Subcutaneous Daratumumab Triplet Improves PFS in R/R Multiple Myeloma

In the phase 3 APOLLO study, patients with relapsed/refractory (R/R) multiple myeloma who had received ≥1 prior line of therapy had a significantly reduced the risk of progression or death by 37% when treated with the combination of subcutaneous daratumumab (Darzalex) to pomalidomide (Pomalyst) and dexamethasone (D-Pd) compared pomalidomide and dexamethasone (Pd) alone, according to results presented during the 2020 American Society of Hematology Annual Meeting.

Moreover, the combination achieved a significantly deeper response, compared with pomalidomide monotherapy, including a higher complete response (CR) rate (25% vs 4%, respectively) and MRD negativity (9% vs 2%).

“Daratumumab is another CD38 monoclonal antibody with multiple modes of action, which have shown not only single agent activity, but also whenever this drug was combined with other standard regimens, either in a lab setting or in the frontline setting, there was a significant improvement in progression-free survival, and also in overall survival,” Meletios A. Dimopoulos, MD, from the National and Kapodistrian University of Athens in Athens, Greece, said during a press briefing.

In the phase 1b study of intravenous D-Pd, the combination induced deep responses and appeared to be well tolerated in patients with heavily pretreated R/R multiple myeloma, including patients who previously received treatment with lenalidomide (Revlimid). Therefore, the FDA approved D-Pd to treat patients with R/R multiple myeloma with ≥2 prior lines of therapy.

Recent studies have found that the subcutaneous formulation of daratumumab is similar in efficacy and safety, compared with the intravenous formulation. Moreover, it has a statistically significant reduction in infusion-related reaction rates and a considerably shorter administration duration of 5 minutes.

In the open-label, multicenter phase 3 APOLLO study (NCT03180736), the researchers evaluated subcutaneous daratumumab plus Pd, compared with Pd alone, in 304 R/R multiple myeloma patients with ≥1 prior line of therapy, including lenalidomide or a proteasome inhibitor.

To be eligible for the trial, patients with only 1 prior line of therapy were required to be refractory to lenalidomide. Prior treatment with anti-CD38 or pomalidomide was not permitted.

All patients received 28-day treatment cycles until progressive disease or unacceptable toxicity. Patients were randomized 1:1 to received D-Pd (n = 151) or Pd alone (n = 153). The D-Pd regimen consisted of 1,800 mg SCa daratumumab every week for cycles 1-2, bi-weekly for cycles 3-6, and every 4 weeks for cycles 7 on; 4 mg pomalidomide on days 1-21; and 40 mg dexamethasone on days 1, 8, 15, and 22. Median duration of subcutaneous administration was 5 minutes (range, 1-22).

Post-treatment follow-up was conducted every 4 weeks for patients who discontinued treatment. Survival follow-up was conducted every 12 weeks following progressive disease or the start of subsequent therapy.

Progression-free survival (PFS) served as the primary end point. Secondary end points included overall response rate (ORR), rates of very good partial response (VGPR) or better and CR or better, MRD‑negativity rate, overall survival (OS), time to response, duration of response (DOR), time to next therapy, safety, and health-related quality of life.

Median age was 67 years (range, 35-90), the majority of patients had ISS stage I (45%), and 35% had cytogenetic risk (presence of del17p, t[14;16], or t[4;14]). Eleven percent of patients received 1 prior line of therapy (median, 2; range, 2-5). In addition, 79.6% of patients were refractory to lenalidomide, 48.0% of patients were refractory to a proteosome inhibitor, and 42.4% of patients were refractory to both. Median duration of treatment was 11.5 months with D-Pd, compared with 6.6 months with Pd.

Compared with Pd alone, D-Pd demonstrated superior PFS (HR, 0.63; 95% CI, 0.47-0.85; P = .0018), representing a 37% reduction in the risk for progression or death. Median PFS was 12.4 months for patients treated with D-PD, compared with 6.9 months in patients treated with Pd alone. Moreover, D-Pd achieved longer PFS in patients who were previously treated with lenalidomide, compare with those who were not (9.9 months vs 6.5 months).

After a median follow-up of 16.9 months, 99 pts (33%) died. The risk for death was decreased by 9% with D-Pd (HR, 0.91; 95% CI, 0.61-1.35); however, survival data are immature and follow-up is ongoing.

Similarly, ORR was higher in the D-Pd group, compared with the Pd group (69% vs 46%; OR, 2.68; 95% CI, 1.65-4.35; P < .0001). CR rates for the daratumumab regimen were also reported to be superior, compared with Pd alone (24.5% vs 3.9, respectively), including VGPR rates (51.0% vs 19.6%).

The researchers also saw a 4.30-fold increase in MRD negativity with D-Pd (9% vs 2%; P = .0102).

The safety profile of D-Pd was consistent with its known profile. The most common grade 3/4 adverse events (AEs) in patients treated with D-Pd versus Pd were neutropenia (68% vs 51%), leukopenia (17% vs 5%), lymphopenia (12% vs 3%), febrile neutropenia (9% vs 3%), and pneumonia (13% vs 7%). Rates of study treatment discontinuation due to treatment-emergent AEs were similar for both arms (2% vs 3%, respectively). The most common reason for treatment discontinuation was progressive disease. The rate of infusion-related reaction rates with the subcutaneous formulation appeared low (grade 1/2, 6%), and only 2% of patients had a local injection site reaction.

“The infusion-related reaction rate was low and administration duration was short, thus increasing convenience for patients and decreasing treatment burden,” Dimopoulos said.

“The vast increasing convenience for patients in decreasing treatment burden (shows that) we could conclude that the subcutaneous D-Pd is an effective and convenient treatment for patients with relapsed refractory multiple myeloma who have received at least 1 prior line of therapy, including lenalidomide and the proteasome inhibitor.”

_Reference:

_{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: 2021 ASH Annual Meeting; December 4, 2020. Abstract 412.}