On November 30, 2021, daratumu­mab/hyaluronidase-fihj and carfilzomib were approved for use in combination with dexamethasone for adults with relapsed or refractory multiple myeloma who had one to three prior lines of therapy.^1,2

Supporting Efficacy Data

Approval was based on findings in a cohort of the ­PLEIADES trial (ClinicalTrials.gov identifier NCT03412565), in which 66 patients with at least one prior line of therapy received the combination product containing daratumumab at 1,800 mg and hyaluronidase-fihj at 30,000 units plus carfilzomib in a 20/70 mg/m² once-weekly regimen and dexamethasone.

Partial response or better was achieved in 56 patients (84.8%, 95% confidence interval = 73.9%–92.5%). At a median follow-up of 9.2 months, the median duration of response was not reached, with responses maintained at ≥ 6 and ≥ 9 months in 85.2% and 82.5% of patients.

How It Is Used

The recommended dose of the combination is daratumumab at 1,800 mg and hyaluronidase-fihj at 30,000 units given subcutaneously once weekly in weeks 1 through 8, once every 2 weeks in weeks 9 through 24, and once every 4 weeks starting at week 25 until disease progression or unacceptable toxicity.

The recommended dosage regimens of carfilzomib via intravenous infusion are 20 mg/m² on cycle 1/day 1; 70 mg/m² on cycle 1, days 8 and 15; and then days 1, 8, and 15 of each 28-day cycle; or 20 mg/m² on cycle 1/days 1 and 2; 56 mg/m² on cycle 1/days 8, 9, 15, and 16; and then days 1, 2, 8, 9, 15, and 16 of each 28-day cycle.

Safety Profile

In the PLEIADES trial, the most common adverse events of any grade (≥ 20%) were upper respiratory tract infection (52%), fatigue (39%), insomnia (33%), hypertension (32%), diarrhea (29%), cough (24%), dyspnea (23%), headache (23%), pyrexia (21%), nausea (21%), and peripheral edema (20%). The most common grade 3 or 4 adverse events included hypertension (21%) and insomnia (6%). The most common grade 3 or 4 laboratory abnormalities were decreased lymphocytes (50%) and decreased platelets and leukocytes (18% each). Serious adverse events occurred in 27% of patients. Adverse events led to discontinuation of treatment in 6%. Fatal adverse events occurred in 3%.

Daratumumab/hyaluronidase-fihj has warnings/precautions for hypersensitivity and other administration reactions, cardiac toxicity in patients with light chain amyloidosis, neutropenia, thrombocytopenia, embryofetal toxicity, and interference with cross-matching and red blood cell antibody screening. It is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase, or any formulation components.

Carfilzomib has warnings/precautions for cardiac toxicities, acute renal failure, tumor-lysis syndrome, pulmonary toxicity, pulmonary hypertension, dyspnea, hypertension, venous thrombosis, infusion-related reactions, hemorrhage, thrombocytopenia, hepatic toxicity, thrombotic microangiopathy, posterior reversible encephalopathy syndrome, progressive multifocal leukoencephalopathy, increased fatal and serious toxicities in combination with melphalan and prednisone in newly diagnosed transplant-ineligible patients, and embryofetal toxicity. 

REFERENCES

1. Darzalex faspro (daratumumab and hyaluronidase-fihj) injection, for subcutaneous use, prescribing information, Janssen Biotech, November 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761145s009lbl.pdf. Accessed December 10, 2021.

2. Kyprolis (carfilzomib) for injection, for intravenous use, prescribing information, Amgen, November 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202714s033lbl.pdf. Accessed December 10, 2021.