Daratumumab Combination Produces Durable Responses in Patients with RRMM

The anti-CD38 monoclonal antibody daratumumab produces durable responses when used in combination with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM), according to recent findings of the GEN503 trial presented at the 2015 ASH Annual Meeting. The combination also demonstrated a favorable risk-benefit profile, lead investigator Torben Plesner, MD, Vejle Hospital in Vejle, Denmark, noted in his presentation of the results.

Daratumumab monotherapy was recently approved by the U.S. Food and Drug Administration as the first targeted antibody therapy for MM.

The GEN503 study takes the drug a step further by combining it with lenalidomide and dexamethasone (DARA+LEN+DEX) in patients with RRMM.

The ongoing, open-label, phase I/II GEN503 trial consisted of two parts:

  • A dose-escalation study in which daratumumab was given at 2 mg/kg to 16 mg/kg plus lenalidomide and dexamethasone
  • A cohort expansion study using the recommended phase II dose (16 mg/kg) plus lenalidomide and dexamethasone

In his presentation, Dr. Plesner focused on the cohort expansion study, in which 32 patients were given weekly 16 mg/kg doses of daratumumab for two 28-day cycles, followed by every-other-week dosing for cycles three through six. Dexamethasone was then administered monthly starting in cycle seven and continued until disease progression or unacceptable toxicity.

Patients also received 25 mg doses of lenalidomide on days one through 21 of each cycle and weekly 40 mg doses of dexamethasone.

The 32 patients in this cohort were treated with a median of two prior lines of therapy (range = 1-3); 11 patients (34%) received prior lenalidomide therapy.

The overall response rate (ORR) was 81 percent, with just over one-third (34 percent) achieving a complete response (TABLE). Taken together, this led to a clinical benefit rate (ORR + minimal response) of 88 percent. Additionally, for 61 percent of the 28 patients who responded to treatment, the responses deepened over time.

“The responses were durable, and they occurred rapidly,” Dr. Plesner said during a press conference discussing the results. “The median time to first response was one month and, with time, the responses improved. The median time to best response was 5.1 months.”

The progression-free survival (PFS) data were also encouraging, he added. “We have not yet reached the median PFS. At 18 months, we have a PFS rate of 72 percent,” Dr. Plesner reported. The overall survival (OS) rate was “impressive,” he noted, with an OS of 90 percent at 18 months.

The drug combination also appeared to be safe. The most common treatment-related adverse event (AE) experienced by patients taking the daratumumab combination was neutropenia, which occurred in 81 percent of patients. Neutropenia was also the most commonly reported grade 3 or 4 treatment-related AE (75%), with other common AEs including muscle spasms (44%), cough (38%), diarrhea (34%), fatigue (28%), and hypertension (28%).

The majority of patients (56 percent; n=18) experienced infusion-related reactions (IRRs), mostly during the first cycle, and these were typically considered mild to moderate. The most frequent IRRs were:

  • Cough (25%)
  • Allergic rhinitis (9%)
  • Nausea (9%)
  • Vomiting (9%)
  • Dyspnea (6%)
  • Nasal congestion (6%)
  • Hypertension (6%)

Over a median follow-up of 15.6 months, 31 percent of patients had discontinued treatment due to disease progression (n=5), treatment-related AEs (n=3), or physician decision (n=2).
Dr. Plesner and colleagues concluded that even after a longer follow-up period, adding daratumumab to standard MM regimens produced rapid, deep, and durable responses without demonstrating any new safety concerns. “Our next step is to continue the work that has been initiated by testing daratumumab in phase III trials for relapsed and refractory myeloma and as part of a first-line treatment for myeloma,” Dr. Plesner said. “It is my hope and expectation that the results of the trials will show significant benefit of adding daratumumab to our treatment programs in these settings.”


Plesner T, Arkenau HT, Gimsing P, et al. Daratumumab in combination with lenalidomide and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: updated results of a phase 1/2 study (GEN503). Abstract #507. Presented at the 2015 ASH Annual Meeting, December 7, 2015; Orlando, Florida.

TABLE. Response Rates for Daratumumab Plus Lenalidomide and Dexamethasone
n (%) 95% CI
Overall response rate (sCR+CR+VGPR+PR) 26 (81) 63.6-92.8
Best response
sCR 8 (25) 11.5-43.4
CR 3 (9) 2.0-25.0
VGPR 9 (28) 13.7-46.7
PR 6 (19) 7.2-36.4
VGPR or better (sCR+CR+VGPR) 20 (63) 43.7-78.9
CR or better (sCR+PR) 11 (34) 18.6-53.2
CI=confidence interval; sCR=stringent complete response; CR=complete response; VGPR=very good partial response; PR=partial response