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Advances in Bispecific Antibody Therapy for Multiple Myeloma: Strategies to Personalize Treatment and Elevate Patient Outcomes

Dear colleagues, ladies and gentlemen, I first of all thank the organizers for inviting me to participate actively here at this morning symposium.

Bispecific Antibodies for MM: Introduction

I would like to go with you about where we come from, where were the bispecific antibodies introduced?

This was especially when we had created a significant unmet need when using proteasome inhibitors, immunomodulating agents and the monoclonal anti-CD38 antibodies in the early treatment of newly diagnosed and early relapses and created the triple-class exposed and triple-class refractory population, and especially patients refractory to the monoclonal anti-CD38 antibodies remained therapeutic challenge.

Here you see the PFS curve of the LocoMMotion trial, a real-world observational trial, where CD38 antibody refractory patients showed a median PFS of 4.6 months and a median overall survival of about a year. In this context, the novel immunotherapies were introduced, developed and investigated in phase I and II trials.

In contrast to CAR T cells, bispecific antibodies are off-the-shelf T-cell engaging treatments. As I will show you now in a few minutes, they show high efficacy and a manageable toxicity profile in relapsed and refractory disease.

Bispecific Antibodies for MM: Targets and Constructs

Let us look shortly on the targets for bispecific monoclonal antibodies. Most of them are directed against BCMA. However, we have also developments acting against GPRC5D, CS1 or SLAMF7, CD38, CD138, FcRH5 as you will hear, and you see also on the right of this graph that the constructs differ. Teclistamab, linvoseltamab are an IgG4. A univalent BCMA binding bispecific antibody is elranatamab. However, for example, etentamig has a dual BCMA binding.

I will focus my talk on the bispecific antibodies, which have now entered the market and are approved.

MajesTEC-1: Teclistamab in R/R MM

The first approved bispecific monoclonal antibody was teclistamab, and Philippe Moreau published that in The New England Journal of Medicine that were the first data on anti-BCMA treatment with this immunotherapies. This was a phase I/II trial where teclistamab was investigated in patients with relapsed and refractory myeloma disease, triple-class exposed with the primary endpoint overall response rate.

MajesTEC-1: Teclistamab Dosing Schedule and CRS

Here you see the step-up doses. This is important for your daily clinical routine. You have three step-up doses. It is a weight-adjusted treatment. You have a 48-hour monitoring after each step-up dose. Then you have a weekly dosing subcutaneous from week two-plus.

You see in the lower part of the slide the incidence of the cytokine release syndrome. It is, as expected, in the majority after the first and second step-up dose overall incidence of CRS described in the trial, a bit more than 70%.

Phase I/II MajesTEC-1: Teclistamab in R/R MM

These are the results. This was a heavily pre-treated patient population, 26% high-risk cytogenetics. Median prior lines of therapy, five. Close to 80% triple-class refractory; 30%, penta-refractory.

In this patient population, teclistamab showed a very promising overall response rate of 63% with a very high CR and VGPR rate and a median PFS of 11.4 and a median overall survival of 22.2 months, so doubling the expected overall survival.

MagnetisMM-3: Elranatamab in R/R MM

Elranatamab, the second BCMA-directed bispecific antibody, entered the market after approval on the basis of the MagnetisMM-3 trial, an international, open-label, randomized phase II study, again in relapsed and refractory disease with two cohorts: one cohort for no prior BCMA-directed therapy and one including patients who had already a BCMA-directed treatment, and elranatamab was given here again subcutaneous with the primary endpoint overall response rate.

MagnetisMM-3: Elranatamab Dosing Schedule and CRS

Let us focus on cohort A here. Elranatamab is given in two step-up doses. It is a flat dose. You come from 12 over 32 to 76 milligram. 48-hour monitoring is needed. Again, you see here the CRS incidence also after better learning curve in the field. We see again most of the CRS after the first dose with an overall incidence of a bit more than 55%.

MagnetisMM-3: Efficacy

Here data on the efficacy, again heavily pre-treated patient population comparable to the patient population in the teclistamab trial with a median PFS here of 17.2 months, overall response rate of 61%. High CR and VGPR rate. The median overall survival here not reached at this time.

LINKER-MM1: Linvoseltamab in R/R MM

Linvoseltamab then was already a second-generation bispecific antibody directed against BCMA, investigated in the LINKER-MM1 trial, again a phase I/II study, again in relapsed disease, triple refractory or triple-class exposed. Patients investigated here with linvoseltamab in several doses. We focus on the approved 200 milligram dose, which was investigated in this trial with the primary endpoint overall response rate again.

LINKER-MM1: Linvoseltamab Dosing Schedule and CRS

Linvoseltamab has a bit different step-up dosing and a different mode of administration. It is not subcutaneous, it is IV. You give the step-up weekly, so day one and eight. Then you have a 28-hour monitoring, and then you go directly to the 200 milligram dose.

You see here the data on the CRS in this a bit more than 100 patients with an overall incidence of CRS of 46%, most of the CRS again after the first step-up dose.

LINKER-MM1: Long-term Efficacy

Here, after a median follow-up of a bit more than 20 months on the 200 milligram dose, which is now approved and available again in a heavily pre-treated patient population and patients already were also allowed to be pre-exposed to an anti-BCMA ADC.

We see a response rate of 70.9%. High CR and VGPR rate. You see that this overall response rate is also documented in patients with high-risk cytogenetics, prior exposure to an anti-BCMA ADC in triple, quad and penta-refractory patients with a median PFS not reached at this time, and a median overall survival of more than 30 months.

Summary: Efficacy of BCMA-Directed TCEs in R/R MM

To sum that up, teclistamab, elranatamab and linvoseltamab have the same target antigen BCMA. They were all investigated in at least triple-class exposed patients. They had a monotherapy efficacy of 61% to 71%, respectively. Here shown median PFS and overall survival rates.

Summary: Safety of BCMA-Directed TCEs in R/R MM

This is the safety summary, and Jens said it already. We know that the main non-hematologic toxicity of all those agents is infection, especially grade 3/4 infection, which is here described in a range of 31% to 45%. However, we all know that in all those trials which were in the majority conducted still during the pandemic, there were early deaths due to infection. So please be careful as it was shown already, that you really intensify supportive care strategies, as we will hear later on in this symposium.

CRS is common, however normally easy to manage with the current guidelines, you will also hear. ICANS per se is rare in the administration of bispecifics.

Posttest 1

Now I go with you to the test again. Based on the clinical trial data and real-world evidence, there are some key differences when comparing the drug, linvoseltamab, with other bispecific antibodies. A major difference includes which of the following? Please read it by yourself and please vote.

Okay. Yes, you learned a lot during this talk. Yes, it is a complicated question, but the answer is D. We have this weekly step-up dosing, and then we have also the option to space out.

Supplemental Administration of IVIG During BCMA-Directed BsAb Treatment Associated With Improved Clinical Outcomes

I would like to continue with the important supplemental administration of IVIG during BCMA-directed bispecific antibody treatment.

These are here more than 200 patients receiving teclistamab or an investigational BCMA-directed bispecific antibody. You see that with the use of IVIG, the infection-free survival for all-grade infection, and especially the infection-free survival for grade 3 or higher infection goes significantly down. So it is key to administer this prophylaxis to your patients.

Targeting GPRC5D in MM

We have a second target where we have an approved bispecific antibody in relapsed and refractory multiple myeloma. You will see great data here on the convention also of this asset. The target is GPRC5D. You see here that this is highly expressed in multiple myeloma as this bar indicates.

However, we have a distinct toxicity profile, which is due to the fact that this targets also expressed on the skin. We know that we have distinct skin and nail toxicities with GPRC5D-directed immunotherapies, and especially we have also phenomenon with the dysgeusia.

MonumenTAL-1: Talquetamab in R/R MM

MonumenTAL-1 was introducing talquetamab in relapsed and refractory myeloma disease. Same thing as I showed you already for the BCMA bispecifics investigated in a phase I/II study, and talquetamab was investigated in two administration profiles: once weekly, twice weekly in different doses. The primary endpoint was overall response rate.

In the dose of 0.8 milligram per kilogram given every second week, as you see here, the Q2 week dose, the overall response rate was 69.5%, and we saw a median PFS of 11.2%. This is the response the drug was approved.

MonumenTAL-1: OS at Extended Follow-up

Here you see updated overall survival data. We focus on the overall survival in the Q2 week cohort. This was at 36 months, 60.8%. If you look on patients who received already prior bispecific antibody or CAR T-cell, you see that the outcome in overall survival is better if you use talquetamab after CAR T-cell rather than after exposure to prior bispecific antibody.

MonumenTAL-1: Safety at Extended Follow-up

You have to note, and this is very important, that this drug has a very distinct safety profile, which might affect significantly health-related quality of life of our patients. We have a high percentage of dysgeusia and skin and nail toxicity. Many patients, as you see here, indicated in this curve, are losing significant weight. You have to be aware of this when treating patients with talquetamab.

Bispecific Antibodies: Mechanisms, Structures, and Resistance

To sum that up, we saw that TCEs have a distinct mechanism of action leading to tumor lysis and cell death. We have different TCE structures and for sure we have to deal in the future also more and more with mechanisms of resistance to TCEs regarding the T-cell dysfunction, T-cell exhaustion, the tumor intrinsic factors enabling resistance and tumor microenvironment factors enabling also resistance and subsequent relapses.

Conclusions: Bispecific Antibodies in R/R MM

With that, I would like to conclude. I showed you that bispecific antibodies are now widely approved for the treatment of triple-class exposed relapsed and refractory myeloma. Approvals are based on single-arm phase I/II trials.

BCMA-directed TCEs are a therapeutic alternative, especially in case CAR T-cell treatment is not available or feasible. Infections are the most relevant. Non-hematologic toxicities. IVIG substitution is key.

GPRC5D-directed TCEs are a therapeutic alternative. Potential adverse effects have to be considered.

Further data continuously being generated. Randomized phase III trials are already published, are shown here in this EHA.

I am happy to hand over to Professor Moreau, who will provide you with an absolute firework of data now. The stage is yours.

The Evidence on Bispecific Antibodies for MM: Future Directions

Other Bispecific Antibodies in Development

Dr. Moreau: Thank you, Katja. Let us talk about future developments of bispecific antibodies.

Rationale for Cevostamab in R/R MM

You discuss about linvoseltamab, teclistamab, talquetamab and elranatamab that are approved. But there are other bispecific in development. This one is interesting. Cevostamab, in fact.

Cevostamab is targeting FcRH5 that is always expressed on the myeloma cells. We have early data with the development of this agent. Interestingly, we are using a fixed duration treatment with cevostamab, and the development was proposed even in patients with a prior BCMA and prior GPRC5D therapy.

Cevostamab from monotherapy to combinations 

This drug is able to rescue patients failing BCMA treatment and failing talquetamab as well. That is quite interesting to see that the dose is already established, 160 milligrams. You see the response rate here for patients with any prior BCMA therapy, that is 30%.

Also we know that we can combine cevostamab with, for example, pomalidomide and dexamethasone. We have a good response rate as well in very advanced patients.

Cevostamab clinical trials: Relapsed MM   

This is the development plan of cevostamab. Interestingly, we know that this agent can be combined in fact with BCMA bispecific antibody. We have early data with the combination with elranatamab, some data as well with the combination with linvoseltamab.

Interestingly, we know that and Adam Cohen from UPenn showed good data with cevostamab as consolidation therapy following CAR T cells. There is this study ongoing, the phase III trial to establish cevostamab in the routine practice, comparing pomalidomide/dexamethasone in very advanced patients versus pomalidomide/dexamethasone plus cevostamab.

Rationale for Etentamig in R/R MM

We also are awaiting for the results of the treatment with etentamig. Etentamig is the another bispecific targeting BCMA. There is this particular low-affinity CD3 binding domain that may reduce the toxicity of this agent.

Interestingly, we know that we can use the monthly administration with etentamig.

MONVISO: Etentamig IV in R/R MM After ≥2 Prior LoT

At ASCO, a few days ago, we heard for the first time about the results of this phase Ib trial with etentamig single-agent in patients with a prior BCMA exposure. The primary endpoint was to look at the safety of this agent that is proposed IV monthly.

MONVISO: Baseline Characteristics (Arm B)

You see that 41 patients with a prior exposure to BCMA were reported. The median number of lines of therapy was six, so a very heavily pre-treated patient population.

MONVISO: Response in Patients Whose Last LoT Was BCMA CAR T (Arm B)

The response rate is quite interesting, with 50% to 60% of the patients that are now going to respond. We have a large development plan with this new bispecific antibody.

Combinations in EMD

RedirecTT-1: Study Design

Another interesting study was the RedirecTT study with the combination, in fact, of talquetamab and teclistamab in patients with extramedullary disease. You know that this study was reported at ASH a few months ago and published in The New England Journal of Medicine.

This is the largest phase II study focusing on true extramedullary disease. 90 patients, very advanced, were treated with a combination of talquetamab and teclistamab every two weeks. After six cycles, patients could receive a monthly administration of talquetamab and teclistamab.

RedirecTT-1: Baseline Characteristics

The median age was 64, very advanced patients. In fact, a lot of them were previously exposed to a BCMA or FcRH5 as well. All of them had a true extramedullary disease with an assessment by PET CT.

RedirecTT-1: Efficacy

When you are looking at the overall response rate, almost 80% of the patients did respond. That is really amazing. When you are looking at the data with talquetamab single-agent or teclistamab single-agent, the response rate in patients with extramedullary disease is not above 40%.

When you are combining the two antibodies and targeting two different antigens on the tumor cells, and we know that EMD is probably the most difficult subgroup of patients to treat in the relapsed setting, amazing response rate. The median duration of response was not reached. The median PFS was 15 months. That is very long.

RedirecTT-1 Phase II EMD (Tal + Tec): PFS and OS at 16.8 Mo Median Follow-up

When you are looking at the PFS analysis, the OS analysis at one year, 73% of the patients are still alive. The median PFS is 15 months.

Combining two agents is probably important. Targeting two different antigens is important. In the future, maybe we are going to use trispecific antibodies for this very difficult subgroup of patients to treat.

Bispecific Antibodies for Early Relapse

You know that the development is very fast, in fact, with bispecific antibodies. They are now proposed for early relapse.

MajesTEC-3: Study Design

At ASH as well, a few months ago, you heard about the MajesTEC-3 study. It is a randomized phase III study for relapsed myeloma patients, all of them previously treated with a PI and lenalidomide. The prospective comparison of DPd or DVd standard of care and mostly daratumumab/pomalidomide/dexamethasone, DPd, versus the combination of teclistamab plus daratumumab.

The primary endpoint was progression-free survival. Almost 600 patients were randomized. The patients were not refractory to CD38 antibody. In fact, the patient population was with only 5% of the patients with a prior exposure to daratumumab.

MajesTEC-3: PFS

The PFS is really amazing. You see the control arm is a good control arm. As expected, a median PFS of 18 months. When you are combining teclistamab and daratumumab, the hazard ratio, 0.17, the best one ever reported in a phase III study for relapsed myeloma patients. That is a 83% reduction in the risk of death or progression.

MajesTEC-3: PFS and OS Subgroup Analysis

When looking at OS and PFS subgroup analysis, all subgroups of patients are really benefiting from the combination, especially patients treated at the time of the first relapse, the hazard ratio is even better, 0.14.

MajesTEC-3: OS

This is the overall survival analysis. The follow-up is almost three years. Already, we have a strong OS benefit that is highly significant in favor of teclistamab/daratumumab. That is amazing to see this plateau here when combining teclistamab with daratumumab.

The patient population enrolled in that study is not exactly the patient population that we are treating, because you know that we are treating now patients with quadruplet upfront and almost all patients are receiving daratumumab frontline. This is not the patient population that was enrolled in MajesTEC-3. This combination is already approved in the US. It is not yet approved in Europe.

MagnetisMM-5: SC Elranatamab Monotherapy and in Combination With Daratumumab in R/R MM

We also have a very similar study with elranatamab, the MagnetisMM-5 with relapsed myeloma patients, earlier relapse. That is a prospective comparison of elranatamab single-agent versus elranatamab plus daratumumab versus standard of care, DPd.

Interesting study for sure. We are awaiting for the results. Probably the results will be presented before the end of this year.

MajesTEC-9: Teclistamab vs PVd or Kd in R/R MM

During this meeting and presented at ASCO a few days ago, you heard about the MajesTEC-9 study. That is a very important trial in my opinion.

Early relapse one to three prior lines of treatment, all patients did receive previously a CD38 antibody and lenalidomide. That is exactly the patient population that we are treating right now upfront with lenalidomide plus daratumumab, a prospective comparison of teclistamab single-agent versus PVd or Kd with a primary endpoint of progression-free survival.

MajesTEC-9: Baseline Characteristics

These are the baseline characteristics. Please look at the refractoriness status at the time of study entry. Lenalidomide refractory, 80% of the patients. CD38 refractory, 85% of the patients. Overall double refractory, more than 70% of the patients. That is exactly the patient population that we are treating daily, in fact.

Teclistamab vs. PVd or Kd in R/R MM: PFS (Primary Endpoint)

These are the data on PFS, the primary endpoint of the study with fantastic rate at 18 months to my opinion. Again, a very strong hazard ratio. This will probably establish teclistamab single-agent that will be approved for sure in the near future.

When thinking of the patient population that we are treating, frontline elderly patients are receiving DRd, the MAIA regimen. When they will progress on lenalidomide plus daratumumab, maybe you will be able to salvage those patients very easily with teclistamab single-agent.

Teclistamab vs. PVd or Kd in R/R MM: OS

These are the overall survival data. Again, a significant benefit with a hazard ratio of 0.6. The paper was published, as you know, a few days ago in The New England Journal of Medicine.

MonumenTAL-3:Tal-D or Tal-DP vs DPd in Patients With R/R MM Who Have Received ≥1 Prior Line of Therapy

In this meeting, we are going also to hear about the MonumenTAL-3 study. Why not, instead of using a BCMA bispecific, looking at talquetamab targeting GPRC5D. This is a prospective comparison in the relapsed setting of standard of care, DPd, versus talquetamab plus daratumumab or talquetamab plus daratumumab and pomalidomide.

The data will be presented tomorrow during the plenary session with a strong benefit of talquetamab-based combination.

Bispecific as Part of Frontline Therapy

The landscape is changing so rapidly that now we are using bispecific upfront during the front-line treatment.

LINKER-MM-4: Linvoseltamab in Patients With NDMM

Bob Orlowski reported at ASH the results of the LINKER-MM4 study. That is a very provocative study, a phase I/II with linvoseltamab that is now approved in very advanced patients. But linvoseltamab was proposed upfront at the dose of 200 milligrams in patients that were naive of any treatment. That was the frontline treatment with four cycles of linvoseltamab.

For transplant-eligible patients, they could subsequently receive autologous stem cell transplantation. For transplant-ineligible patients, they did receive linvoseltamab single-agent until disease progression. So very provocative to treat the patients upfront with a bispecific targeting BCMA.

The primary endpoint was safety.

LINKER-MM-4: Linvoseltamab in Patients With NDMM

When you are looking at the first early results, small number of patients, 86% of the patients did respond. Interestingly, the response was so good that patients that were transplant-eligible were supposed to receive autologous stem cell transplantation after the first four cycles, but many of them declined autologous stem cell transplantation because they were happy to receive these agents, single-agent alone.

We will see with a longer follow-up. This is a platform maybe for the future with a bispecific antibody.

How to Improve DRd (MAIA)

I mentioned that for transplant-ineligible patients, our standard of care is the DRd regimen, the MAIA regimen. Maybe we can improve on the MAIA regimen with bispecific antibody. You know that we have two studies, very similar trials, MajesTEC-7 and MagnetisMM-3, one with teclistamab and one with elranatamab.

And DRd MAIA in both trials is compared with a bispecific antibody teclistamab or talquetamab here, plus daratumumab plus lenalidomide.

Here, same story, elranatamab/daratumumab/lenalidomide. For sure, we can anticipate that those studies are going to be positive.

Do we need really to have a triplet combination when the bispecific antibodies are so strong? Do we need at any cost to have three drugs here versus the DRd regimen? I am not that sure, in fact.

IFM/PETHEMA Philae Trial (M25-586): Etentamig + D Compared With DRd in NDMM Not Eligible for Transplant

We discuss about this new bispecific antibody, etentamig, that is effective in very advanced patients. Currently, the French and the Spanish group are going to work together to use etentamig plus daratumumab versus DRd, two drugs only, in fact, in a phase III study to try to establish the quality of this combination of a bispecific plus a CD38 antibody in frail patients. That is very interesting to look at this cohort of frail patients.

IFM2021-01 TecLille Trial: Tec-Dara and Rec-Len in TNE NDNN

You know that one of the best abstracts at ASH was the TecLille trial with the combination of teclistamab plus daratumumab upfront in transplant-ineligible patients, the first small cohort. 37 patients were treated, all of them transplant-ineligible.

IFM2021-01 TecLille Trial: Tec-Dara (Cohort A) Response Rates

Again, with these two drugs, only without IMiD, without proteasome inhibitors, the response rates were really amazing. VGPR rate after four cycles. The primary endpoint, 95% of response. All patients with a longer follow-up did respond.

PFS and the OS with the one-year follow-up is 100%. Two drugs, no IMiD, no PIs, no dirty old drugs. That is really amazing to see those results.

IFM2021-01 TecLille Trial: Tec-Dara (Cohort A) MRD NGS 10^-6 Evaluation

For MRD 10^-6 in patients that were evaluable for MRD negativity, 100% of response. Maybe the future will be to combine a bispecific targeting BCMA plus a CD38 antibody.

We have to keep in mind that is not only two drugs. You have to add systematically IVIG to reduce the risk of infection.

IFM 2025-01 – ELLEN: Elranatamab in Transplant-Eligible NDMM

The French group as well is looking at bispecific antibodies upfront to challenge autologous stem cell transplantation. This study is ongoing. We have already enrolled 400 patients. The target is more than 800 patients. We are randomizing currently the PERSEUS regimen, in fact, who had combination followed by autologous stem cell transplantation and two agents in the maintenance phase versus a quad upfront, followed by the combination of elranatamab plus lenalidomide.

We will see if we can challenge stem cell transplantation with bispecific antibody. You know that there is this ongoing CARTITUDE-6 study comparing autologous versus cilta-cel. So maybe we can challenge stem cell transplantation as well with bispecific antibody.

Improving Maintenance

We can use those agents to try to improve the maintenance phase following autologous stem cell transplantation. During this meeting, Niels van de Donk is going to update some results on the EMN30 MajesTEC-4 study, maintenance with either lenalidomide that is prospectively compared with teclistamab and the comparison with lenalidomide plus teclistamab.

We also have a very similar study with elranatamab that is currently compared with lenalidomide maintenance in a prospective fashion.

BsAbs in High-Risk Smoldering MM

A lot of development, as you can see, at early relapse and also frontline. Some colleagues are also proposing bispecific antibody in high-risk smoldering multiple myeloma. There is a good rationale to use those agents.

Clinical Trials in High-Risk SMM

At ASCO during the educational session, Nizar Bahlis showed all these ongoing trials with new immunotherapies in high-risk smoldering myeloma. So you can take a look at the educational book. You will see all these tables. High-risk smoldering that can be treated with teclistamab with a fixed duration of two years. There is a similar study that was presented at IMS last September with linvoseltamab, a bispecific targeting BCMA, during two years as well. You know that there is also some trials looking at cilta-cel in high-risk smoldering.

The efficacy results are also very good. 100% of response, with MRD negativity 100%. But small numbers, short follow-up. The therapeutic intent is to potentially cure those patients with a low-tumor burden and a genomic instability that is not as important as very advanced patients, for example.

The T-cell fitness is much better for high-risk smoldering probably as compared with very advanced patients. The rationale is there. We need a longer follow-up for sure.

EMN34 (ERASMM): Fixed-Duration Elranatamab in High-Risk SMM

During this meeting, you are going to hear about the results of this EMN34 study with elranatamab in high-risk smoldering myeloma, elranatamab single-agent with a fixed duration of therapy in patients with a high-risk smoldering with at least two high-risk features, according to the 2/20/20 classification.

The primary endpoint is CR rate.

EMN34 (ERASMM): Baseline Characteristics

Cyrille Touzeau will show that out of 50 patients enrolled, the median age was 65, all of them with at least two high-risk criteria in the 2/20/20 classification.

EMN34 (ERASMM): Response Rates and MRD

The response rate is very good, 90%. The feasibility is good as well. The rate of infection is not very high. Again, a strong rationale. When you are looking at MRD negativity 10^-6, 90%.

This is the first part of the study. Now there will be a second part of this ERASMM study with the addition of daratumumab to elranatamab in order to try to reproduce the results of the TecLille study, for example.

Posttest 2

Now you are going to vote. Which of the following patients would be eligible for enrolment in the LINKER-MM4 trial? Please vote.

1. High-risk smoldering;
2. Newly diagnosed transplant-ineligible only;
3. Newly diagnosed for both transplant-eligible or ineligible; or
4. Relapsed myeloma patients.

Posttest 2: Rationale

Okay. The response is C, transplant-eligible and ineligible patients.

Conclusions

To conclude, I would say that now bispecific antibodies are game changers in very advanced patients for sure. You are using those agents in routine in community hospitals, in academic hospitals. They are now proposed at early relapse. We have one combination of teclistamab/daratumumab that is approved, MajesTEC-3 in the US, not yet in Europe. There is a huge development in the frontline setting, but also in high-risk smoldering myeloma.

I thank you for your kind attention.

Personalizing Bispecific Antibody Treatment in Patients With MM

Dr. Hillengass: Thank you so much, Philippe. Even though I could listen to you talk about bispecific antibodies for hours, I do feel slightly dizzy right now just because of the sheer amount of data that we have.

To loosen things up a little bit, I will talk about one of my patients. I had to change dates and things like that. So no worries. No HIPAA violation here.

Patient Case: 63-Yr-Old White Woman

Just to bring this a bit closer to home, because you saw all the data. At this conference, as we see the data and then we think, “Oh my goodness, how do I implement that in my clinical practice?”

This is a patient of mine who was diagnosed with MGUS. I will just point out a few things where the bispecific antibodies really changed the outcome of this patient significantly. A lot of this is fairly straightforward, but there might be a few things I practice in the US, so I have access to certain things that might not be available yet in Europe at the time that I used them for this patient.

This was a patient with basically standard risk disease. The patient was started outside, so a little bit away from our academic center, and she started with VRd treatment four cycles, but unfortunately only achieved a stable disease.

Patient Case: 63-Yr-Old White Woman

The local doctor added daratumumab. Lo and behold, the patient achieved a partial response. Instead of adding something else or changing something else at the time, because there were no bispecific antibodies in early line available, we went on and gave her a stem cell transplant at our center, and she had only a partial response.

At the time, we had a clinical trial by the BMT CTN that allowed patients to start lenalidomide maintenance. If they are not VGPR or better, they can go on with a CAR T-cell therapy with ide-cel.

Since this was a fairly young patient and she was in great shape or still is, we recommended this trial to her. She was interested and was enrolled and received ide-cel and then restarted lenalidomide maintenance as per the trial.

Patient Case: 63-Yr-Old White Woman

In August of 2023, so less than one year later, unfortunately, the patient already progressed. You can see even though this was based on the initial assessment, a standard risk patient, biologically her disease behaved very differently and still does, unfortunately, until this day.

Because of availability and because of what was approved at the time, we changed her treatment to selinexor, carfilzomib and dexamethasone based on a phase II study, which is also not approved. This is something that we could apply for with the insurance. The insurance agreed to give this to the patient.

The reason why we chose this, and we can discuss this during the talk, was that we wanted to change as much as possible because it was really not IMiD-sensitive anymore at that point. So we try to add other things rather than giving chemotherapy. We asked the insurance to give something a little bit more modern. I know a lot of people have different and sometimes mixed feelings about selinexor. At this point, we changed to this treatment.

This was 2023. If we were in 2026 and this would happen to ask my colleagues, what would be your choice in such a patient? Again, we might have used a bispecific earlier, especially in the US where it is approved. What are your thoughts? Would this be a patient where you would think about bispecifics? She already had a CAR T-cell therapy, and which bispecific would you use? Philippe, what do you think?

Dr. Moreau: Definitely, that is quite a difficult case, because she was exposed to a CAR T. She has very aggressive disease. She is progressing very fast after a BCMA agent. She received daratumumab, a CD38 antibody, but she is not CD38 probably refractory.

We are not using a lot of selinexor. I will try to use a bispecific antibody, if possible. That would be my choice. I do not know if we have to change of target because she received ide-cel. That is exactly the kind of patient that will benefit from the results of the MonumenTAL-3 study that we are going to hear tomorrow, in fact, with the combination of talquetamab/pomalidomide.

Well, that is not approved, but I am always in favor of clinical studies. So I would have enrolled this patient in MonumenTAL-3.

Dr. Hillengass: Yes. I like what you bring up there with the change of the target. There is actually a question. I peeked at the questions in the chat, and please continue to send questions in the chat. I try to read them into this discussion and also at the end.

Katja, if you had access to everything, would you change the target? Would you say you try again with the BCMA because we have more options? What is usually your take on when to change target and when to use the same?

Dr. Weisel: I am totally in line with what Philippe said. However, it could be also worth to see in the bone marrow if BCMA is still expressed in this patient. This would help to probably consider an additional BCMA treatment. We have those data that these drugs are still effective.

Philippe just showed the data on etentamig with promising results in this setting. We also have data from the real-world of CAR T after CAR T. Cilta-cel was approved after ide-cel. However, in this case, I would always try to see if the target antigen is still there.

Dr. Hillengass: Another great point that you bring up. I am so grateful for this faculty. Ja Min, do you have access to BCMA measurement in South Korea? Do you have an easy assay that you can order?

Dr. Byun: We do not have commercial assays, but we can do it in labs. I would also want to throw in that if you have an extramedullary disease at this point, doing some chemo lead-in followed by bispecific would be a good way to go.

Patient Case: 63-Yr-Old White Woman (Cont’d)

Dr. Hillengass: Excellent. Yes. I think you know the case because you had the slides before, because unfortunately this patient actually developed soft tissue disease, which is one of the twists in this.

The patient was started again outside with daratumumab/pomalidomide. She was not daratumumab refractory at this point, had not seen pomalidomide because she came out of a PI and then, as you know, selinexor.

Unfortunately, she developed a GI bleed on the anticoagulation that she needed with pomalidomide. That was not a good option for her after a fairly short period of time. She already progressed again. I show you the M-spike in electrophoresis. She had back pain significantly, so the outside oncologist gave her radiation for her lumbar spine where the major pain was.

Patient Case: 63-Yr-Old White Woman (Cont’d)

Unfortunately, when we did imaging, and I apologize for the artefacts that you can see here sometimes. On the right-hand side, you can see better, this soft tissue disease growing out of the vertebral bodies into the soft tissue, into the lung, in this case. Then there was another lesion in the pelvis.

Both of them were clinically significant and painful for the patient.

Patient Case: 63-Yr-Old White Woman (Cont’d)

The patient received DPACE because at that point again it was not easy. We did not have a lot of time. DPACE is something that you can always do, right? One of my colleagues, Sarah Holstein, calls DPACE the bridge to nowhere, which is unfortunately a very aggressive treatment. It oftentimes helps, but it is not a long-term solution, where again, the bispecific antibodies come into play.

She did not have time at this point because she was in pain, so we admitted her. As inpatient, it was not easy to give her the bispecific antibody. There was some response. You can see here still, this was before the DPACE, there was significant extramedullary disease.

Patient Case: 63-Yr-Old White Woman (Cont’d)

We tried to collect CAR T cells, which is another topic that we have, right? When is the best time to collect CAR T cells? Since she got the ide-cel and, as Katja mentioned, CAR T after CAR T seems to be a good option. But who has access to this?

Since she got the ide-cel in a clinical trial, the commercial product was still available in the US or at least in our area. You can give one CAR T if it is not in a clinical trial. So we collect it for cilta-cel. Unfortunately, that was not successful, which is maybe not a huge surprise if a patient had DPACE before. So we unfortunately did not have this option.

We had access to talquetamab and she got radiation which helped with her pain again in the pelvis mostly. She did respond a little bit and for a short period of time to talquetamab. Then we had access. We have a clinical trial where specifically for extramedullary disease, which we discussed is a very aggressive version of multiple myeloma. We can enroll patients in a combination of carfilzomib, mezigdomide and dexamethasone, and it would make this too long a session if we start talking about the CELMoDs as well.

In the clinical trial, and as Philippe said, clinical trial, if you have access and it fits to the patient, that is always our first choice. So we try to enroll her, but we did not have enough time. Clinical trials take a few weeks until you have enrolled them, have done all the inclusion criteria and said, “Okay, we bridge with talquetamab and we still have that for later.”

So have that for later. Is that something that you ever think about with this huge amount of medications that we have or sometimes do not have access to. Even with the old school drugs, we have so many options. Have you ever thought about keeping something that is working well or that you would think works well for the patient for later, or would you say the best always first? Ja Min, what is your approach?

Dr. Byun: Because one of the younger generation of doctors, I have always lived in a world where we have plethora of treatment for multiple myeloma. I am a big fan of using the best drug first because development always happens. 10 years from now we are going to have better drugs if we keep them alive. Use the best drug first is my go to. Maybe other people have better ideas.

Dr. Hillengass: I see nodding the rest of the faculty. I agree. Someone said in an advisory board and that ages me, of course, “You would not keep LeBron James on the bench in a basketball game”, or Michael Jordan for everyone who is my age and older.

Patient Case: 63-Yr-Old White Woman (Cont’d)

The patient responded. Actually the good news was this patient got the step-up dosing of talquetamab because we just needed a little bit of time to enroll her in the clinical trial. We could not enroll her in the clinical trial because she responded so well.

She was not progressing, did not qualify for the trial anymore. Unfortunately, a few months later, she did progress again and we could enroll her in the trial, again, unfortunately, again showing how aggressive this disease is.

Patient Case: 63-Yr-Old White Woman (Cont’d)

In her case, she did not really respond very well. She responded after two cycles. Then after three cycles, she already progressed again in imaging. As you also know, sometimes in these patients, the serological response and the imaging response do not really align very well.

Patient Case: 63-Yr-Old White Woman

This is how it happened. This is when we prepared those slides where the case ended, but the patient is still alive. What we could do is the patient came out of mezigdomide/carfilzomib. There are rumors that mezigdomide makes CAR Ts or T cells better. We tried again to collect CAR T cells.

At this meeting, I got an email that she collected successfully for cilta-cel. That is something what we do. Guess what we are using for bridging? Talquetamab again. That is maybe one other question again with a switch of targets.

When you have to bridge, what is your bridging, Philippe, if you have a patient for example, cilta-cel or ide-cel?

Dr. Moreau: That is very interesting. We know that when patients are responding to the bridging therapy, their outcome is much better. If you can have a response before the administration of the CAR Ts, the PFS will be much longer. That is very important to select the optimal bridging therapy.

We have some data coming from the US showing that talquetamab could be a very good bridging therapy before a BCMA CAR T infusion that is off-label nevertheless. In some countries, that is possible. In Europe, we are here at EHA, and I know that Katja and the German colleagues also have this experience. Unfortunately, we do not have access to talquetamab in France. That is a pity, but it is like that.

Bridging with talquetamab is interesting, especially for those patients that are penta-refractory, refractory truly to a CD38 antibody, carfilzomib, bortezomib, lenalidomide and pomalidomide. For those patients, we do not have a lot of possibilities. If we can use talquetamab off-label, that is published now in Blood, this is probably interesting.

Dr. Hillengass: Beyond all the other things we already talked about, there is another really great place where the bispecifics can shine.

Optimal Monitoring and Management of Toxicities Related to Bispecific Antibody Therapy

Okay. For the sake of time, I would go on with now the really practice informing recommendations, how to manage, because that is also a question in our chat already. How do we deal with infections? We will hear more now. Professor Byun?

Dr. Byun: Hi. For the next 15 minutes or so, we are going to talk about the optimal monitoring and management of adverse events related to bispecifics.

Agenda: Overview

This is my agenda.

Bispecific Antibodies Approved for MM

We have been talking about these four agents the whole morning. These are the four agents that are in clinic today. As they improve the survivals of multiple myeloma patients, the supportive care is becoming increasingly important to ensure good quality of life and to sustain the efficacy of the treatment.

Agenda: Maximizing Care Strategies

In order to maximize the benefit of these bispecifics, we have to be well aware of the early events that happens when we are initiating the bispecifics, as well as the events that can happen throughout the bispecific use.

II-A. Initiating BsAbs in MM: 2026 Update

As Dr. Weisel has already mentioned, that considering the mechanism of actions of T-cell engagers or bispecifics, we follow a very particular schedule when we are first starting these bispecifics.

BCMA agents usually have three step-up doses. Talquetamab, depending on which regimen you are going to use, have up to four step-up doses. We also want to remember that along the way in the later phases of the treatment, according to the treatment efficacy, the dosing schedule is more spaced out to balance out the toxicity versus the benefit.

We want to keep in our mind that we do not have to do the intensive dosing all the way through. That is very important.

II-A. CRS: What Do We Know?

Let us talk about CRS for a moment, or cytokine release syndrome. We already know that this is a systemic inflammatory response. We know that up to two thirds of the patients are going to have CRS. We know when that is going to happen, and that is more important.

CRS usually happens during the step-up dosing, especially the first two doses. That is when we want to be very vigilant with our patients. The real-world data shows that it pretty much lines up with the pivotal trials.

II-A. How Do We Manage Grade 1-4 CRS in Myeloma Patients?

What do we do when CRS actually does happen? I am not going to go through the whole guideline, but the key takeaway here is that when you are using bispecifics for multiple myeloma, do not be stingy with tocilizumab.

I realize that things are a bit different in the lymphoma world, and it is very different from CAR T-cell therapy, because CAR T-cell therapy needs time for homing, and it is a one shot thing, whereas bispecifics are given in repetitive dosing, which ultimately drives the massive release of IL-6.

Acting early actually prevents the escalation of the cytokine cascade without compromising the anti-tumor activity. Do you do the supportive care? Do you use dexamethasone if your institutional guideline says so, but do not save tocilizumab for later uses?

Do remember that after tocilizumab use, CRP is no longer accurate. We want to be checking for the serum ferritin level as well as procalcitonin as an adjunctive biomarker.

II-A. Tocilizumab Prophylaxis for CRS Management in MM

Next in chain of thoughts, if we know when it is going to happen and if we have a treatment for it, why do not we prevent it from happening altogether? Everybody agrees. More and more data are coming out on the tocilizumab prophylaxis.

How it is done is that it is given at a single dose of eight milligrams per kilogram, one hour prior to the first dose of bispecifics, and some people use it twice according to the step-up dose.

Studies have repetitively shown that it does decrease the risk of CRS significantly, especially the high risk without, again, importantly, not compromising the risk of anti-tumor efficacy. If you are considering an outpatient administration, this is the way to go.

II-A. ICANS management

I am not going to go through the ICANS management in the interest of time. The key takeaway here is that for ICANS management, you need steroids. So do use steroids for ICANS management.

Agenda – Continuing BsAbs: infection prophylaxis and management

Moving on to the next hot topic, which is the infections.

II-B. Do BsAb Increase the Risk of Infection in Patients With MM?

We have to realize that multiple myeloma patients, especially in their refractory/relapsed setting are already at a high-risk for infection because of the disease itself and the prior lines of therapy.

When we are putting these patients on bispecifics, we are basically inserting more stress on them because now we are tampering with T cells as well as B cells on top of neutropenia, because bispecifics do cause cytopenias.

II-B. Infection Profiles During BsAb Use

How do infections during bispecific use look like? First events usually happen during the first three months. Because bispecifics right now are designed to give until progression, the cumulative incidence does not plateau, but rather rises over time. We want to keep a vigilant eye on our patients for infection all the way through, especially if you are using BCMA agents because of the target effect.

BCMA agents are associated with higher risk of infection compared to GPRC5D infections. The most common clinical syndrome usually are in the lower respiratory tract, as pneumonias. Pathogen-wise, bacterial infections are the most common but closely followed by viral infections.

We do not want to forget about the opportunistic infection either. We want to be mindful of the fungal infections as well as the PCP and CMV, which I am going to talk about later on.

II-B. Infection Monitoring & Prophylaxis

I have shown that about 80% of the patients do have infections, and up to 40% or half of the patients who get infections have serious infections. Fortunately, I believe that if we do prophylaxis, these serious infections are preventable in some ways.

The first way to do that is we want to vaccinate all our patients before the start of the therapy, whenever possible. The second thing is that we want to keep an eye out for the red flag signs, a new cough, new dyspnea, new fever, and obviously the recurrent sinusitis and pulmonary infections.

II-B. Infection Monitoring & Prophylaxis: Current Guideline

Sufficient antimicrobial prophylaxis is also very important. The current guidelines suggest that we do antiviral prophylaxis for all our patients all the way through, as well as the PCP prophylaxis all the way through for all our patients.

If the patient is suffering from or has recurrent cytopenias for a prolonged time, we want to be mindful and we might want to consider antibacterial and antifungal agents as well. If you are practicing an endemic area like myself, we want to be mindful of the HPV reactivation. You want to be checking for HPV titer at least every 12 weeks, if possible.

II-B. IVIG: When & Why?

We have been talking about IVIG for quite a bit, so I am not going to go into details. I want to echo Dr. Weisel’s point that IVIG replacement does work. It is one of the most important thing we can do to decrease the risk of severe infections in our multiple myeloma patients undergoing bispecific therapies.

II-B. IVIG: How?

The question is how are we going to do this IVIG replacement therapy? There are three strategies we can use. One is the reactive use, which is using it after the infection has already occurred to prevent from happening again.

We realized that this is not nearly good enough. Most centers offer pre-emptive use which is using IVIG replacements according to the IgG level. We check IgG level every four weeks or monthly. Then if it falls below 400, then we give IVIG. I believe this is the most prevalent method we are using.

Some SIT or some protocols call for primary prophylaxis now which is using IVIG regardless. I do realize that IVIGs are very important and shortage of IVIG does happen. Between the primary prophylaxis and pre-emptive use, you might want to stratify or adopt according to your regional constraints as well as the risk of the patient sitting in front of you.

If you are giving IVIG, we usually do 400 milligrams per kg every four weeks beginning at cycle two, because cycle one is usually the step-up dosing.

II-B. Infection Management

What do we do when infection actually does happen? We have to do an immediate workup and a thorough workup. We want to be holding the myeloma therapy until the problem has been pinpointed and we have solved the problem.

The key takeaway here is that you want to be holding the myeloma therapy during the serious infection treatment. We want to make sure that patients are safe before we start the drug again.

II-B. CMV

I want to take this opportunity because CMV is emerging more and more. I want to take this opportunity to go through the CMV terminology, because I feel that right now CMV infection, the term is being used in quite a desultory manner, should I say.

CMV reactivation and CMV disease is quite simple. CMV reactivation is the detection of CMV DNA viral component in the blood or another site in the seropositive patients. CMV disease is a CMV syndrome or an organ disease, proven end-organ disease. These are simple.

The problem rises in the clinically significant CMV infection. What this is, is that it is a DNA titer reaching the threshold for pre-emptive treatment. The problem is that we do not have an agreement on that threshold for pre-emptive treatment for the bispecific users. We can only draw from our BMT experience, which calls for the pre-emptive treatment at the titer of 500 or above.

I come from an endemic area. What we do is that we check for CMV titer every four weeks, and the threshold for our trigger is a single count of 1000 or higher, or two consecutive counts of 500 or higher. We need to work towards an agreement on the threshold for this pre-emptive treatment. We want to be very careful when you are looking at the CMV data.

Agenda: Class-Specific Toxicities

Next or the last on the agenda is the class-specific toxicities. Here, I am going to be talking about talquetamab or GPRC5D-related problems.

III. GPRC5D: Oral Toxicity

Most of these problems are on-target/off-tumor effects. The most common is the oral toxicity. The severity depends on the patient. There is a wide spectrum of severity. Oral toxicity does happen in GPRC5D users in about 80% of the patients. This can be very debilitating if it develops into dysphagia and people experience weight loss because they cannot taste anything, they do not want to eat anything, and they feel very painful when they are eating something.

I wish I could stand here and tell you I found a miraculous way to overcome this, but I really do not. For TALISMAN trial, we could try something like gabapentin or dexamethasone, oral gargles and stuff like that. The main practical management right now is supportive care, so hydrate and find something like celeries usually work. Find watery substances that work for that particular patient.

I do not really have a good method to overcome this. If it does happen, find a way to get around it. If it becomes a severe problem, stop talquetamab for a while until the problem has been solved.

III. GPRC5D: Skin/Nail Toxicity

The second most common problem is skin and nail toxicity. This also happens in about 60% of the patients. This is also an on-target/off-tumor effect. The severity here again differs.

Management, again, I do not have a very good method except for use of topical corticosteroids and escalate emollients, if you should. When something above grade 3 happens, you might want to consider stopping the drug until the problem has been resolved.

III. GPRC5D : Neurologic Toxicity

Last but not least is the neurotoxicity problem. This neurotoxicity problem is a bit different from the conventional ICANS we are talking about. This happens after the risk of ICANS has passed and usually in a state where the disease is controlled very well.

We do not have a very good idea as to why this happens, the exact pathophysiology behind it. Our assumption is that because there are some GPRC5D protein expression in the cerebellar area, these neurotoxicity presents as like RSC syndrome. People do not talk right and they cannot walk straight. Romberg sign is positive.

I guess there are no ways to prevent it. The key thing is that we want to be very vigilant with our patients. We want to talk to our patients. We want to examine our patients. If the patient is saying that he or she is experiencing new onset of headache or dizziness, we want to be very careful and do a thorough neurologic exam to see if this is going to develop into a more serious problem.

We want to be stopping the drug if something like this happens. If it develops into something more serious, this is something we do not want to restart the drug. Neurologic toxicity does happen, albeit being in a very small amount of patients. If something like this happens, this is a sign that you do not want to start the GPRC5D agents again.

Posttest 3

With that, I would go on to the posttest. Which of the following adverse events occurs more frequently with GPRC5D-targeted therapy compared with the BCMA agents?

1. Infection;
2. CRS;
3. Cough; and
4. Skin-related or nail-related events.

Please vote.

Yes. The answer is D.

Posttest 3: Rationale

We have been talking about GPRC5D-related problems. I am not saying that BCMA just do not cause any skin-related problems, but it is more predominant in the GPRC5D agents.

Posttest 4

The next question is, this patient had a multiple myeloma during using a bispecific. 17 hours after his first full dose, he develops grade 2 CRS with hypotension, unresponsive to fluids. What will you do next? Please vote.

Yes, you got this right. Do not be stingy with tocilizumab when you are using bispecifics for multiple myeloma.

Take-Home Clinical Pearls

This is my last slide, take-home clinical pearls:

• Treat CRS early even in grade 1;
• Do not trust CRP after tocilizumab. Use procalcitonin and ferritin as an adjunctive marker;
• Monitor IgG levels and consider using pre-emptive treatment or pre-emptive replacement of IVIG at level of IgG at 400 or below;
• Layer infection prophylaxis from the start. Be mindful of all the things that can happen at the beginning and throughout the treatment; and
• Be aware of the GPRC5D signatures, the oral skin and nail and sometimes neurotoxicity.

With that, I thank you for your attention. I will give it back to Dr. Jens.

A Final Poll

Dr. Hillengass: Okay. Thank you so much. Great talk. Very relevant. We come to the final questions of our polling.

Poll 3

Do you plan to make any changes in your clinical practice based on what you learned in today's program? We will have questions after this, but please vote first.

Okay. We did our job. You could learn something today. I learned something today. I will not tell you what it was, but thank you so much.

Poll 4

Yes, there is still a polling that you can do also for CME purposes.

Q&A

There are already a few questions, but I would like to reward the people who are in the room. If you have any questions, please feel free to come to the microphones. One question that came up and I will hopefully be able to direct it to my colleagues here.

One question that came up was we have so many different bispecifics now approved. What is your first choice? What is your second choice? And if you have an idea why? You are smiling, Ja Min. Any thoughts?

Dr. Byun: Whatever is available in your country I guess.

Dr. Hillengass: Great answer. Yes. Any other? Katja, do you have? I do not know what is available in Germany right now. Everything.

Dr. Weisel: Everything.

Dr. Hillengass: Good problem to have, right?

Dr. Weisel: First of all, we have to stick to the label. Absolutely. Then it is a matter of normally patients are doing still the step-up in patients. It is a matter of managing the step-up, how long have patients to stay, what are the resources?

For sure patients normally continue also in private oncology practice outside. It is a matter of them interacting with the treating physician and choosing this.

We have, I think a few data, Philippe mentioned that, with bispecifics now also coming or already there with low affinity, CD3 binding which might have a lower toxicity. We have to carefully watch on this. This might again be something influencing the choice.

Dr. Hillengass: Philippe, if you had access to every single bite in every single setting, do you have any preference or do we still have to wait for more data?

Dr. Moreau: A very important question is if you have the choice, are you going to select the GPRC5D bispecific antibody or a BCMA? Honestly, the efficacy is rather identical. When you are looking at the response rate, that is 65% with BCMA, 70% based on the MonumenTAL study with talquetamab.

The safety profile is totally different. I believe that a lot of us are preferring BCMA bispecific antibodies instead of talquetamab. This is my feeling, although we know that we have to be very careful with the infection, and Ja Min and all of us discussed this important point.

Dr. Hillengass: Microphone five, would you mind identifying yourself where you are from?

Speaker: Hi. Liam Burnell from Wake Forest. Very nice presentation. This is a question for the whole panel, but particularly for Philippe. As you see, there is a trend and interest to move bispecific upfront. Then how can we sequence later on CAR T cells if we are moving now by specific upfront? I would like to hear your opinion of all the panel on this.

Dr. Hillengass: Yes, that is a great question that we all struggle with. Maybe because I only ask questions, I answer from my perspective. If you look at this data MRD rates in small cohorts, of course, of almost 100%, that is very intriguing.

What I do think, and it was already brought up, we have to consider treating with bispecific antibodies for limited duration. That will be helpful. In our experience, once patients are in a deep remission for a longer period of time and then can be off treatment, which is also something we have not talked about for the recent past, but now we can because those treatments are so effective, bringing patients in remission.

You might have seen this frontline and this early line trials, oftentimes limited duration. That gives hopefully the body time to recover. The myeloma is gone, hopefully. Then the bispecific antibodies can wash out and the body can recover and then CAR T is good.

I would also like to hear your opinions If you have the choice between CAR T and bispecific, what would you choose first? There is one standard answer, but it is a bit more nuanced than that.

Dr. Byun: If we are starting bispecifics from upfront and that is the way to go. If I had to do a conventional quad therapy, then I would probably use as CAR T-cell first.

Dr. Hillengass: Would you agree?

Dr. Weisel: I agree. Yes, it is the question of being treatment free for the patients. We have curative signals on CAR T. We have to see more data and we are all eager on seeing those trials already completed recruitment. Yes. Currently, yes, CAR T.

Dr. Hillengass: Thank you. We are approaching the end of the session, but there is somewhere in the back. It is a bit dark from here. I Cannot see.

Speaker: You hear me?

Dr. Hillengass: Yeah.

Speaker: Okay. Hi. I have a question. When I check all the trials, there is 30% female, 70% male difference. If you see the cytogenetics, usually the high-risk is about 20% to 30% and standard risk is up to 70% to 80%. In my opinion, should not we treat them a little bit differently because one P53 mutated patient and one standard patient should not be the same, I think.

My other question is shorter, is about the dosage, given every week or every other week. If we look at the belantamab mafodotin, it started with every week, but now it is every three weeks, every four weeks and still working. Maybe we should think about the dosage as well.

Dr. Hillengass: Thank you. Those are great questions. Philippe, any thoughts on the first question maybe?

Dr. Moreau: I think that is true that we are treating all patients the same currently with same schedule, etc.. For patients with high-risk disease, maybe we should treat them differently. We know, for example, in MagnetisMM-3 and MajesTEC, if you are combining, for example, poor cytogenetics and EMD, your response rate is almost 0%.

Probably we should think differently for those patients with high-risk. Perfectly true. For the dosages, well, a lot of us are not waiting for six months or one year to go to the monthly administration. As soon as you are reaching a very good response, since we are treating patients with antibodies with a very long half-life, maybe we can switch to the monthly administration immediately or more quickly for sure.