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Oncologists “On Call”: Our Practical Experiences to Optimizing Bispecific Antibody Therapy in Relapsed/Refractory Multiple Myeloma

Hello and welcome to Decera Clinical Education’s Oncology Podcast. I’m your host, Kendall Schick. On tonight’s episode we are joined by Dr. Muhamed Baljevic from Vanderbilt-Ingram Cancer Center in Nashville, Tennessee and Dr. Johnathan Ticku from the Mayo Clinic in La Crosse, Wisconsin. Today they will be discussing various strategies to optimize the use of bispecific antibodies for the treatment of relapsed and refractory Multiple Myeloma.

This episode is part of a larger educational program titled “Addressing Challenges and Implementing Care Strategies to Optimize BCMA Bispecific Antibody Therapy in R/R MM.” For more information on our guests, along with a link to the education program, please visit the show notes for this episode.

Now, let’s get started and hear what the experts have to say about bispecifics in myeloma.

Dr. Baljevic: Good afternoon. My name is Muhamed Baljevic, and I am Director of Myeloma Program at Vanderbilt. I am joined by my colleague, Dr. Jonathan Ticku from Mayo Clinic. We are talking today about bispecific antibodies and experience, particularly in the outpatient setting and among community centers, sandwiched with experiences from academic environment. We want to thank Decera Clinical for organizing this and helping us connect and learn from each other.

Dr. Ticku: As a community oncologist and getting started with the outpatient step up dosing for bispecific antibodies, we have now a variety of drugs to think about. What are the things that we should take into consideration when selecting these patients? Is there a benefit of choosing one agent versus the other for this?

Dr. Baljevic: Within the BCMA space, certainly in my clinic and what I have observed among my colleagues at my institution, we do not necessarily have a defined preference when it comes to efficacy or safety profiles. Teclistamab came to market on October 22nd, and elranatamab came on market in August 23rd, so nearly a full year later. It is reasonable to assume that most providers have had a little bit longer experience with tec.

However, we have both tec and elranatamab on formulary and approved and in use at our institution. We use them both. One of the things that was part of the reasoning why we included elranatamab on our formula was also the fact that, per label suggestions/recommendations for inpatient hospitalization periods during the step up dosing, is the fact that elranatamab had a 24-hour rather than 48-hour recommended monitoring after second step up dose. Then the third dose, which is the first full weekly dose, could be done fully outpatient.

Patients that are considered desirable for preferential inpatient step up, that would be a situation where you could save some hospitalization days and be more cost-conscious in terms of healthcare utilizations. Certainly, in terms of efficacy, I can briefly cover the fact that, after median follow up of just after 30 months for MajesTEC-1 study, which was registrational for teclistamab, the median overall survival was 22, just over 22 months. It was fantastic.

It was clear that deeper responders were doing better. The overall cohort in terms of PFS was about 11.4 months. Then importantly, those who were in CR response or better median PFS was not even reached. The VR or better responders had a 26.7 months, so more than double in terms of benefits. 

That is really notable. There was a nice real-world data also follow-up recently with a huge number of patients, over 500 patients that had a somewhat shorter follow-up still. What I liked in that study is that most patients that were included, 89% of them, would not have met the defined eligibility criteria from MajesTEC-1. I really enjoy reviewing the real-world data and experiences because these were hundreds of patients that have never been part of the trial data. Six-month overall survival was 73%, six-month PFS was 53%, and median duration of response was 11 months, with CRS and ICAN, and infection occurrences not looking dramatically different at all compared to what we saw.

Then magnetism, of course, was registrational for elranatamab, and day after latest data cut, which was in March of ‘24, 28.4 months of follow-up had a median PFS of 17.2 months, median overall survival at 24.6 months. Also, some nice real-world data, 130 patients or so with elranatamab as well, though this one really had a short median follow-up. Still seven and a half months only, but PFS in an OS we are tracking. I would want to see this cohort for a longer follow-up and then see how it plays out. 

Interestingly, their LDH was found to be a significant predictor of shorter survival and time to disease progression. And also hemoglobin levels. Patients with higher hemoglobin levels were more likely to achieve deep response and longer progression-free survival. Interestingly, also, and this is something that our patients ask us, patients with prior exposure to targeted therapy, had lesser chance of achieving CR or better. This is always something that we are thinking about.

Jonathan, may I ask you, I would really appreciate it and I would love to hear from you how your community-based experience has been with bispecific antibodies, particularly outpatient step up. How often do you and your team fully step up bispecific in the outpatient setting? How often do you - the patients with continuous dosing after they have been stepped up? What is the breakdown between inpatient and outpatient? How do you choose between? That would be interesting, I think.

Dr. Ticku: We actually have the criteria of patients have to have a caregiver, and patients have to live within 30 minutes of the emergency department. We have a little bit more strict criteria on that. Because we are surrounding a larger medical center, within an hour away, a lot of the times if the patients are not able to be considered for outpatient step-up dosing, they will get that inpatient step-up dosing in the referral center.

We always have to consider our own staffing as well, how busy, in the inpatient side. How thin we are as far as staffing in the outpatient clinics, and those really play a part when we are designing our system. We wanted to know which hospital had a longer wait times. Like you are noting previously, with CRS, you cannot have patients like boarding in the ED for eight hours waiting, if they report a fever or etc., from home after a step-up dosing.

We have a lot of these criteria that we follow and plan accordingly. It is usually the lower disease burden patients, patients that are obviously relatively stable fewer comorbidities. Then we will consider those patients. 

For the most part, our plan is the way we set out is prophylactic tocilizumab, because if we are not a high volume place, we need to have those safety measures are really appealing to us and our colleagues in our sister hospitals, community hospitals within our health system. That is the way we have approached it.

We also have this unique feature with our system with remote patient monitoring, where we have this remote patient monitoring system where patients are taking their temperature, blood pressure, etc., once every six hours. Then that is uploaded into a system with a remote patient nursing that is staffed like 24/7. Then the protocol that we have for those nurses during the day, they alert our clinic, and then in the evening they will alert the on call provider.

Then the on call provider will then direct the care from there. It is a little bit more of an intricate system, but it does not have to be that way in a lot of practices. I know a lot of practices around the country are doing it a little bit differently, where patients are just taught to take their temperature and blood pressure per usual and then report it as needed. I think there is a lot of differentiation there. It is not necessary to have such a remote patient monitoring system, but it does take a little bit of the burden off of the physicians. I think that is one of the big things. 

Coming at it from the perspective of being - I trained quite some time ago, where we never had these technologies. We never had biophysics. We never had CAR T-cell. I would never have seen a toxicity like this. Getting people like myself and others comfortable, for instance, we have some doctors that pretty much see only breast cancer. You have to educate them, take a lot of the burden off of busy outpatient clinical practice by using remote patient monitoring. These outpatient step-up dosing models will be more acceptable, so that is where we came from with ours.

Dr. Baljevic: Do you mind if I ask, I find that very interesting, you guys have done tremendous work at Mayo in this space. We have also done several things that will be out. What I want to ask you directly is about utilization of wearables. Do you still use wearables for bispecifics, and in what proportion of patients? Because I can tell you, like you guys, we have for years given CAR-T fully outpatient aid of variables.

It has really facilitated things quite significantly. Then, after the arrival of bispecifics, we actually started using wearables also for monitoring a mitigation of CRS risk, etc. Frankly, we noticed very quickly that it was not really making a huge difference for us. So much so that we have actually stopped using wearables completely in bispecific antibody patients. The rates of CRS, and particularly high-grade CRS, is not really something we commonly observe. Occasionally, we will. We are not finding that this is something that we need to bring back. What are your thoughts there?

Dr. Ticku: Where our remote patient monitoring system is not using a wearable, it is basically like a connected device that will transmit the blood pressure and temperature directly to the remote patient monitoring nurses. It is uploading the information to their dashboard. It is not like that. What you are talking about is a wearable device that is consistently taking temperature. We are not using a wearable device in our setup. The remote patient monitoring is just like an iPad mini that has its own data connection, since we are in more of a rural communities with the community oncology practices, so it has its own GSM data connection they only take their temperature once every six hours and blood pressure once every six hours. 

Dr. Baljevic: For how long?

Dr. Ticku: For about the first 10 days, depending on which bispecific antibody, but in this case, it is about 10 days.

Dr. Baljevic: We have actually various wearables and wearable technologies that are - some of them are continuously in skin context for temperature, heart rate, respirations and then you can put on a separate piece of equipment for blood pressure, etc. What I was mentioning earlier is we learned very early that, not just that we do not need a continuous, but we do not necessarily even need an intermittent collection of vitals at all. 

Patients always have thermometer. They are provided with one and are always instructed to take temperatures should they feel like they might be developing temperature or unwell, etc. In our hands, that level of comparatively a little bit more de-escalated vital monitoring has really been quite feasible, which to us is a welcome observation because, in the process of trying to expand that approach to some of our community site clinics. 

Dr. Ticku: We have looked at a wearable device that sticks on the body, and I think it runs for 90 days or so. I did not feel like that was going to provide a lot of additional benefit to what the patients were already doing. Unless there is something that research wise, they find that is beneficial, but with the prophylactic tocilizumab, I think the CRS rates tend to be much lower.

But we still have to be alert, I think from what I understand, it reduced the grade one CRS, but the grade 2 CRS did not really budge much, so we always will have to be alert to that still.

Dr. Baljevic: I think what might be helpful to really point out is from last year, April or so, NCCN guidelines really made a concerted effort to address this question, and in fact, included the recommendation for consideration of prophylactic tocilizumab for CRS mitigation in all myeloma bispecific antibodies at this point. We have four of them listed with the joining of linvoseltamab that was approved in July just last year.

I think you are alluding to also some of the other data points. I particularly like data from Miami that was published - was presented as an oral and then published recently in blood advances, that looked at all bispecifics. They actually looked at linvoseltamab before it was officially approved. The number of cases there was considerably smaller, but 40 teclistamabs, 23 talquetamabs, 40 elranatamabs were collected in that data cohort.

What they saw is really significant gutting of the CRS all the way down, an average of about 10% or so. Vast majority of that was actually low-grade CRS, grade 1, with only a little bit of higher grade CRS, and ICANS were also actually, for talquetamab certainly, they were touch actually higher, but they were comparable for teclistamab. They were not really observed on elranatamab at all or linvoseltamab. Really encouraging data. Of course, we know from OPTIC as well, depending on which data cut you look, about 10% as well, and most of it is low grade. 

I am very enthusiastic about tocilizumab prophylaxis. Especially for sites that are just starting their experience, I tend to recommend that they lean into it and always try to ask for approval from the payers. If they get it, I see frankly no reason why they should not use it because it would certainly level that risk. Even if the CRS was to happen, likelihood that would be lower grade that can be managed way easier than needing active measures. 

To that point, grade 1 CRS is something that we at Vanderbilt have stopped admitting. I do not know how you do it at Mayo, but we no longer admit any grade 1 CRS. We manage it with pocket decks, which tends to either completely interrupt any further CRS or maybe serious that would have been destined to be higher grade could end up being recurrent grade 1, in which case we do admit, recurrent fevers and such. This has also ended up resulting in a lot of saved hospital days in our clinic.

Dr. Ticku: I think we are using the same approaches. It is really oftentimes also like provider discretion. Typically, we would like to not admit all patients with grade 1 CRS for sure. That is misutilization of resources, we try and call it. The other question I had was that now with the - the one thing I got a question recently from our clinical pharmacist about the IVIg utilization. Now, are you guys using - just right away giving IVIg for monitoring the IgG levels, and 400 or less, like giving IVIg or waiting on that, and are there-

Dr. Baljevic: That is a good question, honestly, because there is been right over the last almost four years, teclistamab came to market in October 22nd, so we are three and a half years out already from the very first bispecific experience. I have kept tracking. Recommendations have shifted earlier, where they were driven by the cut-off to the current. If you pull up either on IMWG recs or NCCN recommendations, where really advisory is very loose and tends to focus around preference of the provider.

If somebody felt more comfortable to just those people, especially early on, regardless of what the level of IgG is, they could do that, and in all likelihood, be supported by guideline recommendations with the payers. I would say we are liberal with IVIg use, also because we have just freshly published our Vanderbilt experience with flat dose IVIg compared to weight-based dosing.

I believe this is a unique piece of data in the world. I do not know that anyone has ever published on this or even that they are using it. We have, over many years, used IVIg with T-cell redirecting therapies, including CAR T and bispecifics, in malignancies across the board. We have used the flat dosing 10 grams to start with, and then if that is basically achieving the need and patients are not having infections and IgG levels are adequate, then we just continue.

That essentially can cut the utilization of IVIg significantly. In a 100 kilogram patient, it would be a quarter dosing compared to what we would normally give per weight-based. Then, people who are not keeping the IgG levels replenished and you can go back up to 20 grams. In our hands, we recently published BCMA and GPRC5D bispecific experience in myeloma with albeit limited number of patients. We will have a follow-up with a larger group of patients.

We did not really notice comparatively to registrational study data, that there was any meaningful difference in terms of severe or mild infections, etc., between either of these groups. We are in fact going to look at this within the consortium to see if there is any meaningful differences between a couple of centers these days that are using it that have accepted to use it with the flat dosing, like we do it, versus everybody else really that is using it weight-based. I think that is been helpful to us because it saves on the utilization of precious resources, which I imagine will become an issue in terms of access.

Dr. Ticku: I often wondered that myself. I feel like we are giving a lot of patients like IVIg continuously all the time. I feel like you wonder if we are going to have to worry about running out of something.

Dr. Baljevic: I remember times when IVIg was in shortage and only available for Guillain-Barré patients. I certainly do not want to claim that this is ready for prime time. We just published a single institution experience, but in our hands and we will soon be publishing our CAR T experience, but this has been very feasible and safe.

That is a slight adjustment to what we do compared to what the guidelines are recommending. We tend to be liberal at the beginning. Then later on, certainly in my clinic for patients who are already achieving response, and I have de-escalated the dosing frequency of bispecifics, particularly BCMA, because they are a bit more associated with infection signals. I tend to then follow more the IgG levels and dose them only when they are less than 400.

The one thing that to be honest, I still do not know about, and in due course we will be learning more, is what the practice might evolve for some of these combination bispecific approaches. Data was already published at ASH, and there is going to be follow-up data published this year because phase 1 is already done. Then there is a series of bispecific plus cell combinations that are really appealing and powerful. I am curious myself how that is going to look and if we might need to consider higher cut-offs, who knows? Like 500 or more.

Dr. Ticku: Going back to that IVIg question, that is always something that is changing. You are starting IVIg right away, and then, irrespective of IgG level, you do not direct it initially at IgG level, or you do not wait.

Dr. Baljevic: Correct. Initially, no. Particularly, in folks that are elderly and already had history of infections, we just like to treat them during the first second cycle, load them up. Particularly also because we are not doing weight-based, so we are doing 10 grams flat. They get some of this.

Then I am curious what you do. I feel comfortable de-escalating in use of bispecifics as soon as I certainly achieve deep response. Even in those patients who achieve VGPR or better after six months or so, I feel comfortable de-escalating at least a little bit to every other week or so, to strike a balance between efficacy and safety. Certainly, in patients who achieve very rapid, deep response, I felt comfortable de-escalating to monthly. I have select patients where we have de-escalated to every two to three months and will soon be showcasing our experience. 

Sloan Kettering, had a 30-plus patient cohort recently, where on redosing of patients who were with prolonged break, among whom 70% CRS was noted, which is study reported. When all of them were re-dosed without any step-up dosing, none of them had CRS, which was really impressive and helpful, I think for community practitioners, beyond academic experience, to know that there is data that shows that it is feasible to resume the dosing without needing to take patients again through re-step up.

Dr. Ticku: Yes. That is exactly - we had some, had a patient that had a break from and we just, resume that without that step up dosing. The other thing we have done is exactly the same. Once the response is generated, we can extend the interval. I think that we take our cues from the folks like yourself and the main centers as far as those decision-making, we follow those clues and experience.

Dr. Baljevic: For sure. I will certainly mention your colleagues at academic location in Rochester have contributed immense amount of data on healthcare utilization between outpatient and inpatient, really demonstrating significant resource saving in those patients who can be feasibly treated fully outpatient. We have actually done some of that analysis, and our data should soon be available. Really serious financial savings when possible to do it, outpatient versus inpatient.

Dr. Ticku: Yes, definitely. I think we have even interestingly enough, we are not that far from a large center, but I think there is a logistical barrier that is very significant for the patients and community practices. Despite being an hour away, many of the patients cannot manage to stay for 10 days in a hotel, relocate with a caregiver for step-up dosing in a main center. 

I think we have seen patients in our practice forgo these type of therapies for that reason. It is all the more reason to be able to draw these patients a little bit to your community oncology practice, and with the help of all these experiences by you and experts around the country like yourselves, it is really going to be helpful for those community oncology patients.

Dr. Baljevic: We are very hopeful, thank you. I think that even if you look the labels are starting to change, the teclistamab label that just got approved actually recommends only consideration of hospitalization for the first two step-up doses, so even that is different compared to initial label for teclistamab.

My hope is also that with some of the other upcoming drugs, I might also mention a etentamig. We have shown data last year at ASCO where the one-step up dosing schedule in cycle one on day one and day four with modified dexamethasone premedication leads to really the lowest CRS reported level in the literature. Relapsed refractory myeloma, the overall success rate was 30%, of which 26% was grade 1 and only 4% grade 2 two. This is already significantly lower, so imagine giving tocilizumab prophylaxis with that agent. That starts already monthly from scratch. 

My hope is that agents like that that are potentially up and coming. But then also elranatamab, different schedules, teclistamab, talquetamab already has per labelled Q2 weekly schedule, which I actually preferentially use. I am curious, how do you like to use the talquetamab?

Dr. Ticku: We are have stuck with our use case of teclistamab, so we have not delved into talquetamab much yet. We are intrigued by this whole idea of this trispecific as well. I know you had just mentioned about a clinical trial. I do believe there is a clinical trial coming down the line with a trispecific antibody that uses tocilizumab prophylaxis. That is directly aimed at this whole idea of getting community oncology practices using these medications. It is a great use case, I think, so it would be interesting to see what happens with that.

Dr. Baljevic: The OPTIC trial was looking at the tocilizumab prophylaxis with teclistamab, and their report of 24 patients, only one occurrence of CRS happened. It was a grade 1. There is actually currently, we are part of that study as well, an arm that is open with dexamethasone premedication only during the step-up dosing periods for a couple of days.

I am very excited to see what that does because imagine the situation if the dexamethasone can approximate the outcomes and CRS mitigation strategies compared to tocilizumab, which is significantly more expensive, and more challenging to keep on formulary, etc. This might really lead to serious improvements in strategies for how to mitigate this risk for broader community use.

Dr. Ticku: We have been working very closely with developing our outpatient step-up dosing. We actually developed it on our own within the Mayo Clinic health system without direct support from the destination practice because we thought it would be more directly applicable to community oncology practices regionally and around the country. We brought one of the PAs on from Rochester for the educational component more recently. We are building this thing out pretty well right now. It is pretty exciting to help.

Dr. Ticku: I think you hit the nail on the head. They support thinking of the community oncology practices from the start, where oftentimes in the big systems, there is a lot of disconnect between the community practice and the main center.

Dr. Baljevic: The reality is vast majority of our myeloma patients are actually still centered in community. There is distances to be considered. I have had patients that colleagues wanted to refer, and because of distance, they just decided they could not. Therefore, we had to choose other therapies that potentially are less impactful and powerful.

I am looking forward to the time when overall accumulation of data in terms of CRS mitigation strategies, infection prophylaxis strategies, and feasibility of step up dosing with different frequencies and even especially different combinations can really start dramatically impacting the overall outlook of this disease. Even potential for curability, because the PFS and MajesTEC-3 for example, is just incredible, but there is infection risks associated, so you just need to strike that balance. Then all these other that we mentioned combos with CELMoDs with PIs MM-20, MM-30 with elranatamab, and others with teclistamab, etc., etentamig as well. I think they will really end up changing the way we use therapies, including in the early line and also frontline. 

Dr. Ticku: I think also what I have noticed since doing this project is that I think the myeloma space is the perfect use case to get this new technology out to community oncology practices because of transplant, and there has been this good communication back and forth usually with a lot of community oncology practices and a destination practice where you have to have those patients back and forth for transplant or transplant evaluation. That communication has been pretty historic, and it is pretty natural for a lot of places.

Dr. Baljevic: I agree definitely. 

Thank you, Doctors Baljevic and Ticku, and many thanks to you, our listeners, for joining us today. As a reminder, to view the full program related to today’s content and to learn more about optimizing BCMA bispecific antibody therapies in R/R MM please click the link in the show notes. And be sure to check back regularly for more episodes on important oncology topics!