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Phase III Trial Supports Efficacy of Subcutaneous Daratumumab in Relapsed/Refractory Myeloma

December 30, 2021

Patients with relapsed/refractory multiple myeloma (MM) who were treated with a combination of subcutaneous daratumumab plus pomalidomide-dexamethasone (Pd) had a 37% lower risk of disease progression or death, compared with those who received Pd alone, according to results from the phase III APOLLO trial. Meletios Dimopoulos, MD, from the National and Kapodistrian University of Athens in Greece, presented these results during the 2020 ASH Annual Meeting.

"This is the first prospective randomized trial where the anti-CD38 monoclonal antibody daratumumab was administered subcutaneously in combination with a standard anti-myeloma regimen such as pomalidomide and low-dose dexamathesone," explained Dr. Dimopoulos. (Previous randomized studies used the intravenous formulation of daratumumab.) "This trial is likely to lead to the approval [of subcutaneous daratumumab plus Pd] by regulatory authorities in Europe for patients whose disease is progressing after treatment with lenalidomide and bortezomib."

In the U.S., the combination of Pd and intravenous daratumumab is approved as a second-line therapy for patients with MM who have received two or more prior lines of therapy, including lenalidomide and a proteasome inhibitor. However, intravenous administration typically requires patients to spend a full day at the clinic for each infusion.

The APOLLO trial enrolled 304 patients with relapsed/refractory MM from 12 European countries, and randomly assigned participants to receive either subcutaneous daratumumab plus Pd (n=151) or Pd (n=153).

"These were typical patients with relapsed or refractory myeloma," Dr. Dimopoulos noted. Sixty percent of patients were over the age of 65, and nearly 35% had high cytogenetic risk (defined as the presence of del17p, t[14;16], or t[4;14]). The median number of prior lines of therapy was two (range = 1-5); however, 10% of patients had only received one prior treatment. Most patients (79.6%) had lenalidomide-refractory disease, 48% had MM that was refractory to a proteasome inhibitor, and 42.4% had disease that was refractory to both.

During a median follow-up period of 16.9 months, 99 study participants (33%) died. The investigators reported that the study met its primary endpoint of improved progression-free survival (PFS) with subcutaneous daratumumab. The median PFS in the daratumumab arm was 12.4 months, compared with 6.9 months in the Pd alone group, translating to a 37% lower risk of disease progression or death with daratumumab (hazard ratio [HR] = 0.63; 95% CI 0.47-0.85; p=0.0018).

Dr. Dimopoulous noted that, in the small subset of patients with only one prior line of therapy, the PFS hazard ratio was 0.7, representing a 30% lower risk of death or disease progression.

"This benefit was essentially seen across all subgroups," he added, including in younger and older patients, patients with different [International Staging System] stages, regardless of prior line of therapy, regardless of cytogenetic risk, and in patients who were refractory to lenalidomide."

Response rates and depth of responses also were greater in the daratumumab group:

  • overall response rate: 69% with daratumumab + Pd vs. 46% with Pd alone
  • complete response rate: 24% vs. 4%
  • measurable residual disease negativity rate: 9% vs. 2%

The investigators found no new safety concerns with the daratumumab combination. Common grade 3/4 adverse events (AEs) with a greater than 5% difference between the two treatment groups included: neutropenia (68% for daratumumab vs. 51% for Pd alone), leukopenia (17% vs. 5%), lymphopenia (12% vs. 3%), febrile neutropenia (9% vs. 3%), and pneumonia (13% vs. 7%). Rates of treatment discontinuation due to treatment-emergent AEs were similar between the two arms: 2% for daratumumab plus Pd and 3% for Pd alone. The rates of death due to treatment-emergent AEs also were similar, at 7% in each group.

The rate of infusion-related reactions with the subcutaneous formulation of daratumumab was low, at 5% (all of which were grade 1/2). Another 2% of patients had local injection-site reactions; again, all were low-grade.

Importantly, they added, the median duration of treatment injection was five minutes, "thus increasing convenience for patients and decreasing treatment burden."

Study authors report relationships with Janssen, which sponsored the trial.


Dimopoulos M, 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). Abstract #412. Presented at the 2020 ASH Annual Meeting, December 6, 2020.


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