As reported in the Journal of Clinical Oncology by Meletios A. Dimopoulos, MD, and colleagues, the final overall survival analysis of the pivotal phase III POLLUX trial has shown a significant benefit with the addition of daratumumab to lenalidomide and dexamethasone after a median follow-up of approximately 6.5 years in patients with relapsed or refractory multiple myeloma.
The trial supported the November 2016 approval of daratumumab in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy on the basis of improved progression-free survival (the primary endpoint) at a median follow-up of 13.5 months.
Meletios A. Dimopoulos, MD
In the open-label trial, 569 patients with progressive disease during or after their last regimen who had received and responded to at least one previous line of therapy were randomly assigned to receive daratumumab plus lenalidomide/dexamethasone (D-Rd; n= 286) or lenalidomide/dexamethasone (Rd; n = 283). All patients received 28-day cycles of lenalidomide at 25 mg once daily (10 mg for creatinine clearance of 30–60 mL/min) on days 1 to 21 of each cycle, and dexamethasone at 40 mg once weekly until disease progression or unacceptable toxicity. Daratumumab was given at 16 mg/kg on days 1, 8, 15, and 22 in cycles 1 and 2; days 1 and 15 during cycles 3 through 6; and once every 4 weeks thereafter. After the positive primary analysis, the study protocol was amended so that patients receiving Rd were offered daratumumab monotherapy after disease progression. The primary endpoint was progression-free survival. At primary analysis, progression-free survival was significantly improved with D-Rd (hazard ratio [HR] = 0.37, P < .001).
At clinical cutoff (end of September 2021), median study treatment duration was 34.3 months (range = 0–85.0 months) in the D-Rd group and 16.0 months (range = 0.2–86.2 months) in the Rd group. Median follow-up at the time of final overall survival analysis was 79.7 months (range = 0.0–86.5 months). Median overall survival was 67.6 months (95% confidence interval [CI] = 53.1–80.5 months) in the D-Rd group vs 51.8 months (95% CI = 44.0–60.0 months) in the Rd group (HR = 0.73, 95% CI = 0.58–0.91, P = .0044).
Overall, 127 patients (44.9%) in the D-Rd group and 210 (74.7%) in the Rd group received subsequent therapy. Among those receiving subsequent therapy in the Rd group, 122 patients (58.1%) received daratumumab as monotherapy (primarily) or in combination regimens. Median time to subsequent treatment was 69.3 months in the D-Rd group vs 23.1 months in the Rd group (HR = 0.40, 95% CI = 0.32–0.50, P < .0001). Among 66 patients in the Rd group who received subsequent single-agent daratumumab after disease progression per protocol amendment, median overall survival was 65.6 months (95% CI = 51.3–73.1 months).
In prespecified analyses, hazard ratios for overall survival favored D-Rd vs Rd in most subgroups, including: patients aged ≥ 65 years (median = 53.1 vs 49.9 months; HR = 0.85, 95% CI = 0.64–1.13); patients with two (median = 53.1 vs 45.4 months; HR = 0.75, 95% CI = 0.50–1.11) or three (median = 59.0 vs 52.0 months; HR = 0.74, 95% CI = 0.41–1.32) prior lines of therapy: those with International Staging System stage III disease (median = 39.0 vs 20.3 months; HR = 0.74, 95% CI = 0.47–1.15); those with high-risk cytogenetic abnormalities (median = 40.0 vs 23.6 months; HR = 0.70, 95% CI = 0.41–1.20); and those with refractoriness to their last prior line of therapy (median = 47.7 vs 33.0 months; HR = 0.74, 95% CI = 0.50–1.08).
In an updated safety analysis, no new safety signals were observed. The most common grade 3 or 4 adverse events in the D-Rd group were neutropenia (57.6% vs 41.6% in the Rd group), 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 or 4 infections occurred in 44.5% vs 28.1% of patients. Serious adverse events occurred in 72.4% vs 52.7%, most commonly pneumonia (17.0% vs 11.4%). Adverse events led to discontinuation of treatment in 19.1% vs 16.0%. Adverse events led to death in 12.4% vs 8.5% of patients. Second primary malignancies occurred in 14.1% vs 10.7% of patients.
The investigators concluded, “D-Rd significantly extended overall survival vs Rd alone in patients with relapsed or refractory multiple myeloma. To our knowledge, for the first time, our findings, together with the overall survival benefit observed with daratumumab plus bortezomib and dexamethasone in the phase III CASTOR trial, demonstrate overall survival improvement with daratumumab-containing regimens in relapsed or refractory multiple myeloma.”
Dr. Dimopoulos, of the National and Kapodistrian University of Athens, School of Medicine, Alexandra Hospital, Athens, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Janssen Research & Development, LLC. For full disclosures of the study authors, visit ascopubs.org.