Thank you very much. It's very nice to be here with you all today. I'm going to be covering some of the efficacy and safety data and toxicity management guidelines for bispecific antibodies and talking about their place in the current multiple myeloma treatment landscape.

[00:04:20]

Novel Therapies in Multiple Myeloma

So this has been a very exciting time for development of new therapies for multiple myeloma, especially in this immunotherapy domain. So over the last 10 years, we have this really amazing list of new FDA approvals, essentially all of them immunotherapies in some form or fashion.

And in the last few years, it really has been the bispecific antibodies that have come on the scene with teclistamab being the first bispecific antibody approved, followed shortly after by talquetamab and elranatamab, and most recently just in July of 2025, linvoseltamab. And then belantamab as a BCMA-directed antibody drug conjugate, which was an early - initially approved in 2022 then withdrawn, read out these really impressive phase III studies that led to its re-approval and full approval in October 2025.

[00:05:13]

Bispecific Antibodies in MM

So I think bispecific antibodies are maybe the most exciting development in myeloma therapy. These are hybrid, heterodimer antibodies where they have 2 specificities: 1 engages a cell surface target on the myeloma cell, most often BCMA B-cell maturation antigen; and on the other arm, they target CD3, which is a component of the T-cell receptor and leads to T-cell activation. So these antibodies really bring together in patients the myeloma cells and the T-cells—activation of the T-cell and killing of the myeloma cell.

And of course, this strategy has been employed in lymphomas as well to great effect and is spreading to even solid tumors with approvals for small cell lung cancer.

So the agents that are approved for multiple myeloma, teclistamab, elranatamab and linvoseltamab target BCMA. Talquetamab targets GPRC5D, which is a new cell surface target. In fact, talquetamab is the only approved drug targeting this new target. And these are all approved in late line of therapy right now, 4 more prior lines of therapy. But as we'll talk about, they are being investigated in early lines of therapy as well.

[00:06:36]

How BsAbs Are Currently Used in Clinical Practice

So, you know, right now these T-cell engaging bispecific antibodies sit alongside CAR T-cells as T-cell engaging immunotherapies. They have the advantage compared to T-cells of being able to be administered off the shelf. So there's no patient-specific manufacturing required. Some of them are given as subcutaneous injections. And you don't need to have the institutional infrastructure to handle cellular therapies, although there are some specific toxicities to these agents that not all centers are able to handle. It's much less of an entry barrier compared to cellular therapies.

And so these agents really make widely available the kind of T-cell engaging therapy and efficacy that you previously could only get with CAR T-cells in the form of an injectable pharmaceutical.

That said, CAR T-cells are still preferred in some cases. And so if we think about where bispecific antibodies are currently used in clinical practice, it is in later line therapy for—instead of CAR T-cell therapies, for patients for whom CAR T-cell therapy may be inaccessible, or for patients who are uncomfortable with the risks of CAR T-cell toxicity because while there are some overlaps, they think of CAR T-cells as riskier therapies, or patients with rapidly growing cells or myeloma, where they can't wait for the manufacturing period for CAR T-cells.

Alternatively, you know, we've seen bispecific antibodies effective in patients who have relapsed after CAR T-cell therapy. So this isn't always an either-or choice. You can clearly get CAR T-cells relapse down the road and respond to bispecific antibodies. And then more recently, although this isn't an FDA-approved usage, we've seen patients benefit from bispecific antibodies as a bridge to CAR T-cell therapy. So maybe somebody whose disease is growing too rapidly to permit collection of manufacturing CAR T-cells, they can collect T-cells for CAR T-cell therapy, then receive a short course of a BCMA—or sorry, GPRC-directed bispecific antibody to cytoreduce them and bridge them and then receive the CAR T-cell therapies.

[00:08:47]

Efficacy of Bispecific Antibodies in R/R MM

So if we just start from the initial studies of these agents, the phase I studies that established their initial efficacy and safety. You see here, the studies for each of the agents, response rates in the 60% to 75% range, which is really remarkable in this very late line therapy population where the median line of therapy was 5-6, including in the MonumenTAL study which investigated talquetamab, the GPRC5D targeted agent. There were many patients in that study who had received prior therapy-directed against BCMA. So these are immunotherapy-exposed patients in some cases.

Really impressive duration of responses in the elranatamab study, not even reached after quite long follow up. Teclistamab median duration of response 24 months, linvoseltamab 29 months. Talquetamab in this Q2 week dosing cohort, 17.5 months, again in some patients who had had prior BCMA-directed CAR T-cells or bispecific antibodies.

Remember, these are single-agent response rates and durations of response. So really unprecedented, except for CAR T-cells, in terms of the results you get with these.

[00:09:58]

Ongoing Phase I/II Trials With Bispecific Antibodies in R/R Multiple Myeloma

And finally, there are a couple other agents still in late phase development. So cevostamab is an interesting compound that targets FcRH5, which is a different cell surface target that no therapy has been developed against yet or approved yet for. And so there's a phase I/II study that has been presented in patients with 6 prior lines of therapy where you had overall response rate of 67%.

And that - and that cevostamab development is going forward in additional studies. And we hope that that will be an FDA-approved agent eventually.

And then etentamig, which is another BCMA-directed bispecific antibody, which has been reported with—in this phase I study, 147 patients, median for 5 prior lines of therapy. Also impressive overall response rate in the 60% to 70% range.

And some of these BCMA-directed ones, especially the later developed ones, may have a lower risk of CRS and some more convenient dosing and scheduling.

[00:10:58]

The Future of Bispecific Antibodies in Multiple Myeloma

So what we see in terms of the future in the use of these agents. And so I mentioned that several trials are investigating these agents in earlier lines of therapy. In fact, 1 of the most exciting results from the most recent ASH meeting, where the presentation and publication of results of MajesTEC-3, which is a trial of daratumumab plus teclistamab vs other daratumumab-containing standard therapies in patients with 1-3 prior lines of therapy, largely who were daratumumab-naive showed really impressive progression-free and overall survival benefit, with about 85% of patients being progression-free after 3 years. And so really unprecedented results in this early line of therapy.

We are seeing some studies investigate both retrospectively and prospectively fixed duration therapy. So especially in these trials where patients are having these very long responses, there are some long-term complexities and maybe even risks with long-term therapy with these agents. And we think that maybe such long-term therapy is not required. So we're starting to see some studies prospectively investigating fixed duration therapy.

There are agents combining bispecifics and CAR T-cells. I mentioned using them sequentially. A study presented at ASH recently using cevostamab, the FcRH5 targeted agent after BCMA-directed CAR T-cells. So engaging 2 different cell surface targets in sequence with T-cell engaging therapies to try and circumvent some of the antigen escape that has been seen with some of these agents.

Similar approaches, multitargeted approaches. So using teclistamab and talquetamab together. So targeting BCMA and GPRC5D in combination, that has shown really remarkable efficacy in the subset of high-risk patients with extramedullary disease. And then combining that concept into 1 drug, the trispecific antibody.

There are 2 promising trispecific antibodies being developed. One mentioned here by J&J, which targets GPRC5D and BCMA together. And then finally even 3 target approaches. And so there's a phase I trial ongoing now from Moderna, where lipid nanoparticle encapsulated mRNA encodes 3 different T-cell engaging molecules. So BCMA, GPRC and FcRH5. So employing this approach to target 3 targets at 1 time.

[00:13:28]

Identifying and Managing Adverse Events Associated With Bispecific Antibodies in Multiple Myeloma

Okay. So as you might expect with such a potent therapy, there are some risks and toxicities to consider.

[00:13:32]

Highlighting the Patient Voice: AEs With BsAbs

And so infection is the number 1 that has emerged with these agents, which we'll talk in more detail about. And of course, as T-cell engaging bispecific antibodies, you do get the same kinds of toxicities that you do with CAR T-cells in terms of cytokine release syndrome, and ICANS, the neurologic toxicity. So ICANS stands for immune effector cell-associated neurotoxicity syndrome.

As we'll talk about, these tend to be more manageable and predictable and lower grade than what you get with CAR T-cells, but still warrant some specialized expertise and treatment pathways in place to manage these, especially in settings that don't have experience with CAR T-cell therapy.

[00:14:16]

Safety of Approved Bispecific Antibodies for Multiple Myeloma

So - so thinking about cytokine release syndrome. So remember this is the febrile reaction that is common with CAR T-cells and bispecific antibodies. And in its simplest form it's fevers. But it has the potential to escalate to shock-like syndrome with hypotension, hypoxia from pulmonary edema and other downstream organ complications.

And so we grade cytokine release syndrome using a system where grade 1 is basically fevers. Grade 2 is fevers with some low oxygen requirement, such as nasal cannula oxygen or fluid responsive hypotension. And then grade 3 and 4 gets into need for vasopressor support more—more ICU level care, higher intensity, oxygenation, like, you know, positive pressure ventilation or in grade 4 case intubation.

So we think of grade 1 and 2 CRS as being pretty manageable, but still requiring some acute intervention, especially for grade 2.

So with that framing, we see with these agents similar cytokine release syndrome rates that approximate the response rate. So with teclistamab and talquetamab be get in the 70% range, elranatamab 58% range. All grade CRS.

Whether these agents actually differ in their CRS risk in practice, or whether this is just some details of the patient population, is a little bit uncertain. But it's possible that the newer agents, particularly linvoseltamab, may have a little bit lower risk of CRS.

ICANS risk, which is 1 of the scarier toxicities with CAR T-cells, is fortunately very rare with bispecific antibodies, less than 5%, almost none of it high grade. And so we think of that as a lower risk compared to with CAR T-cells.

And then we do see hematologic risks with these, neutropenia being prominent. In the case of bispecific antibodies, it tends to be kind of idiosyncratic neutropenia that is very G-CSF responsive. It doesn't really limit dosing for most patients. And then infection. So especially with the BCMA-directed agents, these patients do develop a profound hypogammaglobulinemia that is a result of targeting of normal plasma cells and subsets of B cells that really lead to complete absence of antibody production in these patients. And we'll talk a little bit about what that requires of us in terms of management and prevention.

[00:16:49]

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

So the main way that we mitigate risk of cytokine release syndrome is with the step-up dosing approach. So all of these agents are given initially with smaller doses. And so you give—with teclistamab, for example, it's sort of a 5-fold dose escalation over these few doses. The labels are often, you know, Days 1, 4, and 7; 1, 4, and 8. But if you look in the fine print there, it is permissible to give the next dose after 48 hours in most cases. And so in many of our institutions, we do kind of a Day 1, 3, and 5 approach to expedite that step-up dosing.

The dosing and schedules differ a little bit for each. And then subsequent dosing differs a little bit also. And so with a lot of these agents, it's weekly dosing at first and then extends out to every 2 week or every 4 week eventually. And then some of the newer ones coming down the pike use more extended dosing intervals from the beginning.

But you can think of these agents as roughly weekly at every 2 week agents at first and then extending in patients who are responding.

[00:17:55]

Acute Immune-Related Toxicities: CRS and ICANS

And so, in terms of managing toxicities, what's interesting is that, you know, we think of tocilizumab as—which is an anti-IL-6 receptor antibody as the mainstay of treatment for cytokine release syndrome based on our experience with CAR T-cells. And that was certainly utilized widely in the clinical trials.

For kind of technical regulatory reasons, it didn't make it into the label for other - any of these agents. So I really take these opportunities when I can to emphasize that even though you won't find tocilizumab in the label for these agents, it really is an essential tool for managing cytokine release syndrome.

So the cytokine release syndrome, we see the first sign as fever. As I mentioned, in high grade cases, progressing to hypotension or hypoxia. With ICANS, ICANS can have a variety of manifestations that include just some subtle changes in mental status, sometimes some motor symptoms like tremor, headaches, and in the most severe cases, you can - you can get problems like seizure and cerebral edema. But fortunately, these are exceptionally rare, especially with the bispecific antibodies.

The mainstay of treatment for ICANS is corticosteroids, so the anti-IL-6 receptor antibody. Tocilizumab is not thought to be effective for ICANS. But steroids are - are effective and are the recommended first management.

[00:19:11]

Initiating Bispecifics: Managing CRS

So when we start bispecific antibodies, so the cytokine release syndrome and ICANS risk are for the most part confined to these initial doses. And so it’s very rare for patients to have CRS or ICANS after the second or later full dose. And so it really is during that step-up dosing in the first full dose. Very rare cases of late onset CRS or ICANS.

So patients do require management. And in fact the labels for these drugs suggest inpatient administration. Although many centers are now doing this on an outpatient basis, and we'll hear from Dr Ticku a little bit later about some of the practical aspects of administering these agents, especially in the community setting, where this kind of inpatient hospitalization could be impractical.

But if you do administer an outpatient, you have to have systems in place to closely monitor for cytokine release syndrome and ICANS. And you see here that for grade 1 CRS, you can just observe patients through that without intervention. However, in many cases, we do consider tocilizumab just to expedite the resolution of it for patients’ symptomatic benefit, and to enable moving on to the next step-up doses.

For grade 2 or 3 CRS, you really should be giving tocilizumab at the standard IV dose, and it can be repeated. And especially in higher grades or in tocilizumab refractory CRS, we are using corticosteroids often.

[00:20:42]

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

And so if you look at, for example, MajesTEC-1 - sorry. So increasingly, we are thinking even about using tocilizumab as a prophylactic. And this is especially useful in outpatient dosing settings where you would like, if possible, not to deal with any CRS, especially because it can happen off hours and potentially result in patients having to go to the emergency room. So there have been several prospective studies in which tocilizumab is used before step-up dosing or as part of step-up dosing to prevent CRS.

And what's striking is that it's quite effective. And so you see with teclistamab here, just 1 example, the overall incidence of CRS is 72% without prophylactic tocilizumab. And toci is given prophylactically. It reduces the CRS rate down to 25%.

Now interestingly, it doesn't reduce all of it. And the proportion of CRS that happens tends to be in the grade 2 category more often. So it doesn't completely eliminate it. You still have to be on the lookout for it, but it does greatly reduce the risk of CRS. And it doesn't seem to have any effect on response. And this has been shown with multiple bispecific antibodies over time in - in both prospective study and in kind of retrospective real-world study.

And as a result of these data, tocilizumab is now listed in the NCCN guidelines as appropriate prophylaxis. And so we, at our center, have not had any trouble getting reimbursement for tocilizumab used in this prophylactic way. And it's made outpatient dosing of these patients a lot easier.

[00:22:19]

Grading and Managing ICANS: ICE Scoring Assessment

ICANS. As I mentioned, there are a variety of manifestations. There's this tool called the ICE tool, which is sort of adapted from the Mini Mental Status Exam. It's a very simple to administer scoring system that can help grade ICANS and give some guidance on the intervention strategy.

Again, the mainstay of therapy for ICANS is steroids, initially given at 10 mg every 6 hours or every 12 hours, and patients usually respond promptly to the dexamethasone when given.

And obviously, for both cytokine release syndrome and ICANS in the context of bispecific antibody therapy and step-up dosing, you hold the subsequent dose until these have resolved. And compared to CAR T-cells, that ability to kind of ease in the dose in a controllable way I think has led to the CRS and ICANS predominantly being low grade and lower risk compared to CAR T-cell therapy.

[00:23:18]

BsAb Therapy’s Infection Risk

So infection risk, as I mentioned, is very important. And this seems to be a problem more so with the BCMA-directed bispecific antibodies. Talquetamab, the GPRC5D-directed agent seems to have lower risk of toxicity. And this is mainly in the case of BCMA, thought to be driven by the hypogammaglobulinemia, as I mentioned.

Really all our myeloma therapies, to some extent, cause hypogammaglobulinemia, but there's really nothing like the bispecifics in terms of the consistency and the depth of hypogammaglobulinemia.

[00:23:48]

IVIG Reduces Risk of Serious Infections

Though it's never been prospectively studied, there is consensus now that intravenous immunoglobulin is essential for prevention of infection and serious infection with these agents. And while not studied prospectively in a randomized way, there have been high-quality retrospective studies in patients treated on study with BCMA-bispecific antibodies and in the real-world, that suggests that while you're on IVIG, your risk of high-grade infection is markedly reduced.

Now, interestingly, IVIG does not seem to reduce the risk of low-grade infections. This effect is really confined to the high-grade infections, and this fits with my experience where patients on bispecifics for a long time. With IVIG prophylaxis, they're not having serious high-grade infections, but they are sometimes getting into trouble and frustration with long-term low-grade infections.

So for - the most classic culprit for this is rhinovirus. You have patients with rhinovirus that they have difficulty clearing or COVID and difficulty clearing with kind of low-grade upper respiratory symptoms that can be quite bothersome over time.

[00:24:50]

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

This is just another study looking at the efficacy of IVIG prophylaxis, showing that primary prophylaxis with IVIG really does improve infection-free survival, and especially with high-grade infections.

[00:25:08]

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

So it's important to emphasize that we consider IVIG use essential with these bispecific antibodies. And so with typical myeloma therapy, the practice is to reserve intravenous immunoglobulin for patients who are having a pattern of infections, and not use it universally for patients with hypogammaglobulinemia.

With the BCMA-directed bispecifics, we turn - we - we discard that risk adapted approach. And instead, for anybody who is responding to these agents and therefore going to be on them for a period of time, we recommend IVIG from the start. And – and the official guidelines are for any IgG less than 400, and I agree with that. But I think it's also important you have to think about the effect of the serum M-spike on the measured IgG level. So a patient with an M-spike of 2.5 and an IgG of 2700, even though their IgG is over 400, they really have a functional IgG of just 200.

And if you wait until that M-spike goes away to start the IVIG, you could be delaying the IVIG prophylaxis that the patient needs by many months. And so the minute we see any sign of response, we start giving IVIG and give it monthly at first, and patients may be able to reduce the intensity of IVIG over time.

And using 400 I think is a reasonable goal, although there are some data emerging that may be a little bit higher target. Makes sense. I think 400 is the number that people have stuck with.

And then other infection prophylaxis. So everybody should be on HSV and VZV prophylaxis with acyclovir or similar agent. Patients should be screened for hepatitis B exposure. And patients with positive anti-hepatitis B core antibody, or any active hepatitis B should be monitored prospectively or considered for prophylaxis.

Important when you're thinking about serologies for patients on these agents that the extent to which they cut off antibody production can yield false negative serologies. And when patients are getting a lot of IVIG, of course, you don't know if you're measuring a serology from the IVIG or the patient's endogenous immune system. So think about checking some of those serologies before you start these agents if you're relying on, for example, the hepatitis B core antibody to assess somebody for risk of hepatitis B reactivation.

Colony-stimulating factor can be helpful for managing grade 3 or higher neutropenia. There's no need or no recommendation to give aspergillus prophylaxis for these agents, but all patients should be on pneumocystis prophylaxis. And there were several cases of pneumocystis pneumonia in the trials of the BCMA-directed bispecific antibodies.

Follow guidelines for standard vaccination. Even in the absence of an ability to mount a humoral immune response to vaccinations, these patients may benefit from the T-cell induction that vaccines can affect even in the absence of an antibody response. And so we still recommend, especially the seasonal vaccines for these patients, even if they can't mount antibody responses.

[00:28:11]

Pearls for Managing GPRC5D-Associated AEs

Okay, finally looking at the GPRC5D-targeted agent, talquetamab. This comes with a distinct set of toxicities. And so similar CRS and ICANS risk compared to the BCMA-directed agents. But the GPRC5D target does have expression in certain keratinized surfaces. And so you do get this other suite of toxicities with - with the GPRC5D-directed therapies, namely talquetamab.

And so most prominent for patients are what are referred to as oral and taste toxicities. And so patients can have their taste buds affected in a way that can—and develop xerostomia and a way that can make it quite difficult to eat. And this varies quite a lot patient to patient. Some patients describe it as a minor nuisance. I've had other patients describe it as profound and life changing, with 1 of my patients losing 10 pounds every month as a result of this.

This clearly is a dose-related toxicity. And so, as you get patients further into therapy and you reduce the intensity of dosing, in the case of talquetamab, reducing down to once every 4 week dosing, that does seem to help a lot. In the clinical trial with these agents, you generally didn't see patients stop therapy as a result of this toxicity, suggesting that over time it is manageable, but it can be burdensome.

Listed on the slide are a number of supportive care measures like saliva substitutes, nutrition consultation that can be helpful. There's a set of skin reactions that can happen. So these take 2 forms. One is kind of a generalized macular rash that is very steroid responsive. The second class are a non-painful but kind of unsightly hand and foot peeling that can happen. Skin emollients and low potency steroids can help with this.

And then finally, there's a nail toxicity, where patients nails can become fragile and you - and you get nail bed separation. This is not painful, but it is rather unsightly. Patients usually don't complain about it too, too much. And nail hardeners and vitamin E oil and emollients can be helpful for this.

[00:30:16]

Fatigue With BsAbs

Finally, we're learning that fatigue can be an issue. Fatigue was reported with a high rate in most of the trials with the BCMA-directed bispecifics.

In my personal experience, this tends to be confined to the early couple months of therapy. It is more pronounced in elderly patients receiving these agents. And it does tend to get better with response. And so just a little bit of encouragement to patients that this should pass.

Anemia may contribute. And the anemia with these agents tends to be kind of anemia of inflammation that is most prominent early on. And as the response settles in and some of the inflammation induced by the drugs calms down, patients’ bone marrow become more active and anemia gets better. But this requires some supportive care and counseling to patients.

[00:31:08]

Let's Return to Our Questions

And so with this, I'll turn it back over to Tim to go through some of our questions.

Speaker: All right. Thank you, Dr Garfall.

[00:31:16]

Posttest 1

So let's revisit this first question. Your patient is a 77-year-old with relapsed/refractory myeloma who is receiving a BCMA-bispecific antibody. Is concerned about the risk of infection after being transferred to the outpatient setting after step-up dosing.

In addition to normal prophylaxis for these viruses, which of the following strategies should be employed as part of a standard infection prevention protocol? There are your choices. Please make a selection.

And let's see if we can see some results. It looks like option B started out at 47%. And post-test it has gone up to 58%. So Dr Garfall, would you care to take a moment to elaborate on this?

[00:32:26]

Posttest 1: Rationale

Dr Garfall: Yeah. So there is a - you could look at options B and D as - as similar. And I think the distinction between them is - is maybe the point I was making about the confounding effect of the M-spike. And so in patients who start a bispecific antibody that might have a high M-spike, their IgG might - IgG level may be well above 400, but they are still in need of prophylaxis, especially if that high IgG level is driven by the monoclonal component of the IgG.

And so I think as you get further on into therapy, I think that 400 benchmark is a good one to strive for. And for example, patients can maybe come back down to every other month IVIG if every other month keeps them above 400. And monthly is a good place to start. And so I - I can see why folks picked B, but D I think is a good place to start with monthly replacement and then settling into a target of 400 with time, especially after the serum M-spike goes down.

[00:33:41]

Posttest 2

All right. Thank you very much. And let's go to question 2. In the MagnetisMM-3 trial of elranatamab and BCMA-naive relapsed/refractory multiple myeloma, which of the following outcomes was demonstrated?

All right. There are 4 answer choices. Please take a moment and then select your answer. All right, let's see results.

[00:34:17]

Posttest 2: Rationale

Okay. So option A and not very much change. Would you like to take a moment here, Dr Garfall, to give the rationale here?

Dr Garfall: Yeah. So the high - like the other BCMA-directed bispecifics, the MagnetisMM study  studied elranatamab. And there was very high response rate of 61% with the median duration of response not reached, whereas the other ones have had a median response duration reached suggested that maybe the duration is a little bit better with elranatamab than others.

So B would not be correct because while there is a high response rate, it was not a limited duration. It was quite long duration, especially in this late line of therapy. And ICANS fortunately with the bispecific antibodies has been very rare. And elranatamab as a BCMA-targeted agent is not associated with oral toxicities. The oral toxicities are really only seen with talquetamab, which is the GPRC5D-targeted agent.

Speaker: All right. Thank you so much.

[00:35:29]

Optimizing Care Transition and Treatment Continuation for Patients With RRMM Receiving BsAbs

Now we will move to the next session.

[00:35:35]

Let's Begin With a Question

Pretest 3

But we have a starting question here for everyone. So question number 3. I'm equipped to design multidisciplinary care strategies to support treatment adherence and continuation in patients transitioning from academic to community settings.

1. Strongly disagree;
2. Disagree;
3. Neither agree nor disagree;
4. Agree; or
5. Strongly agree.

Please take a moment and make a selection. And also remember, please submit your questions. I'm sure our faculty would be happy to answer any questions that you have. We'll just move on to you, Dr Ticku.

[00:36:22]

BsAb Maintenance: Academic to Community Cancer Care Center

Dr Jonathan Ticku (Mayo Clinic): All right. Great. Thank you, Dr Garfall, for that excellent presentation there. So I'm going to review the next set from the perspective of a community oncologist and hematologist.

So, more than 10 years in practice, having never seen any toxicity like this before. So I didn't train in the era of CAR T or bispecifics. So from the perspective of somebody who has never obviously seen that in-patient or any step-up dosing toxicity.

So the current state is basically the bispecific antibody maintenance therapy from academic to community center. So initially the step-up dosing is all done at the referral site and then comes out once the step-up dosing phase is complete back to our community practice.

So this slide the house represents the community center and the academic centers represented by the building. These are all the decision-making processes, preparation and that has to go into the whole sequence from community to academic and then back to community.

So essentially, we're trying to educate those patients ahead of time, identify them where we may be able to slot in the bispecific antibody therapies and preparing them. So we also have to identify those patients for ability to even, you know, stay at the academic site for 2 weeks. Oftentimes, these patients have to relocate for 2 weeks with a caregiver. And, you know, we have seen that that hasn't been really feasible for everybody and it's accentuating these disparities in healthcare.

And as Dr Garfall had mentioned, there are newer therapies or new studies like MajesTEC-3, which is providing a dramatic benefit. And this is only going to be more exacerbated in the future. So what we do is try and screen those patients ahead of time, try and identify the caregiver, see if they could, you know, even overcome the barrier to - to relocate.

And then the preparation for accessing—you know, it's follows somewhat the established pathways of stem cell transplants. So if you have a relationship with the academic side already, particularly for the myeloma patients, this is sort of an established pathway.

We educate the patients, and then when they go to the academic site, they do the step-up dosing. They're in there for about 10 days to 2 weeks and then that transfer back. So once you identify that patients is important for to try and figure out that continuity back. So everybody has to be in the loop not only at the academic site, but at the referral site or for the community site from the beginning to successfully stay on track and - and bring that back.

[00:39:39]

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

So this is a slide exactly what Dr Garfall had shown before. All the bispecific antibodies approved in this setting. Hospitalization right now is recommended for all of these drugs to mitigate against severe toxicities. But as he had mentioned, with prophylactic tocilizumab and some data and management, this has been shown to be reasonably feasible as outpatient step-up dosing as well.

[00:40:10]

HCP-Identified Challenges to Transition Care/Treatment Continuation

So as I mentioned before, there are some limitations. But to smooth the process out for care transition and treatment continuation, we'd like to have that piece, the communication because these are barriers definitely. If you have limited cross site communication between the 2 centers, it's very difficult. EHR incompatibility, you know, that can introduce some errors.

You know, REMS requirement is very key. Having not only the community site have the pharmacy, but the providers have to be REMS certified. You know, in the community practice, once you establish a bispecific antibody program, it's not like the referral center where they have a vertically integrated cellular therapy program and the patients are taken care of from the ER to the ICU by that group.

We need primary care doctors engaged in patient, hospitalists engaged, ICU doctors engaged in ER.

And then there's the financial and insurance issues that are a little bit more impactful. In community practices, there's, you know, inpatient giving doses of these antibodies in patient is wrapped up in a DRG. So there is a less margin for absorbing those costs.

[00:41:36]

Highlighting the Patient Voice

So when we think a little bit about, you know, how patients transition back and forth, you know, when there is warm handoffs that makes patients feel good that we're talking and back and forth with the group in academic site, you know, they feel like everything's very coordinated and smooth, especially if they don't have delays. And, you know, they don't have to, you know, reinvent the wheel for you and talk to you about, like, what's been going on. There's adequate communication between each site.

[00:42:10]

Considerations for Transition Between Treatment Centers

Then considerations for the transition between these sites. You know, sometimes there will have to be another insurance authorization. So for instance, our practices, we operate out of 3 community practice sites and 3 different hospitals in 2 states. So, you know, there is a definite insurance authorization that has to be done oftentimes between different places.

And then educating the patients and staff. The staff education is very key here. So like I had mentioned before, when we educate folks, we identified the key stakeholders. And it's not just the physicians and APPs. It's the pharmacists, it's the nurses. It's the emergency physicians, hospital medicine and ICU. And everybody needs to be on the same page when we're developing these programs.

And the handoffs are obviously important when - when the patients come back to the community practices, you know, once they reestablish their - that's when they - the call changes. So they'll call us instead of the referral site, for any toxicity management after hours, etc.

[00:43:25]

Successful BsAb Administration Requires a Team of HCPs

So the successful bispecific antibody administration that requires definitely a team in the community practice is very evident. So physicians, APPs, pharmacists. The pharmacists are very key here as well. We've leveraged our pharmacists significantly across the hospital and outpatient setting. We also have nurse navigator, and they help us keep track of those patients nicely, but nurses can fill that role as well.

The social workers help overcome any social determinants that are very - sometimes difficult for the patients to travel back and forth, like gas cards and things like that helps smooth out that process.

The critical care staff, and I would add the inpatient hospital teams, are very important there. And their role, especially if, as Dr Garfall had mentioned, you know, even with prophylactic tocilizumab, the grade 2 toxicities were still there in those studies. So those are grade 2 patients are often hospitalized.

So the inpatient hospitalist teams have to be very aware of this. And emergency department staff. The administrators will really, mostly know what's going on. So, you know, they'll be a key player here as well.

[00:44:47]

Role of Pharmacists in Comprehensive Care

And often when you're developing an outpatient or a community bispecific program, the administrators often like are facilitating this as well. So it's good to all be on the same page. And this is a slide about the role of the pharmacist in this care. So like I had mentioned, they can carry a lot of this project as well. They can teach in services for nursing and direct the inpatient and - and ER pharmacists on how to - how to identify and - and make sure we have tocilizumab at the sites, the REMS program.

And they don't mitigate financial toxicity for us, but that could be something that's in their wheelhouse. And optimization of the medications and premeds, etc.

[00:45:47]

Pharmacist’s Role in BsAb Therapy

So this is this similar slide here. I would highlight that middle section there. When we have the inpatient pharmacist there helping, if you have an inpatient step-up dosing program, they are going to be key there in helping or comanage the patients in that sense. And then the clinical pharmacist and outpatient pharmacist, I would combine in what I had discussed previously.

They also help manage for us when we - when we have outpatient step-up dosing, they've helped develop algorithms. When the patients call in, there's algorithms developed. And with the help of our pharmacist to help triage that call and tidy everything up and present that to the physician for additional management.

[00:46:45]

Leverage Nurses and Nurse Navigators as Continuity Anchors

Leveraging nurses and nurse navigators, as I mentioned, are very key here. It helps - and there's a little quote, “We build trust with the nurse - with the nurses. They're the one that catches errors.” But I would say like the team that will catch the error. In our community practice, the more you leverage everybody and educate all players, the whole team will catch any errors that could arise.

[00:47:11]

Role of Nurses and Nurse Navigators in Care Transition for Patients Receiving BsAbs

So the role of nurses and nurse navigators, like I said, is important for us. Not every community oncology practice has a nurse navigator, but oftentimes for with some nursing FTE and - and more motivated nursing staff, they're - they're enthusiastic on being able to fill these roles as well. And they'll advocate for the patients, they'll help coordinate, and they will take the initial call for us from the outpatient, you know, step-up dosing patients that that call will initially come to them and they'll sort of help triage that. They'll facilitate all the communication and provide the clinical support as well.

[00:47:52]

Considerations for Managing Key AEs in Outpatient Setting

So considerations for managing these adverse - these toxicities in the outpatient setting. So as Dr Garfall had mentioned, if you're doing just the traditional route of bringing patients from—after the step-up dosing is done in the referral site, then the CRS and ICANS are a lot less prevalent. So you have to be considering the infections that may happen after that and maybe some lower blood counts.

The CRS and neurotoxicities are relatively rare at that point. So regularly educating the staff on toxicities. Our program where we purposely launched with just 1 drug, and then as we start getting more comfortable with this outpatient step-up dosing process, we bring in another drug, teach everybody on that one and then move in from there.

[00:48:57]

Patient and Caregiver Education

So patient and caregiver education. So this is toxicity. How to manage the toxicity as he had mentioned. A lot of places will have caregiver support required for 48 hours after the final step-up dosing. So that requires a lot of education, how to take vitals, how to monitor the temperature, how often to do it.

In the Emory model, I believe they did the vitals once every 8 hours, but oftentimes it's once every 6 hours. In our setup, it’s once every 6.

Educational materials. I'm just going to highlight these booklets and wallet cards. And the bracelets. You know, you'll see a lot more of the companies come out with these bracelets with a QR code. So letting the ER folks know if a patient comes in with these bracelets, they can use their phone to scan that QR code.

So ultimately, this provides a lot of safety. Plus, if somebody comes in with some neurotoxicity and some confusion, the bracelet will provide a little bit of a failsafe. Some places can add like a banner to their EMR, but sometimes it's sort of a big process and inflexibility with these EMR vendors that you can't really just change things on the fly.

So, you know, the bracelets are great.

[00:50:26]

Ways to Ensure Optimal Care Coordination

So optimal care coordination just requires a lot of, like, warm handoffs back and forth. We want to make sure we have a process in place. And however it's done, it's just building on that process and thinking things through with each site. Every outpatient practice is going to be a little bit nuanced. So our model that we've developed is slightly nuanced in each location that we're launching.

We're a big provider of telehealth. We use a lot of telehealth in our oncology and hematology practice, so we can provide support in that way. And, you know, develop from there. And then here the patients connect with the navigators as well. So that's really nice for us.

[00:51:18]

So this is actually a quote from me. I put out on LinkedIn, in the - we put it in here. “Community oncology practices face a growing challenge: how to bring these therapies to - to patients close to home.” And I would just amend that. It's bispecific T-cell engaging therapies to be more clear there.

[00:51:40]

Bispecific Antibodies: Issues Affecting Access

So again, having these issues affecting access. Again it's the patient, their setup, their barriers to travel. That's the biggest one that I've seen in my clinic. And I'm suspecting a lot of community oncology practices are going to be the same. Logistically, how are they traveling back and forth, staying for 2 weeks and needing that caregiver.

What I have noticed, and it's probably comes as no surprise to the people on this call are, you know, when you have somebody that can't afford to go travel and stay for 2 weeks, the people that they know that they're going to lean on for caregiving support are more likely not to be able to manage that either. So it's really - a really a big problem right now. And I think it's going to be exacerbated in the future.

As Dr Garfall has mentioned, there are so many of these bispecifics in production or in trials and even on the solid tumor side now. So the management of those long-term toxicities, we're just going to have to get comfortable with that. And again, now that we have like a more latitude and starting IVIG, hopefully mitigate any of those severe and serious toxicities down the pike. And then the insurance coverage there.

[00:53:01]

Requirements for Successful Initiation of BsAb SUD in Community Practice

So these are requirements for initiation of that same process. And I think I've covered all of these. You know, I will highlight the protocols and logistics. So the each site is going to be different, you know, if there's—usually, where we're developing the outpatient step-up dosing, there is an ICU at those hospitals, and we have protocols and decision-making trees on which patients to offer that to. And as Dr Garfall had mentioned, the patients probably need to have a little bit better performance status and lower disease burden, live about 30 minutes from the emergency department because in case they need the tocilizumab.

The reimbursement, that I just covered before. And then the patient caregiver support and education piece.

[00:54:02]

Patient Selection for Outpatient BsAb Administration

So outpatient selection, I just had highlighted this. PS greater than or equal to 2 is probably not a great idea. Age and comorbidities, high disease burden. I think when we think about this in the myeloma stand - from myeloma standpoint, this is pretty straightforward.

When you start getting into these other solid tumor bispecifics like tarlatamab, you know, those are smokers, so they're not going to have the cardiorespiratory reserve to manage a lot of this. So there's going to be a little bit of nuance with each drug. They're going to have to have reliable transportation. And again, that caregiver oftentimes 48 hours after the final step-up dose.

Access to ICU level care. And - and the pharmacist - our pharmacist has identified all the sites that - that need to have tocilizumab on hand.

[00:55:03]

Feasibility of Outpatient Step-up Dosing Model: Mayo Clinic Model

So the feasibility of the outpatient step-up model. This is a Mayo model. They identified or they enrolled 34 patients in this single institution study, and they all received either teclistamab or talquetamab. The standard premedications were given. And this was basically proof-of-concept of an outpatient step-up dosing model.

So 47% of these patients remained outpatient throughout the entire step-up process without the need for hospitalization. So that's a big win for patients. Nobody wants to sit in the hospital unnecessarily. And here, almost 50% of those patients would have fit that bill. They don't want to sit in the hospital unnecessarily. So, you know, they didn't.

And then 24 of the patients had CRS grade less than 2 managed with steroids, Tylenol and toci. There were 4 cases of ICANS, all less than grade 3. So ultimately, again, proof-of-concept.

[00:56:06]

Feasibility of Outpatient Step-up Dosing Model: Emory Model

So this is the Emory model, and feasibility of their outpatient step-up dosing model. And they had 53 patients and they used teclistamab, elran and talquet. And they used prophylactic tocilizumab. And they had a lot lower rate of CRS in those patients. And that was—Dr Garfall had shown this data a little bit earlier as well. So that is a very nice way to go. And that's actually something we've adopted.

[00:56:46]

Conclusion

So in conclusion, you know, this treatment journey for these patients and receiving these treatments, you know, that follows the pathway of stem cell historically. So, you know, going to the main site and back to the community. But that time frame is pretty compacted instead of, like, having quite a long time between the handoff, it's really requires a lot more close coordination, because that's a 2-week window that everything has to come back.

You know, the nurses, communication, navigators, pharmacists. It requires a multidisciplinary care. And again, the outpatient step-up dosing is feasible.

So thank you.

[00:57:38]

Let's Return to Our Questions

Speaker: Thank you.

Dr Ticku: Tim, go ahead.

Speaker: Yes. So for the audience, I have a few questions for you, and then we'll do audience Q&A. So please remember, if you have a question, please submit it using the question tab.

[00:57:54]

Posttest 3

So our first question here. I am equipped to design multidisciplinary care strategies to support treatment adherence and continuation in patients transitioning from academic to community settings.

1. Strongly disagree;
2. Disagree;
3. Neither agree nor disagree;
4. Agree; or
5. Strongly agree.

Please select.

All right. Let's see what people say. We have moved them up from - let's see, I would say, about 25% agree - strongly agree to now 53% post-test. So congratulations.

All right. Next question.

Dr Ticku: Excellent.

[00:58:50]

Poll 3

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

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

[00:59:08]

Poll 4

And after you answer that one, move to poll 4, which is, to please take a moment to enter 1 key change that you plan to make in your clinical practice based on this education.

[00:59:22]

Q&A

And while you're doing that, let's do audience Q&A. We have an interesting question, I think, which is that, many patients experience therapy fatigue. Has there been any progress in fixed duration therapy with bispecific antibodies? Doctors?

Dr Ticku: I think I could actually - go ahead.

Dr Garfall: Sorry. This is a topic so near and dear to my heart that I almost feel like the question might have been a plant or something, because we are - so I firmly believe that the future of these therapies is fixed duration. And we started at our center a prospective trial for teclistamab, in which patients who have received 6-9 months of therapy and have a good response stopped therapy, with the idea being that, you know, we know from the clinical trials that many patients who stopped therapy for this or that toxicity were able to go on and remain in durable response off therapy for a long time. So we thought this was important to study prospectively, because of the issue with therapy fatigue and also the long-term risk of infections and other immune complications that could potentially emerge with this class of agents for such long-term therapy.

So we recently presented our data at ASH. And long story short, in over 50 patients, now that we've treated in this fashion, it looks like their risk of subsequent disease progression is indistinguishable from what you would expect with continuous therapy. And so we do think that fixed duration therapy is - is - is promising and of course needs to be studied a little bit further and we'll have more data on our study.

But we've been doing this for over 2 years now in some patients and it seems like it's very effective and may limit long-term toxicity. And patients seem to really appreciate the opportunity to stop therapy.

And I'm aware that some of the future studies that are going to be developed with the emerging agents are fixed duration therapy is very much being considered by the companies as they develop their studies, which is encouraging also.

Speaker: Another question. Outside of step-up dosing, when would a patient be readmitted to the hospital while being treated in the community setting? Who would like to take that one?

Dr Ticku: Yeah. Excellent question. Grade 1 toxicities can be managed—grade 1 CRS can be managed outside of the hospital, but anything grade 2 or higher would be admitted. Also any neurotoxicity would admit as well.