Jan van de Winkel, PhD
Adding daratumumab (Darzalex) to lenalidomide and dexamethasone reduced the risk of disease progression by 63% in patients with relapsed/refractory multiple myeloma in the phase III POLLUX trial, according to Genmab, which is developing the CD38-targeted monoclonal antibody with Janssen Biotech.
At a preplanned analysis, an independent monitoring panel recommended unblinding the study and allowing patients in the control arm to receive single-agent daratumumab at progression. Janssen, which licensed daratumumab from Genmab in 2012, plans to discuss these findings and the potential for a new indication with regulatory authorities.
This is the second phase III trial to demonstrate a progression-free survival (PFS) benefit with a daratumumab triplet in relapsed/refractory multiple myeloma. Genmab previously reported 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 POLLUX study is the second key phase III study of daratumumab to meet the primary endpoint at a preplanned interim analysis and demonstrates a favorable benefit-risk ratio. We have now seen that daratumumab can potentially be used to effectively treat relapsed or refractory multiple myeloma in combination with either lenalidomide or bortezomib, two standard of care multiple myeloma treatments,” Jan van de Winkel, PhD, CEO of Genmab said in a statement.
POLLUX randomized 569 patients with relapsed/refractory multiple myeloma to daratumumab combined with lenalidomide/dexamethasone or lenalidomide plus dexamethasone alone. 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.
The primary endpoint of the study was PFS, with secondary outcome measures including overall response rate (ORR) and duration of response. 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
Adverse events (AEs) in the POLLUX trial were manageable, according to Genmab. The safety profile was consistent with outcomes previously reported from the ongoing phase I/II GEN503 trial, which examined both the combination of daratumuamb with lenalidomide/dexamethasone and daratumumab monotherapy.
Genmab and Janssen plan to submit the results for publication and hope to present the data at the 2016 European Hematology Association Congress in June. Full results from the CASTOR trial will be presented in June at the 2016 ASCO Annual Meeting.
Results from the phase I/II GEN503 trial were presented at the 2015 ASH Annual Meeting.1
The addition of daratumumab to lenalidomide/dexamethasone generated an 81% ORR among 32 patients with relapsed/refractory multiple myeloma who participated in the expansion phase of the trial. In this expansion phase, daratumumab was administered at 16 mg/kg on a 28-day cycle along with lenalidomide at 25 mg on days 1-21 and dexamethasone at 40 mg weekly.
The ORR included 11 patients who achieved a complete response (34%), 9 patients with a very good partial response (28%), and 6 patients with a partial response (19%). In a further breakdown of the results, the complete responders included 8 patients (25%) with a stringent complete response.
Patients responded quickly to the daratumumab-containing regimen. The median time to first response was 1.0 month (range, 0.5-5.6 months) and the median time to best response was 5.1 months (range, 0.5-14.4 months). The median duration of response was not yet reached. After 18 months, the PFS rate was 72% and the overall survival rate was 90%.
The most common AEs were neutropenia (84%), cough (50%), diarrhea (44%), and muscle spasms (44%). The study authors noted that these AEs are associated with lenalidomide and dexamethasone. Overall, 50% of the participants experienced serious AEs, but only neutropenia (n = 3), gastroenteritis (n = 2), and pyrexia (n = 2) occurred in more than 1 patient. Infusion-related reactions occurred in 56% of patients, but these typically were grade ≤2 and arose after the first infusion. They were managed with premedication or a slower infusion rate.
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 immunomodulatory agent or who are double-refractory to those therapies.
1. 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). Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 507.