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Simple Summary: Multiple myeloma (MM) is a blood cancer that is still incurable because patients become insensitive to available treatments. The cancerous cells in MM misuse a signaling route, called the NFκB pathway, to make MM more difficult to treat. In our study, we used a new method to measure NFκB pathway activity in cancer cells of MM patients at different stages of disease. We found that NFκB pathway activity remains unchanged during disease development, is independent of the life expectancy of MM patients, and does not predict how well the cancer cells will respond to treatment. However, the cancer cells that survive after treatment of MM patients do show higher NFκB pathway activity. In a subgroup of these patients, the cancer cells also showed higher BFL-1 gene expression. BFL-1 can enhance cancer cell survival after treatment and may therefore be a potential new candidate to target in these patients. Multiple myeloma (MM) is a hematological malignancy that is still considered incurable due to the development of therapy resistance and subsequent relapse of disease. MM plasma cells (PC) use NFκB signaling to stimulate cell growth and disease progression, and for protection against therapy-induced apoptosis. Amongst its diverse array of target genes, NFκB regulates the expression of pro-survival BCL-2 proteins BCL-XL, BFL-1, and BCL-2. A possible role for BFL-1 in MM is controversial, since BFL-1, encoded by BCL2A1, is downregulated when mature B cells differentiate into antibody-secreting PC. NFκB signaling can be activated by many factors in the bone marrow microenvironment and/or induced by genetic lesions in MM PC. We used the novel signal transduction pathway activity (STA) computational model to quantify the functional NFκB pathway output in primary MM PC from diverse patient subsets at multiple stages of disease. We found that NFκB pathway activity is not altered during disease development, is irrespective of patient prognosis, and does not predict therapy outcome. However, disease relapse after treatment resulted in increased NFκB pathway activity in surviving MM PC, which correlated with increased BCL2A1 expression in a subset of patients. This suggests that BFL-1 upregulation, in addition to BCL-XL and BCL-2, may render MM PC resistant to therapy-induced apoptosis, and that BFL-1 targeting could provide a new approach to reduce therapy resistance in a subset of relapsed/refractory MM patients. [ABSTRACT FROM AUTHOR]