Subcutaneous Daratumumab (DARA) + Bortezomib, Cyclophosphamide, and Dexamethasone (vcd) in Patients with Newly Diagnosed Light Chain (AL) Amyloidosis: Overall Survival and Final Major Organ Deterioration Progression-Free Survival Results from the Phase 3 Andromeda Study

Background Systemic AL amyloidosis is characterized by the deposition of immunoglobulin light chains, produced by clonal CD38+ plasma cells, as insoluble amyloid fibrils in vital organs. DARA is a human CD38-targeting monoclonal antibody. ANDROMEDA (NCT03201965) is a randomized, open-label, active-controlled phase 3 study of VCd ± DARA in patients (pts) with newly diagnosed AL amyloidosis. Based on trial results, DARA-VCd is the first and only approved therapy for this condition and is considered standard of care for newly diagnosed pts. We report results of the pre-planned final analysis for major organ deterioration progression-free survival (MOD-PFS; i.e. end-stage renal or cardiac disease, hematologic [heme] progression, or death) and overall survival (OS). Methods Key eligibility criteria included newly diagnosed AL amyloidosis with measurable heme disease, ≥1 involved organ, cardiac stage (Mayo 2004) I-IIIA, eGFR ≥20 mL/min, and absence of symptomatic multiple myeloma. Pts were randomized 1:1 to VCd ± DARA. All pts received bortezomib (1.3 mg/m2 SC QW), cyclophosphamide (300 mg/m2 PO or IV QW), and dexamethasone (20-40 mg PO or IV QW) for six 28-day cycles. DARA SC (1,800 mg; co-formulated with rHuPH20) 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 heme complete response (HemCR) rate. Secondary endpoints included MOD-PFS, OS, organ response rate, and safety. Results A total of 388 pts were randomized to receive DARA-VCd (n=195) or VCd (n=193). Baseline characteristics were well balanced between arms. The median duration of treatment was 21.3 months (mo) for DARA-VCd and 5.3 mo for VCd. Of the 122 pts in the VCd arm who received subsequent therapy, 82 (67%) received subsequent DARA. Median follow-up was 61.4 mo (range: 0.0-71.2). Overall HemCR rate was 59.5% for DARA-VCd and 19.2% for VCd (odds ratio=6.03 [95% CI: 3.80-9.58; P<0.0001]). Significant improvement in MOD-PFS and OS were observed for DARA-VCd compared to VCd treated pts: MOD-PFS hazard ratio (HR)=0.44 (95% CI: 0.31-0.63; P<0.0001); OS HR=0.62 (95% CI: 0.42-0.90; P=0.0121). The median MOD-PFS was not reached for DARA-VCd and was 30.2 mo for VCd. In total, 112 deaths occurred (DARA-VCd=46; VCd=66). The 5-year survival rate was 76.1% for DARA-VCd and 64.7% for VCd. MOD-PFS and OS subgroup analysis results were generally consistent across pre-planned relevant subgroups. Time to HemCR with DARA-VCd (67.5 days) was shorter compared with VCd (85.0 days). Achieving HemCR was associated with improved MOD-PFS and OS from the 6-month landmark analysis and beyond. Pts who achieved HemCR had better MOD-PFS (HR=0.30 [95% CI: 0.19-0.47]) and OS (HR=0.41 [95% CI: 0.23-0.72]), irrespective of treatment received. Median duration of HemCR was not reached in either arm. Cardiac and renal response rates at 6, 12, 24, 36, and 48 mo were about doubled for pts in the DARA-VCd arm compared with the VCd arm. Among 235 cardiac response-evaluable pts (DARA-VCd=118 vs VCd=117), 113 achieved cardiac very good partial response or better (DARA-VCd=76 [64.4%] vs VCd=37 [31.6%]); of these, 64 pts achieved cardiac CR (DARA-VCd=48 [40.7%] vs VCd=16 [13.7%]). The most common (≥5%) grade 3/4 treatment emergent adverse events (TEAEs) were lymphopenia (DARA-VCd 13%/VCd 10%), pneumonia (8%/4%), diarrhea (6%/4%), cardiac failure (congestive; 6%/3%), neutropenia (5%/3%), syncope (6%/6%), fatigue (5%/3%), hypokalemia (2%/5%), and peripheral edema (3%/6%). Systemic administration-related reactions with DARA-VCd occurred in 14 (7%) pts, all were grade 1/2 and most (86%) occurred during the first injection. Treatment was discontinued for TEAEs in 5% of pts for DARA-VCd and 4% for VCd. Conclusion The addition of DARA to VCd resulted in superior outcomes compared to VCd alone, demonstrating deeper and more rapid heme responses resulting in a clinically meaningful and statistically significant improvement in both OS and MOD-PFS, combined with 40.7% cardiac CR. DARA-VCd had a known and manageable safety profile. DARA-VCd significantly improves clinical outcomes for pts with newly diagnosed AL amyloidosis and reaffirms this regimen's position as the only standard of care in this difficult to treat disease.