Sevilla‐Movilla S, Arellano‐Sánchez N, Martínez‐Moreno M, et al. - Multiple myeloma (MM) cell retention, survival, and resistance to different anti‐MM agents, including proteasome inhibitors (PIs) such as bortezomib (BTZ), improve in correlation with the interaction of MM cells with the bone marrow (BM) microenvironment. BTZ downregulates the expression and function α4β1 integrin, a main adhesion receptor mediating MM cell–stroma interactions and MM cell survival, resulting in inhibition of cell adhesion‐mediated drug resistance (CAM‐DR) and MM cell apoptosis. Researchers here examined whether reduced α4β1 expression and activity are maintained or recovered upon development of resistance to BTZ, as a potential rescue of α4β1 function could boost MM cell survival and disease progression. Using BTZ‐resistant MM cells, it was identified that they rescued their α4β1 expression as well as the expression levels were higher than in parental cells. In resistant cells, raised α4β1 expression linked with increased α4β1‐mediated cell lodging in the BM, and with disease progression. Data emphasize that during resistance to BTZ in MM, the upregulation of α4β1 expression and function represents a key event, which might indirectly attribute to stabilize this resistance, as stronger MM cell attachment to BM stroma will regain CAM‐DR and MM cell growth and survival. Ultimately, a strong correlation was observed between high ITGB1 (integrin β1) expression in MM and poor progression‐free survival (PFS) and overall survival (OS) during management of MM patients with BTZ and IMIDs, and combination of high ITGB1 levels and presence of the high‐risk genetic factor amp1q results in low PFS and OS. Results here reveal a novel prognostic value for ITGB1 in myeloma.