Bispecific Antibodies for Multiple Myeloma: Patient Selection, Sequencing, and Adverse Event Management

In this 2-part discussion series, Beth Faiman, CNP, PhD, Cleveland Clinic, Ohio, and Donna Catamero, NP, Mount Sinai, New York, New York, provide an in-depth discussion on the evolving role of bispecific antibody therapies in the treatment of multiple myeloma. 

In this video, they discuss considerations for patient selection, sequencing of bispecifics with CAR-T therapies, and the importance of managing side effects to maintain patients on treatment. The conversation also highlights their real-world experience with these agents and evolving practices in dosing and vaccination strategies to optimize care.

Watch part 2, where they highlight recent updates related to bispecific therapies for multiple myeloma after the ASCO Annual Meeting and EHA Congress.

Transcript:

Beth Faiman: Welcome to APP Institute Oncology. My name is Beth Faiman. I'm a nurse practitioner from the Cleveland Clinic in Cleveland, Ohio, and I specialize in multiple myeloma. Today, I'm joined by my friend and colleague, Donna Catamero. Donna, would you like to introduce yourself and tell us a little bit about your role?

Donna Catamero: Sure. I'm Donna Catamero. I'm a nurse practitioner and the Associate Director of Multiple Myeloma Research at the Mount Sinai Hospital in New York City where I oversee our clinical trial program and portfolio.

Beth Faiman: Thank you for sharing your very important role and we know now that you're an expert on this content. And thank you for joining us on this brief discussion on bispecific antibody therapy for multiple myeloma.

Today, we're going to start with a general overview on bispecific antibodies for multiple myeloma, and then we're going to dive deeper on talquetamab updates in this patient population.

As I mentioned Donna, I want to start with a general overview of bispecific antibodies for our audience. They've been approved for 3 years and there are 3 bispecific antibodies currently approved. There's 2 that target BCMA, that's elranatamab and teclistamab, and one that targets the GPRC5D, G-protein couple receptor class five member D, which is expressed on the keratinized cells.

And so how do they work? Well, CD3-targeted bispecific antibodies recruit these T cells to target cancer cells. And this is achieved by one arm of the bispecific molecule that binds to the CD3 antigen on the T cells and then the other arm binds the tumor-associated antigen, which is BCMA or GPRC5D, which those are the ones that are approved currently in myeloma. Once bound, a synapse forms binding the CD3 on the T cells and the antigen bringing them together and causing cell death, essentially killing the cells. And so, it's a very effective approach.

We also have two CAR-T/BCMA agents currently available. Donna, we're going to dive into side effects in just a moment, but first how would you decide who gets a BCMA bispecific or who gets a BCMA/CAR-T in your patient population?

Donna Catamero: Yeah, so we're using a lot of bispecific antibodies. We were very fortunate at our institution that we had many of these pivotal clinical trials. One thing to mention is that CAR-T is available after 1 prior line of therapy for patients who are refractory to lenalidomide. So, we want to prioritize CAR-T therapy.

So, for those patients who are eligible for CAR-T, we want to make sure that we can get them to CAR-T, so we'll probably not use a BCMA bispecific antibody in those patients. But for those patients who either don't have caregiver support or logistically can't make it to a CAR-T center, bispecific antibodies that target BCMA are a good option for these patients.

But it's also important to note that these bispecific antibodies are approved in later lines of therapy, so 4 prior lines of therapy for these patients. And for those patients who we don't think a CAR-T is going to be optimum for them, we would consider bispecifics that target BCMA.

For GPRC5D, we can use this before1 if we're thinking of a CAR-T therapy, we often give talquetamab prior to CAR-T therapies as it's targeting a different target on the myeloma cell. Between CAR-Ts and bispecific antibodies, these are really now becoming the mainstay of our treatment algorithm for myeloma patients.

Beth Faiman: Yeah, absolutely. I agree. And we were both fortunate to be in Milan around the EHA and the IMWG (International Myeloma Working Group) meetings. And there was a lot of discussion about the sequencing. We still don't know the optimal sequencing, but in general, if your patient is a candidate for CAR T-cell therapy, especially since cilta-cel is indicated for one prior line of therapy, if they're refractory to lenalidomide, for example, if they had an induction consolidation and they're progressing on lenalidomide, to consider it.

But other things we consider are the physical, financial, social situations of our patients. How many prior therapies, as you mentioned, is also super important, what worked and what didn't work? But bispecific antibodies now­—and we'll talk about this in a little bit, we had some updates at the meeting—They're now in clinical trials at newly diagnosed, early on maintenance after stem cell transplant. Again, trying to get better ideas as to patient selection is what the science is looking at right now.

I think you delved into it a little bit before Donna, about how you decide what to select for patients. But I think sometimes for people that have 4 prior lines of therapy, it can be a little bit overwhelming to talk about how these drugs are given. We'll talk about the side effects in a moment, but they need to oftentimes be admitted to the hospital. If it's elranatamab, it's usually about 3 days, and that's based on the onset of CRS. It's days 1 and 3 are the step-up doses. And then we can discharge in many cases.

For teclistamab, the other BCMA-directed bispecific, it's a 7 to 9 day hospital stay, depending on your institutional norms. Again, looking for cytokine release syndrome, neurotoxicity, and assessing for infection risk.

For talquetamab, you still have a longer hospital stay. So again, for people that don't necessarily have a caregiver or if they haven't been sick and in a hospital, it can be quite overwhelming. Donna, when you're talking about bispecific antibodies to your patients, and let's say, this person's had 4 prior lines of therapy, they've progressed through everything, what would that conversation look like? What do you tell patients that want to start on, let's say talquetamab for example?

Donna Catamero: At our institution, for the most part, we're doing this as an inpatient, slowly working our way to an outpatient setting. And this is because we want to monitor our patients for cytokine release syndrome and neurotoxicities. And this is where we see these 2 main side effects during the step-up dosing.

When I get a patient ready trying to start them on a bispecific, I really spend some time with the patients talking about how we're going to use a step-up dosing approach for these patients to mitigate that CRS and neurotoxicity and the rationale for admitting the patient to the hospital during these step-up doses. And then I spend a lot of time, especially if we're starting a patient on talquetamab, there are some on-target, off-tumor side effects, oral toxicities, skin toxicities. And I spend a lot of time with patients really setting expectations on that these, especially the oral toxicities, the likelihood of these occurring.

It's more likely than not that patients will experience some degree of oral toxicity, and then how we try to mitigate these side effects. And I'll refer to the paper I wrote with several of my colleagues in the Seminars in Oncology Nursing, how we try to manage these oral toxicities, skin toxicities, and to really set patient expectations. And with the oral toxicities, which can be the most challenging to manage and really can affect a patient's quality of life, we try to add in some oral solutions, some dexamethasone solution with nystatin. And I know some of these mouth washes are costly to patients, and so there is compliance with a lot of these supportive care options that we do provide patients. It's really important to really get social work involved and other options involved for patient management.

But if we can maintain patients on therapy, and I think this was really highlighted at ASCO when we see longer follow up that patients who stay on therapy have really great outcomes, so have a prolonged progression-free survival. We really spend a lot of time on how we're going to manage skin toxicities, how we're going to manage oral toxicities, and then we want to consider our CRS and neurotoxicities during that step-up dosing, adding in the pre-medications and monitoring the patients very closely.

Beth Faiman: That's a great overview and I would say that it's very similar. For example, I tell people this drug is given every 2 weeks and one of the questions I get, and you probably get too is do I have to come into the hospital every time? And the answer is no, but you have to go to a hospital outpatient, you can't give it at home. And so oftentimes what I'll do is I'll say, you know what? You live about 45 minutes away, let's try to see if there's a center available. The manufacturer of the drugs are really good about locating centers that are certified to give these medications. And so, I'll try to find a nurse in their local community hospital and say, "hey, can you give this patient talquetamab if we get them started on it, would you be able to secure the dose and give it to the patient? I think they're going to be discharged on this date." That collaboration care is really important.

Now you highlight some really important points about talquetamab. Again, GPRC5D is expressed on keratinized cells. We did see some data that was from ASH last year and then also updated here. You mentioned about how keeping patients on treatment, they can have a long remission period. I think a lot of things like holding the dose and reducing the frequency of the dose can sometimes be very effective. So, if they've had a very good response to therapy, you can shorten the dosing interval Q3 weeks or even Q4 weeks if they are month 5, 6 or whatever. And so, Dr Chari had some paper, what is your practice about extending the dosing interval and when do you start doing that in your practice for?

Donna Catamero: And I think really this is the best way to mitigate some of these oral toxicities is dialing it back. And Dr Chari's ASH abstract, I think it was 2023, showed that reducing the frequency to monthly, we saw a decrease in a lot of these skin and oral toxicities without jeopardizing the patient's response to therapy.

In our institution, once a patient receives an optimal response VGPR or CR, we try to quickly dial back the frequency because again, in this past ASCO with longer follow up, we see that if we can maintain patients on therapy, they really have superior outcomes. So maybe by tweaking the frequency or the dosing, we can keep patients on longer.

Beth Faiman: Yeah, absolutely. And then the same thing with teclistamab and elranatamab. Those BCMA-directed bispecifics carry a higher risk of infection than let's say talquetamab. Talquetamab has a skin and oral toxicity, so that's a different side-effect profile. BCMA, you're targeting the B-cell maturation antigen on the plasma cell, so these patients will have hypogammaglobulinemia and recurrent infections in many cases.

And so, supporting them with IVIG, pneumonia prophylaxis with either Bactrim or pentamidine inhaled or oral if they have a sulfa allergy. And then really just educating the patients to report fever, sites of infections. We do hepatitis B screening to look for hepatitis B. For antibody positive, we'll put them on entecavir if they are to prevent them from having hepatitis B activation. And then shingles prevention. Even if they've had the Shingrix vaccine, we still recommend our patients to get acyclovir regularly to prevent them from getting shingles or the herpes virus.

What about vaccinations in your patients with bispecific antibodies? That's a hot topic and we've heard about that at the meetings this year. What do you recommend with vaccinations?

Donna Catamero: Right, so prior to initiating, I want to make sure that my patients are updated with all their vaccines. It's a whole other topic when we're talking about CAR-T therapies, but when patients start bispecifics, we want to make sure that they're up to date, that they're getting their seasonal flu, their seasonal COVID vaccines, and RSV vaccine if they're eligible for one, to provide them with that protection. And so, this can be maybe a hot topic, but we want to make sure that our patients are getting their seasonal vaccines.

And then because we do see that hypogammaglobulinemia with the bispecifics that target BCMA, we add in monthly IVIG and especially through those winter months when we see higher respiratory infection rates. So that's how we try to mitigate some of these infection issues associated with the BCMA bispecifics.

Beth Faiman: Absolutely. In the last couple minutes of our discussion here, so thank you for this. This goes by so fast, at least for us, maybe not you at home, but for us.

Donna, I found 2 really important papers that were updated. One of them was a real-world outcomes paper of patients that were treated with the T-cell engagers. And this was a single-center study that looked at all their patients who had teclistamab, talquetamab, and elranatamab. And of those 79 patients who received at least 1 dose of each of those drugs, we saw it was similar to clinical trials perhaps, but again, these patients wouldn't have qualified for the clinical trials necessarily, but they still had similar outcomes, maybe a little bit worse because they had renal dysfunction.

What are your thoughts about the real world in your experience and how it correlates with what we've seen in clinical trials?

Donna Catamero: Yeah, in the real world, we're not seeing necessarily new safety signals, still very well-tolerated agents and that we can safely give these agents in patients who, as the abstract shows, who are not eligible for clinical trial and they do reasonably well with similar outcomes, maybe like as you said, a little inferior because of the aggressiveness of their disease, renal function, etc. But these are well tolerated therapies that we can offer patients.

Beth Faiman: Yeah, absolutely. And then there was a poster that you wanted to share briefly, Donna, about the talquetamab updates from the MonumenTAL-1 study that helped us with the FDA approval. Do you want to share that?

Donna Catamero: Yeah, so again, with longer follow up, we see that if we can keep patients on therapy--and that's why I think side effect management is key to keeping patients on therapy--that we see improved outcomes, so a longer progression-free survival. And then we actually saw that dosing talquetamab every other week instead of weekly that patients actually do better.

Beth Faiman: Right, right. Well, Donna, I would like to thank you so much for joining me in on this discussion and thank the audience for watching, and please join us for point part 2 of this discussion where we will continue to highlight recent updates on bispecific therapy for multiple myeloma after ASCO and EHA.