EMN recommendations: Prevention and management of CAR-T and bispecific antibody-related adverse events in MM

Patients with relapsed/refractory multiple myeloma (MM) may be treated with chimeric antigen receptor (CAR) T-cell therapy or T cell-redirecting bispecific antibodies (bsAbs).¹ Results from clinical trials have shown these therapies to be efficacious, and they are under investigation as first-line treatment options for patients with MM.¹ With this advancing therapeutic landscape, the European Myeloma Network (EMN) has provided recommendations for the prevention and management of adverse events (AEs) commonly associated with these treatments.² The Multiple Myeloma Hub is pleased to summarize this consensus here.

General recommendations

The most common severe AEs associated with patients treated with bsAbs or CAR T-cell therapy are cytokine release syndrome (CRS), neurotoxicity, cytopenia, infections, and hypogammaglobulinemia.¹ At treatment initiation, patients should be screened for active infections, organ and bone marrow function, and comorbidities. At the step-up dosing stage of either treatment option, patients should be monitored for signs and symptoms of toxicity and the dose should be adjusted according to individual patient response.¹

CRS

In patients treated with bsAbs or CAR T-cell therapy, CRS is generally observed after initial exposure, but can also occur post step-up doses.¹ The signs and symptoms to look out for include fever, fatigue, headaches, myalgias, nausea, hypotension, hypoxia, and organ dysfunction. Managing these signs and symptoms varies according to the severity of the AE, but stepwise dosing should be considered (Figure 1). Macrophage activation syndrome is associated with concurrent CRS, and it is recommended that patients with fever, cytopenias, and hyperinflammatory markers should be monitored for both macrophage activation syndrome and Epstein-Barr virus.¹

Figure 1. Recommendations for the management of CRS by grade of severity* 

CRS, cytokine release syndrome; ICU, intensive care unit; IL, interleukin; IV, intravenous; SBP, systolic blood pressure; TNF, tumor necrosis factor.
*Adapted from Ludwig, et al.²

Neurotoxicity and ICANS

Neurotoxicity affects the central nervous system and can result in activating or deploying endogenous T cells.¹ Immune effector cell-associated neurotoxicity syndrome (ICANS) is the second most common non-hematologic AE associated with CAR T-cell therapy, with an incidence of 2–64% for mild ICANS.² Symptoms include word-finding difficulties, confusion, dysphasia, and aphasia. Although the biological mechanisms of neurotoxicity are not yet fully understood, pro-inflammatory cytokines produced by CAR T-cells are thought to be responsible for pathogenesis.² ICANS is often associated with CRS; therefore, it is recommended that CRS prevention can help manage the development of ICANS.² Patients who develop ICANS without concomitant CRS are advised to be switched to total parenteral nutrition and medication (Figure 2).²

Figure 2. Recommendations for the management of ICANS by grade of severity according to the American Society for Transplantation and Cellular Therapy*

AED, antiepileptic drug; CRS, cytokine release syndrome; CSF, cerebrospinal fluid; CT-MRI, computed tomography-magnetic resonance imaging; EEG, electroencephalogram.
*Adapted from Ludwig, et al.²

Cytopenias and hypogammaglobulinemia

Cytopenias are common following CAR T-cell therapy and bsAb therapy, with incidence of Grade 3 or worse neutropenia recorded in 16–64% of patients receiving bsAbs and 55–95% of patients treated with CAR T-cell therapy.¹ It is recommended that patients with Grade ≥3 neutropenia should receive granulocyte colony-stimulating factor.² Dose administration is dependent on individual patient situation, and treatment initiation is not recommended for patients who have received bsAbs or CAR T-cell therapy within 14 days due to risk of inducing cytokine release.²

Hypogammaglobulinemia is a common AE in patients who have received B-cell maturation antigen therapy; a specific CAR T-cell therapy.¹ Prophylactic administration of 400 mg/kg immunoglobulin (Ig)G at 1–4 weeks is recommended for patients with low IgG concentrations.² Patients with higher IgG concentrations and recurrent bacterial infections who do not respond to antibiotic therapy can be considered for treatment with immunoglobulins, as this may result from an inability to mount an adequate antibody response.¹

Prophylaxis and management of infections

Studies have shown infections are common in patients treated with bsAbs and CAR T-cell therapies; therefore, it is recommended that patients are screened at baseline for hepatitis B, hepatitis C, human immunodeficiency virus, cytomegalovirus, and Epstein-Barr infections.¹ Cytomegalovirus, Epstein-Barr, and hepatitis B reactivation can occur after and during treatment; thus, testing should be considered on an individual case basis. Recommended preventative measures for prophylaxis and management of these infections include vaccination against varicella zoster virus with acyclovir or valaciclovir during treatment until 7 weeks post complete immune reconstitution (Figure 3).²

Figure 3. Recommendations for prophylaxis and management of infections*

CMV, cytomegalovirus; EBV, Epstein-Barr virus; IgG, immunoglobulin G; MRSA, methicillin-resistant Staphylococcus aureus; RSV, respiratory syncytial virus; VZV, varicella zoster virus.
*Adapted from Ludwig, et al.²

Conclusion

The recommended measures summarized above, including premedication, frequent assessment for symptoms and severity of CRS, and step-up dosing, should be considered in patients with MM who are selected for first-line treatment with bsAbs or CAR T-cell therapy. This will ensure management and prevention of AEs associated with these therapies.