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.

— Meletios A. Dimopoulos, MD, and colleagues

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As reported in The New England Journal of Medicine by Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens, and colleagues, the phase III POLLUX trial has shown that the addition of the CD38-targeted antibody daratumu­mab (Darzalex) to lenalidomide (Revlimid)/dexamethasone improves progression-free survival in patients with previously treated multiple myeloma.¹

Study Details

In the open-label trial, 569 patients from 135 sites in 18 countries across North America, Europe, and the Asia Pacific region who had relapsed/refractory disease and had received at least 1 previous line of therapy were randomized between June 2014 and July 2015 to receive daratumumab plus lenalidomide/dexamethasone (n = 286) vs lenalidomide/dexamethasone alone (n = 283).

Daratumumab was given via infusion at 16 mg/kg weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks thereafter. Lenalidomide was given at 25 mg/d orally (10 mg/d for creatinine clearance of 30–60 mL/min) of each 4-week cycle and dexamethasone at 40 mg/wk; the dexamethasone dose was split in the daratumumab group as 20 mg preinfusion prophylaxis and 20 mg the following day. The primary endpoint was progression-free survival.

Overall, patients had a median age of 65 years (range = 34–89 years), median time from initial diagnosis was 3.6 years, median number of previous lines of therapy was 1 (range = 1–11) with 19% receiving at least 3 lines, and 27% had disease refractory to the last line of therapy. Previous therapy included proteasome inhibitors in 86% of patients, immunomodulatory drugs in 55% (including lenalidomide in 18%), and both in 44%; 63% had received autologous stem cell transplant.

For the daratumumab and control groups, respectively, 72% and 66% of patients were white and 19% and 16% were Asian; International Staging System stage was I in 48% and 50% and II in 32% and 30%; and 15% and 17% had high-risk cytogenetics.

Progression-Free Survival

At a protocol-specified interim analysis at a median follow-up of 13.5 months, disease progression or death had occurred in 18.5% of the daratumumab group vs 41.0% of the control group. The hazard ratio (HR) for disease progression or death was 0.37 (95% confidence interval [CI] = 0.27–0.52, P < .001), crossing the prespecified stopping boundary.

Median progression-free survival was not reached (95% CI = could not be estimated) vs 18.4 months (95% CI = 13.9 months to could not be estimated). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI = 78.3%–87.2%) vs 60.1% (95% CI = 54.0%–65.7%).

Hazard ratios favored daratumumab in all subgroups examined, including any number of previous lines of therapy, whether or not patients had received previous lenalidomide, whether or not patients were refractory to previous proteasome inhibitor treatment, and in patients aged ≥ 65 years.

Response Rates

Overall response rates were 92.9% vs 76.4% (P < .001), with complete response observed in 43.1% vs 19.2% (P < .001). Complete response appeared to require several months of continuous therapy. Median duration of response was not reached vs 17.4 months.

Progression-free survival at 12 months was 87.8% vs 73.6% among patients with partial response or better and 91.7% vs 85.8% among those with very good partial response or better. Responses below the threshold for minimal residual disease (one tumor cell per 10⁵ white cells) were observed in 22.4% vs 4.6% (P < .001). Responses below this threshold were associated with improved outcomes.

At the interim analysis, death had occurred in 30 patients in the daratumumab group and 45 in the control group. The Kaplan-Meier rate of overall survival at 12 months was 92.1% vs 86.8%; follow-up for long-term survival is ongoing.

Adverse Events

The most common adverse events of grade 3 or 4 in the daratumumab group were neutropenia (51.9% vs 37.0%), thrombocytopenia (12.7% vs 13.5%), and anemia (12.4% vs 19.6%).

Adverse events of any grade occurring at a frequency ≥ 10% higher in the daratumumab group were neutropenia (59.4% vs 43.1%), diarrhea (42.8% vs 24.6%), upper respiratory tract infection (31.8% vs 20.6%), and cough (29.0% vs 12.5%). Deep-vein thrombosis was reported in 1.8% vs 3.9%. Grade 3 or 4 infection occurred in 28.3% vs 22.8%, with the most common being pneumonia (7.8% vs 8.2%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients (5.3% grade 3).

The investigators concluded: “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. The combination of daratumumab with lenalidomide and dexamethasone is the most active salvage therapy for patients with multiple myeloma reported to date.” ■

Disclosure: This study was funded by Janssen Research and Development. For full disclosures of the study authors, visit www.nejm.org.

Reference

1. Dimopoulos MA, Oriol A, Nahi H, et al: Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 375:1319-1331, 2016.