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 develops 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 years old female was referred in June 2022 with asthenia and abdominal pain. At physical examination, spleen enlargement was detected, with anemia (Hb 10.5 g/dL) and thrombocythopenia (48 x 109/L). Abdominal echography confirmed spleen enlargement (20 cm of longitudinal diameter). Blood tests showed free light chain alteration with a λ/κ ratio of 800. Marrow aspiration showed 60% of λ-restricted immature plasma cells: p53 expression was present in 91% of elements. PET CT scan revealed multiple focal areas of bone increased metabolic activity and a widespread positivity of the spleen with focal areas of higher uptake. Diagnosis of MM with splenic EMD was done and Dara-VMP regimen was started. After the first cycle of therapy, a marked reduction of the spleen size was observed with increase of both Hb level and platelet count. After the 2nd cycle of therapy, however, there was evolution in plasma cells leukemia: Vd-PACE regimen was thus started, but after the 2nd cycle she died in October 2022 from septic shock and multiorgan failure. 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.