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Identifying and Managing Adverse Events Associated With Bispecific Antibodies in Multiple Myeloma
CME/CE Information

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1 2 3
Course Completed
Activity Information

Physician Assistants/Physician Associates: 0.25 AAPA Category 1 CME credit

Pharmacists: 0.25 contact hour (0.025 CEUs)

Physicians: maximum of 0.25 AMA PRA Category 1 Credit™

Nurse Practitioners/Nurses: 0.25 Nursing contact hour

Released: March 17, 2026

Expiration: September 16, 2026

Doris K. Hansen
Doris K. Hansen, MD

Identifying and managing adverse events with bispecific antibodies are obviously very important as we are going to give these therapies more and more, academics and community.

 

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[00:30:54]

 

Poll 6: Our 75-yr-old patient with triple-class refractory multiple myeloma is admitted for inpatient monitoring after initiating a BCMA-targeted bispecific antibody. Seventeen hours after his first full dose, he develops grade 2 CRS with hypotension unresponsive to fluid resuscitation. What is the most appropriate next step?

 

Here is our 75-year-old patient that has triple-class refractory myeloma and is admitted for inpatient monitoring after initiating a BCMA bispecific antibody. 17 hours after his first full dose, he develops grade 2 CRS with hypotension, unresponsive to fluid resuscitation. What is the most appropriate next step?

 

  1. Permanently discontinue the bispecific;
  2. Give tocilizumab IV;
  3. Administer methylpred; or
  4. Continue supportive care with close monitoring and escalate if CRS for sense.

 

Okay. We have a three-way split.  

 

Generally speaking, really the first step in managing grade 2 CRS for these patients is always going to be tocilizumab. Obviously, if that does not work, we escalate to steroids. And then if the situation does not get better, then we will go to methylpred.

 

But usually we will start with tocilizumab as step one. Then you usually add dexamethasone and then consider methylpred. And obviously, you will continue supportive care.

 

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[00:32:22]

 

Acute Immune-Related Toxicities: CRS and ICANS

 

When we think about immune toxicities, there is CRS:

 

  • I tell my patients, and I am sure you do too, if you feel like you have the flu, right, you might have fever, you might have myalgias, headaches, etc.
  • Hypoxia and/or hypotension, like more severe CRS, grade 2, grade 3, is generally not very common for these patients. Obviously, we always want to rule out an infection.
  • First-line for management of CRS is going to be tocilizumab, which is an IL-6 antagonist.
  • And then if refractory, you consider corticosteroids.

 

For ICANS, generally much less common, I would say, with bispecifics than what we see with CAR T. We might see things like confusion, tremors, word-finding difficulty, though other symptoms like neuropathy can manifest.

 

We do frequent neurologic assessment. We use the ICE score. I will show you that shortly. And then generally, for any ICAN-type of toxicities, dexamethasone is preferred, crosses the blood/brain barrier, and generally has been shown to be very efficacious for ICANS.

 

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[00:33:26]

 

CRS: Incidence, Timing, and Severity

 

Here we have CRS: incidence, timing, severity between the different bispecific antibodies. But if we looked at CRS, just any grade, basically ranges between 40-70%. But most of it is generally grade 1, as you see there in orange. It is very unlikely for folks to have, you know, grade 3 or 4 toxicity.

 

Median duration, generally the onset during the step-up dosing, and relatively rare after you go to the full dosing. The more, you know, the more cycles you give, the less likely you are to experience CRS. It is really just limited in that acute initiation step-up dosing period.

 

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[00:34:11]

 

Managing CRS With Bispecific Antibody Therapy

 

Now, how do we manage CRS? The way I really think about this is, let us say, if somebody has grade 1 CRS, well, you hold the next dose, make sure they are diff-repressing, and make sure there is nothing else going on.

 

Grade 2 or higher, probably consider tocilizumab. If that does not work, give dexamethasone. And certainly, if you need to escalate care, you may consider methylprednisolone, as shown there.

 

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[00:34:37]

 

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

 

Now, here we have some long-term data looking at prophylactic tocilizumab with teclistamab. This is in MajesTEC. But essentially, what we see here is that there is a small cohort of patients who received prophylactic tocilizumab versus the majority who did not. And really, what we saw is that for those who did receive tocilizumab, the CRS rate was much less, 25% versus 72%. And it really did not appear to impact responses.

 

As you see to the right, responses were relatively equivalent. So, that is why I think, in practice, we give prophylactic tocilizumab pretty much for everyone following bispecific antibody use.

 

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[00:35:21]

 

Neurologic Toxicity

 

Neurologic toxicity, as noted, very unlikely to see this. Any grade ICANS generally ranges anywhere from 3-9%. Confusion tremors, word finding difficulty, as we talked about. That is more like your ICANS variety. But patients can have neuropathy, headaches, etc. The good thing is that we do not see some of these severe toxicities.

 

For example, we do not see Parkinsonism, we do not see cranial nerve palsies, we do not see cerebellar toxicity. Although, with talquetamab, there have been some case descriptions of ataxia dizziness syndrome, but very rare at that.

 

We use the ICE grading score, which we will show you on the next slide. And commonly, anytime you think ICANS, dexamethasone is really the way to go.

 

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[00:36:18]

 

Grading and Managing ICANS: ICE Scoring Assessment

 

This is the ICE score. Any time before somebody starts CAR T or bispecifics, we get a baseline ICE score. And it just looks at, for example, orientation, naming, can you follow commands? We ask them to write a sentence every day, and we check their attention.

 

Now, if somebody, and you see the scoring, the grading there, if somebody has a score of 7-9, that is grade 1. And then, obviously, as the score lessens, the severity increases.

 

And you might have some patients, right, or patients who are older, they have comorbidities, some of them might have, you know, mild cognitive dysfunction, that is okay. Their starting ICE might be low, but as long as we have that baseline, at least we know that the lower ICE score is not from a bispecific; it is just that they started at that.

 

In terms of how do we manage these patients based on the grading? Generally speaking, if somebody has ICANS, for grade 1, you will hold the dose, and commonly we will observe. We could consider anti-seizure medications for these patients. For grade 2 is, one, definitely hold, and grade 2 and beyond, I mean, pretty much you are going to hold the treatment, and you would start dexamethasone. We commonly give dexamethasone 10 mg every six hours until the neurologic toxicity resolves. And then, if you need, if ICANS is higher grade and more severe, well, at that point, you might consider upgrading to methylprednisolone.

 

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[00:37:48]

 

Outpatient Model for Administration of Bispecific Antibodies: AE Management

 

In terms of an outpatient model for giving bispecific antibodies, some folks or some centers do have, for example, monitoring devices. We here do not. We give our patients a thermometer. We ask them to check their temperature. Obviously, if there are any neurologic changes, if there is a family member or caregiver, hopefully they would let us know about that.

 

Mayo Clinic does the model where they give patients dexamethasone tablets. So, like, let us say if they have a fever, they say, "Okay, call us and go ahead and take the dex," which certainly is interesting, and it seems to work well for them.

 

For grade 1 CRS, obviously, we will ask patients to come in. We also evaluate their neurologic status. We consider giving tocilizumab in the outpatient setting. We monitor them for eight hours. If they do not have a fever, if they do well after, we can consider discharging. If the symptoms do not resolve or they get worse, obviously these patients are going to be admitted for further intervention.

 

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[00:38:54]

 

Outpatient Model for Administration of Bispecific Antibodies: Prophylactic Tocilizumab

 

This is the outpatient model that we showed earlier is a single-center experience where they use prophylactic tocilizumab.

 

This was at Emory, as we talked about. They had a cohort who did not get it and some who did. The Ns are very small. You see they are 15 and 38. Nonetheless, if you look at CRS with or without tocilizumab, we see that those who got to see the grade one CRS about 20% compared to about 67%. And, you know, there is no significant severe CRS per se.

 

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[00:39:30]

 

BsAb Therapy’s Infection Risk

 

Now, infection is probably the one thing I worry the most with bispecifics and you have to be mindful about. So, infection can be multifactorial. Some patients are at higher risk. It could be myeloma-related. Patients are hypogammaglobulinemic or it could be treatment-related depending on cumulative treatment exposures of the patients.

 

So, we talked about hypogam leading to impaired humoral immunity. We talked about T-cell mechanisms, so T-cell exhaustion dysfunction, which will impair cellular immunity. And then if somebody's getting continuous antibody therapy, well, that is certainly going to continue continuously. You know, T-cells are exhausted. They are hypogams. All of these really contribute to the increased risk of infections the longer you are on therapy.

 

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[00:40:26]

 

Class Effect: Incidence of Infection With Bispecific Antibodies in MM

 

This is very important. This is the incidence of infection based on bispecific antibodies.

 

High likelihood of infection rate ranging pretty much 60-70%, but really the grade 3 infections are, I think, what are more important. You see that with the bispecifics, you know, you can get almost to a 50% severe infection rate, so 45%. With GPRC5 talquetamab, thankfully, the infection risk is much less, but they do have those other on target off-tumor like, you know, skin. We talked about dysgeusia, skin rashes, nail changes, etc. So, patients certainly are susceptible to infections during the course of their treatment.

 

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[00:41:07]

 

IVIG Reduces Risk of Serious Infections

 

IVIG significantly reduces the risk of infections, as you see here, particularly severe infections, bacterial infections, among others, and there really have been multiple studies showing that IVIG must be given, and there are even guidelines from the immunotherapy working group on this.

 

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[00:41:28]

 

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

 

This is a study from Mira Mohan from MCW, basically showing that if folks receive IVIG prophylaxis, that improves infection-free survival and grade 3, so severe infection-free survival, compared to those who do not receive prophylactic IVIG. So, primary IVIG.

 

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[00:41:48]

 

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

 

So, this is exactly what I was speaking about. These are the consensus recommendation for the management of bispecific antibodies. Generally, all of our patients will be on antiviral prophylaxis, pretty much, so acyclovir, valacyclovir. We do recommend monthly IVIG for all patients during the continuation of treatment, regardless of IgG levels.

 

Certainly, if they have grade 3, for example, neutropenia, growth factors such as filgrastim and neupogen are recommended, and there is consideration for, although not here, right, for PCP prophylaxis for the short term. We need to monitor CMV levels, as well, in consideration for vaccinations per FDA and CDC guidelines.

 

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[00:42:36]

 

Adverse Events Associated With GPRC5D-Targeted Treatments

 

Now, here we have the GPRC5D toxicities, as you see there to the right. I mean, this is pretty classic, GPRC5D rash and skin peeling that we see in these patients, and then, obviously, we talked about the dysgeusia, inability to taste, weight loss, among others.

 

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[00:42:56]

 

Pearls for Managing GPRC5D-Associated AEs

 

Now, how do you manage these? Not easy to manage, as I am sure you know. Delaying or reducing the dose are certainly going to be main considerations. We want to hydrate. You can use topical ointments, emollients, topical steroids, nail hardeners, vitamin E, among others, and sometimes short courses of steroids can be helpful.

 

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[00:43:22]

 

Posttest 3: Which of the following are the most commonly observed acute toxicities associated with the bispecific antibodies for patients with R/R MM?

 

Which of the following are the most commonly observed acute toxicities, so during the step-up dosing, associated with the bispecific antibodies?

 

  1. Arrhythmia and rash;
  2. CRS and ICANS;
  3. Cytopenias;
  4. ART, respiratory distress syndrome, and diarrhea.

 

Very good. We have an amazing audience tonight. Yes, agreed. So, immune toxicities are most common.

 

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[00:44:04]

 

We can skip this because everybody got it right.

 

[00:444:08]

 

Posttest 4: You are treating a patient with teclistamab who completed step-up dosing and is on cycle 6 of standard dosing. They present with a new fever and general fatigue. What potential AE do you suspect?

 

You are treating a patient with teclistamab who completed step-up dosing and is on cycle six of standard dosing. They present with a new fever and general fatigue. What potential AE do you suspect?

 

  1. CRS;
  2. ICANS;
  3. Infection; or
  4. Disease progression.

 

All right, very good. So, infection is really in the long course is what we worry about with subsequent cycles of bispecifics. Very good.

 

Next, please.

 

[00:44:51]

 

Generally speaking, as we talked about, CRS and ICANS commonly will occur during the step‑up dosing, as you all got that correct. Infections with subsequent dosing are going to be most common.

 

It is unlikely that this patient would have CRS on cycle six.

 

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[00:45:08]

 

InterACT Team Discussion: AEs with BsAbs

 

So, when we think about AEs with a bispecific, considering the potential severity of bispecific antibodies in terms of AEs, what criteria or indicators should prompt community physicians to escalate patient care directly from the ER to the ICU?

 

Any thoughts on that? I can go, but basically, you know, if patient has anything beyond fevers, they have hypotension, hypoxia, obviously, we would consider ICU management.

 

And then community, what strategies can community practices implement to integrate optimal protocols for bispecific antibodies?

 

Generally speaking, happy to take any thoughts here, but prophylactic strategies and ensuring supportive measures are going to be very important.