A masked immunocytokine (MIC) comprised of an immunoglobulin G1 (IgG1) antibody against the tumor-associated antigen (TAA) syndecan-1 (CD138) that is fused to the human cytokine interferon alpha (IFNalpha; IFN-alpha; IFNa) which is attached by a tumor-protease cleavable linker to a peptide mask, with potential immunomodulating and antineoplastic activities. Upon administration, the anti-CD138 antibody-IFNalpha fusion protein QXL138AM targets and binds to CD138 expressed on tumor cells. In turn, the proteases on the cell surface cleave the linker and remove the peptide mask from IFNalpha, thereby enabling IFNalpha to attach to its IFN cell-surface receptor on tumor cells and immune cells within the tumor microenvironment (TME). This initiates direct tumor cell destruction through IFNalpha-induced apoptosis and activates IFN-mediated signal transduction pathways and induces the transcription and translation of genes with interferon-stimulated response elements (ISREs), which activates both innate and adaptive anti-tumor immunity. Syndecan-1, a type 1 transmembrane proteoglycan, is overexpressed in a variety of cancer cells and plays a key role in the regulation of cell growth. The selective activation in the TME enhances the IFN-alpha-mediated cytolytic effect and immune responses against tumor cells while sparing the unwanted effects of systemic immune activation while in circulation.