Subcutaneous Daratumumab Approved for Newly Diagnosed Light Chain Amyloidosis

Amyloidosis cells.

The FDA has granted accelerated approval to daratumumab plus hyaluronidase (Darzalex Faspro®, Janssen Biotech, Inc.) in combination with bortezomib, cyclophosphamide, and dexamethasone (VCd) for the treatment of patients with newly diagnosed amyloid light chain (AL) amyloidosis.

“As immunoglobulin light chains present in AL amyloidosis are considered to be toxic to involved organs, especially the heart, rapid and deep hematologic remission with reduction of these light chains with frontline therapy may be crucial to improving long-term clinical outcomes,” stated Ashutosh D. Wechalekar, MD, Professor of Medicine and Hematology at the University College London, and colleagues in their publication of 1- and 3-month results of the phase 3 ANDROMEDA study (NCT03201965), on which the approval was based.

ANDROMEDA enrolled 388 patients with newly diagnosed systemic AL amyloidosis who had measurable hematologic disease and at least one affected organ according to consensus criteria. Vital organ involvement included cardiac (71%), renal (59%), and hepatic (8%) organs. Patients were randomized to receive six cycles of 1.3 mg/m2 bortezomib, 300 mg/m2 cyclophosphamide, and 40 mg dexamethasone alone or in combination with 1,800 mg daratumumab plus 30,000 units hyaluronidase once weekly for Cycles 1 and 2, once every two weeks for Cycles 3–6, and once every four weeks thereafter as monotherapy, for a maximum of two years or until disease progression.

At a median follow-up of 11.4 months, daratumumab/hyaluronidase in combination with VCd (D-VCd) significantly increased the rate of hematologic complete response compared with VCd alone (42.1% vs 13.5%), with an odds ratio of 4.8. The median time to hematologic complete response was 59 days for both groups. Overall survival data was not yet mature at the time of analysis.

The most common adverse events occurring in at least 20% of patients receiving D-VCd included upper respiratory tract infection, diarrhea, peripheral edema, constipation, peripheral sensory neuropathy, fatigue, nausea, insomnia, dyspnea, and cough. Serious adverse events experienced by at least 5% of patients included pneumonia, cardiac failure, and sepsis.

The prescribing information for daratumumab/hyaluronidase includes a warning that hypersensitivity, cardiac toxicity, neutropenia, thrombocytopenia, embryo-fetal toxicity, and interference with cross-matching and red blood cell antibody screening may occur. Daratumumab/hyaluronidase is contraindicated for patients with New York Heart Association (NYHA) Class IIIB/IV cardiac disease or Mayo Stage IIIB disease, outside of clinical trials.

“These data confirm that initial therapy that achieves rapid and deep hematological responses is essential to improving long-term outcomes in AL amyloidosis,” concluded Dr. Wechalekar and colleagues in their presentation abstract at the American Society of Hematology (ASH) Annual Meeting in December 2020.

The recommended dose of daratumumab is 1,800 mg with 30,000 units hyaluronidase administered subcutaneously into the abdomen over 3 to 5 minutes, in combination with the recommended schedule of VCd.

For More Information

Wechalekar AD, Palladini G, Merlini G, et al (2020). Rapid and deep hematologic responses are associated with improved major organ deterioriation progression-free survival in newly diagnosed AL amyloidosis: results from ANDROMEDA. Blood (ASH Annual Meeting Abstracts), 136(suppl_1):6-7. Abstract 2305. DOI:10.1182/blood-2020-140514

Clinicaltrials.gov (2020). A study to evaluate the efficacy and safety of daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone (CyBorD) compared to CyBorD alone in newly diagnosed systemic amyloid light-chain (AL) amyloidosis. NLM identifier: NCT03201965.

US Food & Drug Administration (2020). FDA grants accelerated approval to Darzalex Faspro for newly diagnosed light chain amyloidosis. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-darzalex-faspro-newly-diagnosed-light-chain-amyloidosis

Darzalex Faspro® (daratumumab and hyaluronidase-fihj) prescribing information. Janssen Biotech, Inc. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761145s002lbl.pdf

Image credit: Ed Uthman, MD. Licensed under CC BY-SA 2.0


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