The relationship of Exosomal RNAs released within the bone marrow microenvironment and Prognosis of patients with multiple myeloma has not been thoroughly studied. This study aims to evaluate which exosomal RNAs can prompt the prognosis of patients with multiple myeloma. Exosomes were isolated from the bone marrow fluid of patients with good treatment effect or not. Then they were characterized by dynamic light scattering, transmission electron microscopy, and Western blot analysis. The isolated exosomes stimulate PRMI8226 cells, observe the migration ability and proliferation ability of PRMI8226 cells. Then we performed exosome miRNA sequencing, performed bioinformatics analysis of differential miRNAs, and evaluated several miRNAs that may affect the treatment effect. To determine the actual value of these miRNAs in clinical applications, we collected a collection of clinical samples for verification. We found that bone marrow-derived exosomes from patients with different therapeutic effects have different effects on PRMI8226 cells. Exosomes with a poor prognosis can promote the proliferation and migration of PRMI8226 cells, while exosomes with a good prognosis have no impact on PRMI8226 cells. The miRNA sequencing results showed differentially expressed miRNAs in exosomes from different sources. These differential miRNAs can be enriched in pathways related to cancer development. Validation in clinical specimens found that exosomal mir-124-3p are highly expressed in patients with poor therapeutic effects. This study suggested exosomal miRNA plays a vital role in the development and treatment of multiple myeloma. Some miRNAs that can promote tumor progression are highly expressed in bone marrow exosomes of patients with poor therapeutic effects, such as hsa-miR-124-3p, hsa-miR-451b, hsa-miR-509-3p. Among them, hsa-miR-124-3 is promising as a predictor of therapeutic effect.