Combating Myeloma: Improving Access and Outcomes With CAR T-Cell and Bispecific Antibody Therapies in Veterans With Relapsed/Refractory Multiple Myeloma

While patients are living longer, doing better, and patients are having increasing numbers of lines of therapy, unfortunately, we still get to the place for the vast majority of patients that they have refractory disease. And this diagram depicts the typical or a schematic of what we would envision a course of myeloma to be with differing durations of this.

We still do stratify patients based on their transplant eligibility, although this is not necessarily meaning that they would all have transplants. And there is certainly some variability in how one might make that distinction. But the difference really is, do we consolidate with stem cell transplantation or do we do continuous therapy at this point in time?

But generally speaking, for the vast majority of patients, they will have recurrent disease 1, 2, 3, 4, or more times following their initial response to treatment. And we know that with each increasing line of therapy, there is attrition and patients not necessarily moving on to the next line of therapy due to comorbidities and toxicities.

[00:09:47]

Patients With Triple-Refractory MM: Treatment Outcome

Patients who are triple-class refractory, which would be IMiDs, proteasome inhibitors, and monoclonal antibodies, such as the anti-CD38 antibodies, have an unfortunately pretty poor prognosis.

Now, this is older data that was published 5 years ago, published before the therapies we are going to talk about today. But you can see that patients, their time to becoming triple-class refractory, at least antedating these therapies and many that we already have, then half of them are triple-class refractory historically before 4 years of time. And with high-risk genetics and becoming triple-class refractory, the overall survival drops off dramatically for patients. And their survival, based on response rate, for patients who are triple-class refractory, you have less than a partial remission, do particularly poorly as far as progression-free survival.

[00:10:44]

LocoMMotion Trial of Real-life Current SoC: Outcomes in All Patients With Triple-Class Exposed MM

This is data that was published about 4 years ago by Maria Mateos, looking at the LocoMMotion trial and current standard-of-care therapy in patients who have been triple-class exposed. And you can see using standard-of-care treatments, which would be our IMiDs, our proteasome inhibitors, and our monoclonal antibodies, that once patients have been triple-class exposed, their median progression-free survival is only about 4 and a half months, and their median overall survival was only about 12 months historically. I am pleased to tell you that the data we are going to go through today is significantly better than that, but just for historical reference.

[00:11:27]

LocoMMotion Trial of Real-life Current SoC: Survival by Response in Triple-Class Exposed MM

When patients, again, like we saw previously, those who have less than a very good partial remission, in the other case partial remission, do much worse than patients who achieve at least a 90% reduction, both in the duration of their remission and in their overall survival.

[00:11:45]

Immunotherapy Era in Multiple Myeloma

What we have, though, really is an era of new treatments. And these are summarized here on this picture, at least some of them, the ones we will talk about today, of immunotherapeutic agents targeting or involving cell surface markers on the myeloma cells, in particular BCMA, which stands for B-cell maturation antigen, as well as GPRC5D, which is also an antigen that is on the surface of plasma cells.

We can engage these antigens in 3 different ways currently. One is via an antibody–drug conjugate, which you can see here at the bottom of the slide, where that is an antibody that has a toxin associated with it that then binds to the myeloma plasma cells. The toxin gets taken into the cell and kills the cell directly.

There is also the ability of that to bind to immune cells, NK cells, and monocytes that also can direct cell-directed therapy. The only antibody–drug conjugate we have currently is belantamab mafodotin, which was reintroduced or re-approved by the FDA this fall.

We have 2 other T‑cell engager types of therapies, those being CAR T-cells. We have 2 of those, idecabtagene and ciltacabtagene. And we currently have actually 4 T-cell engagers in the form of bispecific antibodies, 3 of which target BCMA, teclistamab, elranatamab, and linvoseltamab, and one which targets GPRC5D, talquetamab. And we will talk about these further as we go forward.

[00:13:33]

CAR T-Cell Therapies in R/R MM

So what is our data on CAR T-cell therapy?

[00:13:38]

Holding Therapy, Bridging Therapy, and Lymphodepletion Chemotherapy in MM

So this is a nice schematic to think about how best to manage patients. And we have really learned more and more about this over time. And there is this new description from the International Myeloma Working Group of things holding therapy and bridging therapy before we give CAR T-cell therapy. The concept behind holding therapy is to gain control of the disease before we collect the cells without jeopardizing our ability to do so. Now, this therapy is not standardized at this point in time, but typically includes our known available agents, proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies.

We try to avoid things that are going to impact T-cells, so alkylator agents, polychemotherapy in the form of infusional regimens, and T-cell engagers there. But we want to make sure that we have enough control of our myeloma that we can get them to that apheresis. Once we collect those stem cells and they are being manufactured, then we really want to, via bridging therapy, achieve a deep response.

Because what we increasingly have learned is the deeper the response, the less the toxicity from the CAR T-cell infusion. And so this is a time frame when we can use alternative T-cell engagers, namely those that target different antigens, such as talquetamab targeting GPRC5D in this case of myeloma, prior to a CAR T-cell therapy. And then when we do CAR T-cells, we do give lymphodepletion to reduce the number of lymphocytes within the patient to help modulate the cytokine milieu, and in so doing, reduce the risk of toxicity.

Typically, this is fludarabine cyclophosphamide. So there is some limitation with decreased renal function and the ability to give fludarabine, certainly for a creatinine clearance less than 30. There is limited data using bendamustine in this situation.

[00:15:44]

CAR T-Cell Therapy

So how are CAR T-cells made? CAR T-cells are made by collecting, via apheresis, T-cells from a patient. So typically, this involves placement of an apheresis catheter and then a leukapheresis machine to collect the T-cells.

They are then shipped off to the lab to manufacture them. And the current strategies use viral vectors to introduce the DNA to express an antigen on the surface. Currently, the only commercially available ones are BCMA, followed by a signaling domain that triggers the activity of that T-cell once it is engaged.

Once those cells are manufactured, which usually takes about 5-6 weeks to get those cells back, they then are returned. Lymphodepleting chemotherapy is given, and the cells are re-infused back into the patient, leading to targeting of the myeloma cells and some of the side effects we will talk about in subsequent slides.

[00:16:48]

FDA-Approved Autologous CAR T-Cell Therapies for R/R MM

As I said, we have 2 FDA-approved CAR T-cell therapies for relapsed/refractory myeloma: idecabtagene and ciltacabtagene.

They differ slightly in that ciltacabtagene has 2 BCMA-binding domains, whereas idecabtagene has one. There is work going on looking at the costimulatory domains, but these both have the same. They get lymphodepleting chemotherapy and reinfused, and these are the reported median times to receiving them back. So, 32 days and 35 days. We generally estimate 35-42 for our—just to allow ourselves a little window of time.

When they were initially approved, they were approved based on the KarMMa and CARTITUDE‑1 trials, both of which we will go through, but enrolled patients who had had at least 4 prior lines of therapy, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

Based on the KarMMa-3 and the CARTITUDE-4 trials, expanded indications were granted in April of 2024, such that idecabtagene, based on the KarMMa-3 trial, could be given after 2 or more prior lines of therapy, and ciltacabtagene after 1 prior therapy, as long as patients were refractory to lenalidomide in that setting.

[00:18:12]

CARTITUDE-4: Cilta-cel vs SoC in Lenalidomide-Refractory MM

So the CARTITUDE-4 trial looked at ciltacabtagene, as I said, in patients who had had at least 1 prior line of therapy, so this was 1 to 3 prior lines of therapy, and were refractory to lenalidomide, which is why that is what the label from the FDA is. Patients were either randomized to receiving ciltacabtagene or to what was considered to be standard-of-care therapy at the physician's choice of either pomalidomide, bortezomib, dexamethasone or daratumumab, pomalidomide, dexamethasone and treated until progression. And the primary endpoint was looking at progression-free survival.

[00:18:53]

CARTITUDE-4 (Update): PFS and OS After 34 Mo of Follow-up

This is the data that after almost 3 years of follow-up, and what you can see is the group that received ciltacabtagene, in the blue line, had a 60% progression-free survival at 2 and a half years of follow-up vs only about 25% of those receiving standard-of-care therapy. And there was an improvement in overall survival, or a 45% reduction in the risk of dying, for patients who received CAR T-cell therapy vs those who received standard-of-care therapy. So pretty significant improvements, and certainly in patients with recurrent disease.

[00:19:35]

CARTITUDE-4 vs CARTITUDE-1 Phase Ib/II Trial of Cilta-Cel: PFS and OS in As-Treated Patient Population

If one looks at this based on just the intent-to-treat and compares this between the CARTITUDE-1 trial, which was patients who had at least 4 prior lines of therapy, you can see that patients do better if they are treated earlier on. So their 30-month progression-free survival after 4 or more prior lines of therapy was 54% vs, in the CARTITUDE-4 trial, 68%. And the overall survival on the right-hand side of the slide was also significantly better at 84% vs 68%.

[00:20:13]

CARTITUDE-4 (Patients With Functional High-Risk MM): PFS, Response, and MRD Negativity

So to have functional high-risk disease, which is defined as based on genetics, based on early relapse, you can see that these patients still do better with CAR T-cell therapy, the blue lines, than with the standard-of-care, but perhaps not as good as the population as a whole. Also impressively, almost 2-thirds of these patients, 63%, became MRD-negative if they received ciltacabtagene after 1 prior line of therapy. And even those that had functional high-risk disease also achieved an MRD-negative rate of about 65% after 1 prior line of therapy.

[00:21:00]

CARTITUDE-4: PFS and CRS/Neurotoxicity

Concerns with CAR T-cell therapy are the 2 side effects that are characteristic of T-cell therapy, namely cytokine release syndrome and neurologic side effects, both ICANS and non-ICANS, neurologic toxicity. And I will draw your attention to the left-hand side of the slide. For patients with high-risk and standard-risk disease, that you can see the median progression-free survival on the left-hand side of the slide for patients receiving these different therapies, high-risk receiving ciltacabtagene is the blue circles, with standard-risk being the blue triangles, again, doing better than those receiving standard-of-care therapy.

On the right-hand side of the slide, you can see the incidence of side effects. So CRS is quite common. 76% of patients receiving CAR T-cell therapy developed CRS, but the majority of these were grade 1 or 2, with only 1% of them being grade 3 or 4. Grade 1 or 2, grade 1 is fever alone, grade 2 is fever with either lower blood pressure or the need for nasal cannula oxygen. It is the grade 3 and 4 that are more likely to land in an intensive care unit.

And neurologic side effects were more common in the CAR T-cell population than in the standard-of-care, with about 5% developing ICANS, which is immune cell-associated neurologic syndrome. But more recently, what has been recognized are these cranial nerve palsies, the Parkinsonism types of findings, and peripheral neuropathies that have occurred that are not considered ICANS, but non-ICANS neurologic side effects that occur in about 10-15% of patients that you can see summarized here in the CARTITUDE-4 study.

[00:23:02]

CARTITUDE-4: Safety Update

This data was updated about a year ago at the International Myeloma Workshop. And again, seeing here are infections of all grades, about 64% in ciltacabtagene and 76% in standard-of-care, so not significantly different. Patients with myeloma do have a higher risk of infections across the board.

You can see the risk of second primary malignancies on the right-hand side of the slide. Again, these are pretty heavily pretreated patients that you can see here, but there have been some lymphomas, peripheral T-cell lymphoma, in 2 patients receiving ciltacabtagene on this trial. Notably, there were no new cases of neurologic side effects reported.

[00:23:52]

CARTITUDE-1 Phase Ib/II Trial of Cilta-cel in R/R MM: Long-term Survival Outcomes (≥5 Years)

What I think many of you may have seen but was really impressive this summer is the 5-year follow-up from the CARTITUDE-1 study.

So this is, again, patients who have had at least 4 prior lines of therapy. And you can see on the right-hand side of the slide, a third of these patients are still progression-free on no therapy 5 years after receiving their ciltacabtagene, and a median overall survival of 5 years. This is a population that really did not have therapeutic options available, and this group, a third of them, are doing very, very well at this point in time.

And certainly, if you have patients who have had CAR T-cells, many of them feel so much better off all therapy and are very thankful for this interval of time off treatment.

[00:24:40]

Phase III CARTITUDE-5 and CARTITUDE-6 Trials

There are many ongoing studies, but two I will draw your attention to are CARTITUDE-5 and CARTITUDE-6. CARTITUDE-5 looks at a population of transplant-not-considered or not necessarily transplant-ineligible but not being planned for transplant. These are newly diagnosed patients who received 3-drug therapy with bortezomib, lenalidomide, dexamethasone, and then randomized to maintenance or to ciltacabtagene as a part of their initial therapy. And then the CARTITUDE-6 trial looks at the quadruplet daratumumab VRd and randomizes to stem cell transplantation or to CAR T-cell therapy as part of their initial treatment. This trial is fully accrued at this point in time, and are waiting for outcomes and data on that.

[00:25:34]

KarMMa-3: Trial Design and Baseline Characteristics

Idecabtagene. So idecabtagene, this is the KarMMa-3 trial. This looked at, just like CARTITUDE‑4, looked at a population of patients with prior therapy, and were randomized either to CAR T-cell therapy or to investigator's choice standard of care. And this trial included more options, but 3-drug combinations for the vast majority of them at the investigator's choice.

This trial required 2 to 4 prior lines of therapy, hence why the indication from the FDA was patients had to have had 2 prior lines of therapy to receive idecabtagene. And what you can see on the right-hand side of the slide is they were fairly balanced groups. Median age of 63. The tumor burdens were comparable. The genetic risk status was fairly similar between the 2, but a quarter of the patients in each of the arms had, quote-unquote, ultra-high risk, which is at least 2 or more of the prior high-risk genetic features. Two-thirds were triple-class refractory.

[00:26:38]

KarMMa-3: PFS and Response

And what was seen here, again, the idecabtagene arm was superior to the standard-of-care arm, with a median progression-free survival of about 14 months vs 4 and a half months for those receiving standard-of-care therapy, and a higher overall response rate and a higher duration of remission for those receiving CAR T-cell therapy in this trial.

[00:27:02]

KarMMa-3: OS

This trial did allow crossover from the patients in the standard-of-care arm to the idecabtagene arm at the time of progression. And so what you can see on the left-hand side is the overall survival curve based on the intent-to-treat population. And so the survival curves cross at about 18 months. But if you analyze it, adjusting for that crossover, you can see superiority or a trend towards superiority for idecabtagene vs standard of care. The confidence intervals for the hazard ratio cross, so not statistically significant or does not meet the criteria for true statistical significance. And note that over half the patients did cross over to idecabtagene when allowed to do so.

[00:27:52]

Other Novel CAR T-Cell Approaches

So those are our 2 approved CAR T-cell therapies. But there are some really exciting novel CAR T-cell approaches in development.

[00:28:00]

Anitocabtagene Autoleucel

The first I will draw your attention to is anitocabtagene. So this is another BCMA-targeted CAR T-cell, which is constructed differently. You can see here, the purple squiggles are the BCMA-binding sites. But it also has a small D domain. And so, it allows it to be more compact with higher transduction efficiency of the cells and a faster on, faster off, which is proposed to be the mechanism for lower CRS and lower toxicity.

In the Phase I study of relapsed/refractory disease, there was a 100% overall response rate. And at 2 years, 56% of those patients were progression-free.

[00:28:48]

Phase II iMMagine-1 Trial of Anito-cel in R/R MM: Preliminary Efficacy and Safety Results

This is data from the iMMagine-1 trial, looking at this again in relapsed/refractory, just showing it to you graphically. At 2 and a half years of follow-up, the median progression-free survival was 2 and a half years at a little more than 3 years of follow-up for patients receiving anitocabtagene. And those who achieved deeper responses tended to do better, with the median overall survival having not been reached in this population.

I would tell you that at the ASH meeting that just ended 2 days ago, there was data presented from the iMMagine-2 trial showing even better overall responses and even longer durability, with importantly, no evidence of the nonneurologic toxicity in these patients, and a significantly lower incidence of cytokine release than has been seen with the other therapies. Now, some of that may be due to better disease control, but it is very exciting that there may be an agent that is not associated with this non-ICANS neurologic side effects.

[00:29:59]

Dual-Targeting CAR Constructs

There are also dual-targeting CAR T-cells that have been developed. You can see just a couple of these here, one that targets BCMA and CD19, and one that targets both BCMA and GPRC5D. And these are in clinical development at this point in time, and being studied in the patients with relapsed/refractory myeloma. So, data will be forthcoming.

[00:30:26]

Overview of CAR T-Cell Therapy at the Veterans Health Administration

Tennessee Valley Healthcare System: Stem Cell Transplant/Cellular Therapy Highlights

Within the Veterans Health Administration, the Tennessee Valley Healthcare System opened in October of 2024 for stem cell processing. There are 2 VA medical centers with a stem cell transplant, but the Tennessee Valley is the only one certified for the administration of CAR T‑cell therapy.

[00:30:39]

CAR T-Cell Therapy Within the VA: Advantages

This allows quicker time for patients who are eligible for CAR T-cell therapy for treatment and administration, no single case agreements required, no insurance authorization, and the travel and housing costs are covered by the VA, including benefits for the caregiver, and allowing patients to receive their care within the VA system.

[00:31:10]

MM: Eligibility Requirements

Both agents are available, and requirements are to meet the criteria for relapsed/refractory disease with good organ function, mental health, social work, and dental clearance, and the availability of caregiver support as outlined here on this slide.

[00:31:28]

CAR T-Cell Therapy Referral and Cost Evaluation/Reimbursement (TRACER)

Patients get referred through the Department of Veterans Affairs Central Office TRACER website by their local oncologist. The requirements have to be approved and covered, and then patients go through a rigorous checklist as followed, and patients are assigned to be evaluated within a week.

[00:31:49]

Time Frame: Patient Evaluation to Apheresis

Important because oftentimes these patients have disease that is progressing, and they are in need of rapid evaluation and enrollment and treatment. The goal is really 2 to 3 weeks to the time of cell collection, and patients are brought to Nashville for their cell collection, and housing and so forth are covered. Typically, they are there for about a week to complete the testing.

[00:32:14]

Initial Patient Evaluation

Prior to all of that, there is a video connection vs a face-to-face or a telephone visit that takes about 60 minutes with the patient and their caregiver reviewing their health, their disease history, and the process that is involved for CAR T-cell manufacturing, administration, and treatment, and then communication back to the referring provider.

[00:32:34]

First Visit to TVHS

Typically, again, it is a 1-week visit. The first visit is a 1-week visit to evaluate testing for clearance, education of the patient, collection of the T-cells, and then while those cells are being manufactured, the patient returns back to their home site to receive their bridging therapy with guidance from the CAR T-cell team, and then returns back to the Nashville area for their lymphodepleting chemotherapy, followed by admission for inpatient monitoring for their CAR T-cell infusion.

[00:33:09]

Patient Follow-up and Hospital Departure Process

Initially, the process was 30 days after CAR T-cell infusion until patients would return home. The FDA has shortened this window to require this only to be 2 weeks, and also shortened them from 8 weeks down to 2 weeks. And so it is a coordinated process for the patients to receive their CAR T-cells, get them through the acute phase, and then transition them back to their home team with good communication throughout the process.

[00:33:39]

Bispecific Antibodies in R/R MM

What about bispecific antibodies?

[00:33:40]

Bispecific Therapy Options for Multiple Myeloma

So again, as we mentioned, there are 4 approved bispecific antibodies, 3 of which target BCMA and one that targets GPRC5D. These offer an advantage because they are an off-the-shelf immunotherapeutic strategy that does not require the manufacturing process. Some of these are given subcutaneously. Some of these are given intravenously. They all have step-up dosing to reduce the risks of toxicity.

[00:34:08]

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

The first bispecific that we got was teclistamab, and it began with the MajesTEC-1 trial. Relapsed/refractory myeloma, again, the same patient population, 4 or more prior lines of therapy that were in the initial KarMMa and CARTITUDE-1 trials, with an overall response rate of 63%. And it is just really amazing that we could get such high response rates, even with both of these therapies in a patient population who really did not have treatment options available.

If you divide it, as on the right-hand side of the slide, the patients who have the deepest response tend to remain in remission the longest. So the complete response, or the green line, the very good partial remission, or a 90% drop, is the orange line, and the blue line is the population overall. So the median overall progression-free survival was about a year, but those who got at least a very good partial remission, the median was more than 2 years. And those in complete remission, the median had not been reached when this data was published.

[00:35:14]

Real-world Evidence With Teclistamab in R/R MM: Response and PFS

Looking at real-world evidence with teclistamab and patients, so this is use of these agents in the real world. Many of these patients would not have been eligible for the trials, and yet still a very high overall response rate.

So patients who had not had any prior BCMA therapy in the real world had a 61% overall response rate. Those who had had prior BCMA therapy had about a 49% overall response rate. And you can see the median progression-free survivals in both of these groups on the right-hand side of the slide.

[00:35:51]

Phase II MagnetisMM-3: Elranatamab for BCMA-Directed Therapy-Naive R/R MM (Cohort A)

The second bispecific antibody that was targeting BCMA was elranatamab, and this came from the MagnetisMM-3 trial. So this is from earlier lines of therapy. I should say, we got it from MagnetisMM, but not the MagnetisMM-3 trial, because these are patients who had 1 or more prior lines of therapy.

On average, they had had a median of 5 prior lines of therapy. This drug is given flat dosing. So as opposed to teclistamab, which is based on weight, this is flat dosing with a dose escalation. And you can see a similar overall response rate of 75%, with almost half of the patients achieving a complete response, and a quarter achieving a very good partial remission, and a 2-year remission duration of 67% of patients still being in remission.

[00:36:50]

MagnetisMM-3: PFS and DoR

Here are the differences between the patients who achieve a complete response, the green line vs the group as a whole, and you can see it is significantly better the deeper the responses are for patients receiving this bispecific and all the other bispecifics.

[00:37:06]

Bispecific Antibody Elranatamab After Previous BCMA Therapy

This trial did allow prior BCMA therapy, so it allows us to begin to get at the question of can we give more than one of these agents? And the answer is yes. So in this trial, patients who had had any prior BCMA therapy still had almost a 50% overall response rate, 46%, lower if they had had a prior antibody–drug conjugate. So most of these patients had had belantamab in that category, that is the antibody–drug conjugate, and somewhat higher for patients who had had CAR T-cell therapy, likely because there was a separation in time between engaging T-cells in this process.

This was done in the setting of the COVID era, so there was a high percentage of patients who had COVID-related infections that you can see on the bottom side of the slide, and a comparable CRS rate of about 65%, with very little grade 3 or 4 CRS in this population.

[00:38:08]

LINKER-MM1: Phase I/II First-in-Human Trial of Linvoseltamab for R/R MM

The third BCMA-targeted therapy that we had is linvoseltamab, which was the most recently approved. And again, this is the population of relapsed/refractory disease, very similar in this case, a 71% overall response rate at the recommended phase 2 dose of 200 mg. And you can see the swimmer's plot on the right-hand side of the slide showing ongoing remissions with the arrows in many, many patients on the trial.

[00:38:36]

LINKER-MM1: Phase I/II First-in-Human Trial of Linvoseltamab for R/R MM

Patients who were treated at full dose, you can see here on the left-hand side of the slide, and this has a median progression-free survival, which has not been reached, with 70% of patients still in remission 1 year on therapy, and a 1-year overall survival rate of 75% for patients. And again, this was FDA approved this summer for patients with relapsed/refractory disease after 4 or more prior lines of therapy, which is where all of the bispecifics are approved at this point in time, is after 4 or more prior lines of therapy.

[00:39:14]

Phase II MonumenTAL-1: Talquetamab in R/R MM

Finally, we have talquetamab, which has a different target, GPRC5D, which is a different protein on the surface of plasma cells. And you can see here, there are 2 different dosing schedules for this, a weekly dosing and every-2-week dosing. They both have step-up dosing.

I would tell you that most people dose this ultimately every 2 or even every 4 weeks, and many times even at the lower dose at those later times. That is not the labeled indication, but because of side effects, oftentimes those doses are lowered, and patients do quite well. But a response rate overall of about 74% at the weekly dosing, 70% at the twice-weekly dosing. And even in those who had had prior T-cell redirected therapy, almost the same response rate.

So again, we are switching targets. So the patient population who had had prior T-cell-redirecting therapy had all had BCMA-targeted therapy previously.

[00:40:16]

MonumenTAL-1: DoR and PFS Outcomes

You can see the duration of response based on response. And again, like we have seen previously, the deeper the response, the better it is, the longer it lasts.

[00:40:28]

Bispecific Antibodies in R/R MM: Efficacy by Type of Prior Anti-BCMA Therapy

This table just puts together the 4 commercially available bispecific antibodies. And in the boxes, highlights those that had prior BCMA or antibody–drug conjugate T-cell–redirecting therapy. And you can see that the overall response rate is approximately 45-70% on these therapies. And many patients still achieving complete remission, even if they had had prior T‑cell-redirecting therapy targeting the same antigen.

[00:41:07]

Bispecific Antibody-Based Combination Regimens in MM

So if one antibody is good, there have been many studies looking at combinations.

[00:41:12]

Phase III MagnetisMM-5: Trial of Elranatamab + Daratumumab in R/R Multiple Myeloma

The first of which we will talk about is the phase III elranatamab with daratumumab in relapsed/refractory myeloma, looking at trying to build upon the efficacy with the idea that daratumumab may have activity against NK cells, allowing the increased activity of the bispecific and T-cells engaging those. And you can see in this trial, an overall response rate of 71%. The safety profile was tolerable. There were no dose-limiting toxicities. And over half the patients achieved a complete response with no incidents of ICANS on this trial.

[00:41:54]

TRIMM-2 (Talquetamab + Daratumumab Cohort): Responses

That was elranatamab with daratumumab. We have the TRIMM-2 trial looking at talquetamab with daratumumab. Again, very high overall response rates of 84% with the every-2-week dosing of talquetamab with daratumumab. And you can see even in the population that had prior T-cell–redirecting therapy, almost 70-80% of patients do respond to the combination of this. Again, a different target for the vast majority of these.

And just on Tuesday morning, the data from the MajesTEC-3 trial, including daratumumab with teclistamab, was presented with a 3-year progression-free survival of 83% of patients receiving that combination of therapy. Sorry, we do not have that in the slides for you, but did want to share that with you.

[00:42:52]

Phase Ib/II RedirectTT-1: Teclistamab + Talquetamab in R/R Multiple Myeloma

Could we combine these bispecific antibodies together? Yes. There is the RedirectTT trial looking at combining teclistamab and talquetamab with the idea that you could use your T-cells to target both of these antigens at the same time.

[00:43:08]

RedirectTT-1: Teclistamab + Talquetamab in R/R Multiple Myeloma

And this had an impressive 80% overall response rate in the population of relapsed/refractory disease, with a 1-year progression-free survival of about 75% and an 18-month progression-free survival of 70%. So active.

[00:43:31]

RedirectTT-1: Patients With True EMD Response and PFS

You can see this here more graphically. This actually looks at patients who had true extramedullary disease.

So one of our patient populations that is very difficult to treat is those with extramedullary disease. And even in that population, you can see a 1-year progression-free survival of 61% of patients with extramedullary disease with this combination of antibodies.

[00:43:56]

Next Generation of Targeted Immunotherapies: BCMA x GPRC5D x CD3 Trispecific Antibody

In development, like we have a CAR-T-cell that targets both of these antigens, there is a trispecific antibody targeting BCMA as well as GPRC5D and CD3. And so it has 3 binding sites, 1 for CD3, 1 for GPRC5D, and 1 for BCMA. And this trial showed an overall response rate of 100% in patients who had not had any prior BCMA- or GPRC5D-targeting therapy. Some of the side effects of GPRC5D-targeting therapy are decreased taste, loss of weight due to lack of appetite, skin peeling, and nail changes.

And what the combination or what this trispecific antibody has shown is less impact on taste and less weight loss than talquetamab by itself, and comparable skin and nail differences that occur, which mostly occur with the first few cycles of therapy.

[00:45:00]

Summary of Adverse Events Associated With CAR T-Cell Therapies and Bispecific Abs

Acute Toxicities: CAR T-Cell Therapy and Bispecific Antibodies

So if we talk about adverse events associated with these, so with CAR-T-cell therapy, the acute toxicities really, as I mentioned previously, are cytokine release and then ICANS or immune effector cell-associated neurologic syndromes. Less commonly, there is an HLH syndrome, which can occur, that is less common. Infections and cytopenias are the other acute toxicities that we manage for and watch for and treat appropriately.

These acute toxicities are managed at the treatment center, and they are managed with the therapies on the right-hand side of the slide, so steroids, tocilizumab and anakinra can be used for CRS, seizure prophylaxis for neurotoxicity. And then, less commonly, when there are immune cell syndromes, we will use things such as ruxolitinib as well as anakinra and steroids. Cytopenias are often managed with growth factors, and obviously antimicrobial prophylaxis and intravenous immunoglobulin gets added in.

[00:46:05]

Infection Prophylaxis and Vaccinations

That is part of our infection prophylaxis. All patients receive bacterial, viral, and fungal prophylaxis in the beginning and recommendations for varicella-zoster HSV prophylaxis as well as PJP prophylaxis for patients post-CAR T-cell therapy, followed by IVIG for primary prophylaxis for patients.

[00:46:29]

Effect of IVIG Prophylaxis on Infection-Free Survival in Recipients of BCMA-Directed Bispecific Ab for MM

IVIG has been very important in helping reduce the risk of severe infections in B-cell–directed therapies. This is data from studies looking at bispecifics. And studies that included primary prophylaxis had a lower risk of infections, that you can see here in the blue lines, vs those who did not receive primary IVIG prophylaxis and a lower incidence of grade 3 or higher infections with primary prophylaxis vs those without this.

And so the International Myeloma Working Group has come out with recommendations for implementation of IVIG or gamma globulin supplementation, certainly if the IGG level is less than 400, but at times it gets started earlier than that.

[00:47:20]

CRS: ASTCT Consensus Grading

CRS, as I mentioned previously, grade 1 is a fever. Grade 2 is a fever with either low blood pressure and/or low oxygen level that requires low levels of nasal cannula oxygen. And this is the vast majority of CRS, certainly with the bispecifics and with CAR T-cells, although there is a slightly higher incidence of grade 3 and 4 CRS with CAR T-cell therapy. But these all occur in the acute time frame of those CAR T-cells being given at a CAR T-cell center.

[00:47:56]

ICANS: Grading and Assessment

There are different grading systems utilized to manage immune cell-associated neurologic syndromes.

There is the ICE scoring, which asks questions regarding orientation, naming, following commands, writing sentences, and counting backwards. So the ASTCT ICANS consensus grading looks at the ICE score, as well as the level of consciousness, whether there have been seizures, and are there abnormalities of motor findings. There is also the CARTOX-10, which is an update of the ICE tool to assist in assessing the grade of ICANS.

[00:48:38]

Delayed Incidence of Toxicities

What is important, not just for these acute toxicities, but especially when patients return to their home site, is education on delayed adverse events, namely infections, low antibody levels, or hypogammaglobulinemia, the possibility of cytopenias, and then the non-ICANS neurologic side effects, which can occur. So it is important that patients continue to be followed closely, at least through the first 100 days, and monitor for these.

It is recommended that patients receive their immunizations again, although I will tell you most of these patients are hypogammaglobulinemic, and if you are giving IVIG supplementation, there is really no value in giving them their immunizations, because they will not respond to them. We need to wait until their immune system recovers, they no longer need IVIG supplementation, and then their immunizations can be started.

[00:49:32]

Integrating and Sequencing Immunotherapies for Patients With R/R MM

Deploying Available Agents

How do we sequence these immunotherapies? We really want to deploy the best available therapy as early on in the process.

And so, our first-line therapy really is quadruplet therapy for patients. There are ongoing trials looking at bispecifics and CAR T-cells as part of our first-line therapy. There are, in our early relapse, in the 1 to 3 prior lines of therapy, we have 3-drug combinations that are there.

We cannot yet use bispecifics and trispecifics outside of clinical trials, but we can use CAR T-cell therapy in our 1 to 3 prior lines of therapy. We can only use those bispecifics outside of clinical trials in patients who have had 4 or more prior lines of therapy based on current indications.

[00:50:24]

Strategies to Reduce Health Disparities in the Management of MM

Potential Solutions for Reducing Disparities

So, I will segue a little bit and talk about reducing health disparities in our management of patients with myeloma, and really all patients.

We have challenges with our clinical trials, making them available to all patients. We need to consider broadening our eligibility, designing it so that we can incorporate subgroups, particularly those common to Black patients. There are twice as many Black patients with myeloma as White patients. They tend to get diagnosed earlier, and yet they do not get the same level of care. They do not have the same outcomes, but if they do get the same care as those as White patients, they have comparable outcomes.

So, how do we make this better? They also are low enrollers in our clinical trials, and so we really need to work to expand those to enhance our roles of navigators and getting patients, getting all of our patients access to trials, bringing the trials to the patients, trying to make them more available out in the community and support the resources so that everyone can enroll in these trials.

[00:51:30]

Conclusions

CAR T-cells have high efficacy and durable responses, even in relapsed/refractory disease. Again, a third of patients in the initial CARTITUDE-1 trial are progression-free 5 years later on no therapy. Efforts are ongoing to use these even in earlier lines of therapy where they are likely to be even more beneficial with better, quote-unquote, immune fitness and less refractory myeloma. There are ever-increasing targets and combinations of these therapies for patients, but currently, as I said, bispecifics are only approved after 4 prior lines of therapy, but CAR T-cells can be given as early as 1 prior line of therapy.

[00:52:14]

Let's Revisit Our Patient Cases

Patient Case: 85-Year-Old Man With MM

So, if we go back to our cases, we will start with our 85-year-old gentleman who has had myeloma for 10 years. He initially received 3-drug therapy, which would have been standard-of-care at that time, with VRd followed by a transplant and maintenance with lenalidomide, which he remained on until recurrence at 4 years. Second-line was a triplet of daratumumab, bortezomib, dexamethasone, which worked for 2 and a half years, and then another triplet, elotuzumab pomalidomide dexamethasone, for which he had a partial remission lasting a year and a half, and then carfilzomib, cyclophosphamide, dexamethasone that lasted almost a year.

Now he is on to his fifth line of therapy. He does have some concerns, or there are concerns, about memory loss for this patient.

[00:53:00]

Posttest 1: Which of the following would you recommend as the best next-line therapy for this patient?

And so the question is, what would you recommend as the best next line of therapy for this patient?

1. Carfilzomib + pomalidomide + dexamethasone,
2. Ciltacabtagene autoleucel,
3. Idecabtagene vicleucel, or
4. Teclistamab.

Speaker: And the post-question is now open. Please vote. And we will give everybody a few more seconds to submit the results. And here are your results.

Dr. Huff: Okay. So, yes, the correct answer to this, or the best answer to this, would likely be teclistamab. This patient is now on fifth-line therapy, so he does have access to CAR T-cells as well as bispecifics, but given his age, concerns about memory loss, many people would say teclistamab would be the best option for this patient at this time.

And hopefully, I have convinced you with the data comparing standard-of-care therapies to these therapies that carfilzomib plus pomalidomide plus dexamethasone would likely not be a good option for this patient. All right.

[00:54:24]

Patient Case: 36-Year-Old Woman With MM

Our second case is a 36-year-old woman who was diagnosed in 2024 with stage III high-risk myeloma.

She got quadruplet therapy and a transplant, followed by triplet maintenance therapy, which would not necessarily be standard, but in light of her high-risk disease, many people would give her 3-drug therapy at this point in time. But unfortunately, in spite of this, relapsed 7 months into her maintenance therapy.

[00:54:53]

Posttest 2: Which of the following would you recommend as the best next-line therapy for this patient?

And so, as a second line of therapy, what would you recommend for this patient?

1. Carfilzomib + pomalidomide + dexamethasone,
2. Ciltacabtagene autoleucel with holding bridging therapy,
3. Linvoseltamab,
4. A second transplant, or
5. Teclistamab monotherapy.

Speaker: And the poll is open. Please vote. And just a few more seconds for incoming responses. And here are your results.

[00:55:39]

Dr. Huff: All right. So, yes, the best answer for this patient would be ciltacabtagene. It is the most active of the 2. She is also on second-line therapy. So, it is really the outside of standard chemotherapy, which, again, hopefully with the CARTITUDE-4, I have convinced you that ciltacabtagene is superior to that. That would be the best choice for this patient at this point in time.

And a second stem cell transplant would not be helpful for this patient, given that she only got 7 months out of her first transplant.

[00:56:14]

Patient Case: 82-Year-Old Woman With MM

All right. And our final case is an 82-year-old woman with myeloma who was diagnosed 7 years ago with standard-risk disease.

She received VRd, followed by a transplant and lenalidomide maintenance, and achieved a complete remission. She went off maintenance therapy after 3 years. And a year off maintenance therapy developed recurrence for which she received daratumumab, carfilzomib, dexamethasone and achieved a very good partial remission, but now is progressing through and needs her third line of therapy.

[00:56:44]

Posttest 3: Which of the following would you recommend as the best next-line therapy for this patient?

And so, the question here is, what would you recommend as the next best line of therapy for this patient?

1. Idecabtagene vicleucel,
2. Selinexor + dexamethasone,
3. Talquetamab,
4. Teclistamab.

Speaker: And this poll is open. Please vote. Just a few more seconds for the responses. And here are your results.

Dr. Huff: All right. So, great. So, the best answer here is A, idecabtagene, vicleucel.

She is not a candidate for bispecifics because she has only had 2 prior lines of therapy, so could not get teclistamab or talquetamab. And idecabtagene is superior to standard-of-care, including selinexor + dexamethasone, although that was not an arm within the trial that was there.

[00:57:44]

If we had given ciltacabtagene as well, we might have a debate about this. Many people, because of her age, would be concerned about the higher risk of potential toxicity, and so would opt for idecabtagene in this situation. Some would still give this patient ciltacabtagene, but it was not there as an option.

[00:58:04]

Poll 2: Do you plan to make any changes in your clinical practice based on what you learned in today's program?

All right. So, our final poll is, do you plan to make any changes in your clinical practice based on what you have learned in today's program?

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

Speaker: And I am going to pull this open. And here are your results.

Dr. Huff: Okay. Very good.

[00:58:33]

Poll 3: Please take a moment to text in one key change that you plan to make in your clinical practice based on this education.

And if you could just take a moment, if you are going to make any changes, just scan this QR code and text a response to changes that you might make in your practice or things that might be helpful to you.

Speaker: And you are welcome to put your responses in the chat or Q&A panel if you would prefer to do that instead. Otherwise, you can scan that code and submit your response to us. Dr. Huff, you are welcome to move on. I will collect those in the background.

Question and Answer Session

Dr. Huff: All right. Okay. So, and I have not looked in the chat as yet to see.

Speaker: And there are some questions posed to you in the Q&A section.

Dr. Huff: Okay. Let me find that. Okay. So, the first question is, for patients with an early biochemical relapse only, do you still initiate a TRACER referral or wait for clinical response?

That is probably a VA question, but I would say, it never hurts to get the discussions and let the patient have the opportunity to hear about these therapies and what might be involved. I think the short answer is, and it is a terrible thing to say, but it really is true, it kind of depends. If this is a patient who has a biochemical relapse but has very high-risk disease, so they are relapsing within 6-12 months of their transplant, I would absolutely put it in.

If this is a patient who is been on maintenance therapy for 7-10 years and now has a biochemical relapse, I am not so sure I would send them straight to CAR T-cell therapy at that point in time. So, it is somewhat of a nuanced answer, but I do think we like to talk to people so that they can understand what is involved.

Okay. Do you favor a fixed duration of bispecifics vs continued until progression? We are certainly stopping bispecifics in some patients in complete remission or at least extending them out 8 weeks between doses for some patients.

It is a conversation with the patient, but I am not maintaining them on every 2-week dosing when they are in complete remission. And I have had some patients who had to stop them and have been off them for 2 or 3 years, and still in remission. They did not stop them for bispecific toxicities, but for other reasons.

There is a lot of work ongoing to figure out fixed duration, and I really think that is going to be what is best for our patients. Ideally, is to give them periods of time off therapy as long as we can do it and give them good quality of life and deep responses.

Okay. The next question is, what is the threshold for retreating with the same target if the first exposure was short? I am going to guess if the first exposure is short because it does not work, I usually try to switch targets. The other piece that really is not in this talk is if a patient is a CAR T-cell candidate, they should go to CAR T-cells first. You should do your CAR T-cells before your bispecific. If I give a patient CAR T-cell therapy, and they have a short remission duration, 6 months, I am definitely going to move on to talquetamab as my next line of therapy because that is all we have available right now.

If my patient has a 3-, 4-, 5-year remission off their CAR T-cell therapy, then I might consider using a BCMA target again at that point in time. If a patient is relapsing on one BCMA bispecific, you should move to an alternative target because another one is probably not going to work better. There are some studies ongoing showing different mutation sites, and maybe we will get to the point, like in CML for a particular drug for a particular mutation, but we are far away from that.

And then the last question is, why are not second stem cell transplants used with relapse? And the answer to this is they are at times, but they give a much shorter duration of remission with a second utilization than with the first one. Most centers that do second transplants will only do them in patients who have had at least a 3-year remission from their first transplant.

Like the case here that relapsed in 7 months, you might not even get through the second transplant before this patient would progress further. There are patients who have very long remissions and have stored stem cells and want to do a second transplant. However, the data with CAR T-cells is quite promising at this point in time, and I think you will see even fewer second stem cell transplants going forward, given our CAR T-cell therapies that are available, and generally much better tolerability than a second stem cell transplant for patients.