Bispecific Antibodies for Relapsed/Refractory Multiple Myeloma: A Roundtable of Considerations and Strategies for Implementation Into Clinical Practice

Challenges, clinical considerations and strategies to optimize care for patients treated with bispecific antibodies

Introduction

Jens Hillengass (Roswell Park Comprehensive Cancer Center, Buffalo): Hello, my name is Jens Hillengass. I'm at Roswell Park Comprehensive Cancer Center in Buffalo, New York, and I'm here with Caitlin Costello, who is at the University of California in San Diego. And we want to talk today about comprehensive patient‑centered care in multiple myeloma. And we are considered experts, I think, and we unpack challenges, clinical considerations and strategies to optimize care for patients treated with bispecific antibodies.

[0:00:31]

Treatment Goals and when to Initiate Therapy at Relapse

A short kind of summary of what's important as a background for bispecific antibodies. They are obviously treatment at this time for relapsed/refractory multiple myeloma and as you know, it's not always necessary to start treatment right away when patients show relapse, signs of relapse. There are different types of relapse as you know as well. There are asymptomatic biochemical relapse when the disease is under control for a long period of time and then the immune fixation becomes positive again, or the light chains are creeping up slowly. Those are patients where not necessarily every patient needs a treatment right away, and they can be monitored and closely observed.

Then there are patients who are still asymptomatic but maybe have high risk disease, or the progression in the past has been more rapid or is more rapid now. And I personally tend to treat a bit earlier when the patients really show this rapid kind of progression. For example, a rule of thumb could be a doubling of monoclonal protein in two months or so.

And then of course, there are symptomatic progressing patients with extramedullary disease or other signs of organ damage. And of course, these patients need immediate therapy.

[0:01:49]

Novel Therapies in MM

The therapy in myeloma has changed a lot over the last few decades. As you also know there is some jealousy, I think, in the community, because myeloma has so many new treatment options now. And in the last few years, the real game‑changer with the CAR‑T cells with ide‑cel and cilta-cel on the top, but also the bispecific antibodies, which are the topic of our talk today and our discussions. And as you can see, there are several available and we will go into a bit more detail what these bispecific antibodies are.

[0:02:24]

Bispecific Antibodies in MM

The concept of bispecific antibodies is that it's kind of a double antibody. On the one hand the antibody attaches to CD3 marker on T cells, on immune cells. And on the other side they have a target that is on the cancer cell, in this case the myeloma cell. The currently available bispecific antibodies target either BCMA B‑cell maturation antigen or GPRC5D, and I will go into all the different types that are there. But those treatments are similar from mechanism to the CAR‑T cells but they're off the shelf and they're available and can be given to the patient right away without the need to collect T cells and the need to have bridging or to wait for further treatment  – let me let me stop here. I will start this again. Sorry. Bispecific antibodies are kind of double antibodies that attach on the one side to an immune cell, the T cell with a molecule CD3 on the surface. And on the other side, they attach to BCMA or GPRC5D, which are molecules that are very typical for myeloma cells. And there are several drugs available right now, as you can see on the bottom. Those are approved for patients with relapsed/refractory multiple myeloma with four or more prior lines of therapy. And they have to have been exposed to immunomodulatory drugs, proteasome inhibitors and anti‑CD38 antibodies.

[0:04:05]

MajesTEC‑1: Pivotal, Open‑label, Phase I/II Trial of CD3/BCMA‑Targeted Teclistamab in R/R MM

The studies that have been done to lead to the approval of these treatments and to investigate the efficacy of these drugs and also the tolerability for teclistamab is shown here, the majesTEC‑1 study. And you can see here we are comparing studies, which we are obviously not supposed to, but we usually do it to just get a feeling how it works. Obviously, all these studies had different patient cohorts and were a little bit different in their design but we get a feeling on how these patients responded to the different treatments. And in this case, the teclistamab is one of the CD3 and BCMA antibody or bispecific antibodies. And as you can see here, the duration of response was two years, so 24 months. The median progression free survival 11.4 and the median overall survival 22 months. So just to get a baseline to compare the other compounds as well. And I can say that upfront there's not too much difference, and we will discuss later on how we choose which bispecific antibody we use.

[0:05:12]

MagnetisMM‑3: Multicenter, Open‑label, Single‑arm Phase II Study of Elranatamab in R/R MM

The next drug that has been approved is elranatamab based on the MagnetisMM‑3 study. They can again see here the duration of response was in this case not reached for elranatamab. You can see that on the Kaplan‑Meier plots on the right side, the patients had a really excellent response and were in remission for quite some time. Even the overall survival was really impressive, with again about two years as a median overall survival. If you see the comparator arm was physician's choice and this is what we had available before. But now we have this bispecific antibodies, which are really excellent in their efficacy.

[0:05:55]

MonumenTAL‑1: Open‑label Phase I/II Study of CD3/GPRC5D‑Targeted Talquetamab in R/R MM

Then the first GPRC5D directed treatment, talquetamab. As you can see here, we have the overall response rates, which are really excellent in this pretty heavily pretreated patient population. And you can see the median progression free survival on this side, it's shown for two different schedules. One is a weekly schedule with a lower dose, and the other one is a biweekly schedule with a 0.8mg/kg. And you can see here the progression free survival again in a similar range. And the overall survival. Careful, this is not the median overall survival, this is the overall survival percentage after 24 months that has been reported. But again excellent outcomes in this study.

[0:06:33]

LINKER‑MM‑1: Open‑label Phase I/II Study of CD3/BCMA‑Targeted Linvoseltamab in R/R MM

And then the last of the four that are currently available and approved is linvoseltamab, again in a similar patient population with excellent overall response rates in the higher dose level, with the overall response rate around 70%. So very similar to the others. And then the duration of response over two years and the overall survival in the 30 month range.

So these four available drugs are now approved. And we will talk about more in our discussion how we use them, when we use them, what are the things we have to talk about.

[0:07:08]

Sequencing Bispecific Antibodies in R/R MM

Panel Discussion Questions

And to have this panel, which is the two of us, discussion, the question is when do we use the bispecific antibodies, what do we use first: CAR‑T or bispecifics? And if we have more than one available, which one would we choose in which in which situation? And maybe you can start, Caitlin, what are your thoughts if you if you think about bispecifics right now?

Caitlin Costello (University of California, San Diego): Thank you, Jens, for that really wonderful overview of what I like to call kind of a bit of an embarrassment of riches. I mean, we really, truly have so many options for our patients with relapsed/refractory multiple myeloma, particularly in that late relapse where we think about patients who have had one to three prior lines of therapy. Really looking at patients at fourth and beyond, which historically has been such an unmet need, where we really have had very little to offer, and if historical data proved just how dire it was, we knew that the any drugs that we could come up with, a median progression free survival was probably three months or less, a median overall survival about nine months or less. And so then enter stage left bispecific antibodies and suddenly the data you just presented is we're talking years now.

So I think just to set the stage as you so nicely did, you know we have all these options. But the questions you're asking are so next relevant is what do we do with these all? How do we sequence all of these to make sure we're getting the most bang for our buck out of them, to make sure we're optimizing them, to set them up for the greatest success?

So I think when we're thinking about bispecifics, we can't help but combine it with the conversation with CAR‑T cell therapy, because both of these are T‑cell redirecting approaches where we're really harnessing the strength of the T cell and the immune system to really target the myeloma cells themselves. And I think to answer one question is to say, which should we put the horse or the cart first? You know, I think the CAR‑T probably makes a lot of good sense. So when you're thinking about these patients who have had early or late relapse, CAR‑T cell really offers a great opportunity for providing a treatment free interval, targeting an antigen and then stopping that targeting, allowing the T cell compartment to kind of regroup for them to be kind of reused again for bispecific antibodies later.

So I think broadly, our hope when possible, because it's not always possible, CAR‑T cell is logistically challenging. You may not have a center that's nearby that is available to you. Your disease may not be able to wait for it and for that purpose, sometimes bispecific antibodies have to be used. But if we have an ideal scenario, I think we would all likely appreciate to use CAR‑T cell therapy first, followed by bispecifics.

I think it just brings up the question of the first one to say, you know, if we've done a CAR, how do we then, you know, involve or engage our bispecific antibodies? And let's say for the sake of argument, that I had a patient that had you know, relapse and they've had three prior lines and we did a CAR‑T for BCMA, you know, and they're coming back now a lovely three years later with kind of progressive disease. What's your next approach if you have all these bispecific antibodies, what would you do next?

Jens Hillengass: Yeah, that's a great question. I just wanted to support your statement. We also choose CAR‑T first for several reasons. As you mentioned, there's some theory that the bispecifics kind of exhaust the T cells. That's always in the back of my mind because also when we give treatments leading up to the CAR‑T or to the bispecific antibodies, in my experience, we have to make sure that we are not exhausting the T cells. I'm from Germany, as you can hear from my accent, and you already know, and we use bendamustine and melphalan and all that fun stuff where, where we kill a lot of the T cells and exhaust them. And then afterwards giving a bite is actually pretty challenging. That's something I wanted to throw out there. So try to keep the chemotherapies out of the mix as long as possible so that these cells can do a better job.

And then coming to your question and to your patient, which is a very typical scenario. Fortunately, as you said earlier, right, those patients live much longer now with these treatments and treatment after CAR‑T. I feel actually comfortable using a BCMA directed treatment again.

The reason is we know that BCMA is very stable on the cells because oftentimes when antibodies lose their efficacy or bispecifics or CAR‑Ts, we oftentimes think in part it's at least because the cells, the, the myeloma cells, lose this target, but they downregulate the target. With the BCMA, that's I'm sure there's also some component of this, but I do think T cell exhaustion is also a big factor in losing the efficacy. And therefore I think using another, especially if it's like three years, as you said, which is a pretty good time for those patients. Even in earlier lines of therapy where CAR‑Ts are also approved now, I would feel comfortable using a BCMA directed treatment again. Back in the olden days when we had to switch from – with clonal tiding, we had to switch from one target to another, for example, from a daratumumab to an elotuzumab or something like that. I think that's still relevant. But if the relapse is later, I think we can use the same target and have a BCMA directed treatment. What would you do yourself?

Caitlin Costello: I think you're right on. You're bringing up a great point about the gap between one BCMA targeted therapy to the next. And we do have some kind of real world evidence that tells us the longer the gap, the more likely you'll have benefit with retargeting the same antigen again. But perhaps in a scenario where you've used a BCMA target and you've had a less than, you know, less than expected remission or response time, for example, perhaps that's less than 6 to 9 months, for example, maybe it does make sense to switch targets at that point where, you know, GPRC5D and with talquetamab as you presented, does offer a similar drug, approaching the myeloma just from a different way. And again, perhaps we need to think about the role of the T cells and just how happy and healthy they are to do the job and get it done. But if we think the T cells are robust enough to do it, perhaps there's an opportunity there to switch targets and approach it from a different way.

Jens Hillengass: Yeah. And would you then, at the next relapse, would you then go with a BCMA directed bite, or do you think bite after bite is not a good idea? And I mean, to be fair, there will be slides about this. So we're already talking about it.

Caitlin Costello: But I think this is something we're all learning about in terms of how much pressure can we put on the T cells, because we keep asking them to do the same job to kind of drug after drug, and perhaps they truly do need a bit of a washout, if you will, so that the T cells have a little bit of time to kind of regroup before we do kind of sequential bispecific antibodies. So if we were doing something like any of the BCMA bispecifics and had a, you know, progression, do we want to immediately go to talquetamab, as an example? Or perhaps we try and slot something in between there that is not so heavily kind of weighing those T cells down to allow for some immune recovery that may give greater success to the use of talquetamab later. So I think there's a sequential question there.

What I do hope is going to happen over time is that we will see kind of fixed duration of bispecifics, where if we are treating someone with a bispecific antibody targeting BCMA and they do very well, we are looking more and more about how we can space out the interval between the drug administration or stop the drug entirely and enjoy some, again, treatment free interval, at which point we then perhaps have allowed the T cells to kind of regroup and be able to use them again for targeting with maybe a different target at that point.

Jens Hillengass: And that's also something I think that you experience, like we do as well. We have patients where we have to stop treatment because the counts are not great. And I mean, those are heavily pretreated patients. And then we see they still stay in remission for a long time, right? Not every patient, but a lot of patients, even if the interval is not like it's in the study every week or every other week, with intervals of four weeks and of sometimes eight weeks and even longer, the patients are still in remission.

Actually had, like an anecdote, I had a patient that I wanted to enroll in a clinical trial, but the disease was very aggressive. So we gave one just a step up doses of talquetamab. The patient didn't qualify for the trial anymore because she had a fantastic response. So that is a very good problem to have.

So I completely agree. I hope that we come to a point because for the longest time we gave treatment until progression. Now we finally have the chance. And I can maybe at one point stop treatment or at least give a treatment break.

And I was wondering there, the slides that were provided to us said concurrent treatment of two bispecific antibodies, or maybe bispecific and an antibody like daratumumab. And there are studies out there; I know it's not approved, but I have to say I'm very excited about this option too, because targeting those two very stable, very strong targets at the same time and you're aware, obviously, of the data. I'm actually excited about that. And then we can hit the disease hard and then have a break for the patient so that they can recover, similar to the CAR‑T.

Caitlin Costello: You're exactly right. I think the last thing to mention, and we'll touch on this a little bit later in this presentation, is, you know, when we have so many options to choose from, perhaps we can look at side effect profiles of some of these different bispecific antibodies and choose accordingly, because there are some side effects that may be deal breakers for some of your patients, and perhaps that can inform some of the sequencing and treatment decisions.

Jens Hillengass: Excellent. Good. Then I would go on with a few more slides, which are also addressing some of the discussions that we had already.

[0:17:11]

Real‑world Analysis of Teclistamab Response by Prior BCMA‑Targeted Therapy: Baseline Characteristics

And again, here we talked about real world because now we are using these bispecific antibodies and we get experience with them. And you can see here what we discussed earlier after teclistamab, which is directed against BCMA after a prior treatment with BCMA. And you can see here in this study or in this analysis those patients had mostly CAR‑Ts before, but a lot of them also had the at one time approved belantamab mafodotin, where we also hope that it will be approved again soon. It's currently not. And then other, I guess those were study drugs, also directed against BCMA. And as you can see here, even some patients had several lines of BCMA directed treatment and then got teclistamab. And as you can see in the next slide, the response rates are pretty impressive.

[0:18:04]

Real‑world Analysis of Teclistamab Response by Prior Therapy: Efficacy

I do have to say, I thought about it, I don't have a very good experience why the response to the ADC and CAR‑T in this retrospective analysis was better than CAR‑T or ADC alone. Maybe those patients had a little bit less aggressive disease, or were in a deeper remission or in remission for a longer period of time. Those are just speculations. But as you can see here, even after prior treatment, as we just discussed, BCMA directed therapy can be effective again because as I said, or as we said, the BCMA is very stable on the cells.

[0:18:40]

Elranatamab After Prior BCMA‑Targeted Therapy

And then we talked about elranatamab as well and similar outcomes. If the patients have been pretreated with BCMA directed treatment, there's still a good chance that the patients respond to the treatment again. And then here you can see the outcomes with the Kaplan‑Meier curves, where there was not a lot of a difference and those patients still had a really good response and a fairly good outcome. Still better than a lot of the older drugs that we had before.

[0:19:09]

Talquetamab After Prior TCR Therapy

And then talquetamab, changing the target seems to be very effective in this case. And we will talk about side effects and side effect profile as we discussed, later in this talk. But the overall response rates for patients who have been pretreated with BCMA directed treatment and then get talquetamab treatment, which is directed against the GPRC5D, are really excellent. And still despite other experiences with other drugs with the bispecific seems to be a very effective treatment still.

[0:19:43]

Administration Considerations and Management of ICANS and CRS

And then we want to discuss other things, like the management of side effect profiles and the typical side effects that we know from bispecific antibodies.

Administration Considerations for BsAbs in MM

Caitlin Costello: So we've talked a lot about the who and the when and the how to some degree, but let's really kind of dive down into the logistics and the practicalities of when you as the doc have a patient that you're writing this prescription for, how do you deliver it and what do you expect when you're counseling your patients? And so, you know, all of these different bispecifics we have are more or less similar in terms of what we would anticipate in terms of side effect profiles. We know that cytokine release syndrome is kind of a class effect, if you will, where although these drugs may be dosed slightly differently, whether that's weight based or fixed dosing or what the schedule of the step up dosing – remember, the step up dosing is a critical component to safe administration. We think that with small, kind of what we call priming doses, it allows for, you know, avoidance or risk mitigation of some of the side effects in terms of revving up that immune system. And the package inserts from the FDA approval do give some guidance on recommendations, or suggestions as they say, in terms of appropriate timelines of hospitalization for observation. And the purpose of all of that is so that we can deliver this safely and be prepared for what is most common, cytokine release syndrome.

More or less, you're going to be probably right if you say that two thirds to three quarters of these patients are going to develop cytokine release syndrome, and perhaps there's some variability, again, with different patient selection, maybe there's something different about some of the drugs. Maybe there's something different about how we prophylax against it with lots of corticosteroids and things. But broadly, we know that CRS is one of the most common side effects. And fortunately, ICANS is some of the least common side effects. Something that we've seen and become more commonly kind of aware of and prepared for with CAR‑T cell therapy, ICANS and that neurotoxicity component is something that's considerably and fortunately less common with bispecific antibodies.

But in terms of the target, we can see different on‑target off‑tumor toxicity, which is an important part of this, where we know that the BCMA targeted bispecific antibodies are much more likely to be associated with infectious complications. Whereas talquetamab, which is targeting an antigen, that GPRC5D, which is on keratinized tissue as well, as an on‑target off‑tumor side effect, we can see these patients develop side effects associated with targeting those cells, which are dysgeusia of the mouth, taste loss. Some patients feel dry mouth that can lead to loss of appetite, weight loss as example. And it's in the skin and the nails where some patients can develop skin rashes, scaling or peeling of the skin on the palms and the soles of the hands and the feet, or sometimes a generalized rash at all. So there is a little bit of a target difference when it comes to adverse events for them.

[0:22:44]

Current Recommendations for Step‑Up Dosing When Beginning Bispecific Antibody Therapy

Now, we mentioned the different schedules in terms of how to do this step up dosing. That is slightly different across each of these four approved antibodies, but the package insert does give, as I mentioned, some suggestions where perhaps it doesn't need to be followed to the T as long as we can have the safe infrastructure set up in order to administer this. Broadly, these patients usually have a minimum for teclistamab and talquetamab and elranatamab of at least 48 hours between their doses, again with serially escalating doses in order to help kind of prepare the body, you know, become accustomed to the doses so that ultimately we can reach the target doses. Linvoseltamab was approved more recently as an intravenous preparation or formulation, is given weekly instead of every 48 hours, like the earlier approvals that we saw. And again, as Jens mentioned, talquetamab is the one that has two different dosing schedules, where you can make the decision about whether weekly or bi weekly dosing would be more appropriate for your patient.

[0:23:43]

Acute Immune‑Related Toxicities: CRS and ICANS

Now, CRS, what that looks like is we've all seen a patient come in with what appears to be a sepsis type of picture, is very similar to cytokine release syndrome, where these patients most commonly have fever. We can grade it, where the lowest severity is “just a fever” but we can have increasing grading or increasing severity as these patients develop perhaps tachycardia, hypotension, hypotension that may be requiring volume, fluid boluses and in more severe cases require vasopressor support. We can also see some of these patients develop hypoxia.

This is kind of our typical evaluation with vital signs throughout the time when we know that the likelihood of CRS is greater. And it's important for us to recognize these symptoms at their early onset. Be prepared for management as well. Remember these patients are immunocompromised, so never forget that infection could be a cause of these symptoms that we're seeing. But more likely these patients are developing the known complication of cytokine release syndrome where our first line agent is the anti‑IL‑6 antibody called tocilizumab. This is a drug, I call it an antidote for my patients, that can really help calm down these reactions as they happen, where we can still use corticosteroids, particularly in the outpatient, to allow for these patients to again have further risk mitigation, but also prevention or treatment when these develop.

Now, I mentioned ICANS previously. This is a little bit more of a side effect that is less common. However, this is for all intents and purposes, I describe to my patients the same kind of storm that's happening, but in the CNS. And these are patients that we watch very carefully for this, where we have very specific protocols of asking, who are you? Where are we, what data, what time is it? Can you count? Can you write? Can you tell me what color things are? Can you identify things? Similar to a mini mental‑status examination, where we can more objectively evaluate how they are thinking and concentrating, and look for signs of alterations in their consciousness. And again, have a degree of severity where we can say low level, low grade to higher grade. And with these frequent neurologic assessments and with corticosteroids in our back pocket as our antidote for ICANs, we can be prepared for intervention should the likely scenario occur where these patients develop ICANs.

[0:25:54]

ICE Scoring Assessment

As mentioned, the ICE scoring system is the objective way that we do it, which really helps to guide some of our interventions where perhaps these patients have a point here or a point there, where maybe we can observe them. But with increasing severity and increasing ICE, or decreasing ICE scores I should say, we absolutely intervene with these patients with corticosteroids as our first line therapy.

[0:26:17]

Initiating Bispecifics: Managing ICANS

And then there are additional mechanisms. So we should think about this not just only providing steroids or the antidotes, but really stopping the bispecific antibody, waiting for the ICANS, as an example, to resolve. Thinking about preventive or prophylactic anti‑seizure medications. And depending on the degree of severity, perhaps not rechallenged these patients, should that unlikely event of high grade ICANS occur.

[0:26:41]

Initiating Bispecifics: Managing CRS

CRS, we mentioned in the management the most critical component is that tocilizumab. We know that this is the best antidote that we have short of steroids, which can be used in more refractory or sometimes outpatient settings, which we'll talk about, of ways that we can intervene for CRS. But the broad approach is to say, hold subsequent doses of the bispecific until the CRS has resolved. When CRS is happening, use your tocilizumab. You must have it on hand in order to do it, up to three doses in a 24 hour period, knowing that we can always give additional high dose steroids as needed if the tocilizumab is ineffective.

[0:27:18]

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

So if we know that those drugs work so well for treatment, there's lots of interest in understanding how we perhaps can use them as prevention. And so there are an increasing number of studies that are being done prospectively, and some in some smaller single site studies, that are looking at its use of tocilizumab in a preventative approach where patients just prior to getting their first dose of teclistamab, for example, here were receiving one dose of tocilizumab as prevention. And we can see that the incidence of developing CRS considerably decreased for those patients who received prophylactic tocilizumab. And what is not listed? Well, on to the right there you can see without compromising the effect of the drug. So perhaps this is the beginnings of what we can see, of how we can more safely administer this. And with the kind of impacted hospitals that we surely all have, how we can perhaps get these patients out of the hospital and perhaps give them their drugs and manage any of these symptoms as an outpatient, with a more proactive approach to preventing some of these side effects.

[0:28:21]

Panel Discussion Questions: Role of Tocilizumab in Managing CRS

So this brings us to kind of thinking about what you do in terms of what works for you in terms of managing CRS. How do you do it inpatient, and how can we optimize some of these strategies to get these patients out, outside the hospital? Jens, I'd love to hear your approaches.

Jens Hillengass: Yeah. So that's a great summary. It's really touching all the very important parts. We are in a very special setting. We are PPS[? 0:28:47] exempt. So for us, an admission is actually beneficial to a certain degree. And obviously I discuss it with my patients. It's about the patient mostly. So the recommendation initially, as I said, was to do the step up dosing inpatient, and we do it still inpatient. Some, especially elderly patients, are not very happy about this. They rather want to spend time at home, which I completely support. But we have tried to do as you said, those are recommendations with the days that we have shortened the time a little bit, that we have not done one for eight step ups, but 135 or 136 depending if we know how the patient does, especially if the patient has had a bispecific antibody before, which we have more patients who get one bispecific and then the next. There is some extrapolation. I don't think they're identical, but some extrapolation how they might tolerate the next treatment as well, seeing also how their tumor burden is, how rapidly they are progressing. So taking into account a lot of factors that the patients present with, both with the disease and also their general frailty versus being in in good shape at that point.

We have not done the prophylactic tocilizumab yet because we do the step up inpatient and there they are under supervision, so it's not a problem. So I was wondering, I think you mentioned in preparation that you do that, and I would like to hear how you do it.

Caitlin Costello: It's been a bit of an evolution, if you will, as it always is, as we all try to figure out the best ways to do this and learn from what works and perhaps what doesn't work. But when we first set up our outpatient bispecific program here, the initial approach was to get drug approval insurance authorization for both the bispecific antibody and the tocilizumab. So we were prepared to use it from the get go. And once we had authorized that matter, at that point it didn't really matter when we used it, per se. So eventually, originally in the beginning of outpatient administration, we had a very low bar of using tocilizumab at the first sign of any cytokine release syndrome. So we did not start using it prophylactically from the get go.

We have used it both in the inpatient and outpatient setting for using prophylactic tocilizumab for patients for whom we are more worried that CRS tolerance may be a problem. You know, you're right that not everybody can do outpatient bispecific, and these patients must be admitted. Those who have limited support system – I'll mention this coming up – but limited support system, bulky disease, we know that these patients or I should say comorbidities also you know where perhaps the CRS may may add undue stress to the body. These are scenarios where maybe they're just safer to do it in the hospital but perhaps prophylactic tocilizumab may be, you know, a safer approach for them to do it.

So we've been fortunate so far to be able to use it, you know, early on and occasionally use it prophylactically. But we haven't done it across the board for everybody yet. But I do think as we all are getting more comfortable with it, the tocilizumab shortage as an example, is less of a problem. We certainly are going to be looking to do this now that we have data to support its efficacy and its lack of kind of response, you know, hindrance with it.

[0:32:01]

Management of Other AEs

BsAb Therapy’s Infection Risk

I was thinking of moving to kind of talking about some of the other AEs beyond just CRS prevention and really focusing a little bit on BCMA, understanding that, you know, BCMA, more than non‑BCMA targeting really seems to lead to more significant hypogammaglobulinemia. It seems to impair the humoral immunity a little bit more. You know, there are different reasons why patients have increased risk for infections, and that's one particular reason. But also remember these patients are very heavily pretreated. You know, we have just been pounding their T cells, you know, for all the years of Dex and all the different treatments that they've done, that their immune system is really kind of compromised in that degree. And the longer we are telling their T cells to fight, fight, fight the myeloma, the more tired they get, the more kind of, you know, drug exposure that they're getting. There are different kind of approaches and thoughts as to why that infection risk is increased for our patients, and it's probably multifactorial.

[0:32:56]

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

When we're thinking about the risk of that for these patients, it's just so critical to think a little bit about how we can prevent them. And these patients, it's so important to think about antiviral prophylaxis against HSV and VZV, think about their risk for hepatitis reactivation. But I think most critically, we have learned that instead of waiting for hypogamma to develop, the absolute importance of preventative monthly intravenous immunoglobulin, which can really help shorten that duration of immunoparesis and prevent life‑threatening infectious diseases from occurring. Growth factors are never a problem. We think about, you know, perhaps if these patients are neutropenic, we need to kind of delay their doses, allow for count recovery. As you mentioned, all these patients need PJP coverage. And as best as we can, we should be following guidelines for vaccinations, if possible, before they start their bispecific antibody, which isn't always the case.

So a heightened awareness about the risk of infections is so critical for these patients. I don't know about you, but I've seen some pretty wild viral reactivation, CMV, adenovirus, parvovirus, things that I haven't seen since my allotransplant days, where these patients and their T cells are just so compromised. So think hard about your infectious risk for your patients.

[0:34:14]

Adverse Events Associated With GPRC5D‑Targeted Treatments

When it comes to GPRC5D targeting and the, you know, unique side effects that come with that related to that keratinized tissue, we know that skin and nail can be significant, but we also know that fortunately, it seems to be a bit time limited. Many of these patients have developed some of that palmar and sole skin peeling and skin rash early on in that step up dosing, where we really can help them with sometimes topical corticosteroids, in more severe cases sometimes systemic steroids.

I'll tell you, the dysgeusia and oral events are some of the most challenging side effects we deal with. I think practically, there is no great intervention that can really stop these symptoms from happening. And again, fortunately it seems like it happens worse within the initial step up doses or the early on in the treatment course. We have lots of ideas of how we perhaps can and make it less bad. Maybe with corticosteroid mouthwashes, maybe with, you know, targeting any yeast or fungus infection with thrush type pictures. But I think practically the most helpful, beneficial way for patients who develop significant dysgeusia, weight loss, dry mouth is truly taking either a step back on the dose or on the frequency of the interval of the drug given, you know.

[0:35:27]

Pearls for Managing GPRC5D‑Associated AEs

So some of these pearls in terms of thinking about it is importance of good mouth hygiene, periodontal hygiene, thinking about saliva substitutes, trying to bulk up nutrition as best as you can. And as mentioned you know, topical or sometimes systemic steroids. And as every man loves when I tell them, clear nail polish on their nails is important to prevent snagging. Keeping those nails really nice and short is just critical to prevent kind of tearing of the fragile nails.

[0:35:57]

Real‑world Considerations

Panel Discussion Questions

So I think there's a lot that we've kind of learned about these drugs as they've kind of come to the market and we've all had more and more experience in managing it. You know, I think, Jens, we've talked a little bit about kind of outpatient administration. I would love any of your hot tips on adverse events and how you have figured out how to partner with your community to really get these patients the drugs that they need, but also perhaps keep them in their local communities. What kind of successes or strategies have worked for you?

Jens Hillengass: Yeah. An excellent summary again with especially managing the side effects. As you said, be early, be aggressive in a positive way to treat side effects. Obviously CRS, ICANS, but also these. And I completely agree, I could not predict how it will be when those drugs became available. How the dysgeusia could really be a problem and I have patients really losing weight and having also not only quality of life but really significant health issues with this. And as you said, holding the treatment for a while, and knowing that oftentimes those patients still stay in remission, holding the treatment and then supporting them with this nice table with all the options that we have. But I completely agree. It's not that easy to manage, really.

And what the communication with our colleagues in the community is, we are also academic center. We're a little bit off. We are at between two sites. We have Canada. So in the other direction, there are sometimes long ways for our patients to go with patients traveling five, six hours to get treatments. And we oftentimes do. And those are the patients where we, of course, do the step up inpatient. But we do have a great collaboration with our providers out there, five, six hours away. They all have my cell phone number, they have my colleague’s cell phone number. I think being in conversation is very important and encouraging them to continue the treatment because as we also know those side effects become, at least the CRS and ICANS, become less common the longer the patients are on treatment.

The infection risk is still an issue. But hemato‑oncologists know how to deal with infections. What I try to relate to my colleagues is that they should think of weird infections as well. As you said things that we only see in allogenic transplant patients otherwise. So that if a patient has symptoms that are not explained otherwise, think about maybe even consulting an infectious disease specialist. I have seen, as you said, the weirdest things. A patient who had, I think it was BK virus in the kidney, who had kidney failure, and we treated the kidney failure because we thought it's myeloma related or it's treatment related, and in the end, the nephrologist actually came up with the idea to do a biopsy and then they found the viral whatever, how they diagnosed it. So I really heavily rely also on my colleagues in other specialties.

So I think being open and in discussion and in communication with the colleagues who are treating those patients locally is super important. And since there are still frequent infusions or injections, we should really make sure that the patients have the chance to get this very locally. I'm not sure how it is in your area. Your city is much bigger than ours, but we have a very large rural area around us. I'm not sure how it works with you guys.

Caitlin Costello: Yeah. I think, you know, setting up the infrastructure to provide, you know, this type of drug administration is sometimes an overwhelming just barrier in and of itself. The infrastructure that's required requires, you know, your pharmacists and your nursing staff and your APP staff and the physicians and everybody to kind of be on the same page to do this. And, you know, we've all, I think, started off with the academic centers doing the initial step up dosing, which actually it does help with drug selection. Sometimes when patients are referred over to me for a step up dosing, I ask the community referring doc to say, well, what do you have on formulary, and choose the, you know, bispecific of choice so that the patient can start with me and head back to their local community to continue therapy. So sometimes that question is answered for us.

But I think this is such a critical component of, you know, teaching our community colleagues that, remember, rituximab and daratumumab are hard also. And, you know, there is so much that we admitted these patients and watched them and had to get our feet wet before we really felt comfortable doing it. And I don't think that this is terribly different. You're right, there's so much as hematologists that we are prepared for in terms of management of hematologic, you know, abnormalities or infection risks and I think CRS is going to be kind of one of those next kind of things that we're going to develop such expertise in. And so I think as we are communicating with our community colleagues, the first question is, what drugs should we do that you have that you can continue step up dosing that occurs here and then these patients kind of head back to their local community oncologist to continue on.

[0:41:07]

BsAb Maintenance: Academic to Community Cancer Care Center

I was thinking about talking a bit about, you know, that transition back and forth. And there are quite a few steps that come up to patient selection and that transition back and forth between the community and the academic center, where we are looking for good candidates. We want to see these patients when they've had their, you know, third, maybe third, or they're looking like they're heading toward their fourth line of therapy so that we can really talk to these patients in advance, evaluate their caregiver support, evaluate the rate of their disease progression, and really, truly choose what is the best next appropriate therapy for them. Because if these patients particularly are doing these as outpatient, we really need to have eyes and ears on the patient, you know, at home. And that really does require some good teaching of caregivers, requiring that the patients be within some proximity to the cancer center so that should something happen, which, you know, always happens in the middle of the night, that there is, you know, good opportunity for care at a prepared center for you.

Thinking about then step up therapy, whether the patient is inpatient or outpatient, knowing how we can connect with these patients where, as for example, for us we have them come in in the morning, we evaluate them, we give them their drug dose, and we check in with them later in the afternoon. They have very specific instructions of what to do if: if they were to develop a fever, we provide them with the supplies so that they can check their own vital signs, all throughout the step up dosing.

However, once that step up dosing has been completed, we talk about that transition back to the community practice for ongoing bi specific therapy, preparing our community oncologists and telling them the importance of the IVIg replacement, sending the patients already on their preventative antimicrobials, and kind of staying in touch, just like you mentioned, Jens, so if it turns if side effects happen later on, you know, just to make sure that we are staying in connection so that we can kind of support our community colleagues as best as we can.

[0:43:05]

Bispecific Antibodies: Issues Affecting Access

I think there are still barriers to accessing, you know, and I do think that overall survival in myeloma these days is purely based on access. You know, do you have access to the best drugs that are out there for you? And so when we're thinking about referring these patients over, we want to see these patients when they're kind of on their third line of therapy, and they're heading towards their fourth line of therapy so that we can really kind of keep them in mind for bispecifics. You know, we need to make sure that the insurance authorization happens, we need to think about the logistics of perhaps traveling to the academic center.

Because there's a lot that goes into being a patient these days. I always say it's like a full time job. You really have to be prepared, be organized. We need to educate these patients so they understand what some of the short and longer term toxicities are, let alone obviously communicating and educating our local oncologists so that we as what I like to call a team sport are doing this as a team. You know, the insurance coverage fortunately has been, you know, I should say as always is a problem, but has been less of a problem when we know that this has a very specific indication. So there's a lot that goes into the coordination of delivering a drug like this so that we can safely do it for the patient in connection with their caregiver team, their local oncology, and in the academic setting.

[0:44:25]

Addressing Financial Costs

So there's, you know, lots of opportunities out there. I always give my patients, you know, opportunities to not use Doctor Google if you will, and not use AI and really direct them where I can to the wonderful patient advocacy programs that exist for multiple myeloma. I am obviously biased, but I think there are no greater programs than the patient advocacy groups that are out there for myeloma and I try to give, you know, direct access and materials and, you know, the manufacturers from the pharmaceutical companies have really great support programs. There are ways that we can try and understand the highest risk of, you know, the highest window for cytokine release syndrome and perhaps just think about hospitalization then, so we can keep people at home, thinking about how we can perhaps mitigate those with prophylactic tocilizumab, corticosteroids, and just really building that team together so that we can continue to support these patients, to get them through these just, for some patients, life‑saving drugs.

[0:45:26]

Conclusion

So, you know, I think in conclusion, Jens, you've really nicely outlined and I'm so grateful to do this with you and partner with you, and with our patients and our community oncologists, to really understand what a wonderful class of drugs this is, so we can offer our patients and the importance of being prepared to deliver them in a safe and effective manner. And that really requires education of our patients, education of their caregivers and coordination and, you know, really good communication across the academic and community centers. Perhaps I'll give you kind of the last words here to round us out, to give me some thoughts of where you would take it here and where you see the future.

Jens Hillengass: Yeah. I couldn't agree more. This is really an amazing opportunity to treat the patients at a point where a few years ago, we had nothing to offer anymore. Yeah, it was really a great summary, I think. And we have to establish this as we have established the antibody, the monoclonal antibodies, as we have established the proteasome inhibitors. We have learned to deal with the side effects, we have learned to deliver the treatment, and we have learned how to cooperate between different settings, be it rural, be it city, be it the academic center or the community cancer center or the private practice. I think there are a lot of opportunities specifically in the bispecific antibody area, and we can make it really accessible to patients, we can make it tolerable for patients. And this is just as I said initially, I think it's a game changer and it will help us to treat our patients better and better.

And at one point, for kind of a future outlook, I think those treatments will also be earlier, in earlier lines of therapy, and the patients will be in better shape and maybe will come to a point where we can treat and then the patients have a long period without treatment and can really enjoy a good quality of life, as compared to what we have unfortunately seen in the past where patients passed away quickly and now we have really something where we can offer our patients much more treatment.

[0:47:40]

Final Thoughts

And I think with this, those were my final thoughts. Do you have anything else to add? If not, this was a huge pleasure to do this together with you, and I'm looking forward to further options and opportunities to treat our patients.

Caitlin Costello: The pleasure is all mine. Thank you all for hearing us out today, and we look forward to partnering more with all of you so that we can continue to deliver these wonderful successes for our patients.

[0:48:07]

All right, Catherine, do you have anything?

Catherine: No, that was great. You guys are pros at that. You barely stopped at all. That was really great discussion. I feel like I learned a lot listening to it, so thank you for providing that.

Caitlin Costello: Great.

Jens Hillengass: Thanks for organizing.

[END OF TRANSCRIPT]