BACKGROUND: Multiple myeloma (MM) is more often characterized by clonal plasma cell proliferation restricted to the bone marrow. However, a small percentage of patients with MM develop extramedullary disease (EMD): this type of localization is found in 1.7%-4.5% of the newly diagnosed MM (ND/MM) and in 3.4%-10% of patients with relapsed or refractory disease (RR/MM) and seems to have a bad prognostic impact. In the present report, we describe a very rare case of splenic involvement in a patient with ND/MM. CASE: A 72-year-old female was referred to Santa Rosa Hospital of Viterbo in June 2022 with asthenia and abdominal pain. At physical examination, spleen enlargement was detected, with anemia (Hb 10.5 g/dL) and thrombocytopenia (48 × 10 CONCLUSIONS: Our very rare case of ND/MM with spleen involvement confirms the aggressive behaviour of EMD, with negative prognostic factors (p53 mutation) and failure to frontline highly effective therapy. In the other few cases of spleen involvement reported, however, there were only scarce details about response: as a consequence, collection of similar cases is warranted to fully understand clinical features and possible alternative approaches for these extremely rare patients.