FDA Approves Daratumumab and Hyaluronidase-fihj in Newly Diagnosed Light Chain Amyloidosis

The FDA has granted traditional approval to daratumumab and hyaluronidase-fihj (Darzalex Faspro) for use in combination with bortezomib (Velcade), cyclophosphamide, and dexamethasone (D-VCd) for the treatment of patients with newly diagnosed light chain (AL) amyloidosis.1

On January 15, 2021, the FDA granted accelerated approval to the regimen in this population.2 Both approvals were based on data from the phase 3 ANDROMEDA trial (NCT03201965), in which D-VCd led to an improvement in major organ deterioration progression-free survival (MOD-PFS) vs VCd alone (HR, 0.47; 95% CI, 0.33- 0.67; P < .0001).1 After a median follow-up of 61.4 months, the median MOD-PFS was not reached in the D-VCd arm vs 30.2 months in the VCd arm. Data also demonstrated an improvement in overall survival (OS) in the D-VCd arm compared with the VCd arm (HR, 0.62; 95% CI, 0.42-0.90; P = .0121). The median OS was not reached in either arm.

Previously reported data upon which the accelerated approval was based demonstrated that the hematologic complete response rate was 42.1% in the D-VCd arm vs 13.5% with VCd alone (OR, 4.8; 95% CI, 2.9-8.1; P < .0001).2

What was the ANDROMEDA trial designed to evaluate?

ANDROMEDA was an open-label, randomized, active-controlled trial that enrolled 388 patients with newly diagnosed AL amyloidosis with measurable disease and at least 1 involved organ based on consensus criteria.1

Patients were randomly assigned 1:1 to treatment with D-VCd (n = 195) or VCd (n = 193) alone, and randomization was stratified according to cardiac stage (I, II, or IIIA), availability of transplantation in the local country (countries that do or do not generally provide transplant to patients with AL amyloidosis), and renal function (creatinine clearance, ≥60 ml/min or <60 ml/min).3

Every patient received subcutaneous bortezomib at a dose of 1.3 mg/m2 of body-surface area, oral or intravenous (IV) cyclophosphamide at a dose of 300 mg/m2, and oral or IV dexamethasone at a dose of 40 mg once weekly for 6, 28-day cycles. Patients who were older than 70 years of age, underweight, or had hypervolemia, poorly controlled diabetes mellitus, or previous unacceptable toxicity associated with glucocorticoid therapy, could receive dexamethasone at a dose of 20 mg weekly per physician discretion.

Patients in the investigational arm received 1800 mg of daratumumab per 15 mL administered subcutaneously, coformulated with hyaluronidase, weekly in cycles 1 and 2, every 2 weeks in cycles 3 through 6, and every 4 weeks thereafter until disease progression, the start of subsequent therapy, or a maximum of 24 cycles was reached.

The primary end point was the hematologic complete response rate in the intention-to-treat population. Secondary end points included survival free from major organ deterioration or hematologic progression organ response, OS, hematologic complete response at 6 months, hematologic very good partial response or better, time to and duration of hematologic complete response, time to next treatment, and reduction in fatigue.

What was the safety profile of the regimen?

Any-grade adverse effects (AEs) included diarrhea (D-VCd, 35.8%; VCd, 30.3%), peripheral edema (35.8%; 36.2%), constipation (34.2%; 28.7%), peripheral sensory neuropathy (31.1%; 19.7%), fatigue (26.9%; 28.2%), nausea (26.9%; 28.2%), upper respiratory tract infection (25.9%; 11.2%), lymphopenia (18.7%; 14.9%), hypokalemia (12.4%; 14.9%), neutropenia (10.9%; 6.4%), pneumonia (10.9%; 6.4%), syncope (7.3%; 6.4%), and cardiac failure (9.3%; 7.4%).

The most frequent grade 3 or 4 AEs were lymphopenia (D-VCd, 13.0%; VCd, 10.1%), pneumonia (7.8%; 4.3%), cardiac failure (6.2%; 4.8%), diarrhea (5.7%; 3.7%), syncope (5.2%; 6.4%), neutropenia (5.2%; 2.7%), peripheral edema (3.1%; 5.9%), and hypokalemia (1.6%; 5.3%).

References

1. FDA grants traditional approval to daratumumab and hyaluronidase-fihj for newly diagnosed light chain amyloidosis. FDA. November 19, 2025. Accessed November 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-daratumumab-and-hyaluronidase-fihj-newly-diagnosed-light-chain
2. FDA grants accelerated approval to Darzalex Faspro for newly diagnosed light chain amyloidosis. FDA. January 15, 2021. Accessed November 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-darzalex-faspro-newly-diagnosed-light-chain-amyloidosis
3. Kastritis E, Palladini G, Minnema MC, et al. Daratumumab-based treatment for immunoglobulin light-chain amyloidosis. N Engl J Med. 2021;385(1):46-58. doi:10.1056/NEJMoa2028631