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Syeda Saba Kareem,1 Neena Viswanathan,2 Solmaz Sahebjam,2 Nam D Tran,2 Tyra Gatewood,2 Katherine Tobon,1 Rachid Baz,1 Yolanda Piña,2 Kenneth H Shain,1,3 Sepideh Mokhtari2 1Malignant Hematology Department, Moffitt Cancer Center, Tampa, FL, USA; 2Neuro-Oncology Department, Moffitt Cancer Center, Tampa, FL, USA; 3Tumor Biology Department, Moffitt Cancer Center, Tampa, FL, USACorrespondence: Syeda Saba Kareem, Malignant Hematology Department, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL, 33612, Tel +850-321-4383, Fax +813-449-8246, Email syedasaba.kareem@moffitt.orgAbstract: Leukoencephalopathy in the setting of multiple myeloma (MM) is a rare demyelinating condition, with few reported cases in literature. Daratumumab is a CD38 targeted monoclonal antibody that has been widely used for the management of MM. In the absence of central nervous system (CNS) disease, many medication-induced leukoencephalopathy cases reported with MM, including daratumumab-induced, are associated with progressive multifocal leukoencephalopathy (PML) and John Cunningham (JC) virus. Currently, there are no reported cases of daratumumab-induced leukoencephalopathy among patients without CNS involvement or PML. We discuss 2 patients who developed leukoencephalopathy while receiving daratumumab-based therapy without evidence of PML or CNS disease. Both patients had baseline MRIs without significant white matter changes before daratumumab-based therapy. Patients began experiencing neurological deficits about 6 to 8 months after daratumumab-based therapy initiation. One patient passed away before being assessed for improvement of symptoms with daratumumab cessation. The second patient had some stabilization of symptoms after cessation; however, the leukoencephalopathy remained irreversible. As the class of anti-CD38 monoclonal antibodies expands in MM therapy, we highlight a potential treatment complication and the importance of detecting leukoencephalopathy early among patients recei