In our experience with thalidomide treatment for refractory multiple myeloma (MM), most patients with progressive disease (PD) did not show an increase in M-protein despite the tumor burden of myeloma cells. This finding led us to suspect that proliferation of immature myeloma cells showing MPC-1(-)/CD49e(-) phenotype may be a sign of PD. We report the results of consecutive analysis of the phenotype of myeloma (plasma) cells in an MM patient with PD during treatment with thalidomide. The myeloma cells decreased by thalidomide therapy were mature (MPC-1(+)/CD49e(+)) and intermediate (MPC-1(+)/CD49e(-)) types. When the patient was in the PD state, extramedullary plasmacytoma was recognized without proliferation of myeloma cells in the bone marrow (BM). The phenotype of myeloma (plasma) cells in both of these locations was that of immature myeloma cells (MPC-1(-)/CD49e(-)), and they showed decreased intensity of CD38 expression. The level of immunoglobulin G (IgG) in serum was decreased, and myeloma (plasma) cells in BM did not increase in PD. Although these clinical features may not be specific to MM patients in PD undergoing treatment with thalidomide, we suggest that immature myeloma cells may be resistant to thalidomide.