Addressing Adverse Events With Bispecific Antibodies with Focus on CRS Management


Shared insight on the adverse event profiles of novel bispecific antibody therapies, with specific focus on how CRS can be adequately managed by the health care team.


Ajai Chari, MD:But putting that aside, let’s talk a little bit about adverse effects, too. Does anybody want to start with the adverse effects of BCMA [B-cell maturation antigen] as a class? And also distinguishing if you think there are any differences among the Cheesecake Factory of choices.

Cristina Gasparetto, MD: I think something a bit striking is the infection rate and the amount of suppression and neutropenia, and the different types of infection. Reading some of these presentations, we are going back to CMV [cytomegalovirus] and PJP [pneumocystis jirovecii pneumonia], all different types of infections. So we have to be extremely cautious about that. And then the persistent hypogammaglobulinemia; we need to learn how to aggressively support our patients, how to prophylaxis using antibiotics, and maybe monitor them. I am still around allogeneic transplants. We’re used to seeing patients undergoing Allocord [HPC (hematopoietic progenitor cell) cord blood], and we monitor them weekly for virus reactivation, CMV, HHV6 [human herpes virus 6], EBV [Epstein-Barr virus]. We may need to start thinking about it from that perspective, and start to monitor them regularly.

Ajai Chari, MD: I think you set this up beautifully. Does anybody want to say what they’re doing to prevent these infectious complications with BCMA? What would you recommend to a community practitioner who’s using bispecific BCMA for the first time?

Rafael Fonseca, MD: First of all, I don’t think we know. I think there are a lot of questions right now on how to do that. But the number 1 thing is obviously to monitor for hypogammaglobulinemia. I would say number 2 becomes, obviously, the monitoring for some of these infections. We saw that yesterday at the presentations with PJP and the CMV, as was just said by Dr Gasparetto. I think the biggest question right now in my mind, and I hope maybe we can get a glimpse of this through the studies, even in the real world, is the other infections and antibiotics. Because it’s a bit of a shot in the dark. No one knows what to do with antibiotics. We’ve had studies that are controversial, and novel. Levaquin helped in the first 12 weeks. But now I think the highest risk for infection is going to be in the patient on fifth line who has IgG [immunoglobulin] consistently under 300. I would say, just at the minimum, be very vigilant about infections in these patients.

Ajai Chari, MD: Yes, I would just add that I think the hypogamma [hypogammaglobulinemia] rates that we’ve heard, they’re not being reported consistently. We saw [it] in teclistamab at 72%; I think it’s not unique to that drug. I think we’ve seen it across the board. And I think it’s just a highlight. I personally think we probably need to start IVIG [intravenous immunoglobulin] very early with these patients, and not wait for problems because I’ve been—

Rafael Fonseca, MD: So how do you start the IVIG? I’m going to take the opportunity to ask. How do you do that?

Ajai Chari, MD: What do you mean?

Rafael Fonseca, MD: What level, and do you need a prior infection or not? How do you do that?

Ajai Chari, MD: These patients become hypogamma with below 400 within 1 to 2 months, usually.It’s almost a moot point because everybody’s getting there. So if your insurance company allows it, do it early; if not, wait for the infection. I’ve been caught off guard by serious infections, bacterial infections. I think IVIG; the PJP, I think, is unclear yet, the frequency. But the third and huge thing I just wanted to highlight is COVID-19 [coronavirus disease 2019]. Across the board, CAR Ts and BCMA bispecific, we’re seeing COVID-19-related deaths. It is imperative to quad [quadruplet therapy] vaccinate these patients prior to starting BCMA. Our laboratory has shown basically complete abrogation of BCMA antibody production to COVID-19 vaccine and BCMA bispecific.

Cristina Gasparetto, MD: Do you use AstraZeneca?

Ajai Chari, MD: Exactly. If you don’t have time to do the 4 doses, then give the AstraZeneca product to prophylactic. We don’t want to lose myeloma patients in complete remission to preventable issues. Does anyone want to comment on cevostamab or talquetamab toxicities?

Rafael Fonseca, MD: I can say we have the trial for cevostamab. I think it’s very well tolerated. It’s similar to the other trials. In fact, something that strikes me is the sign-up for the new trials. We’re working on elranatamab, and the primary objective is a reduction of CRS, to keep it at level 1 as much as possible. I think we’re going to get there. We’re going to see strategies for prophylaxis, early introduction of toci [tocilizumab], steroids, etc. It’s not hard to imagine, 2 and 3 years from now, I think that’s going to be much easier. But the bottom line [is], cevostamab is very, very active. The one thing that you never get from the story is, you hear 50% or 70% response rate at the individual level; it can be very profound. So while I have patients that progress on it, I also have patients who are 10 to the minus-6 negative and saying they haven’t felt better ever. We’ll just have to see how this tailors to specific patients.

Ajai Chari, MD: I’ll just put in a few cents about talquetamab toxicity, and then I think CRS we should cover because you brought it up, and it’s a class affected,obviously. Talquetamab, some off-target toxicities, as you alluded to, are nail changes and rashes. Rashes are very manageable early. I think the one that we’re struggling more with is dysgeusia. It’s typically grade 1, but the main management—there have been a lot of attempts to adjust it. But it seems like dose interruption and reduction have been quite effective. The unique thing about talquetamab is we have not seen COVID-19-related deaths. Even though the studies have been going on concurrently with BCMA bispecifics, we do not need to give IVIG. And I’ve even had immunoglobulin recovery in some patients. So it’s a very different profile of drug. And I think these will also be important when we combine these agents. So depending on the cytopenias and infection profile, it will help with this combination strategy. But, Rafael, going back to you, you brought up CRS [cytokine release syndrome]. Can you tell us a little bit about all bispecifics, the frequency and management?

Rafael Fonseca, MD: This is an expected toxicity now with the T cell-mediated cytokine release syndrome. We see it in a significant fraction of patients. It seems like with some of the CAR T cells, we understand it a little bit better. So there’s a point for Dr Patel there, how to manage it. But we do see that. As I mentioned, with talquetamab it was 76%. But it’s still low level. Now it’s critical we get it to the lowest level possible because I think that’s going to be so important for the dissemination of these products in the community; 80% of the patients are in the community. I would love to see community hospitals being able to move into this arena and be able to treat patients with a bispecific antibody. So we need to be very clear. I think there was more concern and fear at the beginning. I feel like we understand it and need to get very practical about how to manage CRS.

Ajai Chari, MD: Omar, do you want to add anything about CRS management strategies that are being explored with the bispecific?

Omar Nadeem, MD: Yes, I think the step-up dosing has really been helpful. You can see with the trials that have been presented using various strategies. I think we’re starting to figure out how to best mitigate that or reduce the severity of it because we know it happens with these classes of drugs. So how can we get to the lowest frequency, but also the lowest grade? And with the step-up dosing, I think that is going to hopefully make it more prime time for outpatient usage. I think that you see it early. You see with the step-up dosing, or at most cycle 1, day 1 dose for most products. And then being proactive, looking out for fever and looking out for any changes in the inflammatory markers. And then not necessarily waiting until the patient is decompensating has become our practice. So people even with sustained grade 1 CRS, we’re intervening instead of waiting because we’ve learned so much about the fact that these therapies are so effective, like tocilizumab against the management of fever related to CRS. It really solves the problem very quickly.

Ajai Chari, MD: So you have a very light finger to trigger toci [tocilizumab].

Omar Nadeem, MD: I agree.

Ajai Chari, MD: What about steroids? Do you want to say anything about steroid use?

Omar Nadeem, MD: Yes, I think so. Right now, if somebody has just a sustained fever, in most cases tocilizumab is sufficient in that particular case. But if you’re starting to see any signs of hemodynamic instability, we tend to give both agents, and this is both agnostic whether it’s about a specific antibody or a CAR T-cell product. We tend to see it more in CAR T cells because I think you see more severity, more severe CRS in that population. But again, we have not seen any of that impact the efficacy. That was a big concern initially—if you’re blocking everything with dexamethasone, perhaps you’re not going to get the benefit of what you’re doing.I think that hasn’t really been seen, thankfully, so we’re able to give it.

Ajai Chari, MD: I think it’s just also worth mentioning, in addition to the step-up dosing, steroids are often included in those priming doses to mitigate that. But fortunately, steroids are the worst drugs from the patient perspective. No patient likes steroids. Generally, bispecifics are steroid-sparing.

Cristina Gasparetto, MD: But it doesn’t seem to occur with time. It’s generally at the beginning.

Ajai Chari, MD: Exactly. Yes. Just up front.

Cristina Gasparetto, MD: It’s just up front. Clearly, we’re learning by observing over a longer period.It’s interesting that it doesn’t happen with the continuation of therapy, right?

Ajai Chari, MD: Yes. Perfect for you, Cristina, since you brought this up. We’re in some ways the least important part of the health care team, right? We signed these orders, and then the magic happens.

Cristina Gasparetto, MD: Yes. It’s true.

Ajai Chari, MD: What is that magic? Who are these people that are helping us?

Cristina Gasparetto, MD: Absolutely, you’re touching upon a very important point. I would not be able to function without my team. My APP [advanced practice provider] and my nurse coordinator are front line. I always say, when I discuss the adverse effects and the toxicity of various drugs, I go to them because they’re there. They’re assessing the patient. I think that they are involved from the very beginning with each single, different strategy. So the education of the team is becoming super important. They are going to recognize the toxicity earlier on, absolutely.

Ajai Chari, MD: Does anybody want to share any other lessons learned? I think we’ve all treated a lot of patients, so for a community doctor who’s seeing their first patient, are there any other lessons you want to impart?

Rafael Fonseca, MD: The importance of communication with the ICU [intensive care unit] team as well as the emergency room. I think they’ve learned through the CAR T cells. We’ve gone from those huddle meetings to now it’s part of what they do. But I think as new members come on board, it’s important that they understand what to look for and when to call on those things as well, too.

Transcript edited for clarity.

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