As reported in The Lancet Oncology by Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens, and colleagues, the phase III APOLLO trial has shown significantly improved progression-free survival with the addition of subcutaneous (SC) daratumumab to oral pomalidomide/dexamethasone in previously treated multiple myeloma.¹

Meletios A. Dimopoulos, MD

Study Details

In the open-label trial, 304 patients from sites in 12 European countries were randomly assigned between June 2017 and June 2019 to receive daratumumab plus pomalidomide/dexamethasone (n = 151) or pomalidomide/dexamethasone (control group, n = 153). Patients had at least one previous line of therapy, including lenalidomide and a proteasome inhibitor, had a partial response or better to at least one previous line of antimyeloma therapy, and were refractory to lenalidomide if only one previous line of therapy had been received. Randomization was stratified by the number of lines of previous therapy (1 vs 2 to 3 vs ≥ 4) and International Staging System (ISS) disease stage during screening (I vs II vs III).

All patients received oral pomalidomide at 4 mg once daily on days 1 to 21 and oral dexamethasone at 40 mg once daily on days 1, 8, 15, and 22 (20 mg for those aged ≥ 75 years) in 28-day cycles. Daratumumab was given at 1,800 mg SC or 16 mg/kg intravenously (IV) weekly during cycles 1 and 2, every 2 weeks during cycles 3 to 6, and every 4 weeks thereafter until disease progression or unacceptable toxicity. All patients who started on SC daratumumab (95% of group) continued on SC administration throughout the trial. A protocol amendment permitted patients starting on IV daratumumab to switch to SC administration on day 1 of cycle 3 or later; among the seven patients (5%) starting on IV administration, four (3%) switched to SC administration, and three (2%) experienced disease progression on IV daratumumab prior to the amendment. The primary endpoint was progression-free survival on central review in the intention-to-treat population.

For the daratumumab vs control groups, median age was 67 years (42% vs 39% 65 to < 75 and 17% vs 20% ≥ 75 years), 52% vs 54% were male, and 89% vs 90% were White. Eastern Cooperative Oncology Group performance status was 0 in 60% vs 50%, 1 in 36% vs 37%, and 2 in 4% vs 12%. ISS stage was I in 45% vs 45%, II in 33% vs 33%, and III in 22% vs 22%. 

Disease was refractory to the last line of therapy in 81% vs 80%; refractory to lenalidomide in 79% vs 80%; and refractory to a proteasome inhibitor in 47% vs 49%, an immunomodulatory agent in 79% vs 80%, and both in 42% vs 42%; refractory to a proteasome inhibitor and lenalidomide in 42% vs 42%; and refractory to lenalidomide at the last prior line in 62% vs 59%.

Progression-Free Survival

Median follow-up was 16.9 months (interquartile range = 14.4–20.6 months). Median progression-free survival was 12.4 months (95% confidence interval [CI] = 8.3–19.3 months) in the daratumumab group vs 6.9 months (95% CI = 5.5–9.3 months) in the control group (hazard ratio [HR] = 0.63, 95% CI = 0.47–0.85, P = .0018). Kaplan-Meier estimates of rates at 18 months were 42% (95% CI = 34%–50%) vs 26% (95% CI = 18%–33%).

Hazard ratios for progression-free survival in stratification subgroups were 0.70 (95% CI = 0.30–1.67) for one, 0.66 (95% CI = 0.48–0.92) for two to three, and 0.40 (95% CI = 0.18–0.90) for at least four prior lines of therapy, as well as 0.62 (95% CI = 0.39–0.98) for ISS stage I, 0.54 (95% CI = 0.33–0.87) for ISS stage II, and 0.75 (95% CI = 0.42–1.32) for ISS stage III disease.

Hazard ratios for other subgroups included 0.85 (95% CI = 0.49–1.44) for high cytogenetic risk and 0.51 (95% CI = 0.32–0.81) for standard risk, 0.74 (95% CI = 0.49–1.12) for patients refractory to and 0.52 (95% CI = 0.34–0.77) for those not refractory to both a proteasome inhibitor and immunomodulatory agent, 0.64 (95% CI = 0.47–0.87) for those refractory to and 0.45 (95% CI = 0.20–1.02) for those not refractory to the last line of therapy, and 0.66 (95% CI = 0.49–0.90) for those refractory to and 0.36 (95% CI = 0.15–0.83) for those not refractory to lenalidomide.

Overall response rates were 69% vs 46%, with a complete response or better in 25% vs 4% and a very good partial response or better in 51% vs 20% (all P < .0001). The median duration of response was not reached (95% CI = 15.2 months to not reached) in the daratumumab group vs 15.9 months (95% CI = 8.3–24.8 months) in the control group. At the time of progression-free survival analysis, overall survival data were not mature; death had occurred in 32% vs 33% of patients.

The median time to subsequent antimyeloma therapy was 23.2 months (95% CI = 13.8 months to not estimable) in the daratumumab group vs 11.8 months (95% CI = 8.9–15.4 months) in the control group. In a prespecified analysis, median progression-free survival after the next line of therapy was not reached (95% CI = 16.6 months to not estimable) in the daratumumab group vs 17.6 months (95% CI = 13.4 months to not estimable) in the control group (HR = 0.79, 95% CI = 0.55–1.14, P = .21).

Adverse Events

Grade ≥ 3 adverse events occurred in 88% of the daratumumab group vs 82% of the control group, with the most common in the daratumumab group being neutropenia (68% vs 51% of control group), infections (24% vs 20%, including pneumonia in 11% vs 6% and lower respiratory tract infection in 10% vs 8%), anemia (17% vs 21%), and thrombocytopenia (17% vs 18%). Serious adverse events occurred in 50% vs 39% of patients, with the most common in the daratumumab group being pneumonia (15% vs 8%) and lower respiratory tract infection (12% vs 9%). Adverse events led to discontinuation of study treatment in 2% vs 3% of patients. Infusion-related reactions, all grade 1 or 2 and all occurring with SC administration, were reported in 5% of the daratumumab group. Second primary malignancies occurred in 2% vs 2% of patients. Adverse events led to death in 7% vs 7% of patients, with death in five patients in the daratumumab group vs no patients in the control group considered at least possibly related to treatment.

The investigators concluded: “Among patients with relapsed or refractory multiple myeloma, daratumumab plus pomalidomide and dexamethasone reduced the risk of disease progression or death versus pomalidomide and dexamethasone alone and could be considered a new treatment option in this setting.” 

DISCLOSURE: The study was funded by the European Myeloma Network and Janssen Research and Development. Dr. Dimopoulos has received honoraria from Amgen, BeiGene, Bristol Myers Squibb, Janssen-Cilag, and Takeda; and has served as a consultant or advisor to Amgen, BeiGene, Bristol Myers Squibb, Janssen-Cilag, and Takeda.

REFERENCE

1. Dimopoulos MA, Terpos E, Boccadoro M, et al: Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO). Lancet Oncol 22:801-812, 2021.