A 46-year-old woman with IgA-lambda myeloma in partial remission, after a tandem autologous hematopoietic stem cells transplantation, complained of progressive lower back pain associated with paraplegia and neurological bladder 6 months after the second transplant. A lumbar puncture revealed atypical malignant plasma cells in the cerebral spinal fluid associated with multiple foci of altered signal intensity of brain and spinal cord demonstrated by magnetic resonance. Considering the lack of efficacious chemotherapies for neurological myeloma, an experimental systemic treatment with topotecan, temozolamide, and dexamethasone associated with concurrent radiotherapy of brain and spinal cord was initiated. During this treatment, the patient rapidly improved with disappearance of back pain, paresthesia, and urinary incontinence lasting 5 months, before dying of progressive disease. The proposed systemic chemotherapy associated with concurrent radiotherapy may have an antitumor activity against MM with CNS involvement.