Background: In multiple myeloma (MM), a variety of genetic events have been described to be associated with disease progression. Besides, the activation of the NF-κB (nuclear factor-kappa B) pathway is suggested of paramount importance for the survival of healthy plasma cells and for MM tumors. The present study hypothesized the possible distinction in the disease biology of new and relapse/progressive MM patients especially in context to dysregulation of NF-κB pathway. Methods: Expression levels of NF-κB pathway genes (NFKB2, NIK, IKB, BCL3, and CCND1) were studied in total bone marrow samples of MM patients using real-time quantitative PCR with SYBRGreen chemistry and fold change values were calculated by comparative ΔΔCT method. Results: Total of 54 newly diagnosed, 14 relapse/progressive patients and 11 healthy controls were included in the study. The median age for newly diagnosed and relapse patients was 57.8 (Range 31-76) and 56.7 (Range 46- 65) years respectively. We found higher expression levels (as fold-change values) of genes in both cohorts of MM patients, however, the difference was non- significant (p > 0.05). In newly diagnosed MM patients, overexpression of NIK and IKB showed a significant association with hemoglobin (p-value = 0.05 and 0.02 respectively) whereas BCL3 and IKB mRNA over expression was significantly associated with serum albumin levels (p = 0.02) and plasma cells percentage (p = 0.04) respectively. Also, overexpression of IKB was found to be associated with International Staging System (ISS) (p = 0.05). On the other hand, in relapse MM patients, CCND1 and NFKB2 showed significant association with hemoglobin (p-value of 0.006 and 0.02 respectively) whereas BCL3 again showed significant association with serum albumin levels (p = 0.04). Conclusions: We suggest that the genetic architecture in new and relapse MM patients is aligned and regulated in a similar way. Also, we might say that certain mutations in the putative genes leads to the constitutive activation of NF-κB pathway by either inhibiting or bypassing the function of the IKB and NIK regulatory complexes. Apparently, there is also a need to further explore the nuclear components that regulate the NF-κB signaling cascade.