The objective of the APOLLO study was to evaluate daratumumab (DARA; subcutaneous) + pomalidomide and dexamethasone (Pd) versus Pd alone in patients with relapsed/refractory multiple myeloma (RRMM) who had received ≥1 prior lines of therapy, including lenalidomide (Len) and a proteasome inhibitor (PI). The data reported here are from the primary analysis.
Patients with RRMM who had received ≥1 prior lines of therapy, including Len and a PI (patients with only 1 prior line of therapy were required to be refractory to Len), and had responded to prior treatment and progressed on or after their last regimen, were eligible for this open-label study. Patients could not have previously taken anti-CD38 or Pd. Patients were randomized 1:1, and stratification was based on the International Staging System (ISS) disease stage and number of prior lines of therapy.
Treatment cycles were 28 days. Patients received pomalidomide (P) 4 mg once daily on days 1 to 21 and dexamethasone (d) 40 mg on days 1, 8, 15, and 22. For patients in the DARA-Pd arm, DARA was given once weekly for cycles 1 and 2, once every 2 weeks for cycles 3 to 6, and once every 4 weeks thereafter. Initially, patients received DARA intravenously (16 mg/kg; n = 7) but after protocol amendment, they received DARA subcutaneously 1800 mg co-formulated with recombinant human hyaluronidase PH20 (Halozyme, Inc). Treatment continued until disease progression (DP) or unacceptable toxicity. Progression-free survival (PFS) was the primary end point; secondary end points included overall response rate, rates of very good partial response or better (≥VGPR) and complete response or better (≥CR), minimal residual disease negativity rate, overall survival, and safety.
In APOLLO, 304 patients were randomized 1:1 to DARA-Pd (n = 151) or Pd alone (n = 153). The median age was 67 years (range, 35-90 years). ISS stage distribution was 45% stage I, 33% stage II, and 22% stage III. The presence of del17p, t(14;16), or t(4;14) was identified in 35% of patients, classifying them as high cytogenetic risk; 11% of patients had received 1 prior line of therapy (median, 2; range, 1-5). A total of 79.6% of patients were refractory to Len, 48.0% of patients were refractory to a PI, and 42.4% of patients were refractory to both. Median duration of treatment was 11.5 months (DARA-Pd) versus 6.6 months (Pd).
At primary analysis, a 37% reduction in the risk for progression or death in patients in the DARA-Pd arm was observed, meaning the study met the primary end point of improved PFS (hazard ratio, 0.63; 95% confidence interval, 0.47-0.85; P = .0018). Median PFS was 12.4 months versus 6.9 months for the DARA-Pd and Pd arms, respectively. At a median follow-up of 16.9 months, 99 patients (33%) have died; survival data are immature. In the DARA-Pd arm, 24.5% of patients achieved ≥CR and 51.0% achieved ≥VGPR, whereas in the Pd arm, 3.9% of patients achieved ≥CR and 19.6% achieved ≥VGPR. The minimal residual disease–negativity rate for the DARA-Pd arm was 9% versus 2% for the Pd arm. Benefits were seen across all prespecified subgroups.
The most common grade 3/4 adverse events (AEs), with a ≥5% difference between arms (DARA-Pd vs Pd), were neutropenia (68% vs 51%), leukopenia (17% vs 5%), lymphopenia (12% vs 3%), febrile neutropenia (9% vs 3%), and pneumonia (13% vs 7%). For DARA given subcutaneously, the rate of injection-related reactions was low (5%) and all were grade 1/2. Grade 1 local injection-site reactions occurred in 2% of patients. Discontinuations because of treatment-emergent AEs were similar between arms (2% DARA-Pd vs 3% Pd).
When compared with Pd, DARA-Pd significantly reduced the risk for DP or death by 37% for this patient population. No new safety signals were observed. The low rate of injection-related reactions and the short administration time (median, 5 minutes) associated with subcutaneous delivery of DARA decrease patient burden, making DARA-Pd an effective and convenient therapy for patients with RRMM who received ≥1 prior lines of therapy, including Len and a PI.
Abstract 412. ASH 2020. December 4, 2020. APOLLO: Phase 3 Randomized Study of Subcutaneous Daratumumab plus Pomalidomide and Dexamethasone (D-Pd) versus Pomalidomide and Dexamethasone (Pd) Alone in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM).