TAS-102/Lonsurf is a new oral anti-tumor drug consisting of trifluridine and 
tipiracil in a 1:0.5 molar ratio. Lonsurf has been approved globally, including 
US, Europe Union, and China, to treat patients with advanced colorectal cancer. 
Ongoing clinical trials are currently conducted for the treatment of other solid 
cancers. However, the therapeutic potential of TAS-102 in hematological 
malignancies has not been explored. In this study, we investigate the 
therapeutic efficacy of TAS-102 in multiple myeloma both in vitro and in vivo. 
We demonstrate that TAS-102 treatment inhibits tumor cell proliferation in six 
human myeloma cell lines with IC50 values in a range from 0.64 to 9.10 μM. Dot 
blotting and immunofluorescent staining show that trifluridine is predominately 
incorporated into genomic DNAs of myeloma cells. TAS-102 treatment induces 
myeloma cell apoptosis through cell cycle arrest in G1 phase and activation of 
cGAS-STING signaling in myeloma cells. In the human myeloma xenograft models, 
TAS-102 treatment reduces tumor progression and prolongs mouse survival. TAS-102 
has shown its efficacies in the drug-resistant myeloma cells, and the 
combination of TAS-102 and bortezomib has a synergistic anti-myeloma activity. 
Our preclinical studies indicate that TAS-102 is a potential novel agent for 
myeloma therapy.