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Subcutaneous daratumumab attains deep response in multiple myeloma
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A subcutaneous formulation of daratumumab exhibited similar pharmacokinetics as the standard IV formulation among patients with relapsed or refractory multiple myeloma, according to results from the phase 1B PAVO study published in Blood.
The higher of the two doses evaluated induced deep, durable responses among patients with heavily pretreated disease.
Subcutaneous daratumumab (Darzalex, Janssen) also appeared associated with a lower rate of infusion-related reactions as the IV formulation, results showed.
“Daratumumab, a human monoclonal antibody targeting CD38, is approved as monotherapy and in combination regimens for patients with multiple myeloma,” Saad Z. Usmani, MD, FACP, chief of plasma cell disorders and director of clinical research in hematologic malignancies at Levine Cancer Institute at Atrium Health, as well as a HemOnc Today Editorial Board Member, and colleagues wrote. “Currently, daratumumab is administered IV. The phase 1b PAVO study evaluated subcutaneously administered daratumumab in combination with the recombinant human hyaluronidase PH20 enzyme [for] patients with relapsed or refractory multiple myeloma.”
The first part of the open-label, multicenter dose-escalation study included 53 patients aged 18 years or older with measurable serum or urine M-protein levels and an ECOG performance status of 2 or less.
All study participants received at least two prior lines of treatment — including a proteasome inhibitor and an immunomodulatory drug — but had not received anti-CD38 therapy.
Patients received a mix-and-deliver formulation of daratumumab and recombinant human hyaluronidase PH20 enzyme administered via subcutaneous infusion.
Evaluated doses — based on the approved weekly 16-mg/kg IV dose for daratumumab — were 1,200 mg (n = 8; median age, 65.5 years) or 1,800 mg (n = 45; median age, 63 years).
Treatment was administered in 28-day cycles on the following schedule: once weekly in the first and second cycles; every 2 weeks in the third through sixth cycles; and then every 4 weeks until disease progression or unacceptable toxicity.
The most common treatment-emergent adverse events among patients who received the 1,200-mg dose were thrombocytopenia, upper respiratory tract infection, insomnia and decreased appetite (37.5% each).
The most common treatment-emergent adverse events among patients who received the 1,800-mg dose were anemia (33.3%), upper respiratory tract infection (26.7%), pyrexia (26.7%) and diarrhea (26.7%).
Infusion-related reactions occurred among one patient (12.%) in the 1,200-mg group and 11 patients (24.4%) in the 1,800-mg group. The majority of reactions were grade 1 or grade 2, and most occurred after the first infusion.
The 1,800-mg subcutaneous dose appeared associated with serum concentrations similar to or greater than those observed with the approved 16-mg/kg IV dose. Researchers reported overall response rates of 25% in the 1,200-mg group and 42.2% in the 1,800-mg group.
Many of the responses reported in the 1,800-mg group deepened over time. Ten patients achieved initial partial response; with further treatment, three subsequently achieved stringent complete response and four achieved very good partial response. Also, one patient in the 1,800-mg group who initially achieved very good partial response subsequently achieved a stringent complete response.
The second part of this study — which is ongoing — will evaluate the co-formulation of daratumumab and recombinant human hyaluronidase PH20 enzyme at the 1,800-mg dose.
“These findings show that subcutaneous administration of daratumumab is feasible [for] patients with multiple myeloma,” Usmani and colleagues wrote. “The 1,800-mg dose of [mix-and-deliver daratumumab plus recombinant human hyaluronidase PH20 enzyme] achieves pharmacokinetic concentrations similar to or greater than those following IV infusion of daratumumab 16 mg/kg, achieves deep and durable responses in patients with multiple myeloma, and has an acceptable safety profile with a low rate of infusion-related reactions.” – by Jennifer Byrne
Disclosures: Usmani reports consultant roles with, research funding from, speakers’ bureau roles with or travel expenses from AbbVie, Amgen/Onyx, Array BioPharma, Celgene, GlaxoSmithKline, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, Skyline or Takeda/Millennium. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Adam Binder, MD
The results of the phase 1B PAVO study coupled with those of the COLUMBA trial, presented at this year’s ASCO Annual Meeting, will lead to significant improvements in the patient experience in the treatment of multiple myeloma.
Since receiving FDA accelerated approval in November 2015, daratumumab, an IgG1k monoclonal antibody targeting CD38, has been integrated into every line of therapy for multiple myeloma, most recently as frontline treatment for transplant-ineligible patients. Although daratumumab is an important addition to the therapeutic options for multiple myeloma, its use presents challenges for patients and infusion centers resulting from infusion-related reactions and long infusion times.
Median duration of the initial dose of IV daratumumab is 7 hours for the first infusion, 4.3 hours for the second infusion and 3.4 hours for subsequent infusions. Rapid-rate infusions of daratumumab being adopted at multiple centers still take 90 minutes. When coupled with travel time to the cancer center, wait times for an infusion chair and the time it takes the pharmacy to mix the medications, patients spend hours if not the whole day at the cancer center. In addition, especially for elderly patients with poor venous access, a port-a-cath may be required given the frequency and duration of daratumumab infusions.
This trial showed that subcutaneous administration of daratumumab at a fixed dose of 1,800 mg in combination with recombinant human hyaluronidase PH20 enzyme was safe and effective. Although the infusion in this trial occurred over 30 minutes, a more concentrated formulation has been developed that can be administered over a 5-minute period, as was done in the COLUMBA study.
In addition to the convenience of rapid infusion, there seems to be a decrease in infusion-related reactions with the subcutaneous formulation. Moreover, all local injection site reactions resolved within 1 to 2 hours of administration. Patients still need to be monitored after the first infusion for an additional 6 hours, but with subsequent infusions they will be able to go home after just a few minutes of therapy.
The adoption of a subcutaneous formulation has the potential to significantly decrease time receiving treatment as well as obviate the need for IV or port-a-cath placement, greatly improving a patient’s quality of life. Indeed, with the right infrastructure, a mixed model of care can exist in which, according to patient preference, this medication can be delivered either at the infusion center or in the comfort of the patient’s home. Daratumumab is a highly active drug in the treatment of multiple myeloma, and this new formulation has the potential to improve the quality of life of those receiving it.
Reference: Mateos MV, et al. Abstract 8005. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
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