Subcutaneous Daratumumab Effective Alternative to IV Formulation for Multiple Myeloma

By Will Boggs MD

May 01, 2020

NEW YORK (Reuters Health) - Subcutaneous daratumumab could offer an effective and more convenient alternative to the intravenous formulation for patients with relapsed or refractory multiple myeloma, according to results from the COLUMBIA trial.

"The subcutaneous formulation of daratumumab is noninferior to the IV formulation, while having the convenience of quick administration and lower incidence of infusion reactions," Dr. Saad Z. Usmani of Levine Cancer Institute-Atrium Health, Charlotte, North Carolina, told Reuters Health by email. "Overall, it is a much patient-friendlier option and will likely get the nod from the FDA (Food and Drug Administration) this year."

Daratumumab's intravenous formulation received initial FDA approval in 2015 as monotherapy for patients with multiple myeloma who have received at least three prior lines of therapy. Administration of the intravenous formulation takes about seven hours for the first infusion and three to four hours thereafter. Infusion-related reactions occur in about half of the patients.

Dr. Usmani and colleagues at 147 centers in 18 countries investigated the efficacy and pharmacokinetics of subcutaneous daratumumab versus intravenous daratumumab in a noninferiority trial of 522 patients with relapsed or refractory multiple myeloma.

Overall, 43% of patients in the subcutaneous group and 44% of patients in the intravenous group discontinued daratumumab, mainly due to progressive disease.

Subcutaneous daratumumab had a reduced administration time (about five minutes) for all dose administrations, compared with intravenous daratumumab.

Overall response rates did not differ significantly between the subcutaneous group (41%) and the intravenous group (37%), the researchers report in The Lancet Haematology.

The mean maximum trough concentration of daratumumab did not differ significantly between the groups (thereby also meeting the pharmacokinetics noninferiority criterion). But trough concentrations in the subcutaneous group were higher in the lightest bodyweight subgroup and lower in the heaviest bodyweight subgroup.

Infusion-related reaction rates were significantly lower for the subcutaneous formulation (13%) than for the intravenous formulation (34%). In the intravenous group, these reactions led to dose interruptions for 31% of patients, infusion terminations in one patient, infusion rate decreases in 10% of patients and treatment discontinuation in two patients.

In contrast, there were no infusion-reaction-related treatment discontinuations, dose interruptions, or incomplete dose administrations in the subcutaneous group.

After a median of 7.5 months of follow-up, disease progression or death had occurred in 51% of patients in both groups, and median survival did not differ significantly between the subcutaneous group (5.6 months) and the intravenous group (6.1 months).

Overall survival data were not mature, but six-month survival was similar in the subcutaneous (88%) and intravenous (83%) groups.

Patient satisfaction scores were consistently higher in the subcutaneous group than in the intravenous group.

Safety profiles were similar in the two treatment groups, and no patients in the subcutaneous daratumumab group developed anti-daratumumab antibodies (versus one patient in the intravenous group).

"Further data are needed to confirm our findings for combination regimens," the authors note.

"This study showed the feasibility, effectiveness, safety, and increased patient satisfaction of subcutaneous daratumumab monotherapy," write Dr. Terri Lynn Shigle and Dr. Qaiser Bashir of The University of Texas MD Anderson Cancer Center, in Houston, in a linked editorial. "The short administration time, fixed dose, and reduced incidence of infusion-related reactions could help to simplify treatment regimens and improve institutional workflows."

"Cost-effectiveness will need to be further evaluated," they note. "As the data regarding the combination of subcutaneous daratumumab with other drugs become available, this formulation is likely to gain wider use."

Dr. Torben Plesner of the University of Southern Denmark, in Vejle, who participated in the phase 1b PAVO study of subcutaneous daratumumab, told Reuters Health by email, "Preparation and administration of daratumumab for subcutaneous use is easier for the pharmacy as well as for the hospital staff in the outpatient clinic and takes much shorter time, which is important for the busy outpatient clinics but also very convenient for the patient."

"The health care systems in all countries are under tough financial pressure, but if the price policy of the manufacturing company allows for a similar price per patient for treatment with subcutaneous daratumumab, I predict a rapid transition from daratumumab IV to daratumumab SC," he said.

Dr. Ajay Nooka of Winship Cancer Institute at Emory University, in Atlanta, Georgia, who recently reviewed the use of daratumumab in multiple myeloma, told Reuters Health by email, "The biggest challenges or questions that arise during the transition from IV to SC formulation are the lack of safety data from ongoing IV administration to SC formulation of daratumumab - all the trials currently done have either used IV or SC formulation but no evidence of safety data for transition."

"We currently do not have the consensus/guidance for how long the patient should be observed after the SC formulation first dose," he said, adding, "Only 3% of patients in SC arm and 2% in IV arms are Black. Are the pharmacokinetic parameters of Ctrough for IV versus SC valid in Black population?"

"The same above questions arose at the time of IV to SC transition with bortezomib (another medication used for multiple myeloma)," said Dr. Nooka, who was not involved in the new research.

Janssen submitted its application to the FDA seeking approval of the SC formulation in July 2019. The company funded the study and employed many of the authors. Dr. Usmani and other coauthors also report ties to Janssen.

SOURCE: https://bit.ly/2yLFr5B and https://bit.ly/2Va7oeM Lancet Haematology, online March 23, 2020.

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