Redefining central nervous system multiple myeloma: From rare phenomenon to emerging entity

Central nervous system involvement in multiple myeloma (CNS-MM) is considered a rare but devastating manifestation of extra-medullary disease (EMD) associated with aggressive biology and dismal outcomes. Treatment advances over the past few decades have improved survival in patients with MM, however, it has not translated into a similar survival benefit for those with CNS-MM. Early recognition and targeted management of CNS-MM remain major clinical challenges.

This literature review summarizes the current literature on epidemiology, risk factors, clinical features, diagnostic modalities, and therapeutic approaches to CNS-MM. It focuses on emerging biomarkers and new treatment options that may affect the natural course of the disease. This review hypothesizes that CNS involvement may represent a distinct biologic entity characterized by unique patterns of tropism, resistance, and microenvironmental adaptation.

CNS-MM typically arises in the context of relapsed or refractory disease and is associated with high-risk cytogenetics, plasmablastic morphology, circulating plasma cells, elevated lactate dehydrogenase, and other sites of EMD. Survival remains poor, with most cohorts reporting a median overall survival of less than 6 months from CNS involvement. Effective therapeutic options in systemic treatment have a limited effect in CNS-MM due to the poor penetration of the blood-brain barrier. Novel therapeutics such as CAR-T cells, bispecific antibodies, and intrathecal chemotherapy have shown isolated activity, but data remains limited.

Emerging diagnostic tools such as CSF-based circulating tumor DNA (ctDNA) and soluble BCMA (sBCMA) may enable earlier detection and dynamic monitoring. While sBCMA has been correlated with systemic disease activity, its role in CSF-based testing for CNS-MM has not been validated. Screening high risk patients may increase the predictive value of these tests. Advances in immune and cellular therapy could expand treatment options but need direction on sequencing of therapies and consideration of maintenance therapy.

In conclusion, this review supports the hypothesis that CNS-MM may represent an underdiagnosed, biologically distinct entity, requiring dedicated diagnostic and therapeutic strategies. Integrating novel diagnostics with CNS-penetrant therapies offers a path forward in managing this ultra-high-risk population. Clinicians should consider screening high risk patients for this entity to affect survival.