ASH Clinical News Hematology Pipeline Update: Drug Updates from the | Page 18

MYELOMA

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 3). 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
TABLE 3. Response Rates for Daratumumab Plus Lenalidomide

and Dexamethasone
N=32
Overall response rate (sCR+CR+VGPR+PR)

n (%)

95% CI

26 (81)

63.6-92.8

8 (25)

11.5-43.4

Best response
sCR
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

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Hematology Pipeline Update

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.”

Reference
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.