Subcutaneous Daratumumab (DARA SC) + Bortezomib, Cyclophosphamide, and Dexamethasone (VCd) in Asian Patients with Newly Diagnosed Light Chain (AL) Amyloidosis: Subgroup Analysis from the Phase 3 Andromeda Study
Authors: Suzuki Kenshi , Wechalekar Ashutosh D. , Kim Kihyun , Shimazaki Chihiro , Kim Jin Seok , Ikezoe Takayuki , Min Chang-Ki , Zhou Fude , Iida Shinsuke , Katoh Nagaaki , Fujisaki Tomoaki , Shin Ho-Jin , Tran NamPhuong , Qin Xiang , Vasey Sandra Y. , Tromp Brenda , Weiss Brendan M. , Vermeulen Jessica , Comenzo Raymond L. , Kastritis Efstathios , Lu Jin 
Published: November 2020

Introduction: Systemic AL amyloidosis is a rare disorder of clonal CD38+ plasma cells characterized by deposition of insoluble amyloid fibrils leading to tissue damage and organ dysfunction. Currently, there are no health authority-approved treatments for AL amyloidosis, and standard of care (SoC) includes therapies developed for multiple myeloma (MM). DARA is a human CD38-targeting antibody for MM. Combining DARA with VCd improved outcomes for AL amyloidosis versus VCd alone in the phase 3 ANDROMEDA study. Here, we report a subgroup analysis of Asian patients (China, Japan, and Korea) from ANDROMEDA.
Methods: Eligible patients had newly diagnosed AL amyloidosis with measurable hematologic disease, ≥1 involved organ, cardiac stage (Mayo 2004) I-IIIA, eGFR ≥20 mL/min, and no symptomatic MM. Patients were randomized 1:1 to receive DARA SC plus VCd (D-VCd) or VCd. All patients received bortezomib (1.3 mg/m2 SC QW), cyclophosphamide (300 mg/m2 PO or IV QW), and dexamethasone (40 mg PO or IV QW) for six 28-day cycles with or without DARA SC (1,800 mg DARA co-formulated with recombinant human hyaluronidase PH20 [rHuPH20]; ENHANZE® drug delivery technology, Halozyme, Inc.) by injection QW in Cycles 1-2, Q2W in Cycles 3-6; after Cycle 6, patients continued DARA monotherapy as maintenance for up to 24 cycles (28-day cycles). Disease status was evaluated Q4W in Cycles 1-6 and Q8W after Cycle 7 until hematologic progression or major organ deterioration. The primary endpoint was overall hematologic complete response (CR) rate; key secondary endpoints included major organ deterioration progression-free survival (MOD-PFS), survival, and safety. MOD-PFS was defined as the time from randomization to any of the following events (whichever occurred first): death, clinical manifestation of cardiac or renal failure, or hematologic progression.
Results: Among 388 randomized patients (D-VCd, n=195; VCd, n=193), 60 were Asian (D-VCd, n=29; VCd, n=31). Baseline characteristics were well balanced between arms and consistent with the intent-to-treat population. The median age was 66 years, 70% and 58% had heart and kidney involvement, respectively, and 60% had ≥2 organs involved. Cardiac stage I, II and IIIA/B were 28%, 28%, and 43%, respectively. The median duration of treatment was 9.2 mo for D-VCd and 5.3 mo for VCd. Median follow-up was 9.4 mo. The overall hematologic CR rate was 59% for D-VCd and 10% for VCd (odds ratio, 13.2; 95% CI, 3.3-53.7; P&lt;0.0001). D-VCd vs VCd achieved higher rates of very good partial response or better (≥VGPR; 93% vs 61%). MOD-PFS favored D-VCd-treated patients (HR 0.21; 95% CI, 0.06-0.75, P=0.0079). A total of 12 deaths occurred (D-VCd, n=3; VCd, n=9). The most common (≥10%) grade 3/4 TEAEs were lymphopenia (D-VCd 35%/VCd 32%), neutropenia (10%/3%), diarrhea (10%/7%), pneumonia (7%/10%), cardiac failure (7%/10%), hypokalemia (7%/10%), anemia (3%/10%), thrombocytopenia (3%/10%), hypoalbuminemia (3%/10%), and syncope (3%/10%). TEAEs leading to treatment discontinuation occurred in 1 patient in each treatment arm.
Conclusion: The addition of DARA SC to VCd was superior to VCd alone in Asian patients, resulting in deeper hematologic responses and improved clinical outcomes, including MOD-PFS, with a safety profile consistent with the overall study population. These data support the use of D-VCd in Asian patients with newly diagnosed AL amyloidosis.

Disclosures
Suzuki: Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria; Takeda, Amgen, Janssen and Celgene: Consultancy; Bristol-Myers Squibb, Celgene and Amgen: Research Funding. Wechalekar:Janssen, Takeda, Caelum, Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:BMS, Takeda, Amgen, Celgene, Janssen: Consultancy, Honoraria, Research Funding. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Zhou:Peking University First Hospital: Current Employment. Iida:Celgene: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding; AbbVie: Research Funding; Merck Sharpe Dohme: Research Funding; Janssen: Honoraria, Research Funding. Tran:Janssen: Current Employment, Current equity holder in publicly-traded company. Qin:Janssen: Current Employment. Vasey:Janssen Research & Development: Current Employment, Current equity holder in publicly-traded company. Tromp:Janssen: Current Employment, Current equity holder in publicly-traded company. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Comenzo:Amgen: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Unum: Consultancy; Caleum: Consultancy; Karyopharm: Consultancy, Research Funding; Prothena: Consultancy, Research Funding. Kastritis:Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria, Other: Travel/accommodations/expenses; Janssen: Consultancy, Honoraria, Other: Travel/accommodations/expenses, Research Funding; Pfizer: Consultancy; Takeda: Consultancy, Honoraria, Other: Travel/accommodations/expenses.

OffLabel Disclosure:
To evaluate the efficacy and safety of daratumumab plus bortezomib, cyclophosphamide, and dexamethasone in Asian patients with AL amyloidosis.