The acquired resistance to bortezomib represents a major obstacle for multiple myeloma (MM) treatment. Studies revealed that the treatment with cyclic adenosine monophosphate (cAMP) may be a promising strategy for MM therapy. Therefore, the present study aimed to explore the mechanism of action of cAMP in MM cells. Our results showed that 8-CPT-cAMP and bortezomib synergistically induced growth inhibition and apoptosis in MM bortezomib-resistant cell lines and primary MM cells, in which protein kinase A (PKA) activation was involved. Furthermore, 8-CPT-cAMP induced the degradation of cyclinD1 and downregulation of myeloid cell leukemia-1 (Mcl-1). Moreover, 8-CPT-cAMP enhanced endoplasmic reticulum stress caused by bortezomib. A synergy between bortezomib and cAMP was also revealed in a murine MOPC315 xenograft model, which was evidenced by the significantly inhibited tumor growth and the improved multiple cancer-related parameters by the combination of the cAMP-elevating compound forskolin and bortezomib. Taken together, this study suggests that the treatment with cAMP may be a promising strategy for enhancing the therapeutic efficacy of bortezomib in MM treatment.