The phase III APOLLO trial evaluated the safety and efficacy of subcutaneous daratumumab in combination with pomalidomide-dexamethasone (D-Pd) in patients with relapsed/refractory multiple myeloma (RRMM) who had received at least one prior line of therapy including lenalidomide and a proteasome inhibitor. Overall, patients given subcutaneous daratumumab along with pomalidomide and dexamethasone were 37% less likely to die or have their disease worsen as compared to patients who received pomalidomide and dexamethasone alone.
Daratumumab (DARA) is a CD38-targeted monoclonal antibody approved for treatment of patients with RRMM. The subcutaneous (SC) formulation of DARA has a similar safety profile as intravenous DARA, with a statistically significant reduction in infusion-related reaction (IRR) rates and a considerably shorter administration duration of only five minutes. In the phase III APOLLO study, 304 patients with RRMM who had received at least one prior line of therapy, including lenalidomide and a proteasome inhibitor (PI), were randomised (1:1) to pomalidomide-dexamethasone (Pd) either with or without DARA SC. All patients received 28-day treatment cycles with pomalidomide 4 mg (orally, QD on days 1‑21) and dexamethasone 40 mg (orally on days 1, 8, 15 and 22 [20 mg for patients ≥75 years of age]). For D-Pd patients, DARA was given once a week for cycles one and two, every two weeks for cycles three to six, and once every four weeks thereafter. Prior to protocol amendment, patients received DARA intravenously at 16 mg/kg (N=7) while after protocol amendment, all patients received DARA subcutaneously (1,800 mg co-formulated with recombinant human hyaluronidase PH20). Treatment was continued until disease progression or unacceptable toxicity.
Patient and disease characteristics were well balanced between the two treatment arms in the study. In total, 79.6% of patients were refractory to lenalidomide, 48.0% of patients were refractory to a PI, and 42.4% of patients were refractory to both. At ASH 2020, primary results of the APOLLO trial were presented. Overall, 95% of D-Pd patients started treatment with DARA SC and the median duration of DARA SC administration was 5 minutes (range: 1-22 minutes). The median duration of study treatment was longer for D-Pd patients (11.5 months) as compared to patients in the Pd arm (6.6 months). In both treatment arms, the most common reason for treatment discontinuation was progressive disease (44% in D-Pd arm vs. 58% in Pd arm). After a median follow-up of 16.9 months, the addition of DARA SC to Pd resulted in a significant improvement in the progression-free survival (PFS), with a 37% reduction in the risk of progression or death (HR[95%CI]: 0.63[0.47-0.85], p=0.0018). The 12-month PFS rate was 52% for patients treated with D-Pd, as compared to 35% for patients receiving Pd alone. Among patients refractory to lenalidomide, the median PFS was reported at 9.9 and 6.5 months for D-Pd and Pd respectively. The observed treatment effect was generally consistent across all investigated subgroups, irrespective of age, ISS disease stage, the number of prior treatment lines, the cytogenetic profile or the ECOG performance status. The triplet regimen also induced a higher objective response rate compared to Pd alone with an ORR of 69% and 46%, respectively (OR[95%CI]: 2.68[1.65-4.35], p<0.0001). This includes a more than six times higher rate of complete responses or better with D-Pd (25% vs. 4%). Also the MRD-negativity rate was increased 4.3 times upon the addition of DARA SC to Pd (2% vs. 9%, p=0.0102).
The safety profile of D-Pd was consistent with the known profiles of DARA SC and Pd. The most common grade 3/4 adverse events with a >5% difference between D-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%). The rate of IRRs with DARA SC was low (5%, all grade 1 or 2), and only 2% of patients had local injection-site reactions (all grade 1). Rates of study treatment discontinuation due to treatment-emergent adverse events (TEAEs) were low and similar for D-Pd and Pd (2% vs. 3%). Finally, also the incidence of TEAEs leading to death were similar for both groups (7% in both cases). The incidence of second primary malignancy was 2% in each treatment group.
Subcutaneous daratumumab in combination with pomalidomide and dexamethasone significantly reduced the risk of progression or death in patients with RRMM who had received at least one prior line of therapy, as compared to pomalidomide-dexamethasone alone. No new safety concerns were observed. Considering the short administration duration and low rates of IRR, the data from APOLLO confirm that D-Pd is an effective and convenient treatment option for RRMM patients who previously received lenalidomide and a PI.
Dimopoulos MA, Terpos E, Boccadoro M, et al. 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). Presented at ASH 2020; Abstract 412.