Daratumumab Granted Priority Review by the FDA for Multiple Myeloma

Daratumumab was recently assigned a priority review designation by the FDA as a treatment for patients who have multiple myeloma.

Craig L. Tendler, MD

Daratumumab was recently assigned a priority review designation by the FDA as a treatment for patients who have multiple myeloma either following at least 3 lines of therapy, which includes both a proteasome inhibitor and an immunomodulatory agent (IMiD), or in those who are double refractory to a proteasome inhibitor and an IMiD, according to Janssen Biotech, the anti-CD38 monoclonal antibody’s developer.

The priority review was based on data from the phase II MMY2002 (SIRIUS) study that were presented at the 2015 ASCO Annual Meeting.1In this trial, daratumumab demonstrated a 65% one-year overall survival (OS) rate and a 29.2% objective response rate (ORR) in heavily pretreated patients who have double refractory multiple myeloma.

The FDA plans to make a decision on the biologics license application for daratumumab within 6 months, placing a decision on March 9, 2016. The priority review follows a breakthrough therapy designation for daratumumab, which was granted by the FDA in May 2013.

“Daratumumab has the potential to be the first anti-CD38 monoclonal antibody approved to treat multiple myeloma, offering these patients an important new treatment pathway,” said Craig L. Tendler, MD, vice president, Late Development and Global Medical Affairs, Oncology, Janssen, in a statement. “The FDA's acceptance of our application for daratumumab marks an important step for people affected by multiple myeloma. We look forward to working with the FDA during this priority review.”

In the pivotal phase II study, the first 34 patients enrolled were given daratumumab at 16 mg/kg (n = 16) or 8 mg/kg (n = 18). Following a response evaluation, the 16 mg/kg dose was selected for future study, with an additional 90 patients enrolled at this dose (N = 106).

Patients in the trial received a median of five prior therapies over a median of 4.8 years following diagnosis. Ninety-six percent of patients were refractory to their last treatment; this includes proteasome inhibitors and IMiD agents (95%).

Responses to daratumumab consisted of stringent complete responses (sCR; n = 3; 2.8%), very good partial responses (VGPR; n = 10; 9.4%), and partial responses (PR; n = 18; 17%). The median duration of response was 7.4 months. After a median follow-up of 9.4 months, 45.2% of patients remained on therapy. The median progression-free survival (PFS) was 3.7 months (95% CI, 2.8-4.6).

Infusion-related reactions (IRR) predominately occurred during the first infusion and were mostly grade 1/2 (all-grade 42.5%). Grade 3 IRRs were seen in 4.7% of patients; however, no grade 4 events occurred. No patients discontinued daratumumab as a result of an IRR.

The most common all-grade adverse events were fatigue (39.6%), anemia (33%), nausea (29.2%), thrombocytopenia (25.5%), back pain (22.6%), neutropenia (22.6%), and cough (20.8%). Overall, 4.7% of patients discontinued treatment due to adverse events. These side effects were not deemed to be associated with daratumumab.

In addition to data from the SIRIUS trial, the application included data from four other studies, including GEN501.2In this phase I/II study, patients who were given daratumumab at 16 mg/kg (n = 42) experienced an ORR of 36%, which included 2 CRs and 2 VGPRs. At this dose, the estimated median PFS was 5.6 months (95% CI, 4.2-8.1), and the one-year OS rate was 77% (95% CI, 58-88).

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 a one-year PFS rate of 65% (95% CI, 28-86).

“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, in a statement when the findings were published. “These findings speak to the potential of daratumumab as an option for patients with multiple myeloma who no longer respond to existing therapies.”

Several phase III clinical trials are looking at daratumumab in various treatment settings for patients with multiple myeloma, with 3 exploring the drug in the frontline setting. Janssen is responsible for commercialization and development of daratumumab, following an agreement with Genmab that was made in August 2012.

"We are pleased that the FDA has granted Priority Review for daratumumab in double refractory multiple myeloma," said Jan van de Winkel, PhD, chief executive officer of Genmab, in a statement. "If approved, daratumumab has the potential to make a real difference in the lives of people who have run out of other treatment options for multiple myeloma."


  1. 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).
  2. 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