Meletios A. Dimopoulos, MD
Combining the CD38-targeted antibody daratumumab (Darzalex) with lenalidomide (Revlimid) and dexamethasone reduced the risk of disease progression by 63% versus lenalidomide and dexamethasone alone in patients with relapsed/refractory multiple myeloma, according to findings from the phase III POLLUX (MMY3003) trial.
“The combination of daratumumab and lenalidomide/dexamethasone potentially represents a new standard of care for relapsed or refractory multiple myeloma patients with at least 1 prior treatment,” lead author Meletios A. Dimopoulos, MD, National and Kapodistrian University of Athens, Greece, said when presenting the results at the 2016 European Hematology Association Congress.
This is the second phase III trial to demonstrate a progression-free survival (PFS) benefit with a daratumumab triplet in relapsed/refractory multiple myeloma. Data recently reported at the 2016 ASCO Annual Meeting showed that adding daratumumab to bortezomib (Velcade) and dexamethasone in the phase III CASTOR trial reduced the risk of progression by 61% (HR, 0.39; P
The phase III international, open-label POLLUX trial randomized 569 patients with relapsed/refractory multiple myeloma to daratumumab combined with lenalidomide/dexamethasone (n = 286) or lenalidomide plus dexamethasone alone (n = 283). Daratumumab was dosed at 16 mg/kg IV once weekly during cycles 1 and 2, every 2 weeks during cycles 3 to 6, and once only (on day 1) of cycles 7 onward. Oral lenalidomide was administered at 25 mg daily for the first 3 weeks of each cycle and dexamethasone was dosed at 40 mg weekly (20 mg weekly in patients older than 75 or with a BMI <8.5). Treatment cycles for both study arms were 28 days. Patients were treated until progression or unacceptable toxicity.
The median patient age was 65 years. The median number of of prior treatment lines was 1, with 19% of patients having received ≥3 lines of therapy. Eighty-six percent of patients had received a proteasome inhibitor; 55% had been treated with an immunomodulatory agent (IMiD), including 18% with lenalidomide; and 44% had previously receiving both a proteasome inhibitor and an IMiD. Across the study population, 27% of patients were refractory to their most recent treatment and 18% were refractory to a proteasome inhibitor; however, no patients were refractory to lenalidomide.
The primary endpoint of the study was PFS, with secondary outcome measures including time to progression, overall response rate (ORR), overall survival, and very good partial response (VGPR). At a preplanned interim analysis in May 2016, the study was unblinded after an independent panel determined the trial met its primary endpoint of improved PFS. Patients in the control arm were allowed to receive daratumumab at progression.
At a median follow-up of 13.5 months, the median PFS was not yet reached in the daratumumab arm versus 18.4 months with lenalidomide/dexamethasone alone (HR, 0.37; 95% CI, 0.27-0.52; P
<.0001). The ORR was 93% versus 76%, respectively, P
<.0001. The VGPR or better rate was 76% with daratumumab versus 44% in the control arm (P
<.0001) and the compete response rates were 43% and 19%, respectively (P
The safety profile was consistent with previously report adverse events (AEs) for single-agent daratumumab and the combination of lenalidomide and dexamethasone. The most common all-grade AEs included neutropenia (59% with the daratumumab triplet vs 43% in the control arm), diarrhea (43% vs 25%), fatigue (35% vs 28%), upper respiratory tract infection (32% vs 21%), anemia (31% vs 35%), constipation (29% vs 25%), cough (29% vs 13%), thrombocytopenia (27% each), and muscle spasms (26% vs 19%).
Infusion reactions related to daratumumab were reported in 48% of patients and were mostly grade 1/2, with 5% experiencing grade 3. Ninety-two percent of these reactions occurred during the initial infusion.
The most common grade 3/4 AEs were neutropenia (52% in the daratumumab arm vs 37% in the control arm), thrombocytopenia (13% vs 14%), and anemia (12% vs 20%). Grade 3/4 infections occurred in 28% of patients receiving daratumumab compared with 23% of patients in the control arm. The most common grade 3/4 infection was pneumonia, which occurred in 8% of patients in each arm. Discontinuation rates due to AEs occurred in 7% and 8% of patients in the 2 arms, respectively.
“Together with findings from the MMY3004 CASTOR trial presented at the American Society of Clinical Oncology Annual Meeting last week, these twin studies help pave the way for the future of daratumumab as a foundational therapy in combination with either of the 2 most widely used classes of therapy,” Peter F. Lebowitz, MD, PhD, global oncology head at Janssen, which is developing daratumumab with Genmab, said in a statement.
In November 2015, the FDA granted an accelerated approval to daratumumab as a monotherapy for patients who have relapsed after ≥3 prior lines including a proteasome inhibitor and an IMiD or who are double-refractory to those therapies. In May 2016, the European Commission granted conditional marketing approval to daratumumab for the treatment of patients with relapsed/refractory multiple myeloma previously treated with a proteasome inhibitor and an IMiD who progressed on their last therapy.
Dimopoulos MA , Oriol A, Nahi H, et al. An open-label, randomised phase 3 study of daratumumab, lenalidomide, and dexamethasone (DRd) versus lenalidomide and dexamethasone (Rd) in relapsed or refractory multiple myeloma (RRMM): POLLUX. Presented at: 2016 European Hematology Association Congress; June 9-12, 2016; Copenhagen, Denmark. Abstract LB2238.
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