Multiple myeloma (MM) is the second most common hematologic malignancy. Bortezomib (BOR), a first-generation proteasome inhibitor, is the basic agent for the treatment of MM and has greatly improved the survival of patients with MM. However, the side effects of BOR (e.g. peripheral neuropathy) occur frequently and almost all MM patients eventually develop resistance to BOR and go on to develop refractory relapsed multiple myeloma (RRMM). Therefore, it is of great significance to find a method to increase the sensitivity of MM to BOR to reduce toxicity and drug resistance. Herein, we found that calcium silicate (CS), a silicate bioceramic that releases Si ions (SIs), enhanced the BOR anti-myeloma effect in vitro in human myeloma cell lines (HMCLs), including BOR-resistant cell lines (U266/BOR). The enhanced anti-myeloma effect of these two agents was demonstrated in primary MM cells regardless of disease status and in MM xenograft mice. Mechanistically, SI enhanced G2/M cell cycle arrest and the inhibition of the NF-κB pathway induced by BOR. These results imply that the combination of SI and BOR (SI/BOR) is a promising way to overcome BOR resistance in MM and RRMM. The future use of nanotechnology to prepare CS nanomaterials as BOR carriers for the treatment of MM and RRMM is a very promising clinical application.