Patients With AL Amyloidosis May Benefit From Subcutaneous Daratumumab/CyBorD Combination

Adding a subcutaneous formulation of daratumumab (Darzalex Faspro) to the triplet regimen cyclophosphamide, bortezomib (Velcade), and dexamethasone (CyBorD) may hold promise for patients with newly diagnosed light chain (AL) amyloidosis who are in urgent need of new treatment options. Data from the phase 3 ANDROMEDA (NCT03201965) trial, which demonstrated the superiority of CyBorD plus subcutaneous daratumumab (Dara-CyBorD) versus CyBorD alone, were presented virtually during the 25th Congress of the European Hematology Association. The experimental combination resulted in deeper and more rapid hematologic responses and led to better clinical outcomes with an acceptable safety profile.

The combination of Dara-CyBorD therapy improved major organ deterioration progression-free survival (MOD-PFS) and resulted in substantially higher organ responses in patients with newly diagnosed AL amyloidosis, according to Efstathios Kastritis, MD, associate professor of clinical therapeutics/medical oncology at the National and Kapodistrian University of Athens in Greece.

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 end point of the phase 3, randomized, open-label, active-controlled study was overall hematologic complete response (CR) rate in the intention-to-treat population. Secondary end points included MOD-PFS, organ response rate, time to hematologic response, survival, and safety.

Results showed that hematologic CR rate was 53% for Dara-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 kidney (54% vs 27%) responses.¹

The Dara-CyBorD combination achieved higher rates of overall hematologic response (92% vs 77%) and very good partial response or better (VGPR; 79% vs 49%) (FIGURE).¹ Among responders, median time to VGPR or better was 17/60 days for the daratumumab arm compared with 25/85 days for CyBorD alone. MOD-PFS favored DARA-CyBorD-treated patients (HR, 0.58; 95% CI, 0.37-0.93; P = .0230).

There were 388 patients randomized to either Dara-CyBorD (n = 195) or CyBorD (n = 193). All patients received weekly cyclophosphamide (300 mg/m² orally or intravenously), bortezomib (1.3 mg/m² subcutaneously), and dexamethasone (20-40 mg orally or intravenously) for six 28-day cycles. Subcutaneous daratumumab was administered weekly by injection in cycles 1 and 2, every 2 weeks in cycles 3 through 6, and every 4 weeks thereafter for up to 24 cycles.

The efficacy and safety profile of intravenous and subcutaneous daratumumab are well characterized. The agent showed no new safety concerns, according to Kastritis. The rate of discontinuation due to treatment-emergent adverse events (TEAEs) was 4% in both arms.

The most common grade 3/4 TEAEs occurring in more than 5% of patients treated on the daratumumab arm were lymphopenia (13% with Dara-CyBorD vs 10% with CyBorD), pneumonia (8% vs 4%, respectively), diarrhea (6% vs 4%), cardiac failure (congestive; 6% vs 5%), neutropenia (5% vs 3%), syncope (5% vs 6%), and peripheral edema (3% vs 6%). Fourteen patients (7%) experienced systemic administration-related reactions with daratumumab-CyBorD; all were grade 1/2 in severity, and most occurred during the fi rst infusion. A total of 56 deaths occurred in the entire trial, 29 patients treated with Dara-CyBorD and 27 who got CyBorD.

Daratumumab is the first and only subcutaneous CD38-directed antibody approved globally. In May of this year, the FDA approved the subcutaneous formulation alone and in combination for the treatment of adult patients with multiple myeloma.²

The manufacturer responsible for producing daratumumab, Janssen Biotechnologies, collaborated with Halozyme Therapeutics to develop the subcutaneous form of the agent. Halozyme’s Enhanze system works to degrade hyaluronan, a polysaccharide found in the extracellular matrix of the subcutaneous tissue, thus allowing large volumes of the drug 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: 25th Congress of the European Hematology Association; June 11-21, 2020. Abstract LB2604. https://bit.ly/32eSmJU}

_{2. FDA approves daratumumab and hyaluronidase-fi hj for multiple myeloma. FDA. May 1, 2020. Accessed July 13, 2020. https://bit.ly/2BYcnKd3}

_{3. Enhanze drug delivery technology. Halozyme. Accessed June 3, 2020. https://bit.ly/3fqTjm2}