Introduction: Extramedullary multiple myeloma (MM) can be detected at diagnosis or in relapsed/refractory disease and is associated with a worse prognosis. Myelomatous pleural effusion (MPE) is rare and has been described for an average of 12 months after the diagnosis of MM. Diagnosis of MPE requires electrophoresis and pleural fluid cytology or pleural biopsy. Cytological examination of the pleural fluid may show degenerative changes that can misdiagnose and histopathological analyzes can delay the diagnosis. Taking this into account, immunophenotyping is a fast and accurate tool for diagnosing the involvement of pleural fluid by MM. We report two cases of MM with MPE in the course of the disease and their outcomes. Case reports. Case 1: a 57-year-old man diagnosed with IgG-Lambda MM, stage DS-IIIB/IPSS II. After 4 months of treatment with a CTD regimen plus zoledronic acid, he achieved a VGPR according to the IMWG criteria. The minimal residual disease (MRD) by flow cytometry (MFC) was detected below the lower limit of quantification (LLOQ = 0.0005%). The myeloma plasma cells (MPC) immunophenotype was high FSC and intermediate SSC, with expressions of CD38bright, CD45bright, CD56, CD81, CD138, cytoplasmic Lambda, with no expressions of cyKappa, CD19, CD27, CD28, CD117. Three months later, before autologous stem cell transplantation (ASCT), MRD = 0,07%, the with loss of CD56 in MPC. MRD at D+100 post-ASCT was undetectable (10-5). He received 1 year of Thalidomide as maintenance therapy. One year and 5 months post ASCT he relapsed with 80% bone marrow involvement and bone lesions. He was treated with 6 cycles of VTD regimen, but the disease became refractory and progressive, despite the subsequent therapies. One year after the first relapse, he was admitted to the ICU with dyspnea and epigastric pain, without fever and cough. An extensive right pleural effusion was diagnosed by chest CT. Thoracentesis was performed and the pleural fluid immunophenotyping diagnosed MPE. The patient died 1 week after from disease activity. Case 2: 52 year-old male, diagnosed as IgG-Kappa MM, stage IPSS I, underwent ASCT after treatment with 4 cycles of CyBorD regimen. FCM -MRD was indetectable (10-5) at D+100 post-ASCT. The disease relapsed 7 months after ASCT, during the maintenance therapy with Bortezomib. Sequentially, the patient has been treated with DRd regimen and after 8 months the MRD was detectable bellow the LLOQ (10-5). The immunophenotype was CD27dim, CD38MEdim, CD56, CD81dim/negative, CD117, CD138, cyKappa, with no expressions of cyLambda, CD19 and CD45. But extramedullary progression was detected by PET-CT with small pulmonary nodules and chest wall mass. The patient received therapy with KCD+Denusumab. MRD = 0,012% after 6 months of treatment, with loss of CD56 in the PCM. Two months later, the patient was admitted to the ICU with tumor lysis syndrome, bilateral pleural effusion. MPE was diagnosed by MFC. He died of septic shock. Discussion: MFC is a useful method for diagnosing MPE. CD56 and CD117 are adhesion molecules that prevent the spread of myeloma plasma cells. Therefore, the absence of both markers may be associated with extramedullary dissemination of MM cells. In addition, the absence of CD27 expression has been considered to be associated with disease progression. It is important to consider these phenotypic characteristics in order to better recognize and elucidate the pathophysiology of MPE in prospective studies.