After more than 4 years of follow-up, the addition of daratumumab to lenalidomide and dexamethasone (D-Rd) continues to significantly improve progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma, according to an update of the phase 3 POLLUX study. Patients on D-Rd also demonstrated deeper responses than patients who received lenalidomide and dexamethasone (Rd) alone.
Although the PFS benefit of D-Rd was observed in patients regardless of prior lines of therapy or cytogenetic risk status, the greatest benefit was seen in patients who were treated earlier with the drug triplet, said Jonathan L. Kaufman, MD, from Emory University in Atlanta, who presented the study results at the 2019 ASH Annual Meeting. According to the investigators, these updated results continue to support the use of daratumumab combination therapies in patients with relapsed or refractory multiple myeloma who have received at least 1 prior line of therapy.
POLLUX Previously Demonstrated PFS Benefit with D-Rd
Daratumumab is currently approved in combination with standard-of-care regimens for the treatment of newly diagnosed and relapsed/refractory multiple myeloma.
The phase 3 POLLUX study enrolled 569 patients who had received at least 1 prior line of therapy. Patients were randomly assigned to either D-Rd (n= 286) or Rd alone (n = 283). Lenalidomide 25 mg was given orally on days 1 through 21 of each 28-day cycle, dexamethasone was given orally at 40 mg/week, and daratumumab was administered intravenously at 16 mg/kg weekly for cycles 1 and 2, biweekly for cycles 3 through 6, and then every 4 weeks thereafter until disease progression.
As previously reported, after a median follow-up of 44.3 months, D-Rd reduced the risk of disease progression or death by 56% in the POLLUX trial and significantly increased the overall response rate (ORR) versus Rd (93% vs 76%) in patients with relapsed or refractory disease. An exploratory end point of the study was PFS on subsequent line of therapy (PFS2), and was defined as time from randomization to progression after the next line of subsequent therapy or death.
D-Rd Leads to Improvements in Multiple End Points
After a median follow-up of about 55 months, treatment with D-Rd is still showing benefit. The drug combination significantly prolonged PFS versus Rd in the intent-to-treat population, at a median of 45 months versus 17.5 months, as reported by the investigators.
D-Rd also significantly prolonged PFS2 versus Rd, at a median of 53.3 months versus 31.6 months in the patients treated with Rd alone and was associated with a significantly higher ORR versus Rd (93% vs 80%), including higher rates of very good partial response or better (80% vs 56%) and complete response or better (59% vs 29%).
Further, the 3-drug combination improved the rate of minimal residual disease (MRD) negativity and was associated with sustained MRD negativity, a valuable prognostic marker in multiple myeloma.
Median time to next therapy for patients who received D-Rd was not reached, versus 22.8 months in the Rd group, and median duration of treatment was 34.3 months in the D-Rd arm versus 16 months in the Rd arm.
Even after longer follow-up, no new safety signals were identified, and similar rates of discontinuation due to treatment-related adverse events were observed for D-Rd versus Rd (17% vs 15%). The most common (≥10%) grade 3/4 treatment-related adverse events observed with the 3-drug combination versus Rd included neutropenia (57% vs 42%), anemia (19% vs 22%), thrombocytopenia (15% vs 16%), pneumonia (16% vs 10%), and diarrhea (10% vs 4%).
At the time of reporting at ASH, 125 deaths had occurred in the D-Rd group versus 144 in the Rd group.
“The significant improvement in PFS2 suggests a potential survival benefit,” added Dr Kaufman. “But overall survival data are still immature.”
