We report a patient with multiple myeloma presenting with a paraspinal plasmacytoma with a marked dissociation between the response obtained in bone marrow (BM) infiltration and that achieved in soft tissue masses. While a complete remission was reached and maintained in BM, extramedullary plasmacytomas were refractory to every line of treatment. Genetic analysis identified the presence of t(4;14) and RB deletion in myeloma cells of both origins. However, a P53 deletion was only detected in plasma cells from extramedullary plasmacytomas. This finding suggests that P53 deletion has a role in the lack of treatment response of extramedullary plasmacytomas.