Second Study Proves Daratumumab's Efficacy in Multiple Myeloma

Findings from a second phase II clinical trial have demonstrated impressive signs of clinical activity with the anti-CD38 monoclonal antibody daratumumab as a monotherapy for patients with heavily pretreated multiple myelom.

Henk M. Lokhorst, MD, PhD

Findings from a second phase II clinical trial have demonstrated impressive signs of clinical activity with the anti-CD38 monoclonal antibody daratumumab as a monotherapy for patients with heavily pretreated multiple myeloma, according to results published in The New England Journal of Medicine (NEJM).1

In patients who received daratumumab at 16 mg/kg (n = 42) in the phase I/II GEN501 study, the objective response rate was 36%, which included 2 complete responses (CR) and 2 very good partial responses (VGPR). At this same dose, the estimated median progression-free survival (PFS) was 5.6 months (95% CI, 4.2-8.1) and the overall survival (OS) rate at 12 months was 77% (95% CI, 58-88).

“What is impressive about this study is that daratumumab monotherapy induced durable responses that improved or deepened over time, and 65% of responding patients remained in remission at 12 months,” said lead author Henk M. Lokhorst, MD, PhD, Department of Haematology, VU University Medical Center, Amsterdam, Netherlands, said in a statement. “These findings speak to the potential of daratumumab as an option for patients with multiple myeloma who no longer respond to existing therapies.”

These findings add to results on single-agent daratumumab that were presented from the phase II MMY2002 (SIRIUS) study at the 2015 ASCO Annual Meeting.2 In this 106-patient trial, daratumumab at 16 mg/kg demonstrated an ORR of 29%, with a stringent CR rate of 3%. The median duration of response was 7.4 months and the median PFS was 3.7 months (95% CI, 2.8-4.6). The 1-year OS rate was 65% (95% CI, 51.2-75.5).

Based on these findings, the developer of the antibody, Janssen Biotech, initiated a rolling submission of data to the FDA, as part of a breakthrough therapy designation received in May 2013. This application, which was specifically for the treatment of patients with multiple myeloma who had received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or who were double refractory to a proteasome inhibitor and an immunomodulatory drug, was completed on July 9, 2015.

In addition to data from the SIRIUS trial, the application also included data from four other studies, including GEN501. Under the Prescription Drug User Fee Act, the FDA is scheduled to assign a review timeline for daratumumab by September 9, 2015.

“Our hope is that daratumumab will offer a new treatment for patients with multiple myeloma who are greatly in need of new options,” Peter F. Lebowitz, MD, PhD, Global Oncology Head, Janssen, said in a statement. “We are confident in our comprehensive development plan for daratumumab, which includes studying the medicine in earlier lines of therapy, both as a single agent and in combination with existing therapies.”

The phase I/II GEN501 study contained two parts. In the first, 32 patients were treated with daratumumab at various doses, in order to find a recommended dose and schedule. In the second phase of the trial, 72 patients received daratumumab at either 8 mg/kg (n = 30) or 16 mg/kg (n = 42). In each group, patients had received a median of 4 prior therapies.

The median follow-up was 16.9 months in the 8-mg/kg group and 10.2 months in the 16 mg/kg arm. In January 2015, all patients in the 8 mg/kg had discontinued due to progressive disease. In the 16 mg/kg arm, 28 patients had discontinued therapy at the time of the analysis, for progressive disease (n = 23), physician decision (n = 4), and adverse events (n = 1; grade 5 pneumonia, unrelated to study drug).

ORR was higher in less heavily pretreated patients, at 56% for those who received 2 or 3 prior lines of therapy compared with 23% in a more heavily pretreated population. The estimated median duration of response in the 8 mg/kg arm was 6.9 months (95% CI, 6.2-10.6). In the 16 mg/kg arm, a median duration of response was not yet reached, with 65% of responding patients remaining progression-free at 12 months (95% CI, 28-86).

The most frequently occurring all-grade adverse events (AEs) with daratumumab were fatigue, allergic rhinitis, and pyrexia. Grade 3/4 AEs occurred in 26% of patients in the 16 mg/kg arm of the study and in 53% of those treated with the 8 mg/kg dose. Serious AEs occurred in 40% and 33% of patients in the 8 and 16 mg/kg arms, respectively. Infusion-related reactions occurred in 71% of the patients.

“As a single-agent therapy, daratumumab showed significant promise against difficult-to-treat disease in our patients with advanced myeloma and who have few other therapeutic options,” senior author Paul Richardson, MD, clinical program leader and director of clinical research at the Dana-Farber Cancer Institute, said in a statement. “Because it targets a key receptor and works through different mechanisms than other available agents, it clearly has merited comprehensive testing in larger clinical trials. Preliminary results from these studies have been very encouraging.”

Janssen, following an agreement with Genmab that was made in August 2012, is developing daratumumab in the United States. If approved, Janssen will also be responsible for commercialization and marketing of the CD38 inhibitor.

“Patients who have relapsed or refractory multiple myeloma currently have very limited treatment options," Jan van de Winkel, PhD, chief executive officer of Genmab, said in a statement. "The results from this first-in-human study of daratumumab, presented in full in The NEJM, show an impressive response rate and duration of response, particularly when you consider that patients in the study had received a large number of prior treatments.”

At this time, several phase III clinical trials are looking at daratumumab in various treatment settings for patients with multiple myeloma. These studies are exploring the antibody in combination with standard therapies, with 3 exploring the drug in the frontline setting.


  1. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma [published online August 26, 2015]. N Engl J Med. doi: 10.1056/NEJMoa1506348
  2. Lonial S, Weiss BM, Usmani SZ, et al. Phase II study of daratumumab (DARA) monotherapy in patients with ≥ 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius). J Clin Oncol. 2015;33 (suppl; abstr LBA8512).