A CD38-targeting antibody has activity in patients with relapsed and refractory multiple myeloma.

  • Major finding: A CD38-targeting antibody has activity in patients with relapsed and refractory multiple myeloma.

  • Clinical relevance: Responders included those with disease refractory to bortezomib and lenalidomide.

  • Impact: Daratumumab may be a useful addition to the armamentarium of therapies for multiple myeloma.

Although proteasome inhibitors such as bortezomib and immunomodulatory agents such as lenalidomide have improved outcomes in patients with multiple myeloma, most patients eventually relapse. Patients whose disease is refractory to these therapies have limited treatment options and have an estimated median survival of only 9 months. The cell surface protein CD38 is highly and specifically expressed on myeloma cells, and preclinical studies have shown that the human monoclonal CD38-targeting antibody daratumumab can kill myeloma cells. Lokhorst and colleagues therefore initiated an open-label, multicenter phase 1-2 trial of daratumumab in patients with relapsed multiple myeloma that was refractory to two or more previous therapies, including proteasome inhibitors, immunomodulatory agents, chemotherapy, and autologous stem-cell transplantation. The two-part study included 32 patients enrolled in the dose-escalation phase and 72 patients enrolled in the dose-expansion phase, and several treatment schedules and infusion protocols were evaluated. The primary endpoint of the trial was to determine the safety of daratumumab monotherapy, and secondary endpoints included analysis of objective response rates, progression-free and overall survival, and pharmacokinetics. Daratumumab was generally well tolerated, and no maximum tolerated dose was determined. In the dose-expansion phase, the overall response rate among patients who received 8 mg/kg was 10%, with 3 partial responses, and 36% in those who received 16 mg/kg, with 11 partial responses, 2 very good partial responses, and 2 complete responses. The median progression-free survival was 2.4 months in the 8 mg/kg cohort and 5.6 months in the 16 mg/kg cohort, with 65% of responders in the 16 mg/kg cohort remaining progression-free at 12 months, and the 12-month overall survival was 77% in both cohorts. These results suggest that targeting CD38 may be an effective strategy for treating patients with relapsed and refractory multiple myeloma for whom other therapies have failed and support further evaluation of daratumumab in larger clinical studies.

Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med 2015 Aug 26 [Epub ahead of print].