H₂S is produced by cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS) or 3-mercaptopyruvate sulfurtransferase (3-MST) in mammals. To identify a role of H₂S in the survival of multiple myeloma (MM) cells, we evaluated effects of their inhibitors on human MM-derived KMS-11 and its bortezomib (BTZ)-resistant KMS-11/BTZ cells. Viability of KMS-11, but not KMS-11/BTZ, cells was reduced by BTZ in a range of 10-30 nM. Na₂S and GYY4173, H₂S donors, promoted proliferation of both KMS-11 and KMS-11/BTZ cells. Aminooxyacetic acid (AOAA), a CBS inhibitor, strongly suppressed cell viability in KMS-11 cells and KMS-11/BTZ cells, an effect partially reversed by GYY4173. On the other hand, inhibitors of CSE and 3-MST exhibited relatively weak cytotoxicity in those cells. Carbidopa and benserazide, known as aromatic L-amino acid decarboxylase inhibitors, reduced CBS activity, and markedly decreased cell viability in KMS-11 cells and KMS-11/BTZ cells. They also reduced phosphorylation levels of NF-κB p65 in KMS-11 cells. Our data suggest that the CBS/H₂S/NF-κB pathway plays a key role in the survival of both BTZ-sensitive and -resistant MM, and that carbidopa and benserazide could be seeds for the development of selective CBS inhibitors, possibly applicable to treatment of BTZ-resistant MM.