Abstract: LB2604

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: Late-breaking Oral Session

Background
Systemic AL amyloidosis is characterized by the deposition of insoluble amyloid fibrils produced by clonal CD38⁺ plasma cells. Daratumumab (DARA) is a human CD38-targeted antibody for multiple myeloma (MM). Combining DARA with CyBorD (a standard-of-care for AL amyloidosis) is a rational approach to improving outcomes for this disease, for which there are no health-authority approved therapies.

Aims
ANDROMEDA (NCT03201965) is a randomized, open-label, active-controlled phase 3 study of CyBorD ± subcutaneous (SC) DARA in patients (pts) with newly diagnosed AL amyloidosis.

Methods
Key eligibility criteria included newly diagnosed AL amyloidosis with measurable hematologic disease, ≥1 involved organ, cardiac stage (Mayo 2004) I-IIIA, eGFR ≥20 mL/min, and absence of symptomatic MM. Pts were randomized (1:1) to CyBorD ± DARA. All pts received cyclophosphamide (300 mg/m² PO or IV QW), bortezomib (1.3 mg/m² SC QW), and dexamethasone (20-40 mg PO or IV QW) for six 28-day cycles. DARA SC (1,800 mg, co-formulated with recombinant human hyaluronidase PH20 in 15 mL) was administered by injection QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter for up to 24 cycles (28-day cycles). Disease status was evaluated Q4W in Cycles 1-6 and Q8W after Cycle 7 until major organ deterioration, death, end of study, or withdrawal. The primary endpoint was overall hematologic complete response (CR) rate (intent-to-treat). Secondary endpoints included major organ deterioration progression-free survival (MOD-PFS), organ response rate, time to hematologic response, survival, and safety.

Results
A total of 388 pts were randomized to receive DARA-CyBorD (n=195) or CyBorD (n=193). Baseline characteristics were well balanced between arms. The median age was 64.0 years, 71% and 59% had heart and kidney involvement, respectively, and 65% had ≥2 organs involved. Cardiac stage I, II and III were 23%, 40%, and 37%, respectively. The median duration of treatment was 9.6 mo for DARA-CyBorD and 5.3 mo for CyBorD. 19 pts treated with DARA-CyBorD and 79 pts with CyBorD received subsequent therapy; 48 of these pts treated with CyBorD received subsequent DARA. Median follow-up was 11.4 (range, 0.03-21.3⁺) mo. The CR rate was 53% for DARA-CyBorD and 18% for CyBorD (odds ratio, 5.1; 95% CI, 3.2-8.2; P<0.0001). DARA-CyBorD achieved higher rates of overall hematologic response (92% vs 77%) and very good partial response or better (≥VGPR; 79% vs 49%). Among responders, median time to ≥VGPR/CR was 17/60 days for DARA-CyBorD compared to 25/85 days for CyBorD. MOD-PFS favored DARA-CyBorD-treated pts (hazard ratio, 0.58; 95% CI, 0.36-0.93, P=0.0224). The 6-month cardiac response rate was 42% for DARA-CyBorD and 22% for CyBorD (P=0.0029); 6-month renal response rate was 54% and 27%, respectively (P<0.0001). A total of 56 deaths occurred (DARA-CyBorD, n=27; CyBorD, n=29). The most common (>5%) grade 3/4 TEAEs were lymphopenia (DARA-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%). Systemic administration-related reactions with DARA-CyBorD occurred in 14 (7%) pts, all were grade 1-2 and most occurred during the first infusion.

Conclusion
The addition of DARA to CyBorD was superior to CyBorD alone, resulting in deeper and more rapid hematologic responses and improved clinical outcomes with an acceptable safety profile. DARA-CyBorD therapy resulted in improved MOD-PFS and substantially higher organ responses in newly diagnosed AL amyloidosis pts.

Session topic: 10. Myelodysplastic syndromes - Clinical

Keyword(s): Amyloidosis, Monoclonal antibody