The first phase III study to evaluate the subcutaneous form of daratumumab has met its primary endpoint, investigators of the APOLLO trial reported at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition.1
The triplet of daratumumab, pomalidomide, and low-dose dexamethasone (D-Pd) significantly reduced the risk for disease progression or death by 37% over pomalidomide/dexamethasone alone in patients with previously treated relapsed or refractory multiple myeloma, according to Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens in Greece.
The findings add support to the use of the easy-to-administer subcutaneous form over the original intravenous form of daratumumab, which takes hours to administer, requires premedication and monitoring, and frequently leads to infusion-related reactions.
Meletios A. Dimopoulos, MD
Robert A. Brodsky, MD
“The nice thing about this, especially in the COVID-19 era, is this drug can be administered quickly in the outpatient setting. It’s basically a 5-minute injection or less. Subcutaneous daratumumab is a big advance and has a high likelihood of changing practice,” said press briefing moderator Robert A. Brodsky, MD, Professor of Medicine and Oncology and Director of the Division of Hematology, Johns Hopkins School of Medicine.
Asked by reporters whether some situations might still call for the intravenous form, Dr. Dimopoulos responded: “Not really. Maybe in the exceptional patient only.”
Median progression-free survival was 12.4 months with D-Pd vs 6.9 months with Pd. D-Pd also achieved significantly deeper responses, including a six times higher rate of complete response and a four times higher rate of minimal residual disease (MRD; also known as measurable residual disease) negativity vs Pd alone, he reported.
Also, of note, Dr. Dimopoulos continued: “The rate of infusion reactions was very low, and the duration of administration was short, thus increasing convenience for patients and decreasing treatment burden…. Thus, subcutaneous daratumumab with pomalidomide and low-dose dexamethasone is an effective and convenient treatment for patients,” Dr. Dimopoulos said.
Another Step for Daratumumab
Daratumumab is an anti-CD38 monoclonal antibody with multiple modes of action, both as a single agent and when combined with other standard regimens. In both the relapsed and front-line settings, daratumumab has been associated with significant improvements; in some studies, an overall survival benefit has been achieved.
In a phase Ib trial, the triplet of intravenous D-Pd produced deep responses and was well tolerated in patients with heavily pretreated relapsed or refractory disease.2 This led to the approval of this triplet in patients who had received at least two prior regimens, including lenalidomide and a proteasome inhibitor.
The subcutaneous formulation of daratumumab and hyaluronidase-fihj has a similar safety profile as intravenous daratumumab (with fewer infusion-related reactions). It is approved for use in the United States, European Union, Canada, and Korea.
About APOLLO
The phase III open-label, multicenter APOLLO study enrolled 304 patients from the European Myeloma Network who had relapsed or refractory multiple myeloma and had received at least one prior line of therapy (including lenalidomide and a proteasome inhibitor). Patients with one prior line of therapy had to be refractory to lenalidomide. Prior treatment with an anti-CD38 antibody or pomalidomide was not permitted.
These typical patients with relapsed or refractory myeloma were primarily older than 65 (60%), with approximately one-third having high-risk cytogenetics. By the International Staging System (ISS), 45% had stage I disease, 33% had stage II disease, and 22% had stage III disease. The median prior lines of therapy were two; 11% had received just one prior treatment. Nearly 80% were refractory to lenalidomide, 48% were refractory to a proteasome inhibitor, and 42% were refractory to both.
All patients received 28-day treatment cycles that included pomalidomide at 4 mg daily plus dexamethasone at 40 mg on days 1, 8, 15, and 22 (20 mg for patients ≥ 75 years of age). For patients given D-Pd, daratumumab at 1,800 mg co-formulated with recombinant human hyaluronidase PH20 was given weekly for cycles 1 and 2, every 2 weeks for cycles 3 to 6, and every 4 weeks thereafter. The primary endpoint was progression-free survival.
“At the time of the analysis, most patients were off study, primarily due to progressive disease, which was higher in the Pd arm,” he noted. “Very few patients went off study because of adverse events or physician’s decision.”
Study Meets Primary Endpoint
Dr. Dimopoulos presented the primary analysis, which was performed after 190 progression-free survival events and at a median follow-up of 16.9 months. The median duration of treatment was 11.5 months with D-Pd vs 6.6 months with Pd.
At that time, median progression-free survival was 12.4 months with D-Pd vs 6.9 months with Pd (HR = 0.63; P = .0018), thus meeting the study’s primary endpoint. In patients who were refractory to lenalidomide, median progression-free survival was 9.9 months vs 6.5 months. At 12 months, the progression-free survival rate was 52% in the daratumumab arm vs 35% in the control arm, he reported.
“This benefit was essentially seen across all subgroups of patients, including younger and older patients, patients with different ISS stages, regardless of prior line of therapy, lenalidomide refractoriness, and cytogenetic risk,” Dr. Dimopoulos noted.
Hazard ratios were 0.51 for the standard-risk group and 0.85 for patients with high-risk cytogenetics; 0.75 for patients with ISS stage III disease and 0.62 for patients with ISS stage I disease; 0.69 for patients younger than 65 and 0.55 for those older than 65.
The triplet was also superior to Pd in achieving deep responses, as follows:
- Overall response: 69% vs 46%
- Very good partial response or better: 51% vs 20%
- Complete response: 25% vs 4%
- MRD negativity: 9% vs 2%.
With a median follow-up of 16.9 months, 99 patients (33%) had died. Survival data are immature; at this point, the hazard ratio for overall survival is 0.91 (95% confidence interval = 0.61–1.35).
Safety Profile
D-Pd had a manageable toxicity profile, consistent with the known safety profiles of daratumumab, pomalidomide, and dexamethasone, Dr. Dimopoulos said. The most common grade 3 or 4 treatment-related adverse events for D-Pd and Pd, respectively, were neutropenia (68% vs 51%), leukopenia (17% vs 5%), lymphopenia (12% vs 3%), febrile neutropenia (9% vs 3%), pneumonia (13% vs 7%), and lower respiratory tract infections (11% vs 9%). Infusion-related events were rare, seen in 6% of the D-Pd arm; local injection-site reactions (all grade 1) were seen in 2% of this arm.
Rates of treatment-related study discontinuation were similar for D-Pd vs Pd (2% vs 3%). Rates of treatment-related adverse events leading to death were also similar (7%), as was the incidence of second primary malignancies (2%).
DISCLOSURE: Dr. Dimopoulos has received honoraria from BeiGene, Amgen, Celgene, Bristol Myers Squibb, Janssen, and Takeda. Dr. Brodsky has received honoraria from UpToDate and has served as an advisor or consultant to and received research funding from Achillion Pharmaceuticals and Alexion Pharmaceuticals.
REFERENCES
1. Dimopoulos MA, Terpos E, Boccadoro M, et al: Apollo: Phase 3 randomized study of subcutaneous daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in patients with relapsed/refractory multiple myeloma. 2020 ASH Annual Meeting & Exposition. Abstract 412. Presented December 6, 2020.
2. Chari A, Suvannasankha A, Fay JW, et al: Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood 130:974-981, 2017.
