Subcutaneous daratumumab regimen effective in pretreated multiple myeloma
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The addition of subcutaneous daratumumab to pomalidomide and dexamethasone significantly extended PFS among patients with pretreated multiple myeloma, according to study results presented at the virtual ASH Annual Meeting and Exposition.
The subcutaneous formulation also appeared well-tolerated, resulting in significantly fewer infusion-related reactions and requiring considerably shorter administration time than the IV formulation, results of the randomized phase 3 APOLLO trial showed.
“The results are quite clinically meaningful,” Meletios A. Dimopoulos, MD, chairman of the department of clinical therapeutics at National and Kapodistrian University of Athens School of Medicine in Greece, told Healio. “In addition to the efficacy and tolerability observed, the subcutaneous formulation is much more convenient and improves quality of life for patients. It reduces the time they need to spend in the hospital, and it reduces the burden for the staff at the outpatient treatment unit.”
The immunomodulatory drug pomalidomide (Pomalyst, Bristol Myers Squibb) in combination with low-dose dexamethasone is standard treatment for patients who received two or more lines of therapy and failed to achieve durable responses to lenalidomide (Revlimid, Bristol Myers Squibb) and a proteasome inhibitor.
“Response rates with this combination range from 30% to 40%, and median PFS is only about 6 months,” Dimopoulos said. “Thus, there is significant room for improvement.”
Daratumumab (Darzalex, Janssen) — a CD38-targeted monoclonal antibody — has shown activity as monotherapy or in combination with other standard regimens for multiple myeloma, and it is approved in the United States for multiple indications for patients with newly diagnosed or relapsed/refractory disease.
However, IV administration of daratumumab takes at least 2 hours and often requires patients to spend a full day at the clinic for each infusion, Dimopoulos said.
A subcutaneous formulation — daratumumab and hyaluronidase-fihj (Darzalex Faspro, Janssen) — is approved in the United States for several of the same indications as the IV formulation, and administration takes only a few minutes.
Dimopoulos and colleagues conducted the open-label, multicenter APOLLO study to evaluate the addition of the subcutaneous formulation to pomalidomide and low-dose dexamethasone for patients with relapsed or refractory multiple myeloma who received at least one prior therapy, including lenalidomide and a proteasome inhibitor.
The primary analysis included 304 patients (median age, 67 years; range, 35-90) from 12 European countries. About 60% of patients were aged older than 65 years.
All patients had ECOG performance status of 0 to 2 and had creatinine clearance values of at least 30 mL/min. Most patients had International Staging System stage I (45%) or stage II (33%) disease. About one-third (35%) had high cytogenetic risk, defined as presence of deletion 17p, translocation t(14;16) or translocation t(4;14).
Patients received a median two prior lines of therapy (range, 1-5). All responded to prior treatment and progressed on or after their most recent regimen.
Most patients (79.6%) — including the 11% of patients who received only one prior therapy — were refractory to lenalidomide; 48% were refractory to a proteasome inhibitor; and 42.4% were refractory to both.
Exclusion criteria included prior treatment with pomalidomide or anti-CD38 agents.
Patients received treatment in 28-day cycles until disease progression or unacceptable toxicity.
Researchers randomly assigned 153 patients to pomalidomide dosed at 4 mg daily on days 1 to 21 and dexamethasone dosed at 40 mg on days 1, 8, 15 and 22 (20 mg for patients aged 75 years or older).
The other 151 patients received the same pomalidomide-dexamethasone regimen plus daratumumab administered weekly in cycles 1 and 2, every 2 weeks in cycles 3 through 6, and every 4 weeks thereafter.
The first seven patients in the experimental regimen received IV daratumumab dosed at 16 mg/kg. After protocol amendment, all patients in the experimental group received the subcutaneous formulation, which consists of daratumumab dosed at 1,800 mg co-formulated with Halozyme’s proprietary recombinant human hyaluronidase PH20 enzyme.
PFS served as the primary endpoint. Major secondary endpoints included overall response rate, rate of complete response or better, rate of very good partial response or better, minimal residual disease negativity rate, OS and safety.
Median treatment duration was 11.5 months for those who received daratumumab and 6.6 months for those who received pomalidomide and dexamethasone alone. Median duration of injection with subcutaneous daratumumab was 5 minutes (range, 1-22).
Researchers performed the primary analysis after 190 PFS events. Median follow-up was 16.9 months.
The study met its primary endpoint of improved PFS in the daratumumab group (median, 12.4 months vs. 6.9 months; HR = 0.63; 95% CI, 0.47-0.85). Researchers observed the PFS benefit across all patient subsets, including patients who were refractory to lenalidomide (median, 9.9 months vs. 6.5 months; HR = 0.63) and those stratified by age, disease stage, number of prior therapies and cytogenetic profile.
Patients assigned daratumumab appeared considerably more likely to achieve hematologic response (69% vs. 46%; OR = 2.68; 95% CI, 1.65-4.35). They also were more likely to achieve complete response or better (25% vs. 4%), very good partial response or better (51% vs. 20%) and minimal residual disease negativity (9% vs. 2%; P = .0102).
Ninety-nine patients (33%) died by data cutoff. Researchers reported an HR for OS of 0.91 (95% CI, 0.61-1.35) with daratumumab; however, survival data were immature and follow-up is continuing.
“We saw a definite PFS advantage, with a 37% reduction in risk for progression, so it likely that this will translate to a survival advantage, as well,” Dimopoulos said.
The experimental regimen exhibited a safety profile consistent with prior reports of subcutaneous daratumumab and pomalidomide-dexamethasone. Researchers observed no new safety signals.
Rates of anemia (any grade, 37% vs. 44%; grade 3/grade 4, 17% vs. 21%) and thrombocytopenia (any grade, 32% vs. 33%; grade 3/grade 4, 17% vs. 18%) were comparable between the daratumumab and no-daratumumab groups.
The most common grade 3 or grade 4 adverse events that occurred more frequently among daratumumab-treated patients included neutropenia (68% vs. 51%), leukopenia (17% vs. 5%), lymphopenia (12% vs. 3%), febrile neutropenia (9% vs. 3%) and pneumonia (13% vs. 7%).
“The higher incidence of neutropenia, neutropenic fever and pneumonia was expected,” Dimopoulos said. “Whenever we administer daratumumab, we see a slight increase in this type of side effect.”
Five percent of patients who received subcutaneous daratumumab developed infusion-related reactions; all were grade 1 or grade 2. Two percent of patients experienced grade 1 local injection-site reactions.
A comparable percentage of patients in the daratumumab and no-daratumumab groups discontinued therapy due to treatment-emergent adverse events (2% vs. 3%) or experienced treatment-emergent adverse events that led to death (7% vs. 5%). Two percent of patients in each group developed secondary primary malignancies.
The results show the regimen is an effective, safe and convenient treatment option for this patient population, researchers concluded.
“This was the first study that used subcutaneous daratumumab in the context of a prospective randomized trial,” Dimopoulos told Healio. “A prior study had indicated subcutaneous daratumumab had equal efficacy with better tolerability as compared with the IV formulation, and our results are reassuring that subcutaneous daratumumab can be added to other effective regimens for the treatment of multiple myeloma.”
In real-world settings, many patients receive front-line treatment with VRd, which consists of the proteasome inhibitor bortezomib (Velcade, Takeda/Millennium), lenalidomide and dexamethasone.
“For patients who start treatment with VRd and progress on lenalidomide maintenance or continuous treatment, I believe this combination is a suitable treatment that may offer them longer PFS than standard-of-care therapies,” Dimopoulos said.
Perspective
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Lisa Hicks, MD
This is the first phase 3 trial utilizing subcutaneous daratumumab rather than the traditional approach of IV daratumumab. To know daratumumab can be given with good efficacy via the subcutaneous route is very important for our patients who spend an awful lot of time in our clinics and our waiting rooms. The results highlight an approach that could save significant time and treatment burden for patients and for clinics.
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Dimopoulos MA, et al. Abstract 412. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
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