The Revised International Staging System (R-ISS) is a simple and powerful prognostic tool for multiple myeloma (MM). However, heterogeneity in R-ISS stage is still poorly characterised, hampering improvement of treatments. We used single-cell RNA-seq to examine novel cellular heterogeneity and regular networks in nine MM patients stratified by R-ISS. Plasma cells were clustered into nine groups (P1-P9) based on gene expression, where P1-P5 were almost enriched in stage III.PDIA6 was significantly upregulated in P3 and LETM1 was enriched in P1, and they were validated to be upregulated in the MM cell line and in 22 other patients' myeloma cells. Furthermore, in progression, PDIA6 was newly found and verified to be activated by UQCRB through oxidative phosphorylation, while LETM1 was activated by STAT1 via the C-type lectin receptor-signalling pathway. Finally, a subcluster of monocytes was exclusively found in stage III specifically expressed chemokines modulated by ATF3. A few ligand-receptor pairs (CCL3/CCL5/CCL3L1-CCR1) were obviously active in monocyte-plasma communications in stage III. Herein, this study identified novel molecules, networks and crosstalk pairs in different R-ISS stages of MM, providing significant insight for its prognosis and treatment.© 2022. Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature.