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Shaji K. Kumar, MD
Shaji K. Kumar, MD
Posted: Monday, April 6, 2026
In a recent review published in the Journal of the National Comprehensive Cancer Network, Christopher R. D’Angelo, MD, and colleagues examined the diagnosis and management of multiple myeloma with central nervous system (CNS) involvement, a rare but increasingly recognized and highly morbid complication brought about by advances in systemic therapies that prolong survival but may be associated with later relapses.
Background
CNS involvement in multiple myeloma occurs in approximately 1% of patients but carries a markedly poor prognosis. It can arise at diagnosis or relapse and may occur independently or alongside systemic disease. Risk factors include extramedullary disease, high-risk cytogenetics, plasma cell leukemia, and elevated lactate dehydrogenase. Patients most commonly present with neurologic symptoms such as visual disturbances, headaches, confusion, or seizures. Diagnostic evaluation relies on brain MRI with gadolinium contrast, which identifies leptomeningeal or parenchymal lesions in most cases, and cerebrospinal fluid analysis demonstrating clonal plasma cells, which is highly sensitive and often obviates the need for invasive biopsy.
Therapeutic Strategies and Treatment Selection
Given the absence of prospective trials, treatment strategies are heterogeneous and largely based on retrospective data. The authors outlined a multimodal therapeutic approach incorporating systemic agents with CNS penetration, intrathecal chemotherapy, radiation therapy, and emerging immunotherapies. Traditional cytotoxic chemotherapy has shown limited efficacy, with median overall survival historically measured in months. Intrathecal chemotherapy, typically using methotrexate and cytarabine, has produced mixed results; some retrospective studies suggest modest survival benefits when combined with other modalities, whereas others show no clear advantage.
Radiation therapy remains a key component of management due to the radiosensitivity of myeloma cells, with response rates exceeding 70% to 80% even at relatively low doses. Craniospinal irradiation and focal radiation are particularly useful for symptom control and as bridging strategies. Newer systemic agents have demonstrated improved outcomes compared with conventional chemotherapy. Immunomodulatory drugs, such as lenalidomide and pomalidomide, can penetrate the blood–brain barrier and have shown encouraging activity in retrospective analyses. Similarly, small molecules such as venetoclax and selinexor may offer benefit in selected patients due to their CNS penetration.
The review also highlights the emerging role of T-cell–redirecting therapies. Although data remain limited, early evidence suggests that BCMA-directed CAR T-cell therapies and bispecific antibodies may be effective, particularly as consolidation following CNS-directed treatment. These approaches appear most beneficial in patients who achieve initial disease control with multimodal therapy.
Overall, outcomes remain poor despite therapeutic advances. As the authors note, “the prognosis for CNS [multiple myeloma] is poor, with reported median overall survival as short as 3 months.”
They conclude that optimal management of CNS multiple myeloma requires individualized, multimodal treatment incorporating CNS-penetrant systemic therapies and local interventions, along with consolidative strategies such as CAR T-cell therapy. In addition, prospective clinical trials and collaborative research efforts are needed to better define effective therapies and improve outcomes in this disease setting.
DISCLOSURE: For full disclosures of all study authors, visit jccn.org.
Journal of the National Comprehensive Cancer Network
