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

What Oncology Pharmacists Need to Know About Targeting BCMA in Early Relapsed/Refractory Myeloma

Anthony Perissinotti (University of Michigan): Thank you very much for joining us. I'll set the stage to give you a little bit of basics of what multiple myeloma is.

Overview of BCMA in R/R MM

I'll set the groundwork for Don before he gets into more complex things. What is multiple myeloma? It is a cancer of your plasma cells that accumulate in your bone marrow and they also produce a monoclonal immunoglobulin or a light chain. And this we often refer to it as the M-protein. And this is often in addition to both the M-protein and the actual plasma cells.

These are what is causing the constellation of symptoms. And these are the things that ultimately lead to the diagnosis of multiple myeloma. And as you all know, that is the CRAB criteria. So having end-organ damage of hypercalcemia, renal dysfunction, anemia or bone disease. So usually these are lytic bone lesions.

Fortunately, this disease is not that common. There's only 36,000 new cases in the United States and it is also a disease of older patients. So when we're thinking about our therapies that we're giving patients, we have to be very thoughtful because there – they can be older and they tend to have multiple comorbidities.

For decades, we essentially were making no progress, very minimal progress. So we moved away from using chemotherapies to novel therapies, bortezomib/lenalidomide. And all of a sudden, we have an inflection point with our novel therapies.

Now we are undergoing the next current inflection point, and that is with our immunotherapies.

Unfortunately, despite all these advancements, we still are not telling our patients that we can cure them. There are certainly subsets that have very long, durable remissions, but ultimately, every patient does relapse and they require additional therapies. And every time they relapse, their – their disease course becomes shorter and shorter.

We have close to a dozen FDA approvals in the last 10 years.

The way that we pick upfront therapy is we pick from each different category. We have proteasome inhibitors. We usually pick bortezomib because it's the most cost-effective and relatively well-tolerated. We then pick lenalidomide/daratumumab and dex. So we use quads for the vast majority of patients. Our BCMA-targeted therapies are used mostly in the relapsed/refractory setting.

But they are moving up earlier, earlier lines of therapy, potentially even in the second-line.

BCMA is overexpressed on multiple myeloma cells. And also the higher the expression usually means worse outcomes for patients. So the main take home message is that this is highly expressed in multiple myeloma cells, and therefore we can use our targeted therapies for it.

With our targeted therapies, especially our immunotherapies, there are a multitude of different mechanisms of resistance. And I'm going to turn it over to Don.

Recent Advances in BCMA-Targeted Agents for R/R MM

David Moore (Atrium Health Levine Cancer Institute): Thanks, Anthony. Now that we know all about BCMA as a target in myeloma, how do we actually go about therapeutically leveraging this with our different treatment options?

We do have a number of different treatment options that target BCMA. The first one we'll talk about is going to be your antibody drug conjugate, belantamab mafodotin. A humanized IgG1 anti-BCMA antibody that is conjugated to a microtubule disrupting MMAF agent.

So this drug has really had quite the story drug development history. So this was originally approved under the accelerated approval pathway based on the single-arm phase II DREAMM-2 trial back in 2020. And just a couple years later, it was voluntarily withdrawn from the market due to failure to show a PFS benefit in what was supposed to be the confirmatory DREAMM-3 trial, where belantamab mafodotin as a single-agent went up against pom/dex.

And so it went off the market for a little bit. It just came back in October 2025. It was FDA re-approved in combination with bortezomib and dexamethasone after at least two prior lines of therapy, including a PI and an IMiD based on the DREAMM-7 trial.

Now, there's also a few other ways that we can target BCMA in the treatment of myeloma. And that's certainly with CAR T-cell therapy. And so we have two products approved by the FDA right now, ida-cel and cilta-cel, based on the original trials of KarMMa and CARTITUDE-1, respectively. And those are more in the deeply relapsed/refractory patients.

And even then, we see very high overall response rates, very deep responses. It is a one and done type of treatment, but it is very operationally complex to actually be able to deliver. We also have some other anti-BCMA CAR T-cell therapies in the pipeline in development, such as anito-cel. And also recognize that there's some other, you know, CAR T-cell therapies that target different antigens in myeloma, such as with GPRC5D that are currently in development right now too.

And then lastly, the other way that we can target BCMA is with our T-cell engaging bispecific antibodies. There are three anti-BCMA bispecific antibodies currently approved by the FDA with a few more in development as well. And then I'll also mention that we have an anti-GPRC5D bispecific, talquetamab.

And so we have teclistamab, elranatamab and linvoseltamab that all target BCMA. They were approved in 2022, ’23 and ’25, respectively. And their original approvals were all on the accelerated approval pathway after at least four prior lines of therapy, including an IMiD PI and anti-CD38 antibody. But as we'll see, we're starting to see these agents come into the early relapse setting here.

We've already seen that now in the past few months.

And so with that, the MajesTEC-3 trial, which was a plenary session at ASH 2025, simultaneously published in England Journal Medicine and then led to an FDA approval just three months later.

So this looked at the combination of teclistamab/daratumumab in an early relapsed setting versus the triplets of either dara/pom/dex or dara/bortezomib/dex, which was mostly DPd. So about 90% DPd. It was essentially investigator's choice, but it was mostly that.

What we did see was really a quite a stark difference in progression-free survival. So at three years, that PFS was 83.4% with tec/dara versus just shy of 30% with the control arm. And this actually led to, I think, the best hazard ratio that's ever been seen in a randomized controlled trial in the setting of multiple myeloma, which was 0.17. So this did lead to, you know, the FDA approval of this combination of tec/dara for adult patients, after at least one prior line of therapy, including a PI and an IMiD based on the MajesTEC-3 trial.

And this is certainly not going to be the end of the story. There's a lot of other ongoing trials and a lot of interest here. And this is not all inclusive, but these are the things that really stand out to me. This is what I'm personally watching out for.

And so there's the DREAMM-10 trial, which is looking at belantamab/mafodotin/len/dex or BRd up the MAIA trial regimen or DRd, which has been, you know, pretty much a stalwart that we've had in the newly diagnosed ineligible for transplant population.

It's going to be curious to see if belantamab/mafodotin can give DRd a run for its money.

There's also the CARTITUDE-6 trial, which is looking at dara-RVd as induction, followed by a randomization to cilta-cel or auto transplant. And so we actually had this at my center and treating some patients on this. This will read out several years down the road, but I think it's going to answer a question of, you know, is CAR T going to potentially replace auto transplant in the newly diagnosed setting?

There's also MajesTEC-4, which is tec/len versus len versus tec after transplant. And then there's MajesTEC-9 with a presentation at ASCO for this. Teclistamab versus standard of care of PVd or Kd has led to improvements in survival in the early relapse setting.

And then there's the MagnetisMM-5, which is kind of a similar design in some respect as MajesTEC-3, which is elranatamab with or without daratumumab versus elranatamab versus DPd again in an early relapse setting.

And then finally, the iMMagine-3 trial, which is, you know, kind of a spiritual successor from CARTITUDE-4 for anito-cel, where it's anito-cel in early relapse versus standard of care.

And so with all these different options that we have, you know, how do we really choose between them? And I think it's important to understand the pros and the cons, the advantages and disadvantages of these three different types of drugs when it does come to targeting BCMA.

So first things first, they all target BCMA, but they all really treat myeloma in different ways. And so belantamab mafodotin is going to be our very traditional antibody drug conjugate. Whereas CAR T-cell therapy is, of course, you know, genetically engineered and modified T cells. And then our bispecific antibody being the newest that we've had T-cell engaging type of therapy.

And so the ADC, the bispecifics are off-the-shelf therapies. They're right there. CAR T-cell therapy can be very, very complex. It's going to be limited to centers with TCT programs. It is, however, a single one-and-done type of treatment approach, which can be attractive to a lot of patients who may be fit enough to be able to go through it.

Of course, toxicity profiles are really quite different between these agents. With the ADC, we have to worry about ocular toxicities. And because of that, there is a REMS program. The REMS program does require additional provider visits for the patient, which is something absolutely to consider.

With our bispecific antibody, there is the risk upfront of those T-cell redirecting toxicities, CRS and neurotoxicity. Same thing with CAR T-cell therapy, albeit with CAR T-cell - It does tend to be a bit more severe than with the bispecifics.

There is a REMS programs for the ADC and the bispecifics. With the bispecific, the REMS programs for them—they just get de-escalated, which is, I think, a nice thing for us in the pharmacy.

While CAR T-cell therapy is certainly the most expensive upfront, while it's not maybe formal pharmacoeconomic analyses versus these other therapies, it potentially might be cost-effective in the terms that you're going to reduce long-term costs related to treatment. So it's a one-and-done, whereas bispecific and the ADC, they are going to require continuous administration on label at this current time.  

So with that, Anthony, how are you all up in Michigan thinking about selecting BCMA-directed therapies in the early relapsed setting for myeloma? How is that discussion going between bispecific, CAR T or the ADC, and then what operational challenges do you face that really helps to lead to that incorporation of these therapies in practice and how you individualize things for patients?

Anthony Perissinotti: Yeah. So I mean, that's like five loaded questions there. And obviously there's no right or wrong answer.

I can tell you, you know, I'm in a center that has both the ability to give CAR T. Not every center has the ability. And so if you don't have the ability, well, either you have to find someone and send them to a CAR T center or you don't give CAR T, right? And that's your easy out of not picking CAR T.

We can also give bispecific antibodies at my center. So it is for an early relapse patient and even honestly, any patient that hasn't received a bispecific or CAR T. Usually, we're debating between those two. We are reserving belantamab a little bit later, mainly because of the ocular toxicities and the logistics associated with that. But I would say majority of the time our goal is to try to get our patients to CAR T, if possible, because our goal is to get our patients off of therapy.

We want a one-and-done therapy. And we hope that we can keep our patients off of therapy for years. Not every patient has those types of responses, but that's what our goal is.

Now, CAR T is not available right away. It can take weeks to months after insurance authorizations and workups. So you have to bridge the patient. Ultimately what ends up happening logistically is we put our patient on a BCMA bispecific antibody as a bridge to CAR T.

Don, how did you guys pick between all three of your BCMA bispecifics?

Donald Moore: It's really important to include the patient in that decision. Generally we try to, with all things considered, try to get patients in early relapse to CAR T, particularly with cilta-cel, which I find to be very helpful to be able to do in the early relapse setting. But exactly, we want to be able to get patients off of therapy.

I think the other part too with it is giving it in the early relapse setting, we have a lot more options available to us to be able to bridge patients to that. And it tends to be a little bit easier hopefully to have a lower burden of disease perhaps. You know, those patients who are just slowly relapsing on len maintenance, you are able to kind of transition them to an easy bridge to be able to get to CAR T-cell therapy.

Otherwise, there's also a lot of patients who are just not interested in going to such an intensive therapy. So it's weighing the pros and cons between trying to actually get them to CAR T versus doing like a dara/tec if they're not dara refractory or even considering other anti-BCMA-directed therapies there, too.

I think the other challenge with belantamab is that your patient has to be not refractory to bortezomib, has to not be intolerant to bortezomib, which actually tends to be a lot of patients more of that relapsed setting. But I think what we're also really starting to see is that these anti-BCMA drugs are really for early relapse now.

And I think the other question that we have is using belantamab for more of an extended therapy. On-label says to give it every three weeks. I will personally say when I do give belantamab, we're not giving it every three weeks. We're probably doing at least, at minimum, you know, every six weeks, probably even more than that, probably every nine to 12 weeks or so.

There's some post-hoc data from DREAMM-7 and DREAMM-8. They really do support that too.

Anthony Perissinotti: Yeah. I completely agree.

Donald Moore: Yeah.

Anthony Perissinotti: Not all centers have the ability to do bispecifics or CAR T. When you're out in the community and you don't have the ability to monitor for CRS and ICANS, belantamab is certainly a great option for those patients. So I completely agree.

Optimizing Patient Outcomes by Effectively Managing Ocular Toxicity Associated With BCMA-Targeted ADCs in R/R MM

Anthony Perissinotti: So in the past, we had no idea why we were seeing ocular toxicities. Because when you think about belantamab, it binds to BCMA, but we don't think that there's much, if at all, any BCMA within the cornea. And so there are two hypotheses of how the damage occurs. One is through simple tear secretion. So as belantamab is circulating through your blood, it can also get distributed into tears. And then as you – as you blink, you can have tears that are bathing your cornea. And there's microscopic amounts of belantamab that can sit on your cornea. And that's why we say don't wear contact lenses.

The second is limbal diffusion. So your —your cornea is not vascular—highly vascularized, but around the eye is. So the limbus perfuses most of your eye. And so because that's vascular and belantamab is circulating in there, you can start depositing into the limbus system.

Now, the reason why belantamab tends to have more peripheral corneal abrasions and cysts is because the blood flow is on the peripheral aspects of your eyes. As things get worse and worse, they start to move more centrally. And that's when you start to see higher grades.

Anthony Perissinotti: So what do we actually do when this occurs. Grade 1, nothing. You can continue the dose. Grade 2, 3 and 4, the approach is essentially the same. Hold the therapy, wait till it resolves to grade 1 or less and then go down one dose level. So in this case scenario, you know, the – the FDA approved dose is 2.5 milligrams per kilogram every three weeks.

What the PI says to do is reduce it to 1.9 every three weeks. And in Don and I’s experience and others, that might not be enough for many of our patients. And what we're finding is that a large proportion of patients end up staying on therapy because it's working, end up pushing it out to every eight weeks, which is every two months. Even some patients push it out to every 10 weeks, 12 weeks or three months.

So you kind of have to find the sweet spot for your patient of where they're benefiting but also where they're not getting inhibited for their daily activities with reducing their visual acuity.

Managing Key Adverse Events Associated With Bispecific Antibodies

Anthony Perissinotti: All right. So let's go through our bispecific antibody toxicity. The big ones are cytokine release syndrome, ICANS, so the neurotoxicity, and then some of the infection-related things, neutropenia. And then with talquetamab, we can see a myriad of other toxicities that we're not going to talk about because today's program is about BCMAs.

So CRS is a cytokine storm, if you will, where you can hyper perfuse organs, end up in the ICU with hypotension and need mechanical ventilation. Obviously, that is a grade 4 reaction, but grade 1 is simply just a fever. Grade 2 is a fever plus hypotension or respiratory compromise where you need a little bit of nasal flow, O₂.

Grade 3 is, you know, you might need some pressors on your way to the unit and requiring high nasal flow.

The treatment of choice by most should be dexamethasone. I know there's a fascination with tocilizumab. So that is currently also a standard of care. But in general, for grade 1, I do nothing, just supportive care. Grade 2, dex or toci.

At my practice, when they're inpatient, I actually just give them a fluid bolus and see if they get better before throwing on dex or tocilizumab. But where I really start to use dex and tocilizumab is grade 3 and grade 4.

Do we see ICANS? Yes. But it's far, far, far less common than ICANS with our CAR T-cell products.

And I think the other thing is you have to think about these myeloma patients are on lots of polypharmacy. They're on many sedating meds, they're on opioids. And so you have to rule out other causes of ICANS before you just say, “Oh no, this is ICANS, start steroids.”

With ICANS, I am more aggressive with treating than CRS, mainly because this can be pretty prolonged and pretty devastating to patients. So I jump on my dexamethasone at earlier grades, usually grade 2, but a prolonged grade 1 I'll also do it. So essentially there are two presentations of ICANS.

One, a patient, you walk into the room and they can't have a conversation with you anymore. They're just completely somnolent, not really making sense, and that requires dexamethasone. The second one is less common, but it's hyper excitatory where they're hallucinating and making things up. They can talk in full sentences, they can answer questions, but they are just almost psychotic and that also requires dexamethasone as well.

Infections are primary issue, not only early on, but after your patient's been on therapy for quite a long time.

You can see that a large proportion of patients will get infections, but also they'll get higher grade infections, grade 3 or higher. Some data to say that talquetamab has a lower incidence and it primarily might be that just BCMA that has a higher incidence, but ultimately all of them can cause infections.

IVIG has been one that the myeloma community is really jumped on and started to use prophylactically. There's, you know, emerging data and accumulating data that suggests that infections, high-grade infections are reduced if you give IVIG prophylaxis.

As far as anti-infection prophylaxis, what Don and I do at our center is we give all of our patients pneumocystis prophylaxis, and also HSV VZV prophylaxis with acyclovir. You do not need antifungal prophylaxis. You do not need antibacterial prophylaxis. But again IVIG is recommended.

Fatigue is something common with our patients that are on therapy for a long time. A lot of it is probably just immune system, energy, and, you know, just being constantly stimulated all the time. Not really any great pharmacological interventions, except for potentially holding doses, spacing doses out if clinically appropriate.

Don, in your practice, how have you been able to manage the toxicities associated with our bispecific antibodies?

Donald Moore: As you alluded to we standardly give everybody anti-zoster prophylaxis with acyclovir. And then we do pneumocystis prophylaxis, but you know, alternatively pentamidine or dapsone, the latter of which after a G6PD test.

I periodically will assess T-cell subset studies just to kind of see where they're at, but they're generally going to be remaining on it.

We also preferentially do primary prophylaxis with IVIG, particularly with dara/tec, because there is an update in the study protocol to essentially mandate that because it did have a very high risk of infections with it. And so that's something I do generally start even in the absence of recurrent infections or anything like that.

The only times I ever add any additional prophylaxis is if someone's got more prolonged high-grade neutropenia, I have certainly seen with anti-BCMA bispecifics that have kind of lingered a little bit longer than I wanted to after giving some GCSF. I might just do a short course of some antimicrobials there too.

A big topic of conversation as of late is the use of prophylactic tocilizumab.

A lot of centers are starting to move to this. We're starting to add this into our repertoire because you know we're also just becoming a very large volume of these patients. It can be operationally challenging for a lot of places.

Anthony Perissinotti: Yeah.

Donald Moore: So pocket dexamethasone our go to approach as far as the treatment of low-grade CRS. And I think it is the hallmark that we can keep patients at home to be able to do this fully in an outpatient setting by doing so.

Anthony Perissinotti: Yeah, I completely agree. I think prophy toci is really more so treating the dysfunctions of the healthcare system as opposed to treating actual CRS. I think we're all very comfortable with a grade 1, a fever, right? And that's what tocilizumab is reducing.

The challenge is we don't have the infrastructure to bring in our patients, to call our patients and make sure that they're safe 24/7. And so, you know, because of staffing issues, I think most centers are using toci mainly because they don't want to have to have all the calls throughout the day, throughout the night of, “Hey, I just had a fever. What do I do? Right?” And it's – it's simple, right? It's take Tylenol and call us back in two hours if you're still fever and or feel unwell, right? It's easy.

But that time commitment could be 10 to 20 or half hour for some patients. And when you think about the sheer magnitude of the amount of patients that we're going to be treating with bispecifics now with the MajesTEC-3 or 9 and all the other data, right? The volume is going to be massive. We can't be treating fever calls all day long. So I get it. I don't like it. I don't think we need it, you know, clinically, but logistically and infrastructurally, I understand why many centers have to do it.

Now, we still give our bispecifics inpatient. So I don't do prophy toci inpatient. I can watch those patient. I can jump on it as soon as possible, right? And that's why I'm more comfortable with these grade 2s of doing nothing, right?

And there's some data that was presented at ASH from, you know, our collective groups that essentially said, “Hey, grade 2, you probably could do nothing but a fluid bolus and monitor your patient. They're going to do perfectly fine. You don't have to jump on tocilizumab, dexamethasone.” But that's in controlled settings, right?

Donald Moore: Yeah.

Anthony Perissinotti: Not every center is used to and comfortable managing CRS like high volume centers are.

Donald Moore: And I think the other thing…

Anthony Perissinotti: Go ahead.

Donald Moore: That goes with it is we need to also really find ways to keep these bispecifics outpatient.

Anthony Perissinotti: Yeah.

Donald Moore: Because they're going to eat up a lot of resources that are, you know, taking away beds from other patients who really need it. And it's also going to be really expensive on our healthcare systems, particularly when these things get into earlier line settings in the newly diagnosed setting too.

Anthony Perissinotti: Totally agree.

Donald Moore: Yeah.

Anthony Perissinotti: How many weeks does it take to reach MRD negativity with our bispecific antibodies? So I mean, it's pretty quick, right? I think most of the time we're not monitoring for CR for at least two to three months or so. And at that point, many patients are already MRD negative.

If you do check early, some patients can become MRD negative, at least by flow cytometry within a month. So that's 10 to the negative four. Now if you're looking at NGS of 10 to the negative five or less, it could take a little bit longer. But these responses are quite rapid, which is unique for immunotherapy. Usually, we think immunotherapy takes forever to work.

Now is it going to get you out of a rapidly progressing multiple myeloma? Probably not. But they are relatively rapid. In those cases, maybe you want to use belantamab to put out a fire and then mop it up with BCMA, CAR T.

Donald Moore: And then the other question we have is how did you start the outpatient process with bispecific antibodies?

This has been a very heavy weight on the pharmacist shoulders at many health systems. One of the things that was really helpful at my own center was it was actually the physicians who really started to get the ball rolling when it came to the needs for admission and we were technically always doing this in the outpatient setting, they were just getting an infusion, going to an OBs for two nights, back out to infusion, back and forth, back and forth.

They become very laborsome doing all those admission and discharge notes and med recs and all that other stuff, and getting the patients in bed control. And so I think the best way to do it is just to get a champion on that other side outside of pharmacy.

We can help a lot when it does come to protocol development, the education and all that other stuff. It's really helpful to get really good, strong provider buy-in and also learn from others. And so, certainly talk to other people who've developed outpatient programs. You're not out there alone trying to do all this.

Anthony Perissinotti: Yeah. And if you have reluctance from your providers, create a coalition within your own group, right? Get your nurses, get your social workers, get a whole village and team up.

Let's put protocols in place. Let's have nursing monitoring parameters. Let's educate people to be able to do this outpatient. Your job is to set your nurses up for success, to teach them how to triage the calls, how to manage the CRS, how to write the notes, how to get a patient to emergency versus stay at home and manage things. So the struggle is real.