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

Kevin Brigle:

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

Mary Steinbach:

Hi, Kevin. Thanks so much for having me, and I'm so happy to be here with my colleague, Kelley. I'm a nurse practitioner at Huntsman Cancer Institute at the University of Utah in Salt Lake City, and I'm excited to get into this today.

Kevin Brigle:

Kelley?

Kelley Julian:

Hi, I'm Kelley Julian. I'm a clinical pharmacist, also working at Huntsman Cancer Institute alongside Mary, which is a privilege and an honor. I'm excited to be here to thread in my thoughts from the pharmacist perspective and chat with you guys today a little bit more about bispecifics and myeloma.

Kevin Brigle:

Okay. In the first part of this series, we talked about bispecific antibodies and compared and contrasted them a little bit with a CAR-T. In the second part of this series, we're really going to focus on clinical trials, and we're going to be looking at just the BCMA-targeted bispecific antibodies. Mary, would you like to go forward with that one?

Mary Steinbach:

Yes. Thanks, Kevin. In our first talk we reviewed CAR-T vs BCMA, trying to define when to use what drug. Kevin talked to us about that recently published IMWG criteria that helps. I think one of my favorite parts of that is this equal access statement that they have about bispecifics. We all know, unfortunately, for better or worse in the real world, access is not equal. One of the best parts of our bispecific antibodies is that they are, what we say, off the shelf, so pretty readily available for any relapsed/refractory patients who have met that 4 lines of therapy, proteasome inhibitor, immunomodulatory drug, CD38 monoclonal antibody.

We know there are right now 2 targets that have FDA approval. Three drugs are out there that target BCMA, which is similar to the CAR-T products we have. Then there's a drug that's FDA-approved that targets GPRC5D. When we encounter a relapse patient—and we'll run through a case study here to help bring it home—you want to think about what our previous therapy has been and what might this patient be eligible for in the future.

I think when we encounter a patient who is not CAR T-eligible for whatever reason, whether that's patient choice or just something else in their life, then we're going to think about a BCMA bispecific, especially if they haven't had exposure to any prior BCMA drugs. I'll introduce a case, and then Kevin and Kelley, we can just run through how to make choices, I think, about using these BCMA drugs, and we'll talk about the side effect profiles with it all, if you guys are good with that.

This is not a real patient, but I think very similar to what we encounter in clinic on a daily basis. A 73-year-old man with IgA kappa multiple myeloma, diagnosed way back in 2020, so about 5 years ago, and at the time had ISS stage I disease, which indicates this is the type of patient who, if fit, should have had induction, transplant, maintenance, and had about 5 years before any progression event. Unfortunately, the disease biology was not in line with that ISS stage I, and this patient very quickly went through 3 lines of therapy.

His first treatment line was dara, Revlimid, Velcade, dexamethasone, then he had transplant. Then he had lenalidomide maintenance, which I think is important to differentiate, because being ISS stage I, len maintenance should be enough for these patients. Unfortunately, he had progression. Went back to daratumumab in combination with lenalidomide and dexamethasone. Then another progression event, went on carfilzomib, cyclophosphamide, dex, and then his fourth line was selinexor, Velcade, dexamethasone. He, shortly after starting seli and Velcade, has a little bit of a response, is fairly symptomatic of that treatment, and unfortunately the response doesn't last long.

Importantly for this patient, he is the caretaker for his wife, who has Parkinson's disease. Though they live close to our hospital at Huntsman, this patient's not able to have a caretaker for 30 days and also leave his wife for 30 days, which really precludes him from a CAR-T therapy. The decision is made to start a BCMA bispecific, and I'll throw it out to you guys. How are you going to choose which BCMA bispecific to use? Kevin, you can start.

Kevin Brigle:

Oh, I would've given that to Kelley first. I think first off, with us it'll be, of the 3 BCMA bispecifics, we have 2 of them on formulary, and so it's obviously going to be 1 of those choices. They both have pretty equal efficacy. The step-up is different and the rates of CRS are different, so a little of that. I think that becomes the challenge in choosing these BCMA-targeted ones. They're all really, really effective, and I don't think you can go wrong maybe choosing one over the other. For us, it's really going to be a formulary. Also, because we're still doing our ramp-ups inpatient, I've often given patients the choice. "Do you want to be in for essentially 4 to 5 days, or do you want to be in for 7 days?" Sometimes that'll flip it as well.

Mary Steinbach:

Yes, that's a good point. That's elranatamab that is the shorter ramp-up period, and then teclistamab is a little bit longer, and I totally agree with you. You never want to tell a patient that it's the toss of a coin, but I think both these drugs are well tolerated. They have similar side effect profiles. There is some suggestion that perhaps elranatamab has a longer progression-free survival, but they were both phase 2 studies that were single arms, so we can't compare them to each other, I think, which is an important point.

At Huntsman, we do some ramp-up outpatient at this point, and so that, days in the hospital, can still be part of the discussion that we have with patients. We also have both those drugs on formulary, and then linvo was more recently approved, so we don't have it quite on formulary yet. Kelley, I'll let you speak a little bit to that and kind of how we make decisions about formulary.

Kelley Julian:

Yes, thank you, Mary. Yes, we have elranatamab and teclistamab on formulary just simply because they were FDA-approved first, and we didn't get a lot of pushback even though they have the same mechanism. The reason being we're involved in clinical trials with different agents and different combinations, and so we wanted to have both options. Both tec and elra are subcutaneous injections. As you alluded to, the ramp-up dosing and the schedule there is a little bit different.

A lot of the times, what makes the decision for us is if the patient's going back into the community, they may only have one option. Is tec or elra the option at the community? Well, then we need to have communication around that and be sure that we start the patient on the therapy that they're going to be going back on and that the outpatient team is set up for locally.

With linvo, just getting the approval very recently, the difference there, it does have a little bit more convenient step-up dosing, and so it's more of like a day 1, 8, 15. One could potentially imagine the patient could discharge, be outpatient for a few days, rather than have a longer admission up at the front end.

I do see that this drug is the third and the same drug class, so there may be some difficulties with other centers adding this to formulary. Another logistical factor there is that it is an IV vs a subcutaneous administration, so there's a little bit of a different logistics component there, but not to say that it's a worse drug. It's just there may be additional barriers there that centers have to think about, either getting all 3 on formulary or potentially pulling 1 back if they want to add linvo because they're liking the data they see there.

There are just a lot of different logistics. They all do have a REMS program, so some of those barriers are there that you have to do no matter what, and so that's a moot point. Those are some other factors that we think about on this side of things as well over at Huntsman.

Mary Steinbach:

Great, thank you. This patient here got started on a BCMA-bispecific, did his ramp-up as an inpatient, had a grade 1 CRS event about 24 hours after that initial dose, which I think is something we see pretty often with all 3 of these drugs, which was well managed with some dexamethasone. This patient did not require any tocilizumab. Again, the treatment for cytokine release syndrome is going to be very institution-specific. We've done a lot of work around do we want to use dexamethasone, how do we want to use the tocilizumab. I think a good take-home from this is there's probably not a wrong answer. The right thing to do is to monitor your patients closely and then have a plan.

There's a lot of literature out there about early use of tocilizumab or prophylactic use of tocilizumab with bispecifics. Again, like a lot of our myeloma data, it can be interpreted in many ways. We have made the choice at Huntsman to not use prophylactic tocilizumab, but we don't hesitate at all to give patients a little bit of some extra dexamethasone when they have that first grade 1 fever.

I think one of the other important side effects we should talk about when we're talking about the BCMA bispecifics, though, is the chronicity of infection and the potential for infection. Kelley, do you want to speak to how we approach this at Huntsman?

Kelley Julian:

Sure, yes. There are really great tables out there and there's some good literature around this. The IMWG has strong recommendations which fall in line with exactly what we do at Huntsman, but in general I'll go through by pathogens.

For antibacterial prophylaxis, what we do is anybody that is neutropenic with an ANC of 500 or less, or trending quickly in that direction, what we do is we put them on an antibiotic such as levofloxacin, appropriately dosed, and then also fluconazole as an antifungal. That covers your standard pathogens there.

We get upfront authorization for IVIG on these patients. We have a communication order in our plan that states, "Please get off for IVIG." Most patients already have IVIG off in this setting, in this relapse setting. For those who don't, we work on that, and we give that at a dose of 400 mg/kg of ideal body weight roughly on a 28-day basis for patients who are on bispecifics, starting with that second month of therapy. We want to get through the ramp-up there and get through the potential phase of CRS and neurotoxicity, and get these patients prophylaxed appropriately.

I think the guidelines have strong recommendations there. If you're hypogammaglobulinemic with an IgG of less than 400, that's kind of a slam dunk. Or if you have recurrent infections, you have strong documentation around that in your notes, then IVIG is a given. There's data out there, small studies, that show the difference in all grade infections for patients who are on IVIG replacement vs not. There's a difference there, especially in grade 3 to 4 infections, that is worth noting. Other things that we do, for HSV and VZV, all of our patients are on acyclovir. That's no different than any other myeloma treatment, it goes without saying.

One interesting thing that we evolved to over time was CMV and how do we think about this. When we first started, we had a CMV titer in all of the day ones of all the cycles for our patients, and we wanted to see what does this looked like. Who gets viremia? Do the titers go up? What do they do? We did this for about a year where we trended the CMV on our bispecific patients, and we looked back and we noted that we had less of an incidence of CMV viremia that is concerning to the point where you need to treat it. We had less than 10%. It was like 7% of patients that we treated with bispecifics needed treatment for that CMV.

We actually changed to now just checking it at the beginning. The cycle 1, day 1, we check the CMV titer. If it's positive, then we determine the monitoring plan from there. If it's negative, then we don't worry about it. That is aligned with the IMWG criteria, so we evolved that over time. Then they've got different recommendations on the immunization schedules. That's all pretty standard, so I won't go into that. As far as checking for hep B, we look at that toward the beginning and we prophylax if needed, if we're concerned about core positivity there, with entecavir and tenofovir. That's pretty aligned with the standards as well.

Then PJP is a big one. We prophylax with, ideally, Bactrim, and if the patient can't tolerate Bactrim, then we look toward usually pentamidine because the patients are coming in monthly for IVIG anyway. There are also other options that can be done for PJP prophy, but we do that for the first 6 months and then we start checking CD4 counts and only peel back on that if the CD4 is strongly right around 200 or more for at least 2 months.

There’s a lot there. I spend a lot of my time talking about supportive care for these bispecific patients, because we've seen what happens if they're not appropriately treated and supported through, and it's not pretty. We try to avoid it all costs.

Mary Steinbach:

Thank you. Kevin, what's your experience been with a relapsed patient on a BCMA bispecific?

Kevin Brigle:

Yes, I don't have a lot to add to that. I think Kelley covered every infection you could think of. I think it is really important when you send those patients back to the community, if they're going back, to know that pathway as well, and for them to make sure they have IVIG in place as well for authorization and those things also. On the plus side, some of those patients are on IVIG before they get the bispecific. That's an easy one. Certainly when you send them back to the community, have that in place, because infection is the real doom for these patients on BCMAs.

Mary Steinbach:

Yes. I think that's a great point you bring up about the transition back to the community. With being a center who tends to start patients from the community on bispecifics, our goal is to get them back as soon as we can. We developed a pathway and a checklist form for nurses and the APPs to be aware of, to then hand patients back to the community. Part of that is going to list obviously their infection status, the prophylaxis they're on, but I think one of the big questions we can get back is when to hold treatment. Each package insert for all 3 of these drugs has very good guidelines about when to hold treatment. They fall in line with the CTCAE recommendations as well.

I think generally speaking, when a patient has had a response on a BCMA bispecific, and whether they're on monthly Q2-week dosing or even off-label, if you only have them on monthly dosing at that point, it's always better to hold when you suspect there's an upper respiratory infection or patients are symptomatic of that. The constant hit to BCMA and the depletion of it on normal functioning lymphocytes for patients really can lead to a B-cell aplasia picture, where it's difficult to rid themselves of viral and bacterial infections once they set in. Holding the drug really can make a difference for these people.

Kelley Julian:

Yes, and give GCSF.

Mary Steinbach:

Yes. Support their counts as needed.

Kelley Julian:

Goes without saying, but I'll just say it.

Mary Steinbach:

Great. Well, I think that wraps up our BCMA discussion. Currently there are 3 FDA-approved BCMA drugs. We're super fortunate to have that. The drugs of choice, I think, are really going to be institution-dependent as Kelley and Kevin both mentioned, what is on formulary. There can be small arguments made for 1 drug over another, I think, depending on the clinical trial data that you're looking at. Overall, all 3 of these drugs work very well for relapsed/refractory patients, even those who have had some form of BCMA prior exposure, if it was remotely back in time for them in their disease course.

Kevin Brigle:

Well, thank you, Mary. Thank you, Kelley. This brings us to the end of our discussion, and I'd like to thank you both for taking the time out of your busy days to be here to talk with us. For more information and other discussions on multiple myeloma, please visit JADPRO online at jadpro.com. Thank you so much and have a great day.