Multiple myeloma (MM) is a malignant, heterogeneous, and incurable hematological neoplasm [1]. It is characterized by the uncontrolled proliferation of malignant plasma cell clones in the microenvironment of the bone marrow (BM), with the production of anomalous monoclonal immunoglobulins present in the blood or urine, and which is associated with organ dysfunction and infections [2], [3].

MM represents 1 % of all cancers, and is the second most common hematological cancer worldwide after lymphoma. In 2022, more than 35,000 patients with MM were diagnosed in the globe [2], [3], [4]. It is more common in men than in women, being twice as frequent in the African-American population, with a median age at diagnosis of approximately 65 years. The 5-year survival rate is estimated to vary from about 50–80 %, depending on disease spreading [5], [6], [7]. Therefore, MM is characterized by a significant death rate, and the mechanisms enrolled are not elucidated.

Despite slow growth in most cases, MM has an incurable profile characterized by episodes of remission, which can lead patients to death at different moments. Therefore, there is a need for search markers to understand why some individuals die very fast, and others live for an extended period after BM transplantation. In this context, the medullary microenvironment has been one of the main focuses of interest in understanding the pathogenesis of MM [8], [9], [10].

The pathophysiology of MM is complex and involves numerous markers of the inflammatory response in the medullary niche. BM stem cells are under the modulatory effect of cytokines and growth factors that are crucial to allow malignant plasmocytes to proliferate and survive by activating fundamental signaling pathways [11], [12], [13]. Although some evidence connects these mediators to clinical aspects of MM, little is known about which markers are related to the reduced survival of patients [14], [15], [16].

In recent years, the transcriptomic-based analysis of MM has provided pivotal information concerning disease characterization, including targets for first-choice treatment [17], disease functional risk [18], predicted risk values [19], immune microenvironment profling, chemoresistance [20], and disease dissemination [21]. Despite these advances, little is known concerning the differential gene profile from hematopoietic stem cells when considering the survival outcome of MM patients. In this context, the present study evaluated the genomic profile of non-transplanted stem cells from patients with MM by comparing patients who died and those who survived longer (at least six months after transplantation). To answer this question, we used a transcriptomic analysis in association with bioinformatics tools to screen the main pathways associated with the outcomes and further validated some selected genes and pathways to address their clinical meaning in the survival context.