CNS involvement in MM is a rare, aggressive but increasingly recognized complication, potentially due to improved survival rates with modern therapies allowing for late relapses in sanctuary sites like the CNS [6]. This “sanctuary-site” relapse may reflect plasma cells seeding the leptomeninges where conventional therapy penetration is limited. Large series estimate its incidence at <1% [4]. The pathogenesis of CNS myeloma is not fully understood but is thought to involve hematogenous spread and direct extension from skull base plasmacytomas. It typically occurs as a relapse phenomenon after multiple lines of therapy [6]. In Jurczyszyn’s multinational cohort (172 patients), only 22% had CNS disease at initial MM diagnosis, while 78% developed it at relapse [6]. Known associations include plasmablastic morphology, high tumor burden, and poor-risk cytogenetics [5]. Our patient’s emergence of CNS disease during apparent marrow CR is exceptional; isolated CNS relapse during systemic remission has been documented only in a handful of case reports.

While imaging studies like CT and MRI can suggest leptomeningeal enhancement or parenchymal lesions, definitive diagnosis relies on CSF cytology demonstrating malignant plasma cells [7,8]. Flow cytometric immunophenotyping of CSF can be particularly useful in identifying the clonal nature of these cells and confirming the diagnosis, especially in cases with low cellularity on cytospin [8]. In our case, the discrepancy between the bone marrow remission status and the florid CNS involvement highlights the importance of considering CNS relapse even in patients with seemingly well-controlled systemic disease.

The diagnosis of CNS myeloma can be challenging and requires a high index of suspicion. Neurologic symptoms (headache, confusion, cranial neuropathies, seizures) should prompt evaluation with imaging and CSF analysis. MRI of the brain and spine is the preferred modality, with leptomeningeal enhancement or masses seen in the majority of cases [7]. In one review, MRI detected CNS involvement in 93% of cases versus 81% by CT [7]. However, imaging can be normal in some patients [7]. In our case, CT and MRI revealed diffuse leptomeningeal enhancement. Regardless, definitive diagnosis rests on CSF examination.

Conventional CSF cytology may demonstrate plasma cells, but sensitivity is limited and false-negatives are common (20–60%) [5]. Flow cytometry markedly improves detection by studying plasma cells clonality, as monoclonal plasma cells confirm the abnormality and malignant nature. In our patient, flow cytometry of CSF confirmed a clonal κ-restricted plasma cell population (bright CD38/CD138) that was not present in bone marrow. Flow methods can detect small numbers of aberrant cells, with reported sensitivity (~94%) superior to cytology (~68%). Indeed, multiparameter flow can identify monoclonal CD38+/CD138+ cells in ~90% of CNS-MM CSF samples [5]. Combining cytology (which allows morphologic and immunocytochemical assessment) with flow (which confirms clonality) is recommended [8]. This approach enabled rapid diagnosis in our patient despite the marrow being clear. Notably, Marini et al. described an MM patient with neurologic symptoms and normal MRI, where CSF flow cytometry (CD56+ plasma cells) provided the diagnosis.

Therapeutic options for CNS-MM are limited and largely palliative. Evidence is anecdotal, but multi-modality treatment is advocated [2]. Typical regimens include intrathecal chemotherapy (methotrexate, cytarabine, corticosteroids) and CNS-directed radiotherapy, often combined with systemic agents that can penetrate the blood–brain barrier (BBB) [9]. Agents like high-dose methotrexate or cytarabine have some CNS activity but limited myeloma efficacy. Bendamustine crosses the BBB and has shown benefit in case reports, usually with concurrent thalidomide/dexamethasone and irradiation [9]. Immunomodulatory drugs (thalidomide, lenalidomide) do penetrate the CNS to a degree [9], and pomalidomide has shown preclinical BBB penetrance [9]. Daratumumab (anti-CD38) has been used intrathecally and systemically in recent cases with some successes [2]. Autologous stem cell transplantation has been reported in some cases with CNS involvement, but its role in this setting remains to be fully defined [6]. Newer agents such as CAR-T cell therapy and bispecific antibodies targeting B-cell maturation antigen (BCMA) have shown promise in relapsed/refractory MM and are being investigated for CNS involvement [10]. In our patient, we instituted intrathecal therapy, CNS radiotherapy, and systemic daratumumab/lenalidomide/dexamethasone.

The prognosis of CNS involvement by MM is dismal [2,6]. In small series and reviews, median survival after CNS involvement is on the order of only a few months [2,6]. For example, Bommer et al. found median overall survival of only 82 days after diagnosis of CNS involvement by myeloma [5]. Jurczyszyn’s multicentre study reported median survival ~7 months from CNS diagnosis, with untreated patients dying even faster (median 2 months) [6]. In that analysis, any active treatment (systemic, IT, or radiation) modestly improved outcomes [6]. We emphasize that even in systemic CR, new neurologic symptoms in a myeloma patient must prompt CNS evaluation. Early CSF analysis including flow cytometry is critical, as it offers rapid and definitive diagnosis enabling timely CNS-directed therapy [5].