On May 1, 2020, the combination of daratumumab and hyaluronidase-fihj was approved for adult patients with newly diagnosed or relapsed/refractory multiple myeloma. This new product allows for subcutaneous (SC) dosing of daratumumab.^1,2 Daratumumab and hyaluronidase-fihj is for SC use only.

The product is a combination of the CD38-targeted antibody daratumumab and recombinant human hyaluronidase in a ready-to-use formulation. The naturally occurring endoglycosidase enzyme hyaluronidase acts to depolymerize hyaluronan, a polysaccharide found in the extracellular matrix of SC tissue. Hyaluronidase (recombinant human) is used to increase the dispersion and absorption of coadministered drugs when administered SC.

Daratumumab and hyaluronidase-fihj is approved for the following indications, for which intravenous (IV) daratumumab has already been approved:

• In combination with bortezomib, melphalan, and prednisone (D-VMP) in newly diagnosed patients who are ineligible for autologous stem cell transplantation.
• In combination with lenalidomide and dexamethasone (D-Rd) in newly diagnosed patients who are ineligible for autologous stem cell transplantation and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy.
• In combination with bortezomib and dexamethasone (D-Vd) in patients who have received at least one prior therapy.
• As monotherapy, in patients who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who are double-refractory to those drug types.

Supporting Efficacy Data

Data supporting the efficacy of daratumumab and hyaluronidase-fihj come from the open-label noninferiority phase III COLUMBA trial (ClinicalTrials.gov identifier NCT03277105) of monotherapy and the open-label multicohort PLEIADES trial (ClinicalTrials.gov identifier NCT03412565), which included cohorts treated with D-VMP and D-Rd.^2,3

In the COLUMBA trial,³ 263 patients were randomly assigned to receive daratumumab plus hyaluronidase-fihj (1,800 mg/30,000 units) and 259 to daratumumab 16 mg/kg IV. Each group received treatment once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24, and once every 4 weeks, starting with week 25 until unacceptable toxicity or disease progression. Patients had to have had relapsed or refractory multiple myeloma and had either received at least three prior lines of therapy, including a proteasome inhibitor, or were double-refractory to a proteasome inhibitor and an immunomodulatory agent. The co-primary endpoints were overall response rate and the pharmacokinetic endpoint of the maximum C_trough on cycle 3, day 1 predose.

Daratumumab plus hyaluronidase-fihj was noninferior to daratumumab IV in both endpoints. The overall response rate was 41% in the daratumumab and hyaluronidase-fihj group (very good partial response or better in 19%) and 37% (very good partial response or better in 17%) in the daratumumab IV group, with a risk ratio of 1.11 (95% confidence interval [CI] = 0.89–1.37). The geometric mean ratio for maximum C_trough for daratumumab plus hyaluronidase-fihj vs daratumumab IV was 108% (90% CI = 96%–122%).

In a cohort of the PLEIADES study, comprising patients with newly diagnosed multiple myeloma who were ineligible for transplantation,² 67 patients received D-VMP, with daratumumab plus hyaluronidase-fihj (1,800 mg/30,000 units) given once weekly from weeks 1 to 6, once every 3 weeks from weeks 7 to 54, and once every 4 weeks, starting with week 55 until disease progression or unacceptable toxicity. The overall response rate was 88%, with very good partial response or better in 64%.

In another cohort of the PLEIADES study, comprising patients with relapsed/refractory disease who had received at least one prior line of therapy,² 65 patients received D-Rd, with daratumumab plus hyaluronidase-fihj (1,800 mg/30,000 units) given once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24. and once every 4 weeks, starting with week 25 until disease progression or unacceptable toxicity. The overall response rate was 91%, with very good partial response or better in 65%.

How It Is Used

Daratumumab plus hyaluronidase-fihj is for SC use only. It should be administered by a health-care provider.

The recommended dose of daratumumab and hyaluronidase-fihj is 1,800 mg/30,000 units, given SC into the abdomen over approximately 3 to 5 minutes. Prescribing information provides detailed instructions on administration schedules for daratumumab plus hyaluronidase-fihj given as monotherapy and when given in combination D-Rd, D-VMP, and D-Vd regimens. No dose reductions of daratumumab and hyaluronidase-fihj are recommended. Withholding treatment should be considered to allow recovery of blood cell counts in case of myelosuppression.

Premedication and postmedication to prevent administration-related reactions and prophylaxis for herpes zoster reactivation are recommended. Prescribing information provides detailed instructions for premedication and postmedication when daratumumab and hyaluronidase-fihj is given as monotherapy and when used in combination therapy. Daratumumab plus hyaluronidase-fihj interferes with serologic testing. Patients should be typed and screened prior to starting treatment, and blood banks should be informed that a patient has received the agent.

Safety Profile

The most common adverse event (≥ 20%) with daratumumab plus hyaluronidase-fihj monotherapy is upper respiratory tract infection. The most common adverse events (≥ 20%) with D-VMP are upper respiratory tract infection, constipation, nausea, fatigue, pyrexia, peripheral sensory neuropathy, diarrhea, cough, insomnia, vomiting, and back pain. The most common adverse events (≥ 20%) with D-Rd are fatigue, diarrhea, upper respiratory tract infection, muscle spasms, constipation, pyrexia, pneumonia, and dyspnea.

The most common hematology laboratory abnormalities (≥ 40%) with daratumumab plus hyaluronidase-fihj are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin.

Among 260 patients receiving daratumumab and hyaluronidase-fihj monotherapy in the COLUMBA trial, serious adverse events occurred in 26%. Adverse events led to dosage interruption in 26%, with those requiring interruption in more than 5% including thrombocytopenia, and to permanent discontinuation in 10%, with those requiring discontinuation in more than two patients consisting of thrombocytopenia and hypercalcemia. Adverse events led to death in 5% of patients, with causes occurring in more than one patient being general physical health deterioration, septic shock, and respiratory failure.

Among 67 patients receiving D-VMD in the PLEIADES trial, serious adverse events occurred in 39%, with those occurring in more than 5% being pneumonia and pyrexia. Adverse events led to dosage interruption in 51% of patients, with those requiring interruption in more than 5% of patients including thrombocytopenia, neutropenia, anemia, and pneumonia. Adverse events led to permanent discontinuation in 4.5%, with those requiring discontinuation in more than one patient consisting of neutropenic sepsis. Fatal adverse events occurred in 3% of patients.

Among 65 patients receiving D-Rd in the PLEIADES study, serious adverse events occurred in 48%, with those occurring in more than 5% including pneumonia, influenza, and diarrhea. Adverse events led to dosage interruption in 63% of patients, with those requiring interruption in more than 5% including neutropenia, pneumonia, upper respiratory tract infection, influenza, dyspnea, and increased blood creatinine. Adverse events led to permanent discontinuation in 11% of patients, with those requiring discontinuation in more than one patient being pneumonia and anemia. Fatal adverse events occurred in 3.1% of patients.

Daratumumab plus hyaluronidase-fihj has warnings/precautions for hypersensitivity and other administration reactions, neutropenia, thrombocytopenia, embryofetal toxicity, and interference with cross-matching and red blood cell antibody screening. Treatment should be permanently discontinued for life-threatening administration-related reactions. Complete blood cell counts should be monitored periodically during treatment and withholding treatment should be considered to allow recovery of neutrophils or platelets. Patients should be typed and screened prior to starting treatment and blood banks should be informed that a patient has received the agent. Use is contraindicated in patients with a history of severe hypersensitivity to daratumumab or any of the components of the formulation. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves daratumumab and hyaluronidase-fihj for multiple myeloma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-daratumumab-and-hyaluronidase-fihj-multiple-myeloma. Accessed May 28, 2020.

2. U.S. Food and Drug Administration: Highlights of prescribing information for Darzalex Faspro (daratumumab and hyaluronidase-fihj) injection, for subcutaneous use. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761145s000lbl.pdf. Accessed May 28, 2020.

3. Mateos M-V, Nahi H, Legiec W, et al: Subcutaneous vs intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): A multicentre, open-label, non-inferiority, randomised, phase III trial. Lancet Haematol 7:e370-e380, 2020.