CNS Involvement of Multiple Myeloma—A Case Series and Narrative Literature Review

Background: Central nervous system (CNS) involvement in multiple myeloma (MM) represents an extramedullary manifestation of the disease, which is often really challenging for clinicians, as the neurological symptoms could easily overlap with those related to hypercalcemia, uremia, high viscosity of the blood, or treatment-related neuropathy. Objectives: this retrospective study was conducted at Fundeni Clinical Institute in Bucharest, aiming to identify and systematically analyze a series of clinical cases diagnosed with extramedullary disease. Methods: We have identified 6 out of 583 patients with CNS involvement in our centre between 2019 and 2025. The diagnosis of meningeal myelomatosis was established through cerebrospinal fluid analysis, whereas CNS plasmacytomas were confirmed by CT-guided biopsy followed by immunohistochemistry evaluation. Results: All cases of CNS involvement occurred at relapse, with intervals from initial MM diagnosis to CNS involvement ranging from 9 months to 10 years. CNS-MM was linked to particular features, such as high-risk cytogenetics (four out of six patients), elevated lactate dehydrogenase, and the presence of extramedullary disease, highlighting its association with aggressive disease behaviour. Discussions: Although CNS-MM is correlated with poor prognosis, prolonged survival in one of our patients resulted from multimodal treatment, which included craniospinal radiotherapy, DPd systemic treatment, and intrathecal therapy (over 39 months). This aggressive approach effectively controlled both systemic disease and high-risk CNS involvement. Immunoglobulin isotype switching is a rare form of clonal evolution in MM, illustrated by the same patient whose disease evolved from IgA kappa at diagnosis to IgA lambda at CNS relapse, showing clonal heterogeneity and providing clinical evidence of clonal evolution. Conclusions: CNS involvement in MM usually occurs in a relapsed/refractory setting in patients with advanced, high-risk disease, and it is usually associated with extramedullary disease. Despite using multimodal therapies, outcomes remain poor, highlighting the need for novel and tailored agents.