Multiple Myeloma

Multiple myeloma is a fairly uncommon but still has about 35,000 newly diagnosed cases in the United States per year. It is a disease or malignancy of the plasma cells, which are our normal cells that are part of the immune system, whose function is to make antibodies to fight off infection. When patients have myeloma, they have abnormal malignant antibodies, which are essentially just large proteins which clog up their bone marrow and their blood and can hurt their organs.

It is twice as common in Black patients than in Caucasian patients. Like most cancers, the median diagnosis is in the 60s here, 65 years old. Historically, we have largely considered the majority of patients incurable. If patients have myeloma and under achieve a remission at some point, if they live long enough, they are very likely to relapse. 

This picture on the right is actually the first sketch of the first documented patient that was diagnosed. She was diagnosed in her 30s here. You can see this was in the mid-1800s. She has a lot of broken bones and looks generally miserable. I like to include this as a baseline so we can see how far we have come in the last 150 years or so.

Cycles of Relapse and Remission in Multiple Myeloma

I did mention cycles myeloma is unfortunately uncurable at this point, and we have patients that cycle through remission and relapse. Typically, we consider the first remission the deepest and the best remission that patients will achieve, and every subsequent relapse after that, it is shorter and shorter until that relapse, so each remission is shorter and shorter until the next relapse. It becomes harder to treat as we go. We have big questions in the myeloma world. How are we sequencing these agents? What combinations are the best? Should we use our best drugs first, etc.?

Novel Therapies in Multiple Myeloma

Good news is we have a lot of novel therapies for patients with myeloma starting in the early 2015 with the approval of daratumumab, and then in 2020 with belantamab and cetuximab. Belantamab was unfortunately withdrawn from the market due to the Phase 3 study not coming to fruition, but however was re-approved earlier last year, in October of last year. In the dark green, we have got two CAR T cell therapies that are approved. Then, most recently, other than belantamab, we have now four bispecific antibodies that we will talk through that are available for these patients.

Depth of Response Matters

I did want to introduce this concept of MRD, or minimal or measurable residual disease. This is essentially the most sensitive test that we have available to detect how much myeloma a patient has. It is a lot more sensitive than the test that we can run in the patient's blood that we typically draw once a month or every two weeks, called the SPEP.

This is a test that is done on the bone marrow that we can send to a next-generation sequencing lab, and we can essentially find if patients have one myeloma cell in a million blood cells. If they have that one cell, we call that MRD positive. If they do not, we call that MRD negative. We know that patients that become or achieve MRD negativity, whether it is one in 1,000,000 or one in 100,000 cells, have longer-lasting survival outcomes.

Amazing Success in Immunotherapy for MM

Again, we do have some new drugs in myeloma, and we have seen some pretty good responses with our traditional mix-and-match approach. We typically match drugs with different mechanisms in the beginning. Then, more recently, we have these one-and-done CAR T cell therapies and some of these bispecific therapies that have come around for patients with multiple relapsed disease.

We have seen really impressive response rates. You can see here on the right and the read the response rates with ide-cel and cilta-cel, which are CAR T cell therapies, and teclistamab talquetamab, elranatamab, and linvoseltamab, which are bispecifics, are double and triple and even higher than some of our more traditional therapies shown in the blue.

Agents Used for Multiple Myeloma

This is a table that essentially just highlights some of these therapies. On the left side, we are typically using a mix-and-match approach where mixing and matching three and four-drug regimens for these patients. Then we have some more novel therapies on the right side. The CAR T cell therapies right now are these one-and-done approaches, where a patient will get a transfusion of CAR T cells and then be done and hopefully be in remission for years and years. Then we have bispecific antibodies and antibody drug conjugates here and the right side middle column. We have got a number of those, which we will go over in more detail going forward.

Importance of B-Cell Maturation Antigen (BCMA)

Today, we are going to talk a lot about BCMA or B-cell maturation antigen. That is important because it is a novel target that we really discovered over the last five or six years. It is really unique target because it is only expressed on the surface of plasma cells and specifically multiple myeloma cells. You are not going to find this on the surface of red blood cells or platelets.

When we have BCMA targeting agents, we are not killing the good cells. We are just going after the plasma cells in these multiple myeloma cells. There is also a concept called soluble BCMA, which is here on the bottom in the middle. Soluble BCMA is important because it is a surrogate marker of disease burden. Patients that have a lot of soluble BCMA in their blood, we know that that is a bad prognostic sign, and so we are able to measure that and prognosticate if disease burden and how well these therapies are working.

BCMA-Directed Immunotherapies

We have a lot of different targets and mechanisms of action. Starting on the bottom left, we have antibody drug conjugates, which I tell my students and residents, if you think back of that Brad Pitt movie with the Trojan Horse, you have got the Trojan horse that comes up to the gate. That is the antibody, and then the drug is hiding inside the Trojan horse. It lets the soldiers out through the gate, and it kills all the bad guys, and that is the drug going to the surface of the myeloma cell, going in and killing the bad guys or the bad myeloma.

Our CAR T cells are genetically engineered cells that are targeted to kill T cells that are targeted to kill the myeloma. We genetically modify these T cells. We reinfuse them into the patient, and the T cells go after the myeloma. Then we have got these off-the-shelf, off-the-counter bispecific antibodies, which are just drugs approved that work like CAR T cells, they bring the myeloma in contact with the T cell, and the T cell engages the myeloma and kills the cancer.

Poll 3

Let us vote. Poll number three. A 62-year-old gentleman with newly relapsed myeloma. His first-line treatment was a quadruplet of lenalidomide, bortezomib, and dexamethasone, followed by an autologous stem cell transplant and lenalidomide maintenance thereafter. Then he unfortunately relapsed. His second-line was carfilzomib, pomalidomide, and dexamethasone. At this point, what is the most appropriate third-line therapy option? Are we looking at

A. Belantamab bortezomib and dexamethasone;

B. Teclistamab monotherapy;

C. Teclistamab plus daratumumab; or

D. CAR T cell therapy.

There may be multiple right answers here. We just wanted to pull and see.

Posttest 1

Posttest one, which of the following best explains the rationale for B-cell maturation antigen or BCMA in patients with early relapsed or refractory multiple myeloma? Is it

A. BCMA is primarily expressed on juvenile B-cells, targeting it reduces treatment complexity;

B. BCMA is overexpressed on plasma cells in myeloma cells and is associated with disease burden;

C. BCMA decreases with disease progression, making early targeting more effective; or

D. BCMA-directed therapy offers no advantage over proteasome inhibitors in early relapse, so formulary placement should be limited to late relapse.

The correct answer here is B, which it looked like 100% of the audience got right. BCMA is really important for patients with relapsed, refractory myeloma because again, it is expressed primarily on plasma cells and multiple myeloma cells. it makes a great target for some of our targeted agents.

CAR T-Cell Therapies in R/R MM

We are going to break this section down. I have got a lot of slides to cover. Again, you have the iPads in front of you which you can view the slides on. They are also downloadable. If I talk too fast, you can download these, or you can take pictures, but you do not have to because you are able to download them. I will talk. CAR T bispecifics, I will turn it over to Anthony. He will talk ADCs, and then Don will break down some of the managed care considerations.

BCMA-Directed CAR T-Cell Therapies in R/R MM

We are starting with CAR T because these were the first products that were approved outside of belantamab Mafodotin because of its withdrawal. We are going to start with CAR T cell therapies. We have two that are currently approved for patients with relapsed, refractory myeloma. The one that was approved was ide-cel based on the arMMa-1 trial.

It was shortly followed by cilta cel, based on the CARTITUDE-1 trial. Essentially, these therapies showed overall response rates that were unheard of in patients with heavily relapsed, refractory disease. These drugs were originally - these two trials were studied in patients that had received at least three or four prior lines of therapy who historical overall response rates for some novel agent that we thought was good at the time was about 30%.

You can see the ORR here towards the bottom, the overall response rates reached 81% and 98% for these products, which was historically very good. We were very excited based on these. You can see the median progression-free survival here on months in the bottom, we have about a year for ide-cel and about 34 months for cilta-cel. On the right side, we have got some upcoming pipeline that I do not have time to talk about today, unfortunately, but it is here for your reference, and that is why you can download the slides.

Pipeline: iMMagine-1 Trial of Anitocabtagene Autoleucel in R/R MM

One in the pipeline that I do have time to talk about is anitocabtagene, which we hopefully expect will be approved in the next 12 months or so. It is being studied in a multicenter, open-label Phase 2 trial called the iMMagine-1. Again, these are heavily pre-treated patients that have received the normal CAR T process.

We leukapheresis their T cells. We send them to a manufacturer where the CAR is added to target the myeloma. If a patient needs disease control. In the meantime, they receive bridging therapy. They undergo lymphodepletion with cyclophosphamide and fludarabine to make room for the T cells to grow and expand. Then they receive here in the red box anitocabtagene autoleucel at the target dose on day zero, one time infusion, and then they are monitored closely thereafter. Primary endpoints here were overall response rates and key secondary endpoints listed below.

iMMagine-1: ORR and MRD Negativity

We saw essentially, based on this early data, that overall response rates in MRD negativity were very good, in line with what we had seen with the previous CAR T cell therapies. Overall response rate of 97% at 12.6 month follow up. Complete response or stringent complete response rates 68% here. 93% of patients were evaluable that were MRD negative at ten to the negative five. That shows you that this therapy really led to very deep responses.

CARTITUDE-1: Cilta-cel in Patients With R/R MM

The CARTITUDE-1 trial, and this was based on Dr. Voorhees ASCO presentation in 2025. The five-year data came out. You can see this Kaplan-Meier curve is essentially achieving a flat line around five years. This is important because when Kaplan-Meier curves show a flat line, we typically associate those flat line with a cure. There is no patients relapsing or dying if the line is flat.

There is a lot of talk in the community, and even in New York Times article about, is this data indicating that there is a possible cure coming for these patients? I think that is controversial at this point. I think the real question is, can we achieve this? Let us talk about and think about this moving forward in our slides, and thinking about using these products earlier and earlier, can we get a better progression-free and overall survival curve are truly flat line?

Moving CAR T-Cell Therapies Earlier in R/R MM

We have that data looking at CAR T and heavily relapsed patients. Then we have some more recent data, the KarMMa-3 and CARTITUDE-4 trials which studied CAR T earlier in lines after one or two prior treatments. Both products again ide-cel and cilta-cel, were compared to physician's choice of best available therapy, and patients received the CAR T cells or best available therapy.

They were followed. Then you can see here the overall response rates again in the 70s and 80 percents. Median progression-free survival for the ide-cel was 13.8 months and not reached at the cut-off for cilta-cel. These products do have novel toxicities, cytokine release syndrome or CRS as well as neurotoxicity. We will talk about those and how to manage those on a subsequent slide.

KarMMa-3: Treatment Response and Final PFS

The KarMMa-3 study, which is the ideal trial, showed overall response rates around 30% higher than the standard of care arm. You can see the PFS curve here, 41% versus 19% in 18 months, so over double that. That led to the approval of ide-cel in the third-line.

CARTITUDE-4: Efficacy

The CARTITUDE-4 study again looked at cilta-cel versus standard of care. You can see the overall response rates here on the left, as well as the Kaplan-Meier progression-free survival curve here on the right. Again, over double 30-month progression-free survival for cilta-cel, which led to the approval of cilta-cel in the second-line for patients after relapse. These patients did have to have refractory disease and had to have disease that was refractory to lenalidomide, so that is important.

Ongoing Phase III Trials With BCMA-Directed CAR T Therapies in R/R MM

There are some ongoing Phase 3 trials looking at these in different types of settings. The CARTITUDE-5 is looking at non-transplant candidates. They receive triplet induction followed by cilta-cel versus what we currently do, where they receive triplet induction, and then just keep on receiving that induction strategy.

We are trying to determine if induction followed by CAR T is better than just keeping on the same thing. The middle column, CARTITUDE-6, is actually comparing CAR T after induction versus transplant, which is our current standard of care, and so that will be interesting if that reads out that CAR T can beat transplant. Then we have the iMMagine-3 that is studying the newer product anito-cel versus standard of care in patients with earlier relapsed refractory disease.

Bispecific Antibodies in R/R MM

That was a lot of CAR T. Let us move on to bispecifics.

Bispecific Therapy Options for R/R MM

Bispecific options for patients with relapsed or refractory myeloma. We actually have three currently approved products. Those are here in the orange. We have got teclistamab, elranatamab, and linvoseltamab. Those all target BCMA and CD3 on the T cells. Again, bringing the T cells in concert with myeloma, and the T cells do what immune cells are supposed to do and kill bad things.

We also have talquetamab, which is a novel target targeting GPRC5D, which is also expressed primarily on myeloma cells and also some keratinized tissue. That is a currently approved option. We have two other products that are in late-phase trials. Cevostamab, which targets a novel target FcRH5, and then etentamig, which is another BCMA targeting antibody here.

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

The first product that was approved was teclistamab, and that was based off the Phase 1, 2 MajesTEC-1 trial in patients that had received at least three prior lines of therapy, including an immunomodulator like lenalidomide and a proteasome inhibitor like bortezomib and anti-CD38 monoclonal antibody like daratumumab.

About a third of the patients had high-risk disease. Median prior lines of therapy here was pretty high at five. A lot of the patients were triple-class refractory. A third of the patients were five-drug penta-class refractory. You can see that if we think back to historical overall response rates in the 30%, we thought was good.

Then, teclistamab, this study came out, and we had overall response rates doubling what we had historically seen outside of CAR T. This was quite good responses in regard to that. Median progression-free and overall survival here on the bottom in that table, 11.4 and 22.2 months, which was unheard of outside of CAR T cell therapy.

Phase II MagnestisMM-3: Elranatamab in R/R MM

Based on that trial, teclistamab was approved after four prior lines of therapy. Then came elranatamab similar patient population, heavily pre-treated. The dosing schedule was a little bit different here. After step-up dosing, patients received biweekly dosing, and then every other month dosing if they achieved certain parameters of response. You can see again overall response rates in the 60% here, similar progression-free survival, and overall survival as well. This led to the approval of elranatamab again in patients after four prior lines of therapy.

Phase I/II LINKER-MM1: Linvoseltamab in R/R MM

The LINKER-MM1 trial led to the approval of linvoseltamab, which is our third BCMA targeting antibody bispecific antibody. Again, in the 200 mg dosing cohort, we saw response rates in the 70 percentile median 12 month progression free survival was 70% 12 month overall survival 75%. Again, impressive results. All of these BCMA targeting agents, including bispecific antibodies, have toxicities just like any drug. Primarily, we saw cytokine release syndrome, and some a handful of patients had neurotoxicity in each of the studies during the step-up phasing doses. Then, primarily after that, we saw infections be primarily the most common type of adverse event later on.

Ongoing Trials with Bispecific Antibodies in R/R MM

We have a number of ongoing trials with bispecific monotherapy. I mentioned cevostamab, etentamig, and then teclistamab in earlier lines of therapy. These are ongoing, and we hope to see mature data shortly.

Bispecific Antibody Combination Therapy

That was bispecific monotherapy. Then, probably the most recent late-breaking things that happened at ASH is bispecific combination therapy.

MajesTEC-3: Teclistamab + Daratumumab in R/R MM

We are really excited about this in the field. The MajesTEC-3 trial was a Phase 3 trial that was an oral abstract at ASH that had a simultaneous publication in the New England Journal of Medicine, and it was a Phase 3 trial that compared the combination of teclistamab, our BCMA targeting bispecific antibody, with daratumumab in patients with earlier refractory disease.

It was an international trial that included tec dara versus two arms of physician's choice, which were daratumumab, bortezomib, and dexamethasone, or daratumumab, pomalidomide, and dexamethasone. The vast majority of patients received daratumumab, Pomalyst, and dexamethasone. The patients that received the bortezomib in combination with dara were typically European patients. There were not many of those patients.

MajesTEC-3: Response and PFS

Primary endpoint was progression-free survival. If you look on the right, the progression-free survival curves around 30% versus 83%, the combination of teclistamab and daratumumab really knocked it out of the park here. This led to the more recent approval of the combination of tec and dara in patients that had received at least one prior line of therapy, including lenalidomide. You can see the overall response here. Rates here on the left also favored the tec dara combination, but I think the progression-free survival here is a lot more important than the overall response rates.

MajesTEC-3: 0S

The overall survival here, even with only a three-year follow-up, was almost 20% better as well. There are not many drugs in multiple myeloma that have shown to increase overall survival. This combination, even at the short follow-up of three years, almost a 20% difference, was quite impressive for most of the myeloma clinicians in the nation and internationally.

Posttest 2

Post-test question number two, wake back up. Based on the results of the MajesTEC-3 trial, which of the following patients is eligible for the combination of tec dara? Is it

A. A patient with relapsed, refractory myeloma after four prior lines;

B. The patient with relapsed refractory myeloma after one prior line, including lenalidomide;

C. A patient after one prior line who was refractory to daratumumab; or

D. A Patient with relapsed disease after two prior lines, including BCMA-directed CAR T-cell therapy, six months prior.

Looks just like the PFS curve. It is almost doubled. Nice work, you all. Based on the MajesTEC-3 trial again, that was published in December, this past ASH meeting, the combination of teclistamab and dara is indicated and approved for patients after at least one prior line of therapy, including lenalidomide.

RedirecTT-1: Teclistamab + Talquetamab in R/R MM

We have got a couple of other combination strategies that we are also - the combination of teclistamab and talquetamab also was an oral abstract at ASH that I was fortunate enough to catch while I was there, in beautiful sunny Florida. This one looked at talquetamab and teclistamab. Talquetamab being that GPRC directed bispecific antibody, and then teclistamab is again our BCMA.

They thought that if we could combine these two novel mechanisms, maybe two would be better than one. That makes sense. That is what they did. Essentially, this was a Phase 1, 2 trial. It did not have a comparator arm, but they saw overall response rates and the recommended Phase 2 level here on the left purple chart of 80%. Then at all dose levels, 78%. We saw pretty good response rates again compared to historical averages. Median follow-up here about a year and a half. You can see the 18-month PFS on the bottom of that right-sided table, 70% with the recommended Phase 2 dosing.

RedirecTT-1: Teclistamab + Talquetamab - EMD Cohort

This again is probably the most important takeaway from this tec tal study. The patients with extramedullary disease, which is essentially disease that is outside the blood and bone marrow. They have a tumours of plasma cells or plasmacytomas that can be located either on their skeleton, paraskeletal, or in an organ like their lungs or somewhere like that.

These patients are the hardest to treat because they typically, these EMD plasmacytomas do not respond to conventional therapies. These patients typically live much shorter and are much harder to treat, and have worse outcomes. The combination of these two bispecific antibodies actually was fairly impressive. This was a major development.

Breaking news at ASH. They saw that one year, 12 month, progression-free survival of 61% in these patients with extramedullary disease, median progression-free survival of over a year. About 93% of the patients responded and deepened response after switching to a less frequent dosing schedule. Good news for patients that unfortunately have EMD, but we have good news using this combo.

Safety of Approved Bispecific Antibodies for Multiple Myeloma

I glossed over the safety so far. Let us talk about safety. We talked about efficacy. We really have unprecedented response rates, progression-free survival, and overall survival advantages for some of these products, but they are not without a cost. Patients have to go through this, and there is a cost associated with every drug and an adverse event.

We mentioned cytokine release syndrome and ICANS or neurotoxicity. Cytokine release syndrome is very common for these T cell-engaging antibodies because they work through the immune system, and when the immune system gets activated, it inflames the body and inflames the blood. These inflammatory proteins leak into the blood and can cause typically CRS, and CRS grade 1 is defined as a fever.

If any of you have received a vaccine before and you had a fever or a temperature after that vaccine, you had grade 1 CRS. Now, when I say CRS, a lot of clinicians, especially in the community, get scared. I would like to just comment like it is just a fever. Grade 1 CRS is a fever. You can see on these bispecific antibodies study around 50%, depending on the study, one third to 50% of patients had grade 1 CRS, which is just a fever.

Grade 2 CRS is a fever, and the patient might have trouble breathing or shortness of breath, or they might have low blood pressure, where they might need oxygen or something, or a fluid bolus to help with that. Grade 3 CRS or grade 4 CRS is when the patient has trouble with blood pressure or trouble with oxygenation, where they need to be in an ICU and receive continuous oxygen or a vasopressor to help their blood pressure.

You can see that the rates of grade 3 and 4 CRS was one in two patients in some of these studies, some of the studies did not have any of those events. The big push has been to move these products into the community and get these products in the outpatient setting, even during the step-up dosing, when CRS and neurotoxicity are the highest. Just a fever for the majority of patients. That is your takeaway. Infections are something we deal with later. As we go on, we will talk about how we prevent and treat infections.

CRS: Clinical Manifestations and Treatment

CRS here again, I cannot say it enough. This may be the most important slide in the whole deck. Grade 1 CRS is just a fever. Grade 2 CRS is a fever with trouble breathing or some blood pressure changes that may need a fluid bolus. Grade 3, 4 CRS are more serious, but very uncommon. A grade 1 CRS based on our guidelines, we are using things like acetaminophen to manage the fever. If acetaminophen does not work, then we can use anti-inflammatories like dexamethasone or corticosteroid.

Some institutions will jump to use something more serious, something like tocilizumab, which is an intravenous interleukin blocker, which can help decrease some of that inflammation, but largely for the majority of patients that have CRS, it is grade 1 and can be managed with something like acetaminophen or dexamethasone.

When it comes to grade 2 CRS, we are typically given our patients dexamethasone. If that does not work, we will move to something like a bigger gun, like tocilizumab. Then, for grade 3 and 4 CRS, again, this is only a handful of patients. They will receive everything until those things do not work. Any type of anti-inflammatory agents, corticosteroids, scheduled corticosteroids, tocilizumab for maybe more than one dose, oxygen, vasopressor support etc.

MajesTEC-1: Longer-term Data on Prophylactic Tocilizumab for CRS With Teclistamab in R/R MM

There is some data, and I do not want to spoil Don's part of the presentation. He is going to go over a lot of the prophy, toci data, but there is a data coming out in a number of different studies retrospectively. Then this was prospective that providing tocilizumab prior to step up dosing can decrease the rates of CRS, and not surprisingly, it works.

You can see here on the left graph that patients without prophy toci had 72% of patients in the MajesTEC-1 trial had CRS, and if they received prophy toci, that rate went from three-quarters to about one quarter 25%. The graph on the right is response rates. I would ignore this graph because only 22 patients received toci.

You cannot really say based with a 22-patient cohort that patients received toci had better response rates, but essentially for safety, providing prophy toci lowers CRS incidence and severity somewhat. The real question is, in my mind, do we need to provide prophy toci if patients are just having a fever? This is a little bit controversial in our field, but I just wanted to present this.

Neurologic Toxicity

Neurologic toxicity. I will gloss over this is very uncommon. Typically, we manage these with steroids. It is typically very manageable. We provide steroids - most institutions provide dexamethasone for patients to take home. They have a prescription if they have any trouble with word-finding difficulties or anything like that. They will take this, and it will resolve after one dose, typically.

ICANS: Clinical Manifestations

Clinical manifestations of neurotoxicity. Typically, it is more like an encephalopathy picture where people may have word-finding difficulties, difficulty writing, thinking clearly. We typically have these patients have a caregiver or someone to help them if they are receiving the outpatient step-up dosing. Typically, we are providing patients, again with steroids to help with this. It is very treatable and again very uncommon.

BsAb Therapy's Infection Risk

Infection risk happens later on after the first cycle typically. It is probably the most difficult adverse event that we are managing. We have really gotten good at managing CRS and neurotoxicity, but infections are hard to manage. There is a number of different risk factors that lead to infection. BCMA therapy over non-BCMA therapies is an issue. T cell mechanisms cumulative toxicities in patients that have received multiple lines of therapy that affect their bone marrow. Infections, and we are going to go over how to manage those here.

Class Effect: Incidence of Infection With BsAbs in MM

These are the rates of infection. Any grade infections in these studies range from 59% to 76% of patients. Grade 3 infections here are about a third of patients in each of the studies had grade 3 infection, so they are not to be taken with a grain of salt.

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

There is more recent data of the effect of IVIG. That is intravenous immunoglobulin supplementation, and on the course of infection, free survival. We found that with routine or prophylactic use of IVIG in patients receiving a BCMA-directed bispecific antibody, that has been able to decrease rates of all grade infections and actually increase infection-free survival. The NCCN guidelines and some of our international myeloma working group guidelines are now recommending IVIg support for patients that are starting on some of these BCMA bispecific therapies.

Consensus Recommendations for Managing Infections in Patients With MM Receiving BsAb Therapy

There are different consensus guidelines. This is the consensus guideline from [?] based out of Dana-Farber. We typically are also providing not only IVIG but antiviral prophylaxis to prevent things like shingles reactivation. We are screening these patients for hepatitis B. If they have that baseline, we are providing prophylaxis with something like entecavir to prevent hepatitis B reactivation.

We talked about IVIG in patients with neutropenia. We can commonly give growth colony-stimulating factors. PJP prophylaxis is also important because we have seen a number of patients with PJP come out as the data matures, and then routine vaccinations for COVID and influenza every season are also important as well.

Fatigue With BsAbs

For sake of time, anyone with myeloma has fatigue. I do not think this is really generalizing to patients that are receiving bispecifics, but there is data that patients receiving treatment experience fatigue. I did not want to gloss over this slide.

BCMA-Directed ADCs

With that, the moment you have all been waiting for, I would like to introduce Dr. Perissinotti, and you get to hear someone other than me talk for a while.

Dr. Anthony J. Perissinotti (University of Michigan): Thank you very much, everybody. James had the monumental task of talking about all of the drugs. I am fortunate enough to talk about one drug with you guys.

Belantamab Mafodotin: A BCMA-Targeted ADC

There is a lot of monoclonal antibodies throughout oncology. There are many antibody drug conjugates in oncology. In multiple myeloma, we have one, and that is belantamab. James already gave us a nice, beautiful picture of Brad Pitt in Troy with his shirt off and entering a Trojan horse and whatnot, so you already got the mechanism of action of our BCMA. Belantamab is a little bit unique.

It has a non-cleavable linker. It cannot be cleaved in the circulation. It cannot be cleaved even in the cytoplasm. It needs to be completely degraded by lysosomes. The second unique aspect is it is negatively charged. Once it is in the cell, it does not leave the cell. Thirdly, there are some immunotherapy-type benefits, whether it is ADCC or just an immunogenic release of antigens that causes our immune system to come and want to kill the cells more. It is a little bit of a more unique antibody.

History of Belantamab Mafodotin

That being said, it also has a little bit of drama. My wife loves trash TV, and honestly, the drama with related to belantamab could easily make a Bravo series. The DREAMM-2 study got the FDA approval of belantamab, but unfortunately, it was removed from the market because of the DREAMM-3 trial, which failed to show a benefit in its primary endpoint, which was progression-free survival.

You are scratching your head like, what the heck? The progression-free survival is longer. It is 11.2 months versus seven, but it was not statistically significant. The hazard ratio - the point estimate here is 1.03. Then you are scratching your head, how is it so much longer? The point estimate is actually favoring the control arm.

This is where looking at Kaplan-Meier curves are really important. What you will see is the Kaplan-Meier curves cross one another. There are some early progressions with belantamab. We will talk about some reasons why. Also, that means that there are some patients that respond to this therapy for a very prolonged period of time.

James and I nerded out about all of our patients that are still on belantamab after the 2020 FDA approval got compassionate use belantamab and are still on it to this day as a monotherapy six years later. Clearly, there are some patients that do benefit from belantamab. We just need to identify who and what combination.

DREAMM-7: Belantamab Mafodotin + Vd vs DVd in R/R MM

The FDA did re-approve belantamab based off of the DREAMM-7 trial. This is a randomized controlled trial of patients with relapsed, refractory multiple myeloma that received at least one prior line of therapy. The control arm was daratumumab, bortezomib, and dexamethasone, and belantamab was used with bortezomib and dex. Belantamab was given every 21 days.

DREAMM-7: PFS

I will challenge James's progression-free survival with my progression-free survival. Here we have tripled progression-free survival, 36.6 compared to 13.2.

DREAMM-7: OS

We have an overall survival benefit with belantamab as well.

DREAMM-8: Belantamab Mafodotin + Pd vs PVd in R/R MM

The story does not stop there because we have a contradictory study somewhat as well. The DREAMM-8, which the FDA did not quite like. They did not like the control arm here. This is not an FDA-approved control arm in the United States. The FDA did not like that very much. This is bortezomib pomalidomide, dex.

The second thing the FDA was a bit confused about was the dosing. We dosed this a little bit differently, 2.5 mg/kg in the first cycle. Then it was a month cycle instead of every 21 days. Then they reduced the dose, and the FDA scratch their head and say, I do not know which dose we should be using.

DREAMM-8: AEs of Special Interest

Even though we saw progression free survival benefit the FDA because of the control arm, because they did not quite know what dose we are supposed to be using, and also because of some of the toxicities, the combination of the DREAMM-8 was not approved, but DREAMM-7 is still approved. You can use that combination, just not the DREAMM-8.

Now, the FDA was not worried about the thrombocytopenia and neutropenia were hematologists. We know how to deal with that stuff, infection same with that. What brought them the most consternation were the ocular toxicities. Close to 90% of our patients would have ocular toxicities. Many of our patients had blurred vision. Some of our patients could become legally blind with this medication. Of course, that brought a lot of pause from the FDA.

DREAMM-7 and DREAMM-8: Ocular Toxicities

Now, fortunately, the vast majority of these ocular toxicities can be managed, and they will be reversed and the vast majority of our patients. Not by doing nothing. We do have to do significant dose reductions and significant dose delays just to keep our patients on these therapies.

Mechanism of Corneal Toxicity

It was somewhat of an unsolved mystery for a very long time as to how is belantamab causing ocular toxicities? There is no BCMA in our eyes. This drug is supposed to be negatively charged. It should not get in and out of random cells. What the heck is going on? There are two proposed hypothesis one is limbal diffusion. On the sides of our eyes we have a very highly vascularized area, the limbus.

As belantamab is going through circulation, your blood flow is carrying belantamab to the limbus. Then eventually, the limbus can give some of that to the cornea and the cornea epithelial cells. It gets uptaken within there. Now, because of the vasculatures on the sides of your eyes, you will start seeing the corneal epithelial changes on the sides.

Then, as things get worse and worse, they start gravitating towards the central. That is one hypothesis. The second hypothesis is tear secretion. There are trace amounts of belantamab in our tears. As we blink, we create more tears, and those tears can get into our cornea as well and cause the ocular toxicities. This really is a corneal issue.

Initially, we call them cysts, but they are not cysts. They are pseudo microcysts that occur. Just to give you guys an idea of what this means. I want everybody to take out your phones. Take a look at your camera on the outside of your camera, you have your lens. It is a piece of glass. That is essentially what your cornea is. Your cornea is this glass.

It is there for two things. Number one, protecting your eyes, but also to allow light into your eyes to get into the retina or your camera. Now, if you feel this camera lens, you feel how beautifully smooth is that? Very nice and smooth. You need a smooth surface. You cannot have debris. You cannot have cracks. You cannot have dirt on your phone or on your cornea. Otherwise, light is going to be bending in all different shapes and sizes, and your retina is not going to know what the heck is going on.

Signs and Symptoms of Corneal Toxicity

What happens? You see this? This is what our patients see. This is what all of you, when you pick up your phone, and you have dirt on your phone, you are going to be like, what the heck is going on with my camera? Why cannot I take a picture? Well, because you have dirt, you do not have that smooth surface for your cornea to really help your retina focus.

What is the first thing you are going to do as troubleshooting? You are going to wipe off your camera, and guess what? Get rid of all that dirt, and we get that nice smooth surface. Now, unfortunately, you cannot do that easily with your cornea. You cannot just wipe off these cysts. It requires time. Patients require anywhere from eight to 12 weeks to be off therapy for the corneal epithelial cells to regrow and become normal and have a more smooth surface.

The Keratopathy and Visual Acuity Grading Scale

Again, I mentioned that most of these occur on the sides of the cell of the eye, and they start to move in centrally. That is how we grade them. Now, I am not going to go through all the ophthalmological signs and symptoms of all these grades, but just know that a grade 1 is mild. Grade 2 is now starting to affect your scene, but it is still on the peripheral sides of your eyes. Now, once we get into grade 3 and 4, it is moving centrally, and your patient is really losing visual acuity to a point that it is dangerous, and your patients can become legally blind from this medication. Again, majority of patients, this will be reversible. Again, we have to do some things to reverse that.

Ocular Toxicities: Prevention and Treatment

One of the things that we can do to prevent this is by just flushing the eye with eye drops. We ask our patients four times a day, do this religiously, because we need to flush any blood flow that went there, that deposited belantamab. Any tears that deposited the drug, we need to flush all that out.

We have our patients take artificial tears four times a day. There is some voodoo also of putting ice on our patient's eyes or cooling masks. Some of the thought is like our breast cancer patients that wear the cooling cap just reduce the amount of blood flow to that area. They do it during the infusion, whether that works or not, I have no idea.

What we do know that does not work, and we know this from a randomized controlled trial, is corticosteroids. They do not help, and they could potentially be harmful. Do not use corticosteroids. Also, you saw the preassessment question of that lady that came in with her contact lenses do not wear contact lenses because that is also going to allow the belantamab to also just concentrate in that area. We need the eyes free. We need them breathing. We need eye drops in, and we need to be diluting all of that.

Monitoring and Managing Belantamab Mafodotin-Induced Ocular Toxicities

The number one thing that actually does help with belantamab ocular toxicities is dose holds. Grade 1, you do not have to hold the patient's asymptomatic, and they are just mild changes. However, when you get into grade 2, grade 3, and grade 4, that is when we have to stop the drug. We have to hold it until it is down to a grade 1 or gone, and then we start reducing the doses.

I have no idea if 1.9 every three weeks is the magical number. I think it is probably even less than that. I think the gaps are probably the most important piece. If the ocular toxicities occur again, that is when we start breaking up our doses to a longer period of time. The package insert says every eight hours.

Extended Dosing Intervals Allow Corneal Recovery Without Compromising Efficacy

Now, within the DREAMM-7 study, they actually analyzed this. They took a look at our patients that required dose reductions. What they found is the median time for onset of the ocular toxicities was six weeks. It took about two doses before a patient started seeing visual acuity issues. It peaks, and then if you stop the drug, it will take anywhere from six to eight, sometimes 12 weeks for our patients' eyesight and the corneal clearance to occur.

That is where we have gotten the eight-week period. Again, James and I have had patients on our services that come to clinic. They are not getting the drug even every three months. Sometimes they are getting a dose here and there every four months or so. We do not know what the magical number is. I do think that the dose delays definitely help.

We do have data that they help and that patients can be on therapy. The other piece of data that we have is that when you look at the patients that require dose reductions and dose delays, and then you look at did you lose efficacy? The answer to that is no. We still saw that the median progression-free survival was 36.6 months, which is pretty much identical to the median.

Now, the astute statisticians in the audience are going to say, well, Anthony, that is a flawed, biased report analysis. There is immortal time bias, and yes, there is, but it still is a very real world analysis that tell me that if I stop my patient's therapy and I delay their therapy even three months, I can still see and I can still see benefit from my patient with belantamab.

Managing Patient QoL Centers on Expectations and Reversibility

Some things that we need to tell our patients, we want to prepare them. We do not want them to all of a sudden be driving and all of a sudden they cannot see at night. Prepare them to know, hey, there are some patients that are not going to be able to drive, especially at night. You are going to see halos in your visual acuity can drop, and so have a buddy when you are driving.

Also reading, there is some patients that are going to require to increase the font. Like James on his phone. He is getting quite elderly. His font size is 52. Those are some things that we have to do to help our patients. Then the most important piece is, okay, after you have done all this, reassure them that in the vast majority of patients, over 90% of patients, this is totally and completely reversible.

Select Ongoing Trials With Belantamab Mafodotin in R/R MM

Lots of other trials in the pipeline to be aware about. Honestly, I think at this moment in time, in this juncture, this is the end of the drama series of belantamab. I do think that this is where we are going to see it for quite some time. A patient that has had two prior lines of therapy, it is an option. How we choose between belantamab and all the 12,000 medications James had already brought up? We will talk about it during the discussion or ask us during the Q&A, but there are some studies to be aware about. I think the DREAMM-7 was really what brought belantamab back onto the market.

Posttest 3

Back to you all here. You have a 78-year-old patient with relapsed, refractory multiple myeloma progressed after two lines of therapy, including dara and lenalidomide. Patient is not a candidate for CAR T cell therapy. There is also some quite a bit of logistical constraints of patient getting to and from your institution, which is a real phenomenon in our cancer centers. Which of the following is the best appropriate FDA-approved BCMA-directed next-line therapy? Is it a could you guess

A. Belantamab Bortezomib dexamethasone;

B. Elranatamab;

C. Linvoseltamab, bortezomib, dexamethasone; or

D. Talquetamab.

Look at that. Did better than James there. That is a survival curve. If I had one to myself. 100%. It cannot get much better than that. Excellent job, ladies and gentlemen. The answer is exactly what you guys all articulated. Look at the benefit 50% - 100% improvement.

Posttest 4

Next question here. A 66-year-old patient early relapsed, refractory multiple myeloma receiving belantamab. Comes to a community ophthalmologist before dose three. She forgot to wear her contact lenses, which tells you that she has been wearing her contact lenses, which she should not have been. Slit lamp exam shows grade 3 keratopathy.

Visual acuity has worsened from a perfect 2020 to 2080, and the ophthalmologist filled out the REMS program that Donnie is going to talk about, and is telling you that the patient had a grade 3 keratopathy. Patient is wondering, what on earth could I have done to prevent this from happening?

A. There is absolutely nothing at all. You should have just - there is nothing that you could have done, and now we can treat with steroids;

B. Continue wearing your contact lenses, use any OTC product, and use steroid eye drops;

C. Use preservative-free artificial tears regularly. Avoid your contact lenses. Hold and reduce the dose to treat; or

D. Stop belantamab, never use it ever again, because this is grade 3.

We literally got 100%. Nobody else answered. I do not want to bring this down. I have never in my history of my 14 years of presenting have ever seen that phenomenon in my life. Let us move on. There is no explanation needed. You guys got all the right answers.

Managing Toxicities

The remainder of these slides, James already wonderfully articulated how to treat CRS. How to treat ICANS. How to treat some of the infections. I just talked about the ocular toxicities. This is just a nice way if you ever want to go back, and you just want to know the toxicities, we have you covered. We have this all inside a nice little section within the slide deck. With that, I would like to yield my time over to Donnie to complete this presentation.

Managed Care Perspectives in R/R MM

Dr. Donald Moore (Atrium Health Levine Cancer Institute): I will round this out by discussing some different types of managed care perspectives with all these new novel therapies that we have been talking about today.

Cost of Care in Multiple Myeloma

With great advancements comes some pretty great price tags because let us face it, multiple myeloma is among one of the most expensive cancers to treat these days, if not the most at this point in time. Even talking about one of our legacy drugs, lenalidomide, looking back about five years in 2021, it was actually the second highest spend in Medicare Part D plans at an annual rate of about $6 billion.

It was second only to DOACs. You think about DOACs, apixaban, rivaroxaban across all these different indications that are very common, AFib, VTE, you name it, and then you have got this one drug for multiple myeloma that is taken up that much share of things. It is a very expensive disease state to treat. The reality is also that for a lot of the types of patients that we are talking about, we are really talking about triple-class-exposed patients who have early relapse, you might require a BCMA-directed therapy.

This is going to be a very expensive patient. For payers in the room, if you have one of these patients in one of your health plans, they are going to be a very expensive beneficiary. It is upwards of about $35,000 monthly on their cost for healthcare, most of which is going to be myeloma-related, and most of which is going to be direct to drug costs related.

Cilta-cel Cost per Responder

With this, we have seen some great efficacy with a lot of these anti-BCMA-directed therapies. While they are effective, are they also cost-effective? I have got a couple pharmacoeconomic studies, really these cost per responder analyses, which tend to be really what is in vogue right now from a lot of the [?] of study standpoints.

The first is what is going to be modelled from the CARTITUDE-4 trial data. Just as a reminder, that was cilta-cel, one of our CAR T cell products versus standard of care. Really, what they did was they modelled this after a US mixed payer perspective with about three-quarters commercial and about a quarter Medicare. Now, there are different cost inputs, which I am going to show on the next slide, are all the things that we would normally think of here, so drug acquisition costs, administration costs, supportive care monitoring, etc.

With cilta-cel being a CAR T cell therapy with manufacturing, there is a few other inputs that go into there as well, like apheresis bridging therapy and fluid flow depleting chemotherapy. Now, from the cost analysis perspective, per treated patient, it is actually a little bit lower with CAR T versus standard of care.

We are looking at $700,000 versus about $840,000. Then the cost per complete responder is pretty high for CAR T, it is about $1 million. When you factor that up against standard of care, it is nearly four times that, it is about $3.8 million. That is likely due to the continuous need for continuous therapy.

When someone does respond to more of a standard of care type of approach. Then the per-month in progression-free survival was about $31,000 with cilta-cel. Maybe a little bit on the lower side of the spectrum, if we are calling 35 an average versus about 42 five for standard of care.

How did we get there from this type of analysis. These are all the inputs here. When you look at cilta-cel down that middle column, we do see there is a few extra inputs for that from a cost perspective. You got to factor in things like apheresis, giving a patient bridging therapy, lymphodepleting chemotherapy, and also some post-infusion monitoring costs as well.

What we actually see is that the pre-progression costs are a little bit higher with CAR T versus standard of care. CAR T is a rather expensive therapy in and of itself. That is a factor about $25,000. What really helps to set the cost effectiveness of this into a different domain is really going to be the post-progression costs, because we do see that being significantly lower with patients who are receiving CAR T in early relapse versus patients who are receiving standard of care. That is where you get the 704 versus about the $100,000.

Key Takeaways

The key takeaways with this is that while there are some higher pre-progression costs with cilta-cell versus standard of care, that might really reflect some additional resources associated with CAR T cell administration. I think it is also important to if you go read the study, the scenario modelling for this also accounted that about a third of patients getting CAR T would get it in the outpatient setting.

Depending on the health system that you may be working with, like I can say for my own, we probably do 80% of our cilta-cel in the outpatient setting. Certainly, when you model it for us, we are probably a little bit different from that type of perspective. The higher post-progression cost totals are going to be seen with standard of care versus cilta-cel.

That is also likely due to the greater efficacy of CAR T cell therapy over standard of care and the reduced need for subsequent treatments. It is also that when you do have patients who require further and further therapy for more triple-class refractory disease, those types of treatments also tend to be more of a higher drug acquisition cost, so they tend to be more pricey in and of themselves.

Cost per Responder Analysis: Teclistamab vs Elranatamab

How about some of the in-class types of pharmacoeconomic analyses out there? Certainly, the bispecific antibodies. We will talk about this from a formulary standpoint. This is a very busy space. We have got first, second and third in class with maybe a fourth on the way. How do these stack up against each other?

There was a recently published cost per responder analysis of teclistamab, our first in class, versus elranatamab, our second in class. What they did have to do here, because it is not modelled directly off of one singular comparative clinical trial, is they did have to do a matched-adjustment indirect comparison to make a little more apples-to-apples from the perspective of the included baseline patients in those trials.

They model that data off of MajesTEC-1 and MagnetisMM-3 that James had presented. Really, their cost per responder analysis was just modelled over six months of treatment cost. Their inputs are very simple. If you have ever read these cost per responder analyses, they are much simpler than your traditional cost-utility analysis. They just had the inputs of drug acquisition costs and drug administration costs.

Now, what they did find was that the cost per responder for teclistamab versus elranatamab was roughly on the order of about $90,000 cheaper with teclistamab versus elranatamab, but that is again, just modelled up to six months’ worth of therapy. Really, that is being driven by the third-line in this table, which is going to be the drug acquisition costs. Really, that is where a lot of the modelling from this came from, is that showing that teclistamab is maybe associated with lower treatment costs in elranatamab in a triple class, exposed relapsed refractory myeloma population.

Belantamab Mafodotin REMS Program

I think that the other major thing that is important for payers to understand about these anti-BCMA therapies is that they are actually very complex from both an operational and a regulatory standpoint for those of us in health system practice who are trying to deliver these drugs to patients. As Anthony alluded to, belantamab mafodotin does have a Rems program that is rather cumbersome and can be logistically complex for patients. That is due to the risk of ocular toxicities. There is a lot of different people who need to enroll into it between prescribers, patients, and healthcare settings, as well as wholesalers and distributors.

Belantamab Mafodotin REMS Requirements

These next couple slides are just a lot of the requirements that are going to be needed for these different parties. I am not going to go through all this in detail, but it is there for your reference.

Belantamab Mafodotin REMS Requirements and Eye Exams

The one takeaway I do want to really shed light on is the need for patients to receive ocular exams from an eye care professional to be able to receive this medication. They do need to get a baseline eye care exam within 28 days of their first dose. Then, for all subsequent doses, it is going to be within 10 days. Patients are really on the clock to be able to get these eye exams and then get into the infusion center to be able to get this medication. The other part I also look at this with this is to is this is potentially a logistical barrier for patients.

This is an extra visit with a different healthcare provider that is outside the context oftentimes of their cancer center. It is an extra copay for them. It could be an ophthalmologist. It could be an optometrist. If it is an optometrist, it might be a different part of their different healthcare insurance benefits, with maybe vision insurance. This is all factors that make it - some of these deliveries, some of these therapies a bit more challenging for patients.

Bispecific Antibody REMS Program

The bispecifics also have REMS programs. These are going to be less challenging, I think, on patients and more so on healthcare systems. Really, these REMS exist for the risk of CRS and neurotoxicity. Prescribers need to enroll. It is a one-time enrolment. It is pretty easy for them. However, the healthcare setting, the dispensing pharmacy we need to be enrolled, and they need to get authorization to dispense codes periodically for some of these medications as well.

Bispecific Antibody Selection and Formulary Considerations

Now, when it comes to the bispecific antibodies, we have got again first, second, third in class, maybe a fourth on the way. It is a very busy space. I find myself a lot thinking of formulary development for myself on the health system side of things. I am surely for the payer side, you probably think about this as well.

Certainly, this is a very complicated, busy space, and it is only going to continue to get more complicated. How should we be thinking through formulary decision-making with this drug class? First and foremost, there is no comparative clinical trials for all these drugs together. We will probably never get them. Likely, we will get some maybe real-world evidence to compare them at some point in time.

Right now, we do not have comparative things for the hard evidence of efficacy and safety. We are left with all the next stuff. We need to consider what is the total cost of care for each of these bispecific antibodies. As we have seen, there is some published data that maybe says there might be a little bit of a difference between some of them.

We also have to understand the operational considerations with managing potentially multiple REMS programs. For a lot of health systems, depending on the size of the health system, they may prefer one, they may have access to multiple, for payers, I am not sure if you all maybe have something that is preferred on your formulary or if you will cover all of them, but knowing that the differences there can be challenging on the end user side of things and trying to deliver these therapies and managing multiple REMS programs.

We also need to really have some good flexibility for this very rapidly evolving drug pipeline, because what we have seen, the approval of dara tec came like that. It was presented at ASH, published simultaneously, and then FDA-approved within months. That is not going to be the last of it. We are going to continue to see more of that.

It is only going to be a matter of time until these things have new combinations or they are in the first-line setting. We also need to really understand the differences in the initiation of the step up dose phase of this because for all of us on the health system side we are all at large academic medical centers, but for a lot of our community based colleagues, they are still struggling to be able to provide bispecific antibodies in the community because of some of the challenges associated with CRS and ICANS.

I will talk about some of the step-up dose challenges in the next couple of slides. It is also important to understand that the dosing schemas for these drugs have really been a work in progress. There is been a lot of updates to the labels and whatnot. I know elranatamab now has a label for every four-week dosing. Teclistamab also has a recent update too. That is an important thing as you are wandering your different claims.

Current Recommendations for Step-up Dosing When Beginning Bispecific Antibody Therapy

For the different step-up doses for these drugs, they do have a number of different observation periods when you do initiate these drug therapies. It does vary between drugs. For tec and tal, they tend to be a little bit more intensive. For each of the first few step up doses in the first full dose does have a 48-hour monitoring window after each one. Those doses are separated by about 48 to 72 hours.

It is a back-to-back-to-back schema, and that might require an inpatient admission. Elranatamab is going to be a little bit less so. It is going to be a 48-hour that followed by a 24-hour. Then linvo is probably the easiest of all of them. They are weekly step-up doses with a 24-hour observation period after the first two. A little bit less intense. My takeaway here is these drugs utilize a lot of resources, and so they can utilize inpatient capabilities.

Outpatient Model for Administration of Bispecific Antibodies: AE Management

Really, what we should be trying to do is eventually get these drugs fully outpatient. I personally I provide these drugs in the outpatient setting. We have a really robust program where I am at LCI in Charlotte. One of the ways that we can really do this is with remote therapeutic monitoring of patients. There are a lot of different CPT codes that are out there that are potentially billable, that can really help health systems stand up, the ability to provide these drugs and the outpatient side, which is going to be good for all of us because, number one, patients do not really want to go in the hospital.

Number two, it is not a good use of healthcare resources. Number three, inpatient admission will almost always increase the total cost of care. The other major portion with this, too, is also having really good protocols for managing low-grade seizures at home. As James had mentioned, giving things like what we call pocket dexamethasone for patients to take the first sign of CRS or neurotoxicity while they are at home, but also having really good routes to getting patients to perhaps a dose of tocilizumab.

I know from personal experience, a lot of us may try to get some pre-authorization for a single dose of tocilizumab if we do need to treat a patient with CRS for it, because we are also trying to keep them on the outpatient side altogether, which again is going to be beneficial for all of us to really reduce the cost of care for treatment.

Outpatient Model for Administration of Bispecific Antibodies: Prophylactic Tocilizumab

The other major portion here, too is if we can reduce the risk of CRS, can that actually help to facilitate outpatient step up dosing, initiation of therapy, and able to get this into community-based places for patients, too? One of the ways we could potentially do that is with prophylactic tocilizumab. There has been a slew of small studies that have evaluated this. I know our friends down at Emory, they have looked at this. What they did find was that risk of CRS is somewhere about 70% of patients can knock it all the way down to about 26%.

Prophylactic Tocilizumab

Then our friends down in Miami, they looked at this across the board for all the myeloma bispecifics. When you give it for the very first dose, you go from again, about 70% down to about 10%. Certainly, that can really reduce health care resources and the need for ER visits, admissions, and all that.

Comparing BCMA Options for Formulary: Advantages/Disadvantages

Tying all this together, how do we really compare all these anti-BCMA options from a formulary perspective? I think that the short answer is, we do not. These are all different fruits. These are apples and oranges to each other. They just target the same antigen. They are not necessarily interchangeable with one another.

It is not that you would cover the ADC, but maybe have a less of a preference for the bispecifics or something like that. It is really understanding that all these drugs, they all have different mechanisms. Some are more T cell redirecting, some are more traditional ADC, ADC, and bispecifics. They are off-the-shelf CAR T is way more logistically challenging.

It is going to be really limited to those transplant centers, big programs that have a TCT unit. Then the REMS program is certainly going to be something that has to be considered when it comes to patient access too. Certainly, the ADC has a REMS program. The Bispecifics have one. There is differences in their toxicity profiles.

The ADC has got more ocular toxicity. The other ones potentially more toxic. They have got the T cell-mediated redirecting immune effector cell toxicities, infections, you name it. Across the board, they are all expensive drugs. CAR T cell therapy is, of course, a one-and-done. It is going to be the most expensive one up front.

A lot of those are probably going to go through to you as single-case agreements. It may be more cost-effective in the long run because it is going to reduce the need for continuous treatment, versus more of a continuous treatment for some of these other different types of modalities that we have.

Factors to Consider When Selecting Therapies

Now, how do we often think through selecting therapy for patients? Certainly, there is a lot of questions. This is a very busy space, and it is very complicated. It is probably not one right answer. Certainly, if a patient does not have a good life expectancy, they have got a poor tolerability for being able to tolerate lymphodepleting chemo and certain toxicities. If they do not have a caregiver, transportation, etc.

If the answer is no to a lot of those, CAR T cell therapy may maybe not the best choice for a patient. Maybe think about more of a bispecific or an ADC. I will say that CAR T cell therapy, with some of the very unprecedented results that we have seen with it is going to be a great option for patients with early relapse, for those with good performance status, and otherwise, even for heavily pre-treated patients, too.

Pipeline: Phase I Study of Trispecific Antibody JNJ-5322 in R/R MM

Last thing I will mention before we start talking about all this stuff together is, for anyone who does have any pipeline or forecasting departments, know that there is also a trispecific antibody that is currently in development right now. I think it actually has a name. I think the name is ramantamig.

This was presented at ASCO last year. This drug has, instead of two binding domains, one to BCMA and one to CD3 It is got a third that also goes to GPRC5D. What we have seen is something we often do not see in oncology, which is a 100% overall response rate. What we see is mostly CR or better. This is something that is really poised to really shake up the multiple myeloma space and the BCMA space altogether. If you have any groups within your organizations that look at what is going on in the pipeline, definitely keep your eye on this one.

Putting It All Together: Case Example and Panel Discussion

Let us take all what we talked about. Let us start boiling some of this stuff down and talk about some of the nitty-gritty things here. I think one of the questions I often get with BCMA-directed therapy, multiple myeloma in general, is, how do we best sequence therapies?

Sequencing: Role of Prior BCMA-Targeted Therapies on CAR T-Cell Therapy Outcomes

We got to think about the lifetime and the journey of patients. Patients are living longer. They are receiving more lines of therapy. Now we have got all these new drugs that all target the same antigen. What do we do with all of them? Certainly, I know that we will probably never get clinical trial data that will ever really answer these questions.

For some of the really good real-world evidence out there, what does it say about giving maybe an anti-BCMA-directed therapy that is not CAR T before CAR T? I think what we have seen is when you do give anti-BCMA therapy before CAR T, you may actually reduce the response rates of CAR T by a bit. This is from a really great real-world analysis for ide-cel.

Sequencing: Outcomes With Bispecific Antibodies After Prior BCMA-Directed Therapy

Conversely, what about with bispecifics? I think what we have seen also in the bispecific space is that when patients certainly start to receive more and more BCMA-directed therapies, potentially the ability to continue to mount a response to it will likely go down. You see on the graph in the left-hand side that 44% is when patients have received more than two BCMA-directed therapies, reducing the efficacy there.

Discussion Topics 1/2

Let us go with the second question first. James, how do you think through sequencing in relapsed refractory myeloma? What drives some of your decision-making? I know I just showed some things about CAR T and bispecifics, but what about the ADC belantamab mafodotin?

Dr. Davis: We have essentially got three tool buckets that we can use. We have got the bispecifics, the CAR T cells, and now we have the ADC belantamab back. I think the first thing is you look at your individual patient. Some patients are not eligible to receive CAR T because they may not have a caregiver that can be with them for a month.

They may not have a means to stay locally near your treatment center. I am in Charleston, South Carolina. Many of my patients travel several hours away to come to Charleston. One of the eligibility criteria is they have to be able to stay in Charleston for at least two to three weeks, sometimes four weeks. That eliminates the - often some patients, and some patients just flat out do not want to do it.

We have good options in both the bispecifics and the antibody drug conjugate now that we present to patients, we say we have got these three buckets. One of them you get treatment, for instance, dara tec you get treatment every week for two months, you get treatment every other week for four months, and then you are on a month injections after that. Sometimes that is too much for patients.

Some patients do not want to travel every week for several months. We also take into account frailty a lot of times belantamab is a really well-tolerated drug outside of the blurry vision in the eye effect. I have patients in their 90s that have been on belantamab single agent for, Anthony mentioned it, for five plus years that get their treatment every three months and are still in complete remission, and come to Charleston two hours. They get their eye exam in the morning. We are fortunate to have an eye center at MUSC, so they get their eye exam in the morning.

We get the grading form from the ophthalmologist within an hour or so of the eye exam. Then we decide whether we are able to give them treatment every eight or 12 weeks. That works really well for some patients. As far as the sequencing goes, I think that is really nuanced. It is based on most of this data is retrospective.

I think that when you are sequencing BCMA to BCMA, what we know is the longer the time period between the two BCMA is, the better. We have data, for instance, the CAR T cell data patients that did better receiving CAR T after belantamab are patients that had six, nine or 12-month break between the two. We also have that data now with bispecifics, Dr. Dima out of Fred Hutch, published for patients receiving teclistamab.

The patients that had a greater than nine-month break prior to their previous BCMA-directed therapy had almost double PFS than patients that did not. BCMA to BCMA longer time period between. Sometimes we may need something like a GPRC5D or a novel target, or a mix and match approach to break that BCMA to BCMA up.

From CAR T, if patients get a longer, let us say they get CAR T first and they get two, three, four years out of it, we are finding that you can give them BCMA because it is been that long after CAR T, but it cannot be said if you are giving by specific first and then they are progressing while on bispecific, CAR T is likely not going to work. I think we are going to see that come out of some of these real-world studies in the next year or so.

Dr. Moore: I think the other major part too, that I have been really thinking about when it comes to, particularly the advent of bispecifics and CAR T in the early relapse setting, is, how do we make that choice between patients? Anthony, how do you really help to compare and contrast these different types of T cell redirecting approaches for patients?

Dr. Perissinotti: I think James articulated it perfectly. What he ultimately said is we have no idea. We have no idea which therapy we should use first. Yes, we have retrospective data and whatnot. There is going to be selection bias. Of course, responding patients are going to respond longer later. Patients that have longer gaps are going to respond better.

We can do all these mental gymnastics and whatnot, but ultimately, we do not know. I can tell you what we do in our practice, whether or not this is the right thing, I do not think anybody truly knows. Our goal is to get our patients to CAR T cell therapy as early as possible, because to James' point, that first shot at CAR T is going to allow that longest duration of being off therapy.

That is what our myeloma patients need. These poor patients are on therapy non-stop every other week, sometimes weekly, sometimes twice a week, for eternity. They are living so long that some of these patients can actually be on therapy for a decade long where they are in and out of your transfusion center. Our goal is to get them off of therapy as soon as possible for as long as possible. Your best shot is to do it up front with CAR T.

Now, there are logistical constraints and real-world constraints that even if I want CAR T right now, I cannot get my patient CAR T, and so it is going to take one, potentially a couple months for insurance authorizations. No offence, guys in the room, but the second aspect is just the slots from the manufacturer. We do not always have slots. We could be kicking the can down the road.

Ultimately, what we end up doing is we put our patients on a bispecific, and whether or not we bridge them or we continue them on whether it is a bridge to CAR T or we continue them on their bispecific, that is a nuanced approach. Then there is patients that are not a CAR T candidate, to James point. Whether it is disease themselves or they do not have a caregiver. When you look at real-world data, which I think this is really important, and you look at whether it is lymphoma or myeloma, probably about a third of patients actually get to CAR T despite being eligible for CAR T.

They have the caregiver, they have whatever, but it is just all the logistical constraints of getting them there. They live four or five hours away, and they cannot just pick up their lives and leave. Ultimately, like, yes, CAR T is fantastic, but a large proportion of our patients do not get to CAR T, and so it comes down to we just use the bispecific and are happy using it because the efficacy is great, but that is the long and the short of it.

We have been avoiding, even though I sounded like a KOL for belantamab 20 minutes ago, we have been using belantamab after all these therapies. The ocular toxicities do worry us, but a frail patient that is not going to tolerate coming in and out for the hospital with CRS and the infections and stuff, that is a patient we might use belantamab in. James had mentioned extramedullary disease.

Maybe that is a patient population. I think everybody is all excited about dual bispecific antibodies. I am not very excited about that. I do not really like it. I think you in the room who has to pay for all this, should not be very excited for two bispecific antibodies. The death rate that we did not mention was quite high. I do worry about those too. I think until we have a true ideally Phase 3 or a larger Phase 2, I would not use the dual bispecific, but I think a lot in the field will completely and utterly disagree with everything I just said about that.

Dr. Moore: I think we got time for one more. What do you guys think about these current agents being able to be moved into earlier lines of therapy and what data exists for those combination approaches?

Dr. Davis: Back to my second or third slide. We know that the first remission is often the deepest and longest-lasting remission for these patients. Why would you save your Patrick Mahomes for the fourth quarter or your John Elway or whoever your quarterback is? You put them in the first quarter, you use your best drugs up front because we know that that remission is going to last the longest.

We have seen that with the movement of CAR T from fifth line out to second-line, we have seen that with bispecific antibodies moving from fifth line now to second-line in combination. We are using our better drugs first. I think it is just a matter of time before we are using BCMA targeting and other some of these novel approaches in front line, whether it is monotherapy or in combination, those trials are just starting to enroll.

I think that we are definitely going to see these move into earlier lines. Hopefully, that means that we can treat patients with finite duration. Then they can go on receive therapy for a year or two, stop and be in remission for five, six, seven, eight, who knows, we might cure them upfront. I think it is a fairly exciting time in myeloma. I am pretty excited myself, Anthony may not be, though.

Dr. Perissinotti: I am very excited. I think it is more feasible for the bispecifics. WE went from doublet to triplet to quads to what would be like penta. Are we going to call them pentas? I do envision that we would see a bispecific. I think that is more feasible than adding CAR T to the mix up front. Whether or not we do it all five together, or you take an ALL-based approach where you get them in remission, you mop up measurable residual disease that James brought up, and then maybe we can see some more plateaus of curves that James showed earlier.

I do think that maybe we probably should be treating this more like ALL, where you are up front, very intensive. Get them as deep as possible and then mop everything up with MRD. Maybe that is our way to cure this disease that has historically been uncurable.

Dr. Moore: I could not agree more. I hope that the next iteration of how we do develop new studies and drugs in myeloma is going to be very much directed towards getting to MRD negativity and de-escalation of therapy. Probably, say you guys are probably the same thing too, is when we started our careers, myeloma was a treat until the very bitter end. Now, at least with CAR T cell therapy, we have got some finite durations for patients so they can get a break at some point in time.

Discussion Topics 2/2

Dr. Perissinotti: Can I put you on the hot seat now?

Dr. Moore: Yes.

Dr. Perissinotti: The audience asked us several questions here. You have a robust outpatient bispecific antibody program. I want to know how do you assess or they want to know how do you assess patients for outpatient therapy. Are there any specific clinical criteria that are used, or does everybody just do it outpatient?

Dr. Moore: Where I work, we do have an outpatient myeloma bi specific program. Not everybody gets it. We do have a mix of both clinical and what I am going to call social factors. On the clinical side, certainly we are not trying to do outpatient administration for a patient who may be very frail, who may also have much more explosive relapse refractory disease, who might really actually just need to be in the hospital because they might have other types of sequelae that need to be controlled as well.

I think that the things that tend to be one of the biggest barriers to doing so is going to be a lot of the social factors. Certainly, there is going to be some issues of geography. Certainly, if a patient lives too far away from our remote therapeutic monitoring catchment area, then they are not going to be able to be a good candidate for it.

I think the other part too is, they need to have a caregiver available. You cannot have somebody who is trying to monitor themselves at home for fever, for CRS, and for neurologic toxicity, and then having them develop that and then try to drive themselves into the hospital or things like that.

That is certainly not going to be something safe for people to be able to do. It is a mix of both social and clinical factors. I would say too, that looking at the programs that are otherwise published from a lot of other groups across this country too, this tends to be a mix of a lot of those types of factors as well.

Dr. Perissinotti: Thank you, Don. James, can you speak more to the prophylactic supportive care that you use for your bispecific antibodies and what you specifically do in your practice?

Conclusions

Dr. Davis: In regards to CRS and ICANS, we do what is in the package insert. That is typically just during the step-up dosing phase. We provide patients with acetaminophen, diphenhydramine, and dexamethasone per the package inserts before the step-up doses. We discontinue all of those per the package inserts if patients have not had CRS with the most recent dose.

As far as infection prophylaxis, this is probably more of what this question pertains to. At my institution, we put everyone on VZV or HSV prophylaxis with something like acyclovir or Valacyclovir. We put everyone on PJP prophylaxis with something like sulfamethoxazole trimethoprim.

If they do not have a sulpha allergy or pentamidine if they do. Then we also have been providing IVIG primary prophylaxis during the - after the step up dosing period, typically with the start of cycle two or sometimes in the middle of cycle one, especially if the patients are receiving the combination of tec and dara, because there are a number of deaths in the MajesTEC-3 trial and prior to them mandating IVIG prophylaxis. We found that the combination of those two can really be infection-causing, especially in those patients.

Dr. Perissinotti: Irrespective of the IgG level, you are starting it.

Dr. Davis: We are, yes.

Dr. Moore: I do virtually the same exact thing.

Dr. Perissinotti: Do you find that insurance authorizations are challenging? Because in the past, it was always number below number equals IVIG. Now the number does not matter.

Dr. Moore: To be frank, I think that sometimes pre-authorization of IVIG is challenging in and of itself because there are times in which it is going to be able to be covered under medical benefits. I can get an infusion. There is a lot of times it is not going to be that I am going to need to send it out to a home infusion, home health, or to a non-hospital-based type of infusion area. I have not gotten too much pushback, I think, on the number. I would also say too that I think a lot of patients going into it are on it already. That might be a factor, that too.