The addition of daratumumab to lenalidomide and dexamethasone led to a 27% reduction in the risk of death compared with Rd alone in patients with relapsed/refractory multiple myeloma.
Meletios A. Dimopoulos, MD
The addition of daratumumab (Darzalex) to lenalidomide (Revlimid) and dexamethasone (D-Rd) led to a 27% reduction in the risk of death compared with Rd alone in patients with relapsed/refractory multiple myeloma, according to updated findings from the phase 3 POLLUX trial (NCT02076009) published in the Journal of Clinical Oncology.
At a median follow-up of 79.7 months (range, 0.0-86.5), the median overall survival (OS) was 67.6 months (95% CI, 53.1-80.5) with D-Rd (n = 286) vs 51.8 months (95% CI, 44.0-60.0) with Rd alone (n = 283; HR, 0.73; 95% CI, 0.58-0.91; P = .0044).
“On the basis of the results of [historical] studies, the previous benchmark for survival in relapsed/refractory multiple myeloma of approximately 4 years has now been extended beyond 5.5 years with the POLLUX OS data,” lead study author Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens, Athens, Greece, and co-authors, wrote in the publication.
POLLUX is a multicenter, randomized, open-label, phase 3 trial that evaluated D-Rd or Rd in patients with progressive disease on or after at least 1 prior line of therapy. Patients who were refractory to lenalidomide were ineligible for enrollment.
All patients received 25 mg of oral lenalidomide once daily on days 1 through 21 of each 28-day cycle and 10 mg once daily if the creatinine clearance was 30 to 60 mL/min, plus 40 mg of dexamethasone once weekly until disease progression, unacceptable toxicity, or death. Patients in the triplet arm received 16 mg/kg of daratumumab intravenously once weekly on days 1, 8, 15, and 22 in cycles 1 and 2, once every 2 weeks on days 1 and 15 in cycles 3 through 6, and once every 4 weeks thereafter.
Findings from the initial analysis performed at a median follow-up of 13.5 months demonstrated a significant improvement in progression-free survival (PFS) with D-Rd vs Rd alone (HR, 0.37; 95% CI, 0.27-0.52; P <.001). D-Rd also led to higher rates of deeper responses vs Rd, with rates of complete response (CR) or better of 43.1% and 19.2%, respectively, and rates of minimal residual disease (MRD) negativity at a sensitivity of 10–5 of 22.4% and 4.6%, respectively (P <.001 for both).
Following the positive primary analysis and protocol amendment, patients who received Rd were offered daratumumab monotherapy after disease progression, discontinuation because of toxicity, or after a washout period.
The primary end point was PFS. Secondary end points included overall response rate, rates of very good partial response or better and CR or better, MRD negativity, time to response, and OS.
Baseline characteristics showed that the median patient age was 65 years (range, 34-89). Approximately half (51.8%) of patients received one prior line of therapy, 84.2% received prior bortezomib (Velcade), 17.6% received prior lenalidomide, 43.9% received a proteasome inhibitor (PI) and an immunomodulatory drug, and 20.6% were refractory to bortezomib.
In a more recent analysis of POLLUX, which was performed at a median follow-up of 54.8 months, D-Rd showed sustained PFS benefit, with a median PFS of 45.0 months vs 17.5 months with Rd alone (HR, 0.44; 95% CI, 0.35-0.54; P <.0001), with continuous deepening of responses and higher MRD negativity rates.
In the final analysis performed by the clinical cutoff date of September 30, 2021, the median study treatment duration was 34.3 months (range, 0-85.0) for D-Rd vs 16.0 months (range, 0.2-86.2) for Rd. The median number of treatment cycles received was 37 (range, 1-90) and 17 (range, 1-94), respectively.
One hundred twenty-two patients in the Rd arm who received subsequent therapy received daratumumab.
Additional findings from the prespecified analysis demonstrated an improvement in OS with D-Rd vs Rd in most subgroups, including patients at least 65 years of age, those who received between 1 and 3 prior lines of therapy, had International Staging System stage III disease, high-risk cytogenetic abnormalities, and refractoriness to their last prior line of therapy or a PI.
MRD negativity rates with a sensitivity of 10–5 were also significantly higher with D-Rd compared with Rd, at 33.2% vs 6.7%, respectively (P <.0001). Notably, MRD negativity was associated with improved OS, regardless of the treatment group.
In total, 44.9% of patients (n = 127/283) in the D-Rd arm and 74.7% of patients (n = 210/281) in the Rd arm received subsequent therapy. The median time to subsequent treatment was 69.3 months with D-Rd vs 23.1 months with Rd (HR, 0.40; 95% CI, 0.32-0.50; P <.0001).
The median PFS on the subsequent line of therapy was 57.9 months in the D-Rd arm vs 32.0 months in the Rd arm (HR, 0.54; 95% CI, 0.43-0.67; P <.0001). The median time to crossover to subsequent therapy with daratumumab after disease progression for patients in the Rd arm was 28.2 months (range, 4.3-79.5).
No new safety concerns were reported with extended follow-up.
The most common grade 3/4 treatment-emergent adverse effects (TEAEs) that occurred in at least 10% of patients on the D-Rd vs Rd arms were neutropenia (57.6% vs 41.6%, respectively), anemia (19.8% vs 22.4%), pneumonia (17.3% vs 11.0%), thrombocytopenia (15.5% vs 15.7%), and diarrhea (10.2% vs 3.9%).
Grade 3/4 infections were more common in the D-Rd arm vs the Rd arm, at 44.5% vs 28.1%, respectively. Serious TEAEs occurred in 72.4% of patients in the D-Rd arm and 52.7% of those in the Rd arm, with pneumonia being the most common (17.0% vs 11.4%, respectively. Rates of TEAEs leading to discontinuation were similar between groups (D-Rd, 19.1%; Rd, 16.0%). In the D-Rd group, 13 patients (4.6%) stopped treatment because of infections vs 11 patients (3.9%) in the Rd group.
TEAEs leading to death occurred in 12.4% of patients (n = 35/283) in the D-Rd arm and 8.5% of patients (n = 24/281) in the Rd arm. The most common TEAEs leading to death were septic shock (1.4% vs 0.4%, respectively), cardiac arrest (1.1% vs 0.4%), sudden death (1.1% vs 0.4%), pneumonia (0.7% vs 1.1%), acute kidney injury (0.4% vs 1.1%), and sepsis (0% vs 1.1%).
Second primary malignancies occurred in 14.1% of patients (n = 40/283) in the D-Rd arm and 10.7% of patients (n = 30/281) in the Rd arm. However, when adjusted for exposure to study treatment, the incidence of second primary malignancies was comparable in the D-Rd (0.35 events per 100 patient-months at risk) and Rd (0.45 events per 100 patient-months at risk) arms.
“Given the high attrition rates observed in real-world studies in Europe and the United States and the observed OS benefits with daratumumab-containing regimens in both newly diagnosed multiple myeloma and now relapsed/refractory multiple myeloma, early use of daratumumab should be considered a standard of care to achieve deep and sustained responses and prolonged disease control,” the study authors concluded.
Dimopoulos MA, Oriol A, Nahi H, et al. Overall survival with daratumumab, lenalidomide, and dexamethasone in previously treated multiple myeloma (POLLUX): a randomized, open-label, phase III trial. J Clin Oncol. Published online January 4, 2023. doi:10.1200/JCO.22.00940