Central nervous system (CNS) involvement in multiple myeloma is a rare and fatal condition occurring in approximately 1% of patients with advanced, refractory disease. In contrast, cytokine release syndrome (CRS) which often progresses to immune effector cell–associated neurotoxicity syndrome (ICANS) are more common complications of T cell redirecting therapies like teclistamab and occur with dosage adjustments.

A 68-year-old woman with relapsing IgA kappa multiple myeloma refractory to multiple chemotherapy agents with no cognitive or functional deficits at baseline began teclistamab in August 2025. Following the first dose escalation (0.06 mg/kg), she developed confusion coinciding with expected ICANS onset. Symptoms transiently improved, but with dose escalations over the next two weeks, she experienced progressive disorientation and vivid visual hallucinations, suspicious for ICANS though without CRS. Laboratory studies showed normal inflammatory markers (CRP 0.8 mg/L, ESR 5 mm/hr, procalcitonin 0.14 ng/mL), corrected calcium 11.4 mg/dL (normalized with denosumab), and no evidence of infection. MRI brain with widespread white matter edema and T2/FLAIR hyperintensities without leptomeningeal enhancement. EEG revealed diffuse left temporal spikes and slowing. Despite high-dose corticosteroids for presumed ICANS, her encephalopathy worsened. CSF revealed normal glucose (100 mg/dL), protein (25 mg/dL), and 2 cells, negative infectious and inflammatory workup. However, additional CSF studies ultimately identified monoclonal plasma cells, establishing CNS myeloma. She was transitioned to hospice.

This case illustrates CNS myeloma mimicking ICANS as neurological symptoms coincided with escalating teclistamab therapy. When severe neurotoxicity occurs without CRS, clinicians should maintain a low threshold for lumbar puncture with cytology and flow cytometry as early identification of CNS myeloma allows for intrathecal chemotherapy and timely coordination among neuro-oncology, hematology, and palliative care teams.