Objective:

To characterize the movement/neurocognitive neurotoxicity after chimeric antigen receptor (CAR) T cell therapy targeting B-cell maturation antigen (BCMA) in patients with multiple myeloma (MM), with an emphasis on dopaminergic imaging and synuclein biomarker findings. 

Background:

A delayed-onset neurotoxicity syndrome resembling Parkinsonism has been increasingly recognized after BCMA-directed CAR-T therapy in MM patients. Reports suggest an on-target, off-tumor cross-reactivity at the level of the basal ganglia as a possible mechanism. However, detailed characterization of dopamine transporter imaging (DaTscans) and synuclein biomarkers have not been systematically reported in patients with MNT. 

Design/Methods:

Single-center case series of MM patients treated with BCMA-directed CAR T-cell therapy and diagnosed with MNT by a neurologist. We collected standard retrospective clinical data. We specifically report results from DaTscans and skin biopsy for phosphorylated a-synuclein when available. 

Results:

We identified 10 patients with median age 61.5 years (IQR 60.3-65.3) and follow-up duration of 15.4 months (12.3-16.5). Eight (80%) patients received cilta-cel product, 1 (10%) received ide-cel, and 1 (10%) received BCMA-targeting trial product (zevor-cel). All patients experienced cytokine release syndrome and 3 patients (30%) experienced ICANS (grade 2-3a). Median time to MNT symptom onset was 32 days (29-50). Nine (90%) patients completed a DaTscan  after MNT onset and 6 (60%) had an asymmetric, abnormally low uptake in the putamen (4 left, 2 right). An additional patient obtained a positron emission tomography (PET) study revealing hypometabolism in bilateral caudate and putamen. One of 6 patients (16.7%) with skin biopsies was positive for a-synuclein. One of 10 patients achieved full recovery from MNT, 6/10 partial recovery, and 3/10 no recovery; 3 (30%) patients are deceased. 

Conclusions:

Our findings suggest dopaminergic pathway involvement in some cases of MNT. One patient had a positive synuclein skin biopsy, which could implicate an underlying synucleinopathy . DaTscans and synuclein biomarkers may provide mechanistic insight and diagnostic utility.