How are CNS manifestations of multiple myeloma managed?

Management of CNS Manifestations of Multiple Myeloma

Central nervous system (CNS) involvement in multiple myeloma should be treated with a combination of intrathecal chemotherapy, radiation therapy, and systemic therapy with agents that cross the blood-brain barrier, particularly immunomodulatory drugs. 1

Epidemiology and Presentation

• CNS involvement in multiple myeloma is rare, occurring in approximately 1% of all multiple myeloma cases during the disease course, and even more rarely at initial diagnosis 2
• CNS myeloma may present as leptomeningeal disease, parenchymal brain lesions, or dural/osteodural involvement, with each having distinct clinical behaviors 2
• Patients with plasma cell leukemia (40%) and skull plasmacytomas (65%) have higher risk of CNS involvement, suggesting hematological and contiguous spread mechanisms 1
• CNS myeloma typically occurs in patients who have received multiple lines of therapy, with a median time from diagnosis to CNS disease of 24 months in some studies 3

Diagnostic Approach

• When neurological symptoms develop in a patient with multiple myeloma, CNS involvement should be suspected and evaluated promptly 4
• Diagnostic workup should include:
  • MRI of brain and spine with contrast to detect leptomeningeal enhancement, parenchymal lesions, or dural masses 4
  • Lumbar puncture with CSF analysis for cytology, flow cytometry, and protein electrophoresis to detect malignant plasma cells 4
  • If a mass lesion is present, consider stereotactic biopsy to confirm the diagnosis 4

Treatment Strategy

Intrathecal Chemotherapy

• Intrathecal cytarabine is recommended at doses of 40-50 mg administered 2-3 times per week until clearance of blasts from CSF, followed by 3 additional treatments 5
• Alternatively, liposomal cytarabine at 50 mg every other week for approximately 6 cycles can be used 5
• For prevention of arachnoiditis during intrathecal therapy, dexamethasone (4 mg three times daily orally) may be administered on days of intrathecal application 5
• The FDA-approved intrathecal dosing of cytarabine ranges from 5 mg/m² to 75 mg/m², with 30 mg/m² every 4 days being most frequently used until CSF findings normalize, followed by one additional treatment 6

Radiation Therapy

• Cranial and/or spinal radiation therapy is recommended for patients with CNS myeloma, particularly those with large mass lesions or CSF flow obstruction 1
• Radiation therapy should be considered as part of the multimodal approach, with 78% of patients in one study receiving radiation as part of their treatment 1

Systemic Therapy

• Immunomodulatory drugs (IMiDs) such as lenalidomide and pomalidomide have shown some ability to cross the blood-brain barrier and should be incorporated into the treatment regimen 7, 1
• In a study of long-term survivors (median survival 17.1 months), treatment typically included a combination of radiation therapy, multi-dose intrathecal chemotherapy, and IMiD-containing systemic therapy 1
• Newer proteasome inhibitors that may cross the blood-brain barrier should be considered, though bortezomib has poor CNS penetration 7
• High-dose systemic chemotherapy, particularly regimens containing agents that cross the blood-brain barrier, should be considered 1

Recommended Treatment Algorithm

1. Initial Management:

   • Begin intrathecal cytarabine 40-50 mg 2-3 times weekly until CSF clearance, then 3 additional doses 5
   • Administer dexamethasone 4 mg three times daily on days of intrathecal treatment to prevent arachnoiditis 5
   • Initiate cranial and/or spinal radiation for mass lesions or leptomeningeal disease 1

2. Systemic Therapy:

   • Incorporate IMiDs (lenalidomide or pomalidomide) as they have demonstrated some CNS penetration 7, 1
   • Consider high-dose chemotherapy regimens that include agents with CNS penetration 1
   • Evaluate newer agents that may cross the blood-brain barrier for inclusion in the treatment regimen 7

3. Monitoring and Follow-up:

   • Repeat lumbar puncture after initial treatment to confirm clearance of malignant cells 6
   • Perform follow-up MRI imaging to assess response of parenchymal or dural lesions 4
   • Continue monitoring for neurological symptoms throughout treatment 4

Prognosis and Outcomes

• CNS involvement in multiple myeloma generally carries a poor prognosis with median survival of only 4.6 months 1
• However, long-term survival (median 17.1 months) has been achieved in some patients using a combination of radiation, multi-dose intrathecal chemotherapy, and IMiD-based therapy 1
• Patients who develop CNS disease after multiple lines of therapy, including novel agents, have particularly poor outcomes with median survival of only 2 months in one study 3

Common Pitfalls and Considerations

• Failure to consider CNS myeloma when neurological symptoms develop in a patient with multiple myeloma 4
• Inadequate treatment intensity - successful outcomes typically require combination therapy with intrathecal chemotherapy, radiation, and systemic agents that cross the blood-brain barrier 1
• Intrathecal cytarabine can cause systemic toxicity, requiring careful monitoring of the hematopoietic system 6
• Potential complications of intrathecal therapy include nausea, vomiting, fever, and rarely, more severe neurotoxicity such as paraplegia or necrotizing leukoencephalopathy 6