Beyond the Basics: Bispecific Antibodies and the Care of Patients with Relapsed/Refractory Multiple Myeloma

Kevin Brigle:

Hi, and welcome to JADPRO's Roundtable discussion on Beyond the Basics: Bispecific Antibodies in the Care of Patients with Relapsed/Refractory Multiple Myeloma. My name is Kevin Brigle, and I'm a nurse practitioner at the Massey Comprehensive Cancer Center at Virginia Commonwealth University in Richmond, Virginia. It's great to have you here, with my colleagues, Mary Steinbach and Kelley Julian. Mary?

Mary Steinbach:

Hi, Kevin. Thanks so much for having me here. As you said, my name's Mary. I work at Huntsman Cancer Institute at the University of Utah, which is in Salt Lake City. And I have the privilege of taking care of multiple myeloma patients.

Kevin Brigle:

Kelley?

Kelley Julian:

Thank you so much Kevin and Mary. I'm thrilled to be here too. I'm Kelley Julian, and I also work at Huntsman Cancer Institute alongside Mary, which is a huge privilege and honor. I've been a clinical pharmacist with the multiple myeloma group here since 2018, so I've definitely seen a lot of changes, and I'm excited to talk with you about some of them today.

Kevin Brigle:

Okay, so let's get started. This is a 3-part series, and in the first part we're going to be talking a little bit about bispecific antibodies and how they work, and comparing them and contrasting them a little bit with CAR-T. We'll move then to some clinical trials, and talk about how these drugs got approved. And along the way, we're going to introduce a few case studies utilizing these agents, and showing you how we might use those particular drugs.

I think in the first part of this talk we'll move on to a discussion on relapsed/refractory multiple myeloma. When we think about multiple myeloma, we know that it's an incurable disease, but it's very treatable. And as we've added more and more agents, patients have been living longer and longer. As we can see on this particular slide, we can look at the first part. We can see, in 1975, survival wasn't so great. We saw a pretty good increase up to the year 2000, likely due to the introduction of autologous stem cell transplant. And then the real revolution came in the subsequent 20 years, when we've seen a very large increase in 5-year survival on these patients. And now, more than 60% of patients live at least 5 years, and a great number of patients are living at least 10 years or better.

These drugs are getting very, very good. I know Mary and Kelley probably have patients, as well, who have been in remission for more than 10 years, and actually really doing quite well. In the early 2000s when I started, median overall survival was 3 to 4 years. And now we talk to patients with good side genetics, and median overall survival is at least around 10 years then, as well. And again, when patients relapse, we have lots of options and I'll show you that in the next slide.

But I would like to ask the question then, to Mary and Kelley. So patients relapse, and we know there are different types of relapses. Do either one of you care to expound upon the different types of relapses, and when we might consider changing treatment?

Mary Steinbach:

Sure, I'll take this one on. Thank you, Kevin. Relapsed/refractory multiple myeloma can be defined in a number of ways, but one of the general things to remember is that you want to define what a patient's disease characteristics are, and then the IMWG.

IMWG has a great slide in the NCCN guidelines that tells us what biochemical progression is, which is just going to be an increase in a patient's monoclonal protein, or perhaps their serum free light chains, and they're otherwise asymptomatic. But then we have symptomatic progression, which means perhaps the patient presents with a new CRAB criteria, or a myeloma-defining event like developing a bone lesion. Those types of relapses tend to mean the patient should change treatment, or go on a new line of therapy sooner. Biochemical progression can be something that is just monitored, and you have frank discussions with the patient about when the best time to either initiate treatment or change treatment should occur.

I think it's important when we're talking about bispecific antibodies because, at this point in time, they are all approved at 4 lines of therapy or more. And so, a line of therapy is defined by treatment regimen, and again, there are very strict academic definitions for a line of therapy. I think in the real world, we can think of a line of therapy as current treatment that the patient's on, and if they've had exposure to a proteasome inhibitor, a CD38 monoclonal antibody, an immunomodulatory drug, and have had 4 different combinations of those drugs, then they are eligible for bispecifics.

Kevin Brigle:

Okay, very good. And Kelley, I would interject in there, too. Are you utilizing MRD at all, when we talk about progression and changing therapies?

Kelley Julian:

I think we use MRD a lot, and we don't have a good answer necessarily specific to relapse. I think we look at MRD in our practice largely post-transplant, and we're looking at it post CAR-T, and are these patients who are eligible for bispecifics in that window? I think the answer is yes, but we've had issues in the past, with MRD being not necessarily covered by all insurances. And Mary, I don't know if you want to add anything there, because I don't necessarily order that test. But as far as determining what line of therapy, I think it's kind of hit or miss still, as if we're using MRD in this setting, because usually it's a pretty frank relapse if we're talking about bispecifics.

Mary Steinbach:

Yes, I would just add to that, that at this time point, there are no recommendations to define progression, or the need to change therapy by a change in MRD status for a patient. And so, remember MRD is defined by bone marrow biopsy results, at this point in time, so we're currently not making clinical decisions based on it. Does it weigh heavily, in the back of our mind, when we know a high risk patient is now MRD positive, and they had previously been MRD negative? Yes, but we are not making decisions to initiate new treatments just with that change.

Kevin Brigle:

Okay. Sounds pretty much like what we do here as well, so all sounds good.

In this next slide then, we really have a timeline of the various drugs that were developed from 1960 through current day. I kind of divide this artificially into 4 sections, and the first section would really be the kind of old style, where we had just melphalan and prednisone, from the 1960s. As we move then into the 1980s, we can see again that development of autologous stem cell transplant for treating patients. And that's of course where we started to see a little bit of an increase in overall survival, certainly an increase in progression-free survival.

And then really the next era is that first revolution, and that's kind of the novel drugs that came about. That was a development of the immunomodulatory agents, thalidomide, pomalidomide, and lenalidomide, in combination with the proteasome inhibitors, bortezomib and carfilzomib. They added a lot, and we really started to see increased overall survival at that time.

The next really big revolution that I recall is when we finally got some immunotherapy in multiple myeloma, and that was in 2015, with the approval of daratumumab and elotuzumab. Daratumumab, specifically, turned out to be a very good drug in anti-CD38 monoclonal antibody, very rapidly moved up the line from fourth line up into first line therapy. Another similar drug with a slightly different mechanism of action, isatuximab, then also an anti-CD38, was approved as well.

And then what I would really call, and these are my names by the way, the era of enhanced immunotherapy, and that came about in 2021 with the development and approval of CAR-T therapy. In 2021 with ide-cel being approved, and in 2022, with cilta-cel being approved. And both of those, then, importantly target BCMA on the cell surface of the myeloma cell.

And then right on the heels of that was the approval of the first bispecific antibody, teclistamab, which also targeted BCMA, followed by talquetamab, elranatamab, and then just the most recent approval as well. And then, if we think about CAR-T, again, great drugs, they really re-engineer our immune system. Bispecific antibodies do function, just slightly, a little bit differently. And we'll go into that then as well.

If we move to the next slide here, we can actually see the drugs that are currently approved, the bispecific antibodies, and their targets. And those that target BCMA would be teclistamab, elranatamab, and linvoseltamab then, as well. And again, those are the same ones that target CAR-T, is that BCMA. Talquetamab targets the GPRC5D protein on the myeloma cell surface. And then, there is another one in development, cevostamab, which targets FcRH5 on the cell surface. And there are of course others then in clinical trials, as well.

Basically, each of these targets is going to be present on the malignant myeloma cell in greater quantities than it is on the normal plasma cell. But of course, there are side effects. None of these are perfect, and their side effects are really related to the fact that there are some of the targets on normal cells, and other cells that aren't on the immune system.

When we think about the mechanism of action of these particular drugs, then as well, we can see on this particular slide, we should have talquetamab, which targets GPR5C on the left, excuse me, on the right. And then the other 3 drugs on the left. And basically, these drugs are, they're 2-armed monoclonal antibodies. One arm is going to bind CD3 on a T cell, and the other arm is going to bind the target on the myeloma cell.

There's this immunological synapse that takes place that the T cell is activated, there’s this release of cytokines, and this release of cytokines then leads to the destruction of the multiple myeloma cell. And so it really just depends upon which target that we're looking at.

If we were to compare and contrast this then, with CAR-T, and this particular slide, again, CAR-T is shown here on the right. And it's a bispecific antibody, it's either infused by IV or by sub-Q injection into the patient. And that's where, again, the synapse between the CD3 and the multiple myeloma cell take place. CAR-T, on the other hand, is a little bit different. And we harvest a subset of lymphocytes, we send them off to the pharmaceutical company to be re-engineered. Sometimes that'll take anywhere from 2 to 4 weeks. Those are brought back, and then re-infused back into the patient.

So whereas the bispecific antibodies are essentially utilizing all 300 billion T cells that are present in our body at any one point in time, to kill the myeloma cells, the CAR-T specifically engineers a subset of those cells to take care of the myeloma cells. And in fact, as we get rid of the normal T cells, these patients get lymphodepleting therapy prior to, so we actually have room for expansion of the CAR T-cells to do their business, as well.

So the primary concerns basically of any of the either bispecific antibodies or the CAR-T are going to be two very specific side effects, which are cytokine release syndrome or CRS, and the neurotoxicity that can be associated with activating the immune system. And in fact, the bispecific antibodies all have a REMS risk evaluation and mitigation strategy associated with their use, for the black warning black box warnings of CRS and neurological toxicity.

And interestingly, CAR-T had that very same REMS and black box warnings up until this past month, when the FDA took that off. They felt, apparently, that the side effects were well known, and well enough controlled, that they felt comfortable doing so.

And so we actually, if you were to compare CRS and neurotoxicity, you'll see it a little bit higher in CAR-T than you will in the bispecific antibodies. And one of the reasons is because with bispecific antibodies we can do what is called step-up dosing. We can control the amount of T-cell activation that's present. So, all the different bispecifics, as Mary and Kelley will discuss, have different step-up dosing and different premeds that we use as well, which will help control that toxicity.

So, again, these bispecific antibodies all have a REMS requirement for not only the provider, but for the institution and for the pharmacy then as well. And so I guess my question, Mary and Kelley, so obviously we have the certification. But when you get referrals from the outside and then you send the patient back, have you had troubles with the referring institution getting REMS-certified in any way, shape, or form? I know we have, so I'm just curious.

Kelley Julian:

I'll start, Mary, and then you can fill in the gaps. We've worked with a lot of different community sites where we practice in Salt Lake City. We're a catchment area for 5 surrounding states, and so we've actually even been and traveled to a couple of these places and worked with these teams. Everybody's a little bit different. I would say we try to be proactive on the frontend in setting up the REMS program, and sharing our REMs with them, and what works well and what hasn't. From the pharmacist perspective, I would say that we started with our REMS program and we had an authorized representative that was not within the pharmacy group, and then we went through our first audit a year later, and we ultimately ended up changing that. Just because, as you mentioned, you've got the prescriber component of the REMS, and then you've got the health-care setting and the dispensing pharmacy component.

So, to keep track of all of the different pieces for those audits that can come through on an annual basis, we found that to have an authorized rep in the pharmacy group that's keeping track of everyone's training and able to look at all the different dispense codes, it's helpful to do it in that way. So we had that learning the hard way, and we've kind of encouraged our community sites to model after that.

I don't think we've had any major specific issues. I have spoken with different pharmacists that are practicing throughout the nation, and everyone has interpreted REMS a little bit differently for all of these drugs. And depending upon, like as far as, do you put in the authorization code upon verification? Or do you put it in the plan sooner than that? Those types of things are kind of open for debate and discussion, but good record keeping is the main thing that we've shared, and having everything in place prior to the patient starting therapy is critically important.

Mary Steinbach:

Yes, I think I'll just add a little bit of the provider's perspective. So, you guys both mentioned that the REMS for these bispecifics, the prescribing provider needs to be REM-certified. As a nurse practitioner at Huntsman, I am not a prescribing provider, and so I don't have REM certification for these bispecifics, but I am the person assessing and evaluating patients while they are on this. So you need educational knowledge about cytokine release syndrome and ICANS, and how to do the dose ramp-up, and monitor patients. But I don't personally have to have REM certification, nor do any nurses in an infusion suite who are taking care of these patients, which I think could be, or we heard feedback, that that is an area of concern for some community sites as they try to deliver these drugs. There's also a portion of REMS where, if you are an institution that is not providing the ramp-up for the patient, so this patient comes back to you after the risk window for CRS and ICANS is over, that simplifies the REMS a little bit.

So, my best advice to any provider out there who's interested in prescribing a bispecific for a patient is, first of all, do it. They are game changers for relapsed/refractory patients. But also, contact the drug company of the product that you'd like to use, because they have a number of programs set up to make transitions like this easy. And I think a lot of times, especially in academic medicine, we forget to rely on our industry partners for the education and knowledge that they put together about their products. And in my experience, figuring out the REMS based on the specific product is kind of the easiest.

We do have 3 currently, or sorry, 4 FDA-approved bispecifics in the relapse space at this time, as Kevin mentioned, 2 of which are Johnson & Johnson drugs, and so that can be helpful when you are part of 1 REMS, you're a part of the other. There's a Regeneron drug, and then there is a Pfizer drug. And all of industry is super helpful in figuring this out for people.

Kevin Brigle:

The word I heard most there: education. So I think that's the key one. So anyway, education about the REMS program, and certainly about these toxicities, of course. But I think the other thing we have to think about are those long-term things, which will be infections and skin problems, and some oral things. And I know Mary and Kelley will talk about those as well.

Again, CAR-T is very effective, bipecifics are very effective. And so, which one do we choose? If we look at NCCN guidelines, or we look at where they're positioned, we know that CAR-T is approved second line, whereas bispecifics, as I mentioned, are going to be status post-4 lines of therapy. So if a patient is second line, it can sometimes be a no-brainer. We don't really have a choice between the 2, and we would opt for CAR-T. But there are a lot of patients who fall into that gray area, where they've been through a lot of different lines, and are eligible for both.

And so, what do we follow there? It's best usually to follow established guidelines, and the International Myeloma Working Group recently, at the start of the year, came out with some guidelines. Their recommendation is, if at all possible because there's more data, to use CAR-T first. Especially as our CAR-T products are all BCMA-targeted, and we know that the CAR-T works a little less well if they've had bispecific antibodies prior to. Again, use CAR-T if at all possible, and then move on from there.

And again, not everybody's going to be eligible for CAR-T, not everybody's going to have access to it. It has to be done at specialized centers, and not everybody can wait for it, either. You have manufacturing that has to be done, as well. So with patients with rapidly progressing disease, for those patients then, we'll have to move to a bispecific in lieu of CAR-T.

So then before we move on to the final section, I just do want to put up the final slide here. This is just, "What's the future of bispecifics?" I'm going to move on to trispecifics. And these two abstraction posters presented at ASCO this past month. One is looking at a trispecific utilizing the target to both BCMA and CD38. And the other one is a trispecific looking at targets to both BCMA and the GPRC5D, as well. So more to come on these. They also had really good response rates and so a lot more to come in terms of bispecifics, and trispecifics then, as well.

So that brings us to the end of this discussion, and I'd like to thank my colleagues, Mary Steinbach and Kelley Julian, for taking the time out of their busy days to talk with me. For more information, and to view other discussions on multiple myeloma, please visit JADPRO online at  jadpro.com. Thanks so much, and have a great day.