IMWG immunotherapy committee consensus guidelines and recommendations for optimal use of T-cell-engaging bispecific antibodies in multiple myeloma
This document discusses the toxicity and management of cytokine release syndrome and neurological complications associated with bispecific antibody therapy. Cytokine release syndrome is a systemic inflammatory reaction caused by T-cell activation, leading to the release of pro-inflammatory cytokines. The clinical presentation of cytokine release syndrome can range from isolated fever to severe reactions. Bispecific antibodies currently in clinical development for multiple myeloma induce cytokine release syndrome, which is mostly grade 1 or 2. The frequency of cytokine release syndrome varies between different bispecific antibodies due to factors such as the number of step-up doses, pre-medications, route of administration, and CD3-binding affinity. The onset of cytokine release syndrome is typically within 24 hours of intravenous infusion and after at least 24 hours with subcutaneous administration.
Diagnostic investigation of cytokine release syndrome involves a detailed medical history, physical examination, and laboratory investigations. Complete blood counts, comprehensive metabolic panels, inflammatory markers, and coagulation tests are recommended. A full infectious investigation should also be considered. C-reactive protein concentrations are not useful for monitoring after the use of tocilizumab, but procalcitonin might be of value. Broad-spectrum antibiotics should be considered if neutropenia co-exists. Bispecific antibodies should not be administered during an active infection. Prophylactic use of tocilizumab, an IL-6 receptor-blocking antibody, has been evaluated to reduce the incidence of cytokine release syndrome.
The grading and management of cytokine release syndrome involve different strategies based on the severity of the syndrome. Tocilizumab is recommended for the treatment of grade 1 cytokine release syndrome, and early intervention is encouraged. Supportive care should be initiated, and second-line therapy can be considered if cytokine release syndrome persists or recurs. Severe cases might require intensive monitoring and support in an intensive care unit.
Neurological complications associated with bispecific antibodies include headache, immune effector cell-associated neurological toxicity, and peripheral neuropathy. Headache is a non-specific neurotoxic event and often responds to treatment with acetaminophen. Immune effector cell-associated neurological toxicity is less common and typically occurs concurrent with cytokine release syndrome. Peripheral neuropathies are mostly sensory and can be associated with a previous history of peripheral neuropathy. A delayed parkinsonian syndrome has been reported with BCMA-targeted CAR-T cell therapy but not with BCMA–CD3-targeted bispecific antibodies.
The frequency of neurological complications in clinical trials varies between different bispecific antibodies. Headache and immune effector cell-associated neurological toxicity are reported in a small percentage of patients, mostly grade 1 or 2 events. Peripheral neuropathy is observed in a higher percentage of patients, with a previous history of peripheral neuropathy being common.
The evaluation and management of neurotoxicity involve neurological examinations, scoring systems, and diagnostic investigations to exclude other potential causes. Corticosteroids, particularly dexamethasone, are the preferred treatment for immune effector cell-associated neurological toxicity. Prophylaxis with non-sedating anti-epileptic drugs can be considered. Persistent neurotoxicity might require a neurology consultation and the use of alternative agents. Peripheral neuropathy can worsen on therapy and might require temporary interruption or steroid treatment.
Important Points:
- Cytokine release syndrome is a systemic inflammatory reaction caused by T-cell activation and the release of pro-inflammatory cytokines.
- Bispecific antibodies currently in clinical development for multiple myeloma induce cytokine release syndrome, which is mostly grade 1 or 2.
- The frequency of cytokine release syndrome varies between different bispecific antibodies due to various factors.
- Diagnostic investigation of cytokine release syndrome involves a detailed medical history, physical examination, and laboratory investigations.
- Prophylactic use of tocilizumab has been evaluated to reduce the incidence of cytokine release syndrome.
- The grading and management of cytokine release syndrome involve different strategies based on the severity of the syndrome.
- Neurological complications associated with bispecific antibodies include headache, immune effector cell-associated neurological toxicity, and peripheral neuropathy.
- The frequency of neurological complications in clinical trials varies between different bispecific antibodies.
- The evaluation and management of neurotoxicity involve neurological examinations, scoring systems, and diagnostic investigations.
- Corticosteroids, particularly dexamethasone, are the preferred treatment for immune effector cell-associated neurological toxicity.
- Prophylaxis with non-sedating anti-epileptic drugs can be considered.
- Persistent neurotoxicity might require a neurology consultation and the use of alternative agents.
- Peripheral neuropathy can worsen on therapy and might require temporary interruption or steroid treatment.
Authors:
Paula Rodriguez-Otero, Saad Usmani, Adam D Cohen, Niels W C J van de Donk, Xavier Leleu, Jaime Gállego Pérez-Larraya, Salomon Manier, Ajay K Nooka, Maria Victoria Mateos, Hermann Einsele, Monique Minnema, Michele Cavo, Benjamin A Derman, Noemi Puig, Francesca Gay, P Joy Ho, Wee-Joo Chng, Efstathios Kastritis, Gösta Gahrton, Katja Weisel, Chandramouli Nagarajan, Fredik Schjesvold, Joseph Mikhael, Luciano Costa, Noopur S Raje, Elena Zamagni, Roman Hájek, Niels Weinhold, Kwee Yong, Jing Christine Ye, Surbhi Sidhana, Giampaolo Merlini, Tom Martin, Yi Lin, Ajai Chari, Rakesh Popat, Jonathan L Kaufman, on behalf of the International Myeloma Working Group
Citation:
Lancet Oncol 2024; 25: e205–16
https://doi.org/10.1016/S1470-2045(24)00043-3