This transcript was automatically generated from the video recording and may contain inaccuracies, including errors or typographical mistakes.

From Evidence to Action: Expert Strategies for Individualizing CD38-Based Quadruplet Therapy in Transplant-Eligible NDMM

Hello to everyone, and first of all, thank you very much for inviting me to this meeting, in which my talk is going to be based on a background on targeting CD38 in multiple myeloma.

IMWG Criteria for Diagnosis of MM

In this slide, I just have a reminder about the diagnostic criteria for multiple myeloma, and all of you know that it is based on the presence of at least 10% of clonal plasma cells in the bone marrow or any proven bony extramedullary plasmacytoma, but the patient has to present one or more SLiM-CRAB features. Based on this, we can do the diagnosis of multiple myeloma.

Recommended Diagnostic Evaluation for NDMM

But after the diagnosis, here you can see the recommended workup for the correct characterization of the patients with multiple myeloma at the moment of diagnosis. It's important to have, together with the medical history and physical examination, the evaluation of hemogram, biochemistry, all protein studies, and also, very importantly, the bone marrow aspirate, plus or minus biopsy, with flow cytometry, FISH, and next-generation sequencing in order to characterize well the disease, as well as adequate functional imaging techniques for the adequate characterization of the disease.

Risk Stratification in NDMM

This is extremely important because this will allow us to stratify myeloma patients according to risk. Today we know that the risk is not only based on the presence of cytogenetic abnormalities, LDH, circulating tumor cells, or extramedullary disease; we are incorporating also patient-based factors in relation not only with the chronological age, but the frailty and performance status, as well as the organ function and comorbidities. All these factors are going to be clearly relevant.

Let's Begin With a Question

I would like to start with a clinical question, a clinical case.

Pretest 1

This is a 76-year-old man that presents with fatigue, weight loss, and new back pain. Labs show hemoglobin of 9.5 g/dL, serum creatinine of 1.3, serum M-protein 3.8. The bone marrow biopsy confirms 50% of clonal plasma cells, and the diagnosis is myeloma. FISH demonstrated a t(4;14) translocation, and as a comorbidity, the patient has controlled hypertension. The patient is independent in all activities of daily living; performance status is 1. Which would you recommend as the most appropriate?

1. Autologous stem cell transplantation;
2. Doublet therapy such as Len-Dex;
3. Triplet therapy such as DRd or VRd; or
4. Quadruplet regimen such as Dara-VRd or Isa-VRd.

Please vote.

Individualizing Treatment in the Era of Novel Agents

Okay, it is good to see how the majority of you will select a quadruplet for this 76-year-old fit, newly diagnosed myeloma patient, maybe non-eligible for autologous stem cell transplantation. After an adequate stratification, what we usually do in our clinical practice is to distinguish if the patient is transplant-eligible or not transplant-eligible.

How Important Is It to Distinguish Between TE and TIE?

This distinction today does continue being important, especially because we are in the process of defining what is the cure for patients with multiple myeloma. We know that one of the most relevant surrogate markers for the definition of cure is minimal residual disease negativity rate, and we are going to see how, in general, patients eligible for autologous stem cell transplantation will reach higher levels of MRD negativity rate.

Defining Cure in Multiple Myeloma: Potential Surrogate Markers

This is what the International Myeloma Society is going to plan as a cure. This is applicable for both transplant-eligible or transplant-ineligible patients, and it is basically based on the presence of MRD negativity rate sensitivity 10^-6 sustained for at least five years, of course together with a serological complete response and functional imaging negative.

New European Guidelines for Management of MM Patients

These are the European guidelines that we have now for the management of newly diagnosed myeloma patients. If we focus on both transplant-eligible and transplant-ineligible, we can see how anti-CD38 monoclonal antibodies take a part of the first line of therapy regardless of the transplant eligibility. I, personally, consider that the incorporation of the anti-CD38 monoclonal antibodies to the first line of therapy significantly increases the MRD negativity rate, and we are going to see how this will translate into better outcomes. Definitely, this will contribute to achieving the main goal we have in this population: MRD negativity rate, because this is going to be the potential surrogate marker for cure.

Immune-Based Therapy: Targeting CD38

What about the mechanism of action of the drugs we are using now in the first line? We know that CD38 is an optimal target in myeloma, and when we use anti-CD38 monoclonal antibodies, we are going to see a direct antitumor effect derived from the activation of the complement cascades as well as the activation of macrophages, as well as a direct antitumor effect, direct apoptosis. But in addition, we are going to see also an immunomodulatory effect because all immunosuppressive cells present in the bone marrow microenvironment express CD38. We are going to see a depletion of this CD38, and the final result is an enhancement of the immune system that is going to contribute to deepening the responses over time as well as to prolonging the progression-free survival.

2026 Treatment Recommendations for the Treatment of NDMM

These are the guidelines that we see now, and as I previously told you, we are going to distinguish between transplant-eligible and transplant-ineligible. In principle, we are going to see how in the transplant-eligible, the MRD negativity rate we are going to see is higher, but definitely, these combinations are applicable to all patients.

Rationale for IMiD + CD38 mAb Combinations

What is the rationale for combining anti-CD38 with immunomodulatory drugs?

Based on what I previously said, we know that the immunomodulatory drugs are going to enhance the NK cell-mediated antibody-dependent cell cytotoxicity (ADCC). They are going to increase the activity of macrophages, they are going to increase the CD38 expression, and definitely, they are going to enhance the cytotoxicity.

The same is applicable to the proteasome inhibitors – and there is also a synergistic and a good rationale in order to combine proteasome inhibitors with anti-CD38 monoclonal antibodies because of the synergistic activity observed in preclinical studies enhancing the NK cell-mediated ADCC, improving the myeloma cell lysis. This is the rationale, and the final result that we see in the clinic is better efficacy because of these combinations.

Factors Driving Treatment Decisions in MM

Here you can see again factors that can potentially drive treatment decision in multiple myeloma. Of course, we have to evaluate the risk, but we have also to evaluate the frailty of the patients in order to select what is the most appropriate therapy for these patients.

2026 Treatment Recommendations for the Treatment of NDMM

We distinguish in principle between transplant-eligible and transplant-ineligible. Within the transplant-ineligible, the majority of the patients are going to be fit and also eligible for the quadruplets but without autologous stem cell transplantation.

Is There Still a Role for Transplant in the Era of Quadruplets?

Just a practical consideration based on the fact that we know that transplant is very effective in patients with high-risk cytogenetic abnormalities. We see on the right-hand side of the slide the efficacy of the transplant after Dara-VRd across the different subgroups of patients, including the high-risk subgroup of patients. I would recommend you to try to do autologous stem cell transplantation also in the transplant-ineligible population if they present high-risk biology and they are potentially eligible for autologous stem cell transplantation in order to try to overcome the poor risk that these patients with high-risk present, especially if they don't receive autologous stem cell transplantation.

Fit Patients With High-Risk NDMM May Still Benefit From Transplant

The same is applicable for IMROZ and HD7, so this means that the same concept is applicable for Dara-VRd or isatuximab plus VRd.

When Should Transplant Still Be Considered in the Era of Quadruplets?

Other populations in which I, personally, consider that transplant is relevant in order to reach the maximum benefit are patients with suboptimal depth after induction quadruplet. If the patients don't achieve at least VGPR or the minimal residual disease is positive, transplant can be a good rationale in order to improve the quality of the response. Patients maybe with extramedullary disease or bulky disease at diagnosis, we know that this population is also at high risk, and sometimes the use of high-dose melphalan followed by autologous stem cell transplantation can contribute to inducing complete response or optimal responses in these patients. In addition, if we do transplant, it is possible to incorporate, based on PERSEUS, minimal residual disease sustained for at least one year for stopping therapy, and this is going definitely to be very convenient for the patients, and we will be able to evaluate if these patients are potentially cured.

2026 Treatment Recommendations for the Treatment of NDMM

So in the future, and before finishing my presentation, I think that T-cell redirecting therapy will be incorporated into the first line of therapy, so maybe our next discussion will be which patient is eligible for T-cell redirecting therapy, for antibody-drug conjugates, CAR Ts, or bispecific monoclonal antibodies.

Let's Return to Our Question

Before moving to the next speaker, I would like to repeat again the same question.

Posttest 1

Just a reminder, a 76-year-old newly diagnosed myeloma patient with a t(4;14) translocation, and what would be your option?

1. Autologous stem cell transplantation;
2. Doublet therapy;
3. Triplet therapy, or quadruplet regimen as Dara-VRd; or
4. Isa-VRd.

Just also a reminder that t(4;14) translocation alone is not considered a high-risk cytogenetic abnormality. Please, you can vote.

Okay, almost 80% consider a quadruplet as an option, which I consider that it is completely logical to treat this patient with a quadruplet. Thank you very much.

Conclusions

These are the conclusions I finalized just before.

Leveraging Anti-CD38–Based Quadruplets for Personalized Treatment of Transplant-Eligible NDMM

Dr. Philippe Moreau (University Hospital Hotel-Dieu): Good evening, and let's speak now about anti-CD38-based quadruplets for the treatment of transplant-eligible and transplant-ineligible patients as well.

Let's Begin With a Question

Let's start with a question.

Pretest 2

You have in front of you a 62-year-old man with newly diagnosed multiple myeloma. He received induction with a quadruplet combination followed by autologous stem cell transplantation, and at day 100 post-transplant, the bone marrow assessment shows MRD negativity at 10^-5 by NGS. He has tolerated therapy well and asked whether additional treatment is necessary. What is the most appropriate management approach?

1. Discontinue therapy and observe, given MRD negativity 10^-5;
2. Proceed with lenalidomide plus daratumumab maintenance therapy;
3. Omit maintenance and monitor MRD serially;
4. Delay maintenance unless MRD converts to positive.

Please vote.

Okay, so the majority, two-thirds, are proposing Len plus daratumumab maintenance, but some of you are also proposing to stop treatment and observe, given a very good response, MRD negativity, but also some of you are proposing to delay maintenance until MRD converts to positive.

Phase III Trials Comparing Triplet vs Quadruplet Therapy in Transplant-Eligible NDMM

So, let's speak about maintenance, but also, quadruplet combination before autologous stem cell transplantation.

You know that we have now four Phase III trials looking at triplet versus quadruplet therapy in transplant-eligible patients frontline. CASSIOPEIA did compare VTd versus VTd plus daratumumab, PERSEUS VRd versus VRd plus daratumumab. IsKia recently published looked at KRd versus KRd plus isatuximab, and the German GMMG-HD7 study looked at VRd versus VRd plus isatuximab. In fact, across all trials, the quadruplet combination is associated with a higher rate of response, a higher rate of MRD negativity, and a significant improvement in progression-free survival. So, we should try, if possible, to use quad combinations for all patients.

CASSIOPEIA: VTd ± Daratumumab in Transplant-Eligible NDMM

The first study was the CASSIOPEIA study, that did compare VTd both before and after stem cell transplantation versus VTd plus daratumumab in transplant-eligible patients. There was also a second randomization: observation versus Dara maintenance.

CASSIOPEIA: Efficacy by MRD (Flow Cytometry; 10^-5) Before Maintenance

The depth of response before maintenance is in favor of the quad combination, with MRD negativity rates much higher on an intend-to-treat basis with the quad, 64% versus 44% at 10^‑5.

CASSIOPEIA: Updated PFS From First Randomization

This depth of response translated into a better progression-free survival. We do have now a very long follow-up of 18 months, and there is also, at the end of the day, an overall survival benefit when patients are receiving from the very beginning daratumumab in combination with the triple combination VTd.

PERSEUS: D-VRd vs VRd, Confirmation That Targeting of CD38 Benefits Transplant-Eligible Patients

PERSEUS looked at VRd versus VRd plus daratumumab both before and after autologous stem cell transplantation. In the Dara arm of the study, patients did receive a maintenance with two drugs, daratumumab plus lenalidomide, and in the VRd arm, patients did receive Len maintenance single-agent until progression. Interestingly, patients were enrolled up to the age of 70 years, and that's very important for your routine practice.

PERSEUS: PFS and MRD Negativity ≥ CR Rates

The primary endpoint was progression-free survival, and there was a strong benefit of the addition of daratumumab with a hazard ratio of 0.42. So that's a 58% reduction in the risk of death or progression. This four-year PFS of 84% in the Dara arm of the study is the best ever reported, in fact, in a Phase III study for transplant-eligible patients.

MRD negativity was also increased significantly, 10^-5, but also 10^-6 with the addition of daratumumab.

PERSEUS: Subgroup Analysis of PFS Based on Revised Cytogenetic Risk Status

Nevertheless, when we are focusing on patients with high-risk disease, poor cytogenetics at the time of diagnosis, we cannot overcome the poor prognosis of this population of patients. You see that there is a significant difference for Dara-VRd standard risk versus Dara-VRd high-risk. So this patient population is remaining a very difficult to treat one, despite the use of a quad combination.

PERSEUS: PFS by Sustained MRD Negativity ≥ CR Status

Interestingly, we have a higher rate of sustained MRD negativity at one year, but also at two years. The number of patients who are reaching this sustained MRD negativity during two years is much higher with Dara-VRd. You see that the progression-free survival is really amazing for those patients, above 95%.

PERSEUS: Significantly Longer Projected PFS With DVRd TE NDMM

We can try to predict what will be the estimated median PFS with a mathematical model that is accepted by the authorities, and especially the NICE in the UK. You see that Dara-VRd will be probably associated with a median PFS of 17 years. That is really very impressive, for sure.

GMMG-HD7: Isa-VRd vs VRd for Transplant-Eligible NDMM (Part 1)

The German study looked at VRd versus VRd plus isatuximab, a Phase III study, and the progression-free survival is also in favor of the quad combination.

GMMG-HD7: First Primary Endpoint, End of Induction MRD Negativity by NGF (10-5 ), Was Met in ITT Analysis

The primary endpoint of the study was MRD negativity, 10^-5, after induction prior to high-dose therapy. The study met its primary endpoint with a significant benefit in favor of the quad combination, as you can see on the slide.

Secondary Endpoint of Part 1: PFS From First Randomization

The PFS from the first randomization was highly improved as well, with a hazard ratio of 0.7. So we have two consecutive studies that did enroll patients up to the age of 70 years, as well for the German group, showing a significant benefit for PFS with the quad combination.

Phase III Trials Triplet vs Quadruplet TE

Just to summarize, MRD negativity rates are much higher with quads. PFS is significantly improved. Sustained MRD negativity rates are high, and this also improves progression-free survival. We have only one study, the one with the longest follow-up, CASSIOPEIA, that is showing an OS benefit, and there was really no safety issue when we are adding a CD38 antibody to a triplet, and quad combos are now standard of care. Marie-Louise showed you the European guidelines that are now proposing, in fact, quads systematically if possible.

IMPORTANT ISSUES

We nevertheless have some important issues. What is the optimal maintenance?

The First Phase III Study Evaluating Isa + RVd for Induction and Maintenance in TE NDMM Patients

You know, lenalidomide was considered a standard of care, but the German study is currently comparing in a randomized fashion Len versus Len plus isatuximab, and we are awaiting those results probably by the end of this year.

PERSEUS: D-VRd vs VRd, Confirmation That Targeting of CD38 Benefits Transplant-Eligible Patients

We know already that in the PERSEUS study, Len plus Dara was proposed in the Dara arm, and Len until progression in the VRd alone arm. When patients had sustained MRD negativity during one year, it was possible to stop daratumumab after two years of maintenance. Definitely, this is a very important proposal. You know that PERSEUS is now approved by the European authorities, and we must try systematically to implement MRD during maintenance in order to stop daratumumab. That was possible in the study in more than 75% of the patients. When we are looking at MRD negativity rates during maintenance with Len-Dara, definitely, the rates are increasing over time, showing the benefit of these two agents.

IMPORTANT ISSUES

Can we propose an MRD-adapted strategy?

MIDAS: MRD-Driven Strategy Following Isa-KRd Induction

That's a very important issue now. You know that the French group looked at, into the MIDAS study, a quad induction with Isa-KRd six cycles, and then MRD was systematically assessed. Patients with standard-risk MRD-negative after induction were randomized to receive, yes or no, autologous stem cell transplantation. Those patients with a high-risk disease, patients remaining MRD-positive after six cycles of Isa-KRd, were randomized to autologous stem cell transplantation and to tandem high-dose therapy.

MIDAS: Patients’ Disposition

Interestingly, two-thirds of the patients were MRD-negative after induction, and they were randomized to stem cell transplantation for 242 of them versus no autologous stem cell transplantation upfront. One-third of them were randomized in arm C to single or arm D to a tandem stem cell transplantation.

MIDAS: MRD Negativity

What are the results? At the end of the day, the primary endpoint was MRD negativity 10^-6 before maintenance. Indeed, there is strictly no difference yet in terms of MRD negativity 10^-6 when comparing arm A and arm B with or without single stem cell transplantation. No difference as well when we are comparing single versus tandem stem cell transplantation 10^-6 for patients remaining MRD-positive after induction.

So this is showing that probably in the future, we need obviously to have a longer follow-up and to see the PFS analysis of this important study. But probably in the future, we are going to adapt our treatment according to MRD negativity.

Patients Not Eligible for High-Dose Therapy and Autologous Stem Cell Transplantation

Let's speak briefly now about patients not eligible for autologous stem cell transplantation, patients that are above the age of 70 years.

Patients Not Eligible for High-Dose Therapy and Autologous Stem Cell Transplantation

EHA-ESMO Guidelines 2021

You know that the European guidelines recently published by Thanos Dimopoulos are now proposing as a first option either DRd according to the MAIA schedule or a quadruplet combination with VRd plus a CD38 antibody. When comparing those guidelines 2025 versus those published in 2021, you see that VRd is now downgraded to a sort of second option.

SWOG S0777: VRd Improves Survival vs Rd in NDMM

VRd was one of the standards of care during a long period of time based on the PFS benefit versus Len-Dex.

MAIA: Updated PFS and OS

We know that DRd, the MAIA regimen, was also widely used with a strong PFS but also an overall survival benefit versus Len-dexamethasone.

But now we have studies showing that quadruplet combinations in fit patients are interesting.

IMROZ: VRd ± Isatuximab in Transplant-Ineligible NDMM

The first one was the IMROZ study comparing VRd followed by Len-Dex versus VRd plus isatuximab upfront or followed by isatuximab and Len-Dex. The progression-free survival was the primary endpoint of the study, and patients were enrolled if they were older than 65 years of age.

IMROZ: PFS and MRD Negativity Rate

Indeed, you see that there is a strong PFS benefit with a median follow-up of five years. The control arm, the VRd arm, is a very good one. As you can see, we have a 60-month PFS of 45%, in fact. That is very good for VRd. But if you are adding isatuximab to VRd, definitely you are highly improving MRD negativity rates, as you can see on the right-hand side of the slide, but also significantly progression-free survival with a hazard ratio of 0.6. That is a 40% reduction in the risk of death or progression. Based on this study, Isa-VRd is now approved by the European authorities and can be proposed, in fact, in fit patients.

IMROZ: PFS Subgroup Analyses

The subgroup analysis of PFS into IMROZ is showing that the quad is better than the triplet for all patients with the exception of patients with poor cytogenetics. I would say disappointingly there is no difference in terms of progression-free survival when we are adding isatuximab.

IMROZ: Isa-VRd Improves PFS vs VRd in Both Frail and Non-Frail Patients

We know that a small subgroup of patients were frail in the IMROZ study, and those patients are doing quite well. In fact, their outcome is not strictly superposable to patients non-frail treated with the quadruplet, but it is also feasible to propose Isa-VRd in a subgroup of some frail patients.

CEPHEUS: Study Design

You know that the CEPHEUS study compared as well VRd versus VRd plus daratumumab. Interestingly, this study had a primary endpoint of MRD negativity. This is the first trial looking at MRD negativity as a primary endpoint. The study met its primary endpoint.

CEPHEUS: Primary Endpoint of Overall MRD-Negativity ≥ CR (10–5 and 10–6) Rates and PFS

MRD negativity rates are significantly higher with Dara-VRd versus VRd alone, and this depth of response at 10^-5 but also 10^-6 translated into a significant progression-free survival benefit. You see that the results are quite superposable to those of the IMROZ study. We have now two trials showing that the quad with the CD38 antibody is better than a triplet with a strong PFS benefit.

CEPHEUS TIE Subgroup: Overall and Sustained MRD Negativity ≥ CR Rates

When we are looking at sustained MRD negativity rates in the PERSEUS trial, there is also an improvement, significant improvement at 12 and 24 months, indeed.

BENEFIT: Study Design

The third trial that looked at the quad versus a triplet is the BENEFIT study, an academic trial from the French group that did compare Isa-VRd versus not VRd. The control arm is not VRd. The control arm is Isa-Len-Dex. That's a control arm that is including a CD38 antibody. The primary endpoint of the study—and of note, bortezomib was proposed weekly as we are currently doing in the routine practice. The primary endpoint was MRD negativity at 10^-5 after 18 months.

BENEFIT: Isa-VRd Achieves Higher MRD Negativity Than Isa-Rd

The study met its primary endpoint as well, showing a significant MRD negativity rate in favor of the quad versus Isa-Len-Dex. We are still awaiting the PFS analysis. Probably next year, we will hear for the first time the PFS data of BENEFIT. It means that we have now three trials that are significantly showing that the quad is better than a triplet.

Overview of mPFS in Phase III Trials in Transplant-Ineligible NDMM

This is all the trials that we did in the last 40 years, almost 40 years of treatment for transplant-ineligible patients. You see that now with quadruplet combinations into IMROZ, BENEFIT, and CEPHEUS, we are reaching very long PFS, very high rates of MRD negativity. This is really good for the patients, for sure.

IFM2017-03: Study Design

Nevertheless, we still have a group of patients that are frail. Transplant-ineligible patients is a very heterogeneous patient population.

For frail patients, the French group recently reported a prospective comparison of Len low-dose Dex versus Len plus daratumumab without dexamethasone. The goal was to try to stop dexamethasone very, very quickly in order to reduce the toxicity, especially infection, with the addition of daratumumab in order to increase the efficacy.

IFM2017-03: PFS (Primary Endpoint) and OS

The primary endpoint was progression-free survival. You see that on almost 300 patients, the randomization was 2:1. There is a significant PFS benefit and OS benefit as well. You see the PFS is quite good. Very elderly patient population, frail.

We can adapt the treatment of our patients in our routine practice.

Frontline Therapy NDMM

This is my conclusion, my last slide. Up to 70 years when patients are fit, we should use a quad followed by autologous stem cell transplantation and probably Len plus a CD38 antibody during the maintenance phase. For patients from 70-80 years, when they are fit, a quad combination can be proposed with a significant PFS benefit. For patients above the age of 80 years or frail patients, we can adapt the MAIA regimen with Dara-Len and stopping Dex very, very quickly.

Let's Return to Our Question

Let's return to our question now.

Posttest 2

You remember, a 62-year-old man with standard-risk cytogenetics, induction with a quad followed by stem cell transplantation, and at day 100 post-transplant, the patient is MRD-negative. What are you proposing?

1. Discontinue therapy;
2. Len-Dara maintenance;
3. Omit maintenance and monitor MRD serially; and
4. Delay maintenance unless MRD converts to positive.

The majority of you is now proposing Len-daratumumab maintenance.

And this is, to my opinion, a very good choice. On top of this, if you are able to monitor MRD during maintenance, you will be able to stop daratumumab after sustained MRD negativity during one year.

I thank you for your attention, and the next speaker is Professor Dimopoulos from Athens, Greece.

Maximizing Patient Outcomes With Novel Administration Methods and Strategies for Supportive Care

Dr. Meletios-Athanasios Dimopoulos (Kapodistrian University of Athens): Thank you very much. Despite the tremendous improvements in the outcome of patients with myeloma, we still have to improve the supportive care of the patients because several of the treatments that we use are associated with toxicities, and mitigation of these toxicities or treatment of these toxicities will allow the patients to remain on therapy.

Let's Begin With a question

Let's begin with a question.

Pretest 3

We have a subcutaneous on-body injector, or OBI, for isatuximab, which is being studied to improve the administration of anti-CD38 therapy in myeloma. Which aspect of anti-CD38 therapy is least likely to change with the use of an OBI system versus IV infusion?

1. Premedication to reduce infusion-related reaction;
2. Time required for drug administration;
3. Patient convenience during treatment;
4. Duration of patient monitoring after administration. Which is least likely to change.

Please choose now.

Okay, so an overwhelming majority decided that the premedication to reduce infusion-related reaction will remain the same. I think this is a good choice, and let's move now to the presentation.

On-Body Delivery Injector (OBI) for Subcutaneous Isatuximab Administration

What is this on-body delivery injector, or OBI, for subcutaneous isatuximab administration? We know that isatuximab is as active as daratumumab in the treatment of patients with myeloma, but for many years it had to be given intravenously. So, the development of this innovative technique, which can use this device, which is placed on the abdomen of the patient, has several advantages. There is no need to adjust for body weight. It is essentially a hands-free administration. The needle is so small that you cannot see it or feel it. There is no need for hyaluronidase. The injection volume is about 10 mL, and very importantly, the flow rate is individualized, and it is based according to the subcutaneous interstitial pressure. And of course, there is a potential for home administration.

IRAKLIA: Isatuximab SC On-Body Injector vs IV Administration With Pomalidomide-Dexamethasone in RRMM

Of course, in order to get approval for the OBI administration of isatuximab, there has to be prospective randomized trials, and two of them were conducted by using a standard combination of isatuximab with pomalidomide and dexamethasone, which is one of the most effective regimens. This combination used either IV or subcutaneous isatuximab.

IRAKLIA: Coprimary Endpoint Met—Noninferior ORR With SC OBI vs IV Isatuximab

To make a long story short, there was no difference in the response rate. You can see identical VGPR or better rate.

IRAKLIA: Coprimary PK Endpoint Met—Noninferior C trough With SC OBI vs IV Isatuximab

There was no significant difference in the geometric mean ratio of the drug. So, the distribution was essentially the same.

IRAKLIA: Higher Patient Satisfaction With Isa SC OBI vs IV Isatuximab

Of course, patients were more satisfied with an OBI administration of isatuximab because they did not have to undergo the intravenous administration. It took much less time. They didn't have to receive an intravenous catheter.

IRAKLIA: Lower Infusion Reaction Rates With Isa SC OBI vs IV Isatuximab

And very important, the lower infusion reaction rates with the subcutaneous versus intravenous isatuximab, which can be seen here. Essentially, there is an elimination of the reactions.

IZALCO: Isatuximab SC On-Body Injector vs IV Administration With Carfilzomib-Dexamethasone in RRMM

The other trial is IZALCO, where isatuximab was added to carfilzomib-dexamethasone in relapsed/refractory myeloma. We know this is a very effective, very active regimen in patients with myeloma. In this particular study, isatuximab was given on a randomized fashion, either IV or subcutaneously.

IZALCO: OBI and Manual SC Isatuximab Show Comparable Efficacy and Exposure

Again, we see a similar response rate, high responses, similar responses with the two administrations. So, we expect the OBI administration of isatuximab to be approved for the everyday use of patients with myeloma. This will facilitate those patients who benefit from isatuximab-based combinations.

Supportive Care & Complications

Pretest 4

So, another question is, which supportive care intervention is universally recommended for patients who initiate anti-CD38-based therapy, regardless of individual risk factors?

1. Antibacterial prophylaxis;
2. Antifungal prophylaxis;
3. Antiviral prophylaxis for herpes virus;
4. IVIG replacement therapy;
5. Growth factor support.

You may choose now.

Okay, let's see. Okay, so almost 50% decided that antiviral prophylaxis for herpes virus is universally administered, regardless of individual risk factors. Of course, IVIG replacement can be indicated, especially for patients who have low levels of IgG.

Okay, let's move now to the other supportive measures that are important for the treatment of our patients with myeloma.

Steroids: The Drug We Love and Hate

We know that steroids have been used for many, many years in the treatment of myeloma. And actually, single-agent high-dose dexamethasone is one of the most active treatments for single-agent therapy for myeloma, associated with a response of 40% in previously untreated patients. However, this comes at a cost, not only high-dose dexamethasone, but also the standard weekly dose of dexamethasone, which we have been using for many years. We all know the side effects of long-term exposure of patients to steroids, to dexamethasone. Of course, today, we try to reduce the dose of dexamethasone in older patients, and also reduce the dose after a few courses of steroids. However, still, steroids remain as part of the treatment of the majority of patients with myeloma, and we have to try to mitigate the side effects.

Peripheral Neuropathy

Peripheral neuropathy has been a significant problem in the treatment of patients with myeloma. We remember the very severe peripheral neuropathy associated with the use of thalidomide in myeloma several years ago. We remember the peripheral neuropathy which was associated with intravenous bortezomib, especially when given twice weekly. With the pioneer study of Philippe Moreau, we today administer bortezomib subcutaneously, most of the times weekly outside clinical trials, and we know that we reduce the dose of bortezomib as soon as there is evidence of any degree, any grade of peripheral neuropathy. We will not wait for grade 2 or more. There are other measures that may help the patient to remain on treatment with this useful drug.

VTE Prophylaxis – Risk Stratification

We have to remember that DVT, deep vein thrombosis, is an important complication of patients with myeloma, especially at the time of initial treatment, when many patients suffer from bone pain, they have reduced mobility, and also we know that myeloma is associated with a hypercoagulable state. Today, we have several measures and several scales that we can apply that will help us to decide what type of prophylaxis we will use. For example, for patients at low risk for deep vein thrombosis, we will use aspirin. However, for patients at higher risk, intermediate or higher risk, we will use anticoagulants. DOACs today are very helpful. We don't need to keep the patient on heparin for an extended period of time.

Managing Infection Risk in Multiple Myeloma: Prophylaxis Strategies

Infections. Myeloma, by definition, especially when the patients are symptomatic, is associated with impaired humoral immunity. We know that the patients are at risk for severe infections, catastrophic infections, especially with encapsulated organisms, pneumococcus, Haemophilus, and we apply routine prophylaxis according to the type of the treatment of the patient. We routinely give anti-herpes prophylaxis in the majority of the patients that get treatment.

We also give trimethoprim-sulfamethoxazole to prevent Pneumocystis jirovecii. And of course, today, we use more and more intravenous immunoglobulin or subcutaneous immunoglobulin. We know that this is absolutely recommended as a preemptive therapy for patients who will get treatment with bispecifics, but also even with anti-CD38 or anti-BCMA ADCs, we know that frequently the patients develop low levels of IgG, and this can be mitigated by the administration of immunoglobulins.

Vaccination for Myeloma Patients – IMWG Recommendations

Vaccination is important. We advocate influenza, the inactivated influenza vaccine, preferably with a two-dose series of high-dose influenza vaccine, regardless of age. We also advocate the inactivated pneumococcal vaccine. We have now the pneumococcal 23-valent polysaccharide, which is the one that gives the best protection to the patient. Of course, only inactivated vaccines are given, and after high-dose therapy, we have to repeat the vaccination that the patients have received. Also for RSV, respiratory syncytial virus, we advocate the vaccine, and also for herpes zoster.

Use of Bone-Targeted Agents in Myeloma: IMWG Recommendations

Bone disease has been a significant problem in patients with myeloma. It used to be a very significant problem several years ago when the patients were presenting with more advanced disease and when treatments were less efficacious than today, but still, bone-protecting agents are recommended as a routine administration, especially for patients who receive anti-myeloma therapy. You don't need to have obvious symptomatic or asymptomatic bone lesions. As soon as the patient is started on therapy for myeloma, we should consider either zoledronic acid or denosumab to protect the bones of the patient. Of course, today, we administer denosumab or zoledronic acid on a regular basis for about a year, and then, according to the response of the patient, we can reduce it to every three months.

IMWG Recommendations: Mechanical Approaches

Renal failure, renal impairment is a significant problem of myeloma patients. About 20%, they present with moderate or severe renal impairment. 5%, they present with dialysis requirement. We know that with the very effective therapy we have today, we manage to reverse renal impairment in more than 50% of the patients. This is more difficult if the patient has received a lot of non-steroidal anti-inflammatory drugs because they induce permanent damage of the kidney, and we know that mechanical approaches that used to be investigated a decade ago are not really giving much. The most important thing is to identify these patients and start therapy immediately, and we know that you can administer steroids at a higher dose, proteasome inhibitors, and anti-CD38 without a need for a dose reduction.

Conclusions

To conclude, we have tremendous advantages in the therapy of patients with myeloma. In parallel, we have to think of the supportive care because this way we can improve the quality of the life of our patients, and also we will allow the patient to remain on effective therapy, avoid dose reductions, and the delay of therapies.

Let's Return to Our Question

Let's now return to our question.

Posttest 3

Already, for the subcutaneous administration of isatuximab, we have these options that you have seen before. So, please, again, select the most appropriate answer.

Okay, so already the majority had responded correctly, and there is an increase to almost 80%.

Let's go to the next question.

Posttest 4

Which supportive intervention is universally recommended for patients initiating anti-CD38-based therapy, regardless of individual risk factors?

1. Antibacterial;
2. Antifungal;
3. Antiviral for herpes virus;
4. IVIG replacement therapy;
5. G-CSF.

Please choose now.

Okay, let's see. Antiviral prophylaxis for herpes virus, from 44%, it was increased to 67%. I believe this is the correct answer.

We can see that.

Roundtable Discussion Points

And now there are several points that we can discuss. There may be several questions. We have a few minutes left. So, maybe I can start with Maria-Victoria. For example, for VTE prophylaxis, do you prefer DOAC versus heparin? You start with heparin, and then you switch to DOAC, or from the beginning?

Dr. Mateos: So, basically, in the clinical practice, and basically in terms of approvals in our country, we feel comfortable starting with heparin, low molecular weight heparin, during the first cycles, and once the patient has responded, unless very high-risk factors are present, we move to aspirin.

Dr. Dimopoulos: Okay, that makes sense. Philippe, we know today that we're using IVIG or subcutaneous immunoglobulins more liberally than in the past, and of course, the recommendation for bispecifics is to start from the beginning. For patients who are not receiving bispecifics, let's say the majority of patients who are on anti-CD38, or some patients who receive belantamab-based combinations, what is your policy regarding replacement of IgG?

Dr. Moreau: Yeah, that's a very good question, Thanos, and indeed, it's obvious that when we are using bispecific antibodies targeting BCMA, and not GPRC5D, but BCMA, we should systematically use IVIG replacement. This is what we are doing from the very beginning in order to reduce the rate of grade 3 and 4 infection. Outside the use of bispecific antibodies, to be honest, I'm not using so much IVIG replacement, mostly in elderly patients in the relapsed setting when they are experiencing at least one or two severe infections per year, and then during the summer, during the wintertime, I'm using IVIG. I'm checking the IgG level, but that's for a very small subgroup of patients, for sure.

And one question for you, Thanos, because we did receive questions from the audience that's totally different from the supportive care discussion. Are you, in your routine practice, using MRD to discuss, to select, to adapt the treatment of patients? And one question was related to transplant-eligible patients. Are you, for example, deferring stem cell transplant for patients that are MRD-negative after induction already? And the same question for Maria-Victoria subsequently.

Dr. Dimopoulos: Yes, thank you. So no, we advocate high-dose therapy for everybody, but we use MRD to support patients who sometimes are hesitant. For example, if we have a patient that is MRD-positive after induction, as Maria-Victoria presented, I mean, if you have residual disease, either at the molecular level or at the measurable level, this is, in my mind, an even stronger indication for high-dose therapy. So we use this argument to try, quote-unquote, to convince or to present to the patient the benefits of high-dose therapy.

Dr. Mateos: And just to complement what Thanos said, of course, we continue offering autologous stem cell transplantation to all transplant-eligible patients, regardless of the minimal residual disease. Well, you are one of the investigators of the MIDAS study, and definitely I think that in the future, risk and response can potentially guide autologous stem cell transplantation, but not yet. In clinical practice, to complement what Thanos said, sometimes, if the patient is MRD-negative after induction, we give a transplant to the patient, thus continue, of course, in MRD-negative. Sometimes we skip consolidation, and we go directly to maintenance based on this situation. So this is basically it.

In terms of practicability, we know that the duration of maintenance therapy is going to be adapted to the minimal residual disease negativity. And I think that we will use it more and more in the future.