Multiple myeloma (MM) is a malignant plasma cell neoplasm with complex biology and heterogenous course. Interferon regulatory factor 4 (IRF4) transcription factor, important key developmental stages of hematopoiesis, represents an excellent potential therapeutic target. The present work aimed to investigate the expression status of IRF4 in the diagnostic bone marrow biopsy (BMB) cores of MM patients. This prospective study included 62 newly diagnosed MM patients. The expression of IRF4 was assessed in the BMB by immunohistochemistry (IHC). The data were correlated to the patients’ clinico-pathological features, response to treatment and survival rates. IRF4 expression was observed in 50% of MM patients (31/62). IRF-4 positive patients were more frequently male patients (P = 0.018), have immunoglobulin heavy chain (IgH) translocations (P = 0.05) and tended to present with a higher platelets count (P = 0.07). Multiple myeloma patients presenting with urine M-protein had worse overall survival (OS) than negative cases (P = 0.012). Normocellular BM aspirate (BMA) was associated with better OS than hypercellular and hypocellular BMA (P = 0.006). Patchy distribution of plasma cells in BMB was associated with better disease-free survival (DFS) while diffuse infiltration had the worst (P = 0.019). Of note, after treatment, MM patients had significantly lower percentage of BMA plasma cells, platelet count, β2 microglobulin and creatinine levels (P = 0.037, < 0.001, 0.022 and 0.026, respectively). Had higher albumin level (P = 0.007), compared to initial investigations. No significant association was found between IRF4 expression and the patients’clinical outcomes. Patterns of plasma cells distribution in BMB, BMA cellularity and urine M-protein are prognostically relevant in MM.