does not increase dramatically with the same population. We are going to announce at ASCO that the MRD negativity rate in the eligible patient, in the available patient is again 82% suggesting that at least for the ADC, belantamab, it seems that the daratumumab addition to that may not be so helpful like in bispecific antibodies.

[EVANGELOS TERPOS: 05:24.4]

And I think that this is exactly what you mentioned from the preclinical point of view.

[FLORENT MALARD: 05:28.7]

And this is very important because it truly supports that it affects through the immune system. Also of the dara, not a direct effect, mainly on the myeloma cell line.

[EVANGELOS TERPOS: 05:37.9]

And possibly if this is, also, let’s say, supported by bigger studies, it might help with the de-escalation, as you mentioned. So, we do not need all these drugs together.

[MOHAMAD MOHTY: 05:49.0]

Wendy, can I ask you about the patient experience when it comes to delivering these different new agents targeting BCMA? And let’s focus, for instance, on, because for CAR-T cells they are usually hospitalized. But in the outpatient setting, for bispecifics versus antibody drug conjugates versus just monoclonal antibodies like daratumumab or isatuximab.

[MOHAMAD MOHTY: 06:15.4]

Is there any significant different experience from one drug to another?

[WENDY BURSEY: 06:22.5]

I mean, I think the infection risk has become a key point right now. And how we manage that infection risk. And from a nursing perspective, it becomes a big part of my assessment with the patient and how frequent they’re having infections and how we help prevent that and support them.

[WENDY BURSEY: 06:46.6]

So supporting the patient through this time, has become key with nursing. I think nursing has had a really big role.

[MOHAMAD MOHTY: 06:55.8]

Is frequency of administration a matter of concern? How frequent you have to give a drug? Is this something that matters?

[WENDY BURSEY: 07:05.8]

I mean, I think patients are having fewer visits to the center. They’re not having to see us as often. And they’re quite enjoying that, you know, with the CAR-T, not sort of one and not continuing on treatment has become quite a quite a treatment, they’ve really liked not coming to see us.

[MOHAMAD MOHTY: 07:29.5]

Thank you. Mariví, one last question about, because you alluded to the quadruplet. And maybe we don’t need all of these drugs together. But let me try to be controversial here because we are in the controversies. The results of CEPHEUS and IMROZ are already, they have put the bar very high.

[MOHAMAD MOHTY: 07:52.6]

So, what are our expectations? For instance, Evangelos mentioned a trial testing Bela-VRd, while you’re advocating for actually minimizing into two drugs. So how do you feel about this?

[MARÍA VICTORIA MATEOS: 08:10.3]

Well, you alluded to CEPHEUS and IMROZ with quadruplets, and I would say, how can we improve these two quadruplets selected basically for transplant- ineligible, unfit patients.

[MARÍA VICTORIA MATEOS: 08:26.6]

So, quadruplet followed by triplet as continuous therapy. Can we increase the MRD negativity rate with BCMA-targeted therapy? Maybe, yes. It’s 60%. So, we have a possibility for increasing up to 80 or almost 90%.

[MARÍA VICTORIA MATEOS: 08:45.9]

I would try to eliminate the maintenance part and maybe, with the incorporation of BCMA, not do the quadruplet. We discuss maybe it is possible to go to bela just with lenalidomide and dexamethasone or to move to a bispecific or why not trispecific with the data we know that there is a clear synergistic effect, fixed duration or based on minimal residual disease negative.

[MARÍA VICTORIA MATEOS: 09:13.5]

Why not CAR-T? We maintain the induction part, we give BCMA CAR-T and no more treatment. So, I think that, and of course also maybe bispecific monoclonal antibody with CELMoDs. So, the idea is to try to select and to explore new combinations, de-escalation in comparison with the quadruplets, but for me to increase the MRD negativity rate and to try to eliminate the second part of these quadruplets will be key for this population.

[MARÍA VICTORIA MATEOS: 09:50.2]

And maybe if we modify and we optimize CEPHEUS and IMROZ in this direction, we will eliminate the barrier or fit and frail, and this will be applicable to all populations.

[MOHAMAD MOHTY: 10:04.8]

This is definitely a lovely conclusion because actually Mariví mentioned all the keywords and the topics that will be discussed during this COMy Congress.

[MOHAMAD MOHTY: 10:21.1]

So now it’s time to conclude this symposium. So, please help us to measure the educational impact of this activity.

[MOHAMAD MOHTY: 10:38.4]

Please remember to complete meet the evaluation form and to claim your credits. Thank you very much for your attention.