The POLLUX clinical trial to assess the efficacy of daratumumab in combination with lenalidomide and dexamethasone

In October 2016, Meletios A. Dimopoulos, Philippe Moreau and collaborators, published the results of the POLLUX clinical trial in the New England Journal of Medicine. The study was designed to assess the efficacy of daratumumab in combination with lenalidomide and dexamethasone, for the treatment of multiple myeloma (MM). In this open-label, phase 3 trial, 593 patients were recruited (between June 2014 and July 2015, at 135 sites in 18 countries) with relapsed or refractory MM, and were randomly assigned into two treatment groups: daratumumab in combination with lenalidomide and dexamethasone, or lenalidomide plus dexamethasone alone (control). The primary end point was progression free survival (PFS) with various secondary endpoints.

Treatment:

• Treatment cycles were 28 days
• Daratumumab was administered (intravenously) at a dose of 16 mg/kg: cycles 1-2: on days 1, 8, 15, and 22 for 8 weeks; cycles 3-6: every 2 weeks (on days 1 and 15) for 16 weeks; cycles 7 onwards: every 4 weeks
• Lenalidomide was administered (orally) at a dose of 25 mg on days 1 to 21 of each cycle if the creatinine clearance was more than 60 ml/min (or a dose of 10 mg daily if the creatinine clearance was 30 - 60 ml/min)
• Dexamethasone was given at a dose of 40 mg weekly:
  • For the daratumumab group, the dose of dexamethasone was split: 20 mg - prior to infusion with daratumumab (as preventative measure for infusion-related reactions) and 20 mg - the next day
  • Dexamethasone could be reduced to 20 mg/week for patients who were 75 years or older, had a BMI < 18.5, or had previous unacceptable side effects associated with glucocorticoid therapy

Key Findings:

• 569 patients were recruited: daratumumab - 286 and control group (283)
• Median age = 65 years (range, 34-89 years)
• At the point of data cut-off (March 2016) 23.3% (66 pts) (daratumumab) and 47.0% (132pts) control had discontinued treatment
• Median follow-up = 13.5 months
• Events of disease progression or death = 18.5% (53 pts) vs. 41.0% (116 pts) HR = 0.37 (95% CI, 0.27-0.52; P<0.001)
• Kaplan-Meir rate of PFS (12 months) = 83.2% (95% CI, 78.3-87.2 %) vs. 60.1% (95% CI, 54.0-65.7%)
• Median PFS = not reached (95% CI, could not be estimated) vs. 18.4 months (95% CI, 13.9 to could not be estimated)
• TTP = 148 events: 15.4% (44 pts) vs. 36.7% (104 pts); HR = 0.34 (95% CI, 0.23-0.48; P<0.001)
• Rate of PFS (12 months) = 85.7% (95% CI, 80.9-89.4) vs. 63.2% (95% CI, 57.1-68.8%)
• Subgroup analyses confirmed the benefit of daratumumab across all groups, and the benefit was observed regardless of previous therapy or prior exposure to lenalidomide
• ORR (patients with evaluable responses) = 92.9% vs. 76.4% (P<0.001); similar in ITT population
• VGPR = 75.8% vs. 44.2%, (P<0.001)
• CR = 43.1% vs.19.2%, (P<0.001)
• Threshold for minimal residual disease (1 tumor cell per 10⁵ white cells) = 22.4% vs. 4.6% (P<0.001)
• Median duration of response = not reached (95% CI, could not be estimated) vs. 17.4 months (95% CI, 17.4 months to could not be estimated)
• Rate of PFS (at 12 months, patients with a PR or better) = 87.8% (95% CI, 83.1 - 91.3) vs. 73.6% (95% CI, 67.0- 79.1)
• Rate of PFS (patients with a VGPR or better) = 91.7% (95% CI, 87.1-94.8%) vs. 85.8% (95% CI, 78.1-90.9%)
• Deaths at interim analysis = 30 pts vs. 45 pts
• OS (at 12 months) = 92.1% (95% CI, 88.2-94.7%) vs. 86.8% (95% CI, 82.2-90.3%)

Safety

• Serious AEs = 48.8% vs. 42.0%
• Most common AE: Pneumonia = 8.1% vs. 8.5%
• AEs leading to treatment discontinuation = 6.7% vs. 7.8%
• AEs occurring at a frequency of ≥ 10% in daratumumab vs. control: neutropenia, diarrhea, upper respiratory tract infection, and cough (although most can be attributed to longer exposure to treatment).
• Deep-vein thrombosis = 1.8% vs. 3.9%
• Neutropenia (grade 3 or 4) = 51.9% vs. 37.0%
• Thrombocytopenia (grade 3 or 4) = 12.7% vs.13.5%
• Rate of infection (grade 3 or 4) = 28.3% vs. 22.8%
• AE leading to death = 3.9% (11 pts) vs. 5.3% (15 pts): acute kidney injury (0.4% vs. 1.1%), septic shock (1.1% vs. 0.4%), pneumonia (in 0.7% both groups)
• Secondary primary cancer: 2.8% vs. 3.6%
• Infusion-related reactions = 47.7%; 92% occurring during the first infusion
• Reason for discontinuation of treatment: progressive disease = 14.1% vs. 34.2%; AEs = 6.7% vs. 8.2%

The results of this trial show significant benefit from the addition of daratumumab to the backbone regimen of lenalidomide plus dexamethasone, conferring a 63% reduction in risk of disease progression to MM patients that had received one or more prior therapy. This study was similar to the CASTOR study, which assessed the efficacy of daratumumab in a triple therapy regimen, with a backbone of bortezomib and dexamethasone (see MM Hub article). Data from this study was also instrumental in the formation of a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA), recommending the use of daratumumab in combination with lenalidomide and dexamethasone, for the treatment of adult patients with MM who have received at least one prior therapy. This would extend the previously approved indication for use as a monotherapy in RRMM patients, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and demonstrated disease progression on the last therapy. See MMHub article.

Abstract

Background Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma. Methods In this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival. Results At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2. Conclusions The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. Daratumumab was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy. (Funded by Janssen Research and Development; POLLUX ClinicalTrials.gov number, NCT02076009 .).