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AEs With CAR T-Cell and Bispecific Antibody Tx in MM
Thinking Through Key Considerations for Emergency Medical Professionals on the Management of Patients With Myeloma Receiving CAR T-Cell Therapy or Bispecific Antibodies

Released: May 22, 2024

Expiration: May 21, 2025

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Key Takeaways
  • Bispecific antibody and CAR T-cell therapies have a significant role in the treatment of patients with relapsed/refractory multiple myeloma, with recent labeling changes shifting the administration of CAR T-cell therapy to a broader patient population.
  • Toxicities such as cytokine release syndrome and neurotoxicity are common, potentially serious adverse events associated with both classes of therapy, and it is critical that emergency medical professionals recognize common symptoms and have an awareness of general management strategies.

In recent years, we have seen an expansion of the treatment armamentarium for multiple myeloma (MM), with CAR T-cell therapy and bispecific antibodies gaining approval in the relapsed/refractory (R/R) setting. Due to the risk of cytokine release syndrome (CRS) and neurotoxicity, all CAR T-cell and bispecific antibodies therapies are available through a REMS program. Some sites may administer these therapies in an outpatient setting and toxicity may present following discharge if the treatment is administered inpatient, so it is critical that emergency medical professionals have an awareness of common toxicities associated with these agents and general management strategies.

Which patients with MM are receiving CAR T-cell therapy and bispecific antibodies?

Two CAR T-cell therapies—ciltacabtagene autoleucel and idecabtagene vicleucel—were initially FDA approved in the fifth-line setting. In April 2024, both indications were expanded to include earlier lines based on the CARTITUDE-4 and KarMMa-3 trials, respectively. Ciltacabtagene autoleucel is indicated after 1 or more prior line of therapy, including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), and disease refractory to lenalidomide. Idecabtagene vicleucel is indicated after 2 or more prior lines of therapy, including an IMiD, PI, and CD38 monoclonal antibody (mAb). With the shift of CAR T-cell therapy to earlier lines, more patients will be eligible for these treatments compared to use in later lines.

Currently, 3 bispecific antibodies are approved for R/R MM, with 2 BCMA-directed therapies (elranatamab and teclistamab) and 1 targeting GPRC5D (talquetamab). All are indicated after 4 or more prior lines of therapy including a PI, IMiD, and CD38 mAb.

What is the most common toxicity with CAR T-cell therapy and bispecific antibodies?

Common toxicities associated with both CAR T-cell therapy and bispecific antibodies are shown in the table below, with CRS, immune effector cell-associated neurotoxicity syndrome (ICANs), and infection being the hallmark adverse events (AEs) of both classes of therapy. In general, acute toxicities are often managed by healthcare professionals (HCPs) at the treating center, and delayed toxicities may be managed by HCPs at the treating center or by the primary oncologist within the community.

When is CRS and neurotoxicity most likely to occur in relation to the administration of each agent?

For the bispecific antibodies, CRS and neurologic toxicity typically occur early, within the first cycle and after the first or second step-up dose. CRS may present within 1 to 2 days of drug administration, and neurotoxicity occurs after about 2 to 4 days, depending on the specific agent administered. With CAR T-cell therapy, occurrence of CRS is more variable; it typically occurs after approximately 1 day with idecabtagene vicleucel, and after approximately 1 week with ciltacabtagene autoleucel. Neurotoxicity follows a similar pattern, with general appearance after approximately 2 and 10 days for idecabtagene vicleucel and ciltacabtagene autoleucel, respectively. Patients receiving CAR T-cell therapy should be monitored at least daily for 7 to 10 days following administration for signs and symptoms of CRS and neurologic toxicity. Periodic monitoring for delayed neurotoxicity for 4 weeks is recommended.

How do CRS and neurotoxicity typically present?

Patients with CRS typically present with a high fever and symptoms such as malaise, rigors, and anorexia. In more severe cases, patients may experience hypotension, hypoxia, and/or organ dysfunction. The grade of CRS is determined based on the presence of fever, with or without hypotension and hypoxia and based on the treatment required for management. Once alternative etiologies are ruled out (eg, infection, heart failure, pulmonary edema), tocilizumab with or without corticosteroids is standard treatment. Hospitalization, including critical care, may be warranted for higher grade CRS.

ICANS is a type of neurotoxicity seen with both the bispecific antibodies and CAR T-cell therapy, and may present with symptoms including altered mental status, tremor, dysphasia, aphasia, impaired motor skills, and somnolence. More severe cases may result in seizures and cerebral edema. The treatment of neurotoxicity varies by drug class. The treatment of CAR T-cell–associated neurotoxicity (in the absence of CRS) is largely driven by steroids and supportive care. Neurotoxicity (without ICANS) related to bispecific antibody therapy is managed by supportive therapy unless grade 4, where steroids are indicated, and ICANS is managed with earlier initiation of steroids (grade 2 and above).

CRS often precedes the clinical presentation of ICANS. Though both CRS and ICANS may occur simultaneously, ICANS typically occurs after the resolution of CRS. In most cases, CRS and ICANS are reversible with no lasting impact on neurologic status.

How can patients ensure that all healthcare teams, including those in the ER, are informed about their medical history involving either CAR T-cell therapy or bispecific antibody therapy? What measures can the patient’s care teams take to assist with this?

Patients should be given wallet cards with information on the specific product they have received as well as the date of administration. The patient’s care team should ensure that patients and caregivers have this information and understand the importance of sharing it with any healthcare teams. Other care teams can also question whether the patient has cancer and if they have recently received any treatment for their cancer.

Does sequencing CAR T-cell therapy and bispecific antibodies result in more severe CRS/ICANS or infections with the second immunotherapy treatment?

Although data are limited in this space, generally no increase in toxicity has been observed with any particular sequence of available therapies.

Can you talk more about the FDA warnings regarding safety with CAR T-cell therapy, particularly for patients with myeloma? 

Following reports of T-cell malignancies after CAR T-cell therapy administration, including with the BCMA-directed therapies used in MM, the FDA has updated the labeling for both products approved in MM to include the risk of T-cell malignancies. T-cell malignancies may present as early as weeks after the infusion and may be fatal. This new warning is in addition to the previous warning of secondary malignancies, including MDS and AML, with CAR T-cell therapy. These are uncommon but significant risks, and HCPs should have a thorough conversation with patients so they understand all the potential risks of treatment.

In summary, with the role of bispecific antibodies and CAR T-cell therapy continuing to expand in the treatment of R/R MM and the potential shift in the site of administration to the outpatient setting, it is crucial that HCPs recognize the most common toxicities and understand general management strategies and their importance.

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