The transferrin receptor 1 (TfR1) is a meaningful target for antibody-based cancer therapy given its overexpression on malignant cells and its central role in cancer pathology. We previously developed a mouse/human chimeric IgG3 targeting human TfR1 (ch128.1), which exhibits significant antitumor activity against multiple myeloma (MM) in xenograft models of SCID-Beige mice bearing disseminated ARH-77 or KMS-11 tumors. This activity is observed in early and late disease stages of disseminated KMS-11 tumors and, in this model, the mechanism of antitumor activity is Fc-mediated, involving macrophages. As human IgG1 is the isotype of choice for therapeutic antibodies targeting malignant cells and has several advantages compared with IgG3, including established manufacturability, we now developed an IgG1 version of ch128.1. A single dose of ch128.1/IgG1 shows significant antitumor activity, not only against early and late stages of disseminated KMS-11 tumors (Asian origin) but also against these stages of disseminated disease following injection of human MM cells MM.1S (African American origin) or its variant that is resistant to dexamethasone MM.1R. Treatment with the Fc mutant version of ch128.1/IgG1 (L234A/L235A/P329S) with impaired effector functions fails to confer protection against MM.1S and MM.1R tumors, indicating a crucial role of the Fc fragment in the antitumor activity, similar to its IgG3 counterpart. In fact, we found that ch128.1/IgG1, but not the mutant, elicits antibody-dependent cell-mediated cytotoxicity and antibody-dependent cell-mediated phagocytosis in the presence of murine bone marrow-derived macrophages. Our results suggest that ch128.1/IgG1 is a promising therapeutic against human B-cell malignancies such as MM.