Abstract
Cluster of differentiation 20 (CD20) expression is rarely observed in multiple myeloma (MM) and is typically associated with immature plasma cell morphology and aggressive clinical behavior. Cold agglutinin disease (CAD) is also uncommon in MM and usually suggests other hematologic malignancies. We present a rare case of CD20-positive MM complicated by CAD in a 77-year-old woman who initially had pancytopenia, bone pain, and renal failure. Diagnostic work-up revealed light chain MM with kappa restriction, cast nephropathy, and diffuse CD20 expression in plasma cells. She was treated with bortezomib, cyclophosphamide, and dexamethasone (VCD), achieving hematologic improvement and partial renal recovery. During the third cycle, she developed severe anemia and hemolysis due to cold agglutinins, which were managed successfully with corticosteroids and supportive care. Retrospective immunohistochemistry confirmed CD20 positivity. This case underscores the diagnostic and therapeutic complexity of atypical MM presentations and highlights the importance of re-evaluating immunophenotypic features when the clinical course deviates from expectations. While CD20-targeted therapies are not routinely used in MM, their relevance in selected subtypes warrants further exploration. Our case illustrates the potential for paraneoplastic hemolysis and phenotypic diversity in MM, emphasizing the need for a multidisciplinary approach to diagnosis and management.