Extramedullary disease is an aggressive presentation at diagnosis and relapse for multiple myeloma (MM) patients. Central nervous system (CNS) is a very rare manifestation of the extramedullary disease, accounting for less than 1% of MM on diagnosis and relapse. Neurological symptoms are unspecific and usually attributed to other causes. We present two patients with CNS-MM at relapse after autologous stem cell transplant highlighting the importance of clinical suspicion and interdisciplinarity at diagnostic workup as well as the need for intensive therapeutic options on such rare and aggressive cases. The presence of neurological abnormalities in anamnesis and physical examination on a patient with MM should always prompt to suspect of a CNS involvement, and active investigation must be undertaken. MRI is the standard radiological method to detect CNS-MM, with histopathological corroboration by stereotactic biopsy and CSF evaluation alongside. Treatment of CNS-MM should include two essential approaches—be able to cross the BBB and treat the systemic disease. There is no standard therapy for this extramedullary relapse, and a tailored and multiple therapy should be promptly started—intrathecal therapy, radiotherapy, and systemic therapy, including an immunomodulator.
Despite novel agents and increased better outcomes over the last years, multiple myeloma (MM) is still an incurable disease marked by a relapse-remission pattern [
A 49-year-old man with no relevant past clinical history was diagnosed with MM IgG/lambda, Durie–Salmon stage IIIA, and International Staging System (ISS) stage III in August 2011. He presented with anemia and extensive lytic bone lesions. His bone marrow assessment showed 33% of abnormal plasma cells, CD38+ve, CD19−ve, CD56+ve, CD45−ve, and lambda+ve and no alterations on fluorescence in situ hybridization (FISH) of selected plasma cells. He was treated with bortezomib and dexamethasone (VD) for four cycles, achieving a very good partial response (VGPR), followed by stem cell mobilization with an intermediate dose of cyclophosphamide (4 g/m2) collecting enough cells for two grafts, and he underwent his first autologous stem cell transplant (ASCT), after high-dose melphalan (200 mg/m2) in January 2012. He maintained a VGPR at day 100 assessment.
In August 2014, he presented with severe back pain leading to a progression evaluation. He had new lytic bone lesions on the skull and lumbar vertebrae, hypercalcemia, anemia, and acute renal failure. A new bone marrow assessment was performed with 40% of abnormal plasma cells and no FISH abnormalities identified. He was treated with bortezomib, thalidomide, and dexamethasone (VTD) for four cycles reaching only a partial response (PR), followed by high-dose melphalan and was submitted to a second ASCT in January 2015. At day 100, he had a VGPR and was kept on observation.
Nine months after the second ASCT, he was admitted to the emergency room in a comatose status (Glasgow Coma Scale 9). His blood workup was normal without anemia, hypercalcemia, or acute renal failure. Brain computed tomography showed two large extra-axial lesions (a right one with 3.5 cm in the coronal plane and a left one with 1.4 cm in the coronal plane), spontaneously hyperdense and with strong contrast enhancement, a posterior extension of the lesion with dura mater infiltration, and diffuse involvement of the calvaria. Due to rapid neurological deterioration, the patient was operated by neurosurgery with resection of the right frontoparietal lesion with invaded dura and bone flap. The anatomopathological exam showed an extensive collection of plasma cells with high mitotic activity, multiple apoptotic bodies, and extension to the adjacent bone. FISH analysis of the excised cerebral mass showed del17p13.2 (72%) and del1q21 (30%). His bone marrow had no plasma cells, no FISH abnormalities, and no serum or urine monoclonal component, besides the serum immunofixation Ig/lambda and abnormal free light chain ratio (Figure
(a, b) Two massive extra-axial tissue lesions (right: 3.5 cm in the coronal plane; left: 1.4 cm in the coronal plane), spontaneously hyperdense and with strong contrast enhancement; posterior extension of the lesion with dura infiltration; diffuse involvement calvaria; (c–e) surgical removal of the frontoparietal bone flap with adherent soft tissue lesion and dura mater; (f–i) plasma cells with high mitotic activity and apoptotic bodies. (HE, 200x); invasion of the bone. (HE, 400x); (j, k) 1p32/1q21 and 17p13.2 (TP53) copy number changes evaluated by FISH: (j) (17p13.2, red), (k) (1p32, green and 1q21, red), (j) del17p13.2 (30%), and (k) 1q21 gain (72%).
A 66-year-old man with no relevant past clinical history was diagnosed with MM IgA/lambda, Durie–Salmon stage IIIA, and ISS stage III in December 2014. He presented with anemia, hypercalcemia, and extensive lytic bone lesions on skull, thoracic, and lumbar vertebrae and long bones. His bone marrow showed 40% of plasma cells, CD38+ve, CD138+ve, CD19−ve, CD56−ve, and CD45+ve, with del13q (87%). He was treated with bortezomib, thalidomide, and dexamethasone for four cycles, achieving a complete remission (CR). He was proposed for ASCT with stem cell collection after steady mobilization with G-CSF and underwent high-dose melphalan (200 mg/m2) followed by ASCT in May 2015. On day 100 evaluation, he remained in CR.
In November 2015, he went to the daycare hospital with refractory nausea, holocranial headaches, confusion, diplopia, and loss of muscle strength in the upper right limb with three days duration. His blood workup was normal without anemia, hypercalcemia, or acute renal failure. A cerebral scan was performed showing spontaneous hypodense areas with intense cortical contrast enhancement in the bilateral insula, anterior temporal predominance of the left sulci, engorgement of the left choroid plexus, right cerebellar tentorium, right prepontine cistern and pituitary gland, supratentorial ventricular dilatation with transependymal edema, extensive leptomeningeal infiltration, and focal low density on the sphenoid body. A lumbar puncture was performed with the cerebrospinal fluid (CSF) analysis showing 39 cells, of which 88.7% were monoclonal plasma cells CD38+ve, CD19−ve, CD56−ve, and CD45-het, with lambda restriction and all with del1q21 on FISH. His bone marrow had no plasma cells, no FISH abnormalities, and no serum or urine monoclonal component, besides the reappearance of serum immunofixation IgA/lambda and abnormal free light chain ratio (Figure
(a) Spontaneous hypodense areas with intense cortical contrast enhancement in bilateral insulae, anterotemporal predominance of the left grooves, engorgement of the left choroid plexus, right cerebellar tent, the right side of the prepontine cistern and pituitary gland, supratentorial ventricular dilatation with transependymal edema, focal area of lower density in the body of sphenoid, and extensive leptomeningeal infiltration. (b) 35 cells (87% neoplastic plasma cells). (c) 1p32/1q21 copy number changes evaluated by FISH: 1p32, green; 1q21, red and 1q21 gain (100%).
Both cases represented great challenges in clinical practice. No guidelines and recommendations are evident in how to approach or treat CNS-MM. In the past years, many reports suggest that extramedullary disease, including CNS-MM, increased with the use of novel agents and autologous stem cell transplant [
Clinical manifestations are usually unspecific and heterogeneous, like headaches and cognitive dysfunction, resembling other common neurological diseases or chemotherapy-related side effects making the differential diagnosis hard in clinical practice [
Contrast-enhanced MRI is the standard radiological method to detect CNS-MM, but sensitivity is lower for hematological malignancies (20–37%) than for solid tumors (85%) [
There is no independent prognostic factor for the development of MM-CNS. Some reports show that the high-risk patients share some classic features related to adverse prognosis such as lambda and IgD subtype, high-burden disease, stage III by Salmon–Durie, high lactate dehydrogenase (LDH), and high beta2-microglobulin [
There are some hypotheses that emerge as an explanation of CNS involvement by MM. The first hypothesis relates to the hematogenous spread in which plasma cells and earlier cells with a specific phenotype can induce metastasis to distant places as extramedullary disease including the CNS [
Regarding the treatment of CNS-MM, significant data are sparse, and there is no standard of care advised for these cases [
Immunomodulators can cross the BBB. Thalidomide can be detected on CSF after an oral administration of 100 mg/day, peaking a concentration of 30% to 60% as compared to the plasma [
Bortezomib has a limited penetration through the BBB in animal models, with few reports showing its inefficacy in CNS-MM patients [
Intrathecal chemotherapy (ITC) is mostly used in several hematological malignancies with CNS involvement with diverging results [
Brain and neuraxial radiation, as there is a well-known pattern of plasma cell radiosensitivity, seems an essential coadjuvant therapy in CNS-MM [
Standard chemotherapy used on MM as alkylating agents penetrates the BBB very poorly, with only 10% of melphalan levels found at LCR of treated patients [
Our patients were treated according to presentation and performance status. In Case 1, the exuberance of presentation demanded a life-saving approach with the surgical approach, systemic therapy, radiotherapy, and immunomodulators. In Case 2, due to the absence of intraparenchymal tumor, the patient was treated with intrathecal chemotherapy, radiotherapy, and immunomodulators. We believe that the aggressive management of these patients followed by a continuous therapy with an agent that cross the BBB improved their survival comparing to published data.
Prognosis of CNS-MM is dismal across all series and case reports, with a post-CNS-MM survival of 3 to 6 months and does not appear to be different in patients treated with novel agents compared to those treated with conventional drugs [
These cases illustrate unusual patterns of CNS-MM involvement that could envisage two different hypotheses for CNS relapses such as the direct contiguous spread from the eroded lytic lesions of the skull (more probable in Case 1) and hematogenous spread of plasma cells (more probable in Case 2). Although rare, CNS involvement by MM should be considered in MM patients with neurological deficits/symptoms. There is no standard therapy for this extramedullary relapse, and a tailored aggressive therapy should be promptly started—ICT, RT, and systemic therapy, including an IMID. Even in the era of novel therapies, the prognosis of CNS involvement remains dismal, highlighting the need for adequate CNS penetration in MM novel drug development to improve these patients’ outcomes.
Verbal and written consent was obtained from the patients for using this case for publication purposes. All data used in this case report were anonymized.
RB: grants from Celgene and SPH/APCL/Amgen; advisory board and speaker honoraria from Celgene, Janssen, Takeda, and Amgen. FT: grant SPH/APCL/Amgen; advisory board and speaker honoraria from Celgene, Janssen, Takeda, and Amgen; JEG: advisory board and speaker honoraria from Abbvie, Janssen, Pfizer, and Roche. JB, MJS, BC, JC, CM, and PS report no conflicts of interest.
RB was the patient’s primary hematologist and performed data collection and wrote the manuscript. MJS, JC, CM, PS, and BC were involved in diagnostic tests and treatment plan and revised the data and the drafted paper. JEG and FT revised and supervised the drafted paper.