Subcutaneous daratumumab noninferior to IV formulation, more tolerable for advanced multiple myeloma
A subcutaneous formulation of daratumumab appeared noninferior to the standard IV formulation among patients with relapsed or refractory multiple myeloma, according to results of the randomized phase 3 COLUMBA trial published in The Lancet Haematology.
“The rationale to develop a subcutaneous formulation of daratumumab [Darzalex, Janssen] was to improve the convenience of administration, as the IV formulation may take several hours to administer,” Saad Z. Usmani, MD, FACP, division chief of plasma cell disorders at Levine Cancer Institute at Atrium Health and a HemOnc Today Editorial Board Member, told Healio. “The COLUMBA trial showed that the subcutaneous formulation is noninferior to the IV formulation and appears to have better tolerability.”
The ongoing, multicenter, open-label, noninferiority trial included 522 adults with relapsed or refractory multiple myeloma recruited across 147 sites in 18 countries.
All study participants had ECOG performance status of 2 or less. They also had received at least three previous lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or were double refractory to both.
The researchers randomly assigned patients 1:1 — based upon baseline body weight, number of previous therapy lines and myeloma type — to subcutaneous daratumumab (n = 263) dosed at 1,800 mg and co-formulated with 2,000 U/mL recombinant human hyaluronidase PH20 enzyme, or 16 mg/kg IV daratumumab (n = 259). Among these patients, three in the subcutaneous group and one in the IV group did not receive treatment and could not be evaluated for safety.
Baseline patient demographics appeared generally well-balanced between the subcutaneous and IV groups, including median age (65 years vs. 68 years). Most patients in each group were men (52% vs. 58%), were white (79% vs. 78%), and had received a median four or fewer previous therapies (66% vs. 68%).
Participants received daratumumab once weekly for the first two cycles, followed by once every 2 weeks for cycles three to six and once every 4 weeks afterward, in 28-day cycles until disease progression or toxicity.
Overall response and maximum trough concentration served as primary endpoints. Researchers conducted efficacy analyses in the intention-to-treat population.
At median follow-up of 7.5 months (interquartile range, 6.5-9.3), 111 patients in each group remained on treatment. Patients received a median six cycles of treatment per group.
Results showed an ORR of 41% in the subcutaneous group vs. 37% in the IV group (RR = 1.11; 95% CI, 0.89-1.37).
The geometric means ratio for trough concentration between the two groups was 107.93% (90% CI, 95.74-121.67). Maximum trough concentration in the subcutaneous group was 593 mg/mL compared with 522 mg/mL in the IV group.
Researchers observed a significantly lower proportion of infusion-related reactions in the subcutaneous group vs. the IV group (13% vs. 34%; OR = 0.28; 95% CI, 0.18-0.44). The most common treatment-emergent grade 3 to grade 4 adverse events included anemia (13% in the subcutaneous group vs. 14% in the IV group), neutropenia (13% vs. 8%) and thrombocytopenia (14% for both).
Seven patients (3%) in the subcutaneous group and 11 patients (4%) in the IV group developed severe pneumonia. Researchers observed one treatment-associated death in the subcutaneous group and four treatment-associated deaths in the IV group.
Median PFS was 5.6 months (95% CI, 4.7-7.6) in the subcutaneous group vs. 6.1 months (95% CI, 4.7-8.3) in the IV group (HR = 0.99; 95% CI, 0.78-1.26). OS data were not mature.
“It is our hope that this convenient option of subcutaneous daratumumab will receive regulatory approval and can be used in clinical practice soon,” Usmani told Healio. – by Jennifer Southall
For more information:
Saad Z. Usmani, MD, FACP, can be reached at Levine Cancer Institute at Atrium Health, 1000 Blythe Blvd., Charlotte, NC 28203; email: firstname.lastname@example.org.
Disclosures: Janssen Research & Development funded this study. Usmani reports consultant/speakers bureau roles with and/or research funding/travel expenses from AbbVie, Amgen/Onyx, Array BioPharma, Celgene, GlaxoSmithKline, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, Skyline and Takeda/Millennium. Please see the study for all other authors’ relevant financial disclosures.