Carfilzomib (CFZ) is a second-generation proteasome inhibitor approved for treating relapsed/refractory multiple myeloma (MM). The clinical formulation utilizing sulfobutylether-beta-cyclodextrin to solubilize CFZ (Captisol, CFZ-CD) shows, however, short circulation time, lack of cell selectivity, and unmet antitumor efficacy. Here, we designed and prepared A6 peptide (sequence: KPSSPPEE)-tagged core-disulfide-cross-linked biodegradable micelles (A6-PMs) for targeted CFZ therapy of CD44-overexpressing LP-1 human MM in vivo. A6-PMs had a small size of about 40 nm and stable CFZ encapsulation. CFZ-loaded micelles (CFZ-A6-PMs) showed a glutathione-triggered drug release profile with negligible drug leakage under physiological conditions. CFZ-A6-PMs displayed good proteasome activity inhibition and more potent apoptotic activity than CFZ-CD and nontargeted CFZ-PMs toward LP-1 MM cells in vitro. The in vivo fluorescence images revealed that Cy5-labeled A6-PMs induced much higher tumor accumulation than the nontargeted Cy5-labeled PMs controL The systemic administration of CFZ-A6-PMs to subcutaneous LP-1 xenografts in mice brought about notably more potent tumor suppression, higher survival rate and lower systemic toxicities than clinically used CFZ-CD formulation. These A6-tagged core-disulfide-crosslinked micelles appear interesting for targeted delivery of proteasome inhibitors to CD44(+) MM.