SSTN_IV, a syndecan-1-targeting peptide chimera, reverses immune suppression and inhibits myeloma progression

Despite therapeutic advances, multiple myeloma (MM) remains incurable, largely due to relapse and the emergence of drug resistance driven by clonal evolution and alterations in the bone marrow (BM) microenvironment that support tumor survival. This highlights the need for novel therapeutics targeting both tumor cells and the supportive BM niche, particularly for patients with relapsed/refractory MM. Syndecan-1 (Sdc1/CD138), a heparan sulfate proteoglycan, is abundantly expressed on both the surface of myeloma cells and within the MM microenvironment. It plays a critical role in MM pathogenesis by promoting cell survival, angiogenesis, and immune evasion. This study investigates a novel chimeric peptide, SSTN_IV, which disrupts Sdc1-mediated mechanisms to inhibit MM progression. Using murine VQ models of advanced MM, we evaluated the effects of SSTN_IV on tumor growth, metastasis, and the tumor microenvironment. Our results demonstrate that SSTN_IV effectively inhibits MM cell invasion, induces apoptosis, and reverses immune suppression in vitro. Importantly, in VQ mice, SSTN_IV significantly prolonged survival, reduced tumor burden, and improved BM cellularity. When combined with the frontline MM chemotherapy agent bortezomib, SSTN_IV conferred the greatest survival benefit, substantially reducing MM cells in BM, alleviating extramedullary disease, and restoring hematopoiesis. Furthermore, human BM microarray analysis using proximity ligation assay confirmed that Sdc1 forms complexes with receptor tyrosine kinases and integrins in human MM tumors targeted by SSTN_IV, but not in normal BM. These findings highlight SSTN_IV's potent anti-myeloma activity and support its potential as a promising therapeutic strategy for advanced and relapsed/refractory MM.