Overall, our data showed that a crowded 3D microenvironment i) makes visible the paracrine bi-directional crosstalk between HS-5 stromal and MM.1S myeloma cells, ii) suggests that cell-to scaffold interactions exert a negative effect on the amplitude of NF-κB responses in both myeloma and stromal cells; iii) highlights that about 30% of MM.1S myeloma cells are extremely sensitive to molecules secreted by IL-1β-activated HS-5 stromal cells, iv) suggests that IL-1β is a key mediator in the crosstalk between HS-5 and MM.1S cells in our MM models, and potentially in MM patients. Here, IL1B is linked to plasma cell myeloma.