Central nervous system involvement in multiple myeloma as a first manifestation of relapse and potential diagnostic...

Central nervous system involvement in multiple myeloma (CNS-MM) is a rare complication usually observed in advanced relapse or refractory settings. The detection of malignant plasma cells in the cerebrospinal fluid (CSF) on the basis of morphology and flow cytometry (FCM) confirms this extra-medullary lesion. The records of 459 MM patients treated between 2016 and 2025 were reviewed, identifying four cases with CSF involvement. CSF and bone marrow samples were processed and analyzed on the basis of morphology and FCM using a dedicated 9-color panel to detect malignant plasma cells. Interleukin-6 (IL-6) and interleukin-10 (IL-10) concentrations were also measured in the CSF using Cytometric Bead Assay. Three patients were in complete remission when CSF analysis revealed CNS-MM. Two patients presented no cerebral lesions, although spinal cord compression was observed for one of them. Two patients presented interference in FCM analysis, supporting the penetration of daratumumab into the CSF. Interleukin measures in the CSF showed low or undetectable IL-10 levels but elevated IL-6 concentrations in some cases. Overall prognosis was poor, with the death of three patients and only one remaining alive at 2 years. CNS-MM could be the first sign of relapse among patients previously in complete remission. It should be envisaged in the case of any myeloma patient with unexplained neurological symptoms, even when imaging is negative. Flow-cytometry panels need to be optimized for plasma-cell detection, especially among patients treated with anti-CD38 antibodies. Identifying patients at risk remains crucial, but prognostic biomarkers such as IL-6 still require validation.