XmAb5592 strongly inhibits growth of established myeloma tumors in vivo and eradicates tumors in mice. The in vivo anti-myeloma activity of XmAb5592 was determined in a therapeutic setting using a xenograft model of human RPMI8226 MM cells. (A) SCID mice with palpable RPMI8226 tumors (30-92 mm³) were randomized into groups (n = 11), and then treated with vehicle (PBS) or 0.3, 3 or 9 mg/kg of XmAb5592, twice weekly for 7 doses (↓) by intraperitoneal injection. Tumor growth is presented as group mean volume ± SD. A dose dependent anti-tumor effect is evident (day 41 MTV = 484, 159 and 123 mm³ for 0.3, 3 and 9 mg/kg, respectively; P ≤ .001 for both 0.9 vs 3 mg/kg and 0.9 vs 9 mg/kg). (B) Antitumor activity of XmAb5592, anti-HM1.24 IgG1, or anti-HM1.24 Fc-KO was compared in vivo, at 9 mg/kg (n = 15). XmAb5592 is significantly more effective at blocking tumor growth compared with the IgG1 analog (day 46 MTV = 47 and 192 mm³, respectively, P ≤ .001). In addition, on day 46 there were 7 tumor-free mice in the XmAb5592-treated group and only 1 tumor-free mouse in the anti-HM1.24 IgG1-treated group. The anti-HM1.24 Fc-KO shows no antitumor activity, indicating the importance of FcγR engagement. Data are mean ± SD.