Daratumumab Approved in Europe for Multiple Myeloma


The European Commission has granted conditional marketing approval to daratumumab (Darzalex) for the treatment of patients with relapsed/refractory multiple myeloma previously treated with a proteasome inhibitor and an immunomodulatory agent who progressed on their last therapy.

Jan van de Winkel, PhD

The European Commission has granted conditional marketing approval to daratumumab (Darzalex) for the treatment of patients with relapsed/refractory multiple myeloma previously treated with a proteasome inhibitor and an immunomodulatory agent (IMiD) who progressed on their last therapy, according to Genmab, which is developing the CD38-targeted monoclonal antibody with Janssen Biotech.

The approval—which was based on data from the phase II SIRIUS MMY2002 study,1 the phase I/II GEN501 study,2 and 3 other supportive studies—is contingent on results from confirmatory trials.

A combined analysis3 from the MMY2002 and GEN501 trials found that at a mean follow-up of 14.8 months, the estimated median overall survival was 20 months (95% CI, 15 months — not yet estimable) with daratumumab (16 mg/kg) monotherapy in heavily pretreated patients with myeloma. The overall response rate (ORR) in this population was 31% and 83% of patients achieved at least stable disease.

“At Genmab we are driven by a desire to improve the quality of life for cancer patients and their families. The approval of the marketing application for Darzalex provides the opportunity to do just that for multiple myeloma patients living in the EU and represents a landmark event for these patients and their families, as well as for Genmab and Janssen,” said Jan van de Winkel, PhD, CEO of Genmab.

In the MMY2002 study, the first 34 patients enrolled received daratumumab at 16 mg/kg (n = 16) or 8 mg/kg (n = 18). After a response evaluation, the 16 mg/kg dose was selected for future study, with an additional 90 patients enrolled at this dose.

Patients in the trial had received a median of 5 prior therapies over a median of 4.8 years following diagnosis. Ninety-six percent of patients were refractory to their last treatment, including proteasome inhibitors and IMiDs.

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).

The GEN501 study contained 2 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. Patients who received daratumumab at 16 mg/kg experienced an ORR of 36%, which included 2 CRs and 2 VGPRs.

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

In a pooled analysis from 3 clinical trials, the adverse events (AEs) with single-agent daratumumab were manageable, according to Genmab. AEs occurring in ≥20% of patients included infusion-related reactions (IRRs), fatigue, pyrexia, cough, nausea, back pain, upper respiratory tract infection, anemia, neutropenia, and thrombocytopenia.

Discontinuations due to AEs were reported for 4% of patients; however, none of the discontinuations were considered treatment-related. About half of the patients receiving daratumumab had infusion-related reactions, 91% of which occurred during the initial infusion. Severe IRRs included bronchospasm, hypertension, and hypoxia.

Daratumumab is a fully human monoclonal antibody that binds to glycoprotein CD38. Once bound, the antibody interacts with natural killer cells by mimicking the normal interaction between CD38 and CD31. This interaction elicits antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity resulting in antitumor activity.

The FDA granted daratumumab an accelerated approval in November 2015 as a monotherapy for patients with multiple myeloma following at least 3 prior therapies. The indication is specifically for patients following progression on a proteasome inhibitor and an IMiD or for those who are double refractory to a proteasome inhibitor and an IMiD. A full indication for daratumumab in the United States is contingent on the results of ongoing confirmatory studies.


  1. Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomized, phase 2 trial. Lancet. 2016;387(10027):1551-1560.
  2. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373(13):1207-1219.
  3. Usmani S, Weiss B, Bahlis NJ, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2015;126(23):abstract 29.
Related Videos
S. Vincent Rajkumar, MD
Muhamed Baljevic, MD
Sundar Jagannath, MBBS
Sundar Jagannath, MBBS
James Ignatz-Hoover, MD, PhD
Sundar Jagannath, MBBS
Elias Jabbour, MD
Joseph G. Jurcic, MD
Krina K. Patel, MD, MSc
Minoo Battiwalla, MD