Adding Subcutaneous Daratumumab to CyBorD Improves Outcomes for AL Amyloidosis

Subcutaneous daratumumab (Darzalex Faspro) may be a promising treatment for newly diagnosed patients with light chain (AL) amyloidosis who are in urgent need of new treatment options, according to data presented at the virtual 25th Congress of the European Hematology Association.

Primary results from the phase 3 ANDROMEDA (NCT03201960) trial demonstrated that the addition of subcutaneous daratumumab to the triple combination CyBorD—comprised of cyclophosphamide (Cytoxan), bortezomib (Velcade), and dexamethasone (Ozurdex)—was superior to CyBorD alone, resulting in deeper and more rapid hematologic responses and improved clinical outcomes with an acceptable safety profile.

The combination of subcutaneous daratumumab with CyBorD therapy improved major organ deterioration progression-free survival (MOD-PFS) and substantially higher organ responses in patients with newly diagnosed AL amyloidosis, according to Efstathios Kastritis, MD, with the Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens.

Systemic AL amyloidosis is a rare disease characterized by insoluble amyloid fibril deposition in tissues and organs. There is no approved treatment and about 30% of patients die within the first year of diagnosis. Treatment with the CyBorD combination has improved outcomes, but sustained hematologic response is needed to reverse amyloid-mediated organ dysfunction and improve overall survival.

The primary endpoint of the phase 3, randomized, open-label, active-controlled study was overall hematologic complete response (CR) rate in the intent-to-treat population. Secondary endpoints included major organ deterioration progression-free survival (MOD-PFS), organ response rate, time to hematologic response, survival, and safety.

Results showed that hematologic CR was 53% for subcutaneous daratumumab-CyBorD compared with 18% for CyBorD alone (OR, 5.1; 95% CI, 3.2-8.2; P <.0001). The 6-month organ response rate was nearly doubled for patients treated with the addition of subcutaneous daratumumab versus CyBorD alone for both cardiac (42% vs 22%) and renal (54% vs 27%) responses.¹

The daratumumab combination achieved higher rates of overall hematologic response (92% vs 77%) and very good partial response or better (79% vs 49%). Among responders, median time to ≥VGPR/CR was 17/60 days for the daratumumab arm compared with 25/85 days for CyBorD alone. MOD-PFS favored DARA-CyBorD-treated pts (HR, 0.58; 95% CI, 0.37-0.93; P = .0230).

A total of 388 patients were randomized to receive subcutaneous daratumumab-CyBorD (n = 195) or CyBorD (n=193). All patients received cyclophosphamide (300 mg/m2 by mouth or IV weekly), bortezomib (1.3 mg/m2 subcutaneous weekly), and dexamethasone (20-40 mg by mouth or IV weekly) for six 28-day cycles. Subcutaneous daratumumab was administered by injection weekly in Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter for up to 24 cycles (28-day cycles).

The efficacy and safety profile of IV and subcutaneous daratumumab are well characterized. This trial showed no new safety concerns related to daratumumab, according to Kastritis.

The rate of discontinuation due to treatment-emergent adverse events (TEAEs) 4% in both arms. A total of 56 deaths occurred (daratumumab-CyBorD, n = 29; CyBorD, n = 27). The most common (>5%) grade 3/4 TEAEs were lymphopenia (daratumumab-CyBorD 13%/CyBorD 10%), pneumonia (8%/4%), diarrhea (6%/4%), cardiac failure (congestive; 6%/5%), neutropenia (5%/3%), syncope (5%/6%), and peripheral edema (3%/6%). Fourteen (7%) patients experienced systemic administration-related reactions with daratumumab-CyBorD; all were grade 1/2 and most occurred during the first infusion.

Daratumumab is the first and only subcutaneous CD38-directed antibody approved globally to treat multiple myeloma. On May 1, 2020, the FDA approved the subcutaneous formulation alone and in combination for the treatment of adult patients with multiple myeloma.²

Janssen Biotech, which manufactures daratumumab, collaborated with Halozyme Therapeutics, which develops the drug delivery technology. Halozyme’s Enhanze system works to degrade hyaluronan, a polysaccharide found in the extracellular matrix of the subcutaneous tissue, thus allowing large volumes to be delivered in a single subcutaneous injection.³

References

1. Kastritis E, Palladini G, Minnema MC, et al. Subcutaneous daratumumab + cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in patients with newly diagnosed light chain (AL) amyloidosis: primary results from the phase 3 ANDROMEDA study Presented at: the 25th Annual European Hematology Congress: Virtual. June 11-21, 2020. Abstract #LB2604
2. Darzalex Faspro. Package insert. Janssen Biotech Inc; 2020. Accessed June 12, 2020. accessdata.fda.gov/drugsatfda_docs/label/2020/761145s000lbl.pdf
3. Halozyme. Enhanze drug delivery technology. Accessed June 3, 2020. halozyme.com/enhanze/overview/default.aspx