Multiple myeloma (MM) is clonal proliferation of malignant plasma cells in the bone marrow.¹ Multiple myeloma can present as extamedullary disease (EMD) in 5% of cases either through hematogenous spread or via bone cortex into the contiguous tissue.^{2 3} In such cases it is seen as either leptomeningeal disease, or as space occupying lesion.⁴  It can involve multiple organs like lungs, pleura, liver，lung，spleen, pancreas, kidney and lymph nodes, digestive tract, thyroid, heart, testis, ovary and skin.⁵

Patients with MM often have neurologic complications namely: peripheral neuropathies, spinal radiculopathies, cranial nerve palsies, spinal cord compression, and a host of metabolic encephalopathies. However, Infiltration into the Central nervous system (CNS) is rare in MM and has very poor prognosis.³ It can occur at any stage in MM.

We present a case of multiple myeloma with CNS infiltration during course of treatment.

A 75 year old gentleman, diagnosed case of multiple myeloma for the past 15 years, presented with altered sensorium and fever for 5 days. At the time of presentation the patient was on maintainance therapy.

His Myeloma FISH panel showed deletion of 13q and gain 1q. MRI and CT scan of brain was performed to rule out any large bleed and both were negative for the same. No structural abnormality- any parenchymal or space occupying lesion was noted in MRI and CT scan. EEG revealed non-generalized and non-specific neurophysiological disturbances.

Hematological investigations revealed Hb 101 gms/L, TLC - 2.7x10⁹/L, Platelets 99x10⁹/cu.mm. The peripheral blood smear was normal and did not show any plasma cells. Bone marrow examination (aspiration and trephine biopsy examination) was performed. It was variably cellular and showed normal trilineage hematopoiesis without any increase in plasma cells.

CSF examination revealed infiltration by many plasma cells. (Fig1). These were positive for CD38 on flow cytometric immunophenotyping. CSF culture did not show any growth on gram staining. Ziehl-Neelsen staining was negative for acid fast bacilli and no fungus was identified on India ink preparation. Cytomegalovirus/Epstien-Barr virus serology was negative.

malignant clonal proliferation of plasma cells in the bone marrow with clinical manifestations like hypercalcemia, anemia, renal dysfunction and bone lesions (CRAB).^{1, 6} MM can manifest at extramedulary sites like lungs, lymph nodes, spleen, digestive tract, pleura and in central nervous system.² According to our reference study done by QU Xiao-yan et al⁴. CNS myeloma is characterized by the presence of plasma cells in the CNS which was seen in our case study also. Though plasma cells can be seen in infectious causes also, they were ruled out by the means of gram staining, Ziehl-Neelsen staining and culture studies. CNS infiltration in a case of MM can happen via two methods – direct or hematogenous spread.

In our case, the patient was a already diagnosed case of multiple myeloma for the past 16 years and was treated with chemotherapy, with last cycle in 2016.  Suddenly the patient started having neurological non-specific symptoms. When investigated for the same it turned out to be extramedullary infestation of the multiple myeloma which is a rare phenomenon with no increase in plasma cells in peripheral blood film as well as in bone marrow. Flow cytometry was done on cerebrospinal fluid and it showed the presence of CD38 positive monoclonal plasma cells.  Any abnormalities with the chromosome 13 or 11 leads to poor prognosis in case of multiple myeloma. In our case FISH was done and it was noted that there was deletion of chromosome 13q.

In right clinical setting, presence of plasma cells in CSF should be taken as suspicious of myelomatous infiltration.⁷ This can help in prompt treatment and better chances of patient survival

The prognosis in multiple myeloma cases with cns manifestation is poor. This case is reported to stress that although rare, myeloma can involve CNS during treatment course.

Pathologists and clinicians should be aware about this rare occurrence.

Myeloma patients with CNS symptoms should be evaluated thoroughly to rule out CNSinvolement by myeloma as it carries poor prognosis.3

The majority of CNS-MM cases are in patients who have received MM therapy prior to CNS involvement   is generally short and may depend on subsequent treatment.

The prognosis in multiple myeloma cases with CNS manifestation is poor. This case is reported to stress that although rare, myeloma can involve CNS during treatment course.

Pathologists and clinicians should be aware about this rare occurrence. Myeloma patients with CNS symptoms should be evaluated thoroughly to rule out  CNSinvolement by myeloma as it carries poor prognosis.³

1. Firth J. Haematology: multiple myeloma. Clin Med (Lond). 2019;19:58-60.
2. Rasche L, Bernard C, Topp MS, Kapp M, Duell J, Wesemeier C, et al. Features of extramedullary myeloma relapse: high proliferation, minimal marrow involvement, adverse cytogenetics: a retrospective single-center study of 24 cases. Ann Hematol. 2012;91:1031-7.
3. Egan PA, Elder PT, Deighan WI, O'Connor SJM, Alexander HD. Multiple myeloma with central system relapse. Haematologica. 2020;105:1780-90.
4. Qu XY, Fu WJ, Xi H, Zhou F, Wei W, Hou J. Clinical features of multiple myeloma invasion of the central nervous system in Chinese patients. Chinese medical journal. 2010;123:1402-6.
5. Farheen S, Singh A, Yadav P, Tripathi P, Sen A. Central nervous system involvement: A rare detour for myeloma cells-case report of an usual presentation!. J Appl Hematol. 2021;12:213-6.
6. Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. The lancet oncology. 2014;15:e538-48.
7. Jurczyszyn A, Grzasko N, Gozzetti A, Czepiel J, Cerase A, Hungria V, et al. Central nervous system involvement by multiple myeloma: A multi-institutional retrospective study of 172 patients in daily clinical practice. Am J Hematol. 2016;91:575-80