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A subcutaneous formulation of daratumumab (Darzalex Faspro) met the primary endpoint of progression-free survival (PFS) as part of combination therapy for relapsed multiple myeloma, data from a randomized trial showed.

Median PFS almost doubled, from 6.9 months with pomalidomide (Pomalyst) and dexamethasone (Pd) to 13.4 months with the addition of daratumumab (D-Pd), including a 50% improvement in median PFS in patients with lenalidomide (Revlimid)-refractory disease.

The addition of the anti-CD38 antibody also increased depth of response, as 25% of patients achieved complete response or better status as compared with 4% of patients randomized to the two-drug regimen. Four times as many patients treated with the three-drug regimen attained minimal residual disease (MRD)-negative status, reported Meletios A. Dimopoulos, MD, of the University of Athens in Greece, during the American Society of Hematology virtual meeting.

"[D]aratumumab in combination with pomalidomide and dexamethasone has been approved for several years in the United States. However, in the absence of a prospective, randomized trial, this combination was not available outside the United States," Dimopoulos said during a press briefing. "I believe that this trial may lead to such an approval and also establish the role of subcutaneous daratumumab as a standard of administration for patients who may benefit from this drug."

Dimopoulos pointed out that a subcutaneous option also confers quality-of-life benefits for patients and healthcare providers by reducing administration time from hours to a few minutes.

The D-Pd regimen with intravenous daratumumab induced in patients with heavily pretreated multiple myeloma, and provided the basis for FDA approval of the regimen for myeloma that had progressed on two or more prior regimens. In laboratory and clinical studies, the subcutaneous formulation of daratumumab similar to those of the IV formulation, leading to of the formulation earlier this year.

Despite the regulatory approval and proof of noninferiority to IV daratumumab, no phase III trial had evaluated the D-Pd regimen with the subcutaneous formulation of the antibody. Dimopoulos reported findings from the phase III APOLLO trial that compared Pd and D-Pd in patients who had received one or more prior regimens for multiple myeloma.

Investigators randomized 304 patients to the two regimens, and treatment continued until disease progression or development of unacceptable toxicity. The primary endpoint was PFS.

The study population had a median age of 67-68, a disease duration of 4-4.5 years, and a treatment history that included a median of two prior regimens; 60-70% had standard-risk cytogenetics. Dimopoulos reported that 80% of the patients had lenalidomide-refractory disease and 42% were refractory to both lenalidomide and a protease inhibitor.

The median administration time for daratumumab was 5 minutes and ranged from 1 to 22 minutes. Patients remained on the three-drug regimen almost twice as long as compared with Pd (11.5 vs 6.6 months). The most common reason for treatment discontinuation was disease progression, and 2-3% of patients in each treatment group discontinued because of adverse events.

After a median follow-up of 16.9 months, treatment with D-Pd was associated with a 37% reduction in the hazard for disease progression or death as compared with Pd (95% CI 0.47-0.85, P=0.0018). The proportion of patients who remained progression free at 12 months was 52% with D-Pd and 35% with Pd. The lenalidomide-refractory subgroup had a median PFS of 9.9 months with D-Pd and 6.5 months with Pd. Dimopoulos said the PFS benefit was consistent across prespecified subgroups.

The D-Pd regimen led to an overall response rate of 69%, including very good partial response (VGPR) or better in 51% of patients, as compared with 46% and 20% in the control arm, respectively, representing an odds ratio of 2.68 for hematologic response for patients in the D-Pd arm (95% CI 1.65-4.35, P<0.0001). Additionally, 9% of patients assigned to D-Pd achieved MRD-negative status versus 2% in the Pd arm (P=0.0102).

Dimopoulos said the safety profile of D-Pd was consistent with the known toxicities associated with subcutaneous daratumumab and the pomalidomide-dexamethasone combination. Subcutaneous daratumumab was associated with a 2% incidence of local injection-site reactions, all of which were grade 1 in severity. Each treatment group had a 2% incidence of secondary malignancy.

The trial results have very practical implications for patients and providers, suggesting a potentially substantial savings of time and treatment burden for patients and clinic personnel, said Lisa Hicks, MD, of the University of Toronto.

"Knowing that daratumumab can be given with good efficacy via the subcutaneous route is very important for our patients," said Hicks, who moderated a press briefing that included Dimopoulos's presentation. "Patients spend an awful lot of time in our clinics and waiting rooms."

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