In patients with multiple myeloma, the heparan sulfate proteoglycan syndecan-1 (CD138) is shed from the surface of tumor cells and accumulates in the serum and within the extracellular matrix of the bone marrow where it promotes tumor growth and metastasis. In the present study we discovered that commonly used anti-myeloma drugs stimulate syndecan-1 shedding both in vitro and in animals bearing myeloma tumors. Enhanced shedding is accompanied by increased syndecan-1 synthesis prior to drug induced tumor cell death. Addition of a caspase inhibitor blocks the drug-induced shedding of syndecan-1 in vitro indicating that shedding is linked to the onset of apoptosis. ADAM inhibitors or siRNA targeting ADAMs blocked drug-induced shedding suggesting that upregulation or activation of ADAMs is responsible for cleaving syndecan-1 from the tumor cell surface. These results reveal that myeloma chemotherapy stimulates synthesis and shedding of syndecan-1, a potentially negative side effect that may lead to the accumulation of high levels of syndecan-1 to establish a microenvironment that nurtures relapse and promotes tumor progression. Interestingly, we also found that chemotherapeutic drugs stimulated syndecan-1 shedding from pancreatic cancer cells as well, indicating that drug-induced shedding of syndecan-1 may occur in many cancer types. Overall, our results indicate that the use of metalloproteinase inhibitors (to inhibit syndecan-1 shedding) in combination with chemotherapy may represent a novel therapeutic strategy to prevent re-establishment of a microenvironment conducive for tumor relapse. © 2013 International Society of Matrix Biology.