Adding Daratumumab to Therapy Improved MOD-PFS and Organ Responses in Newly Diagnosed Light Chain Amyloidosis Patients

The accumulation of insoluble amyloid fibrils generated by clonal CD38+ plasma cells characterizes systemic light chain amyloidosis (AL). Daratumumab, a human CD38-targeted antibody indicated for the treatment of multiple myeloma, is being developed for the treatment of AL. By adding daratumumab to the standard of care for AL of cyclophosphamide, bortezomib, and dexamethasone (CyBorD), Efstathios Kastritis, MD, and fellow investigators evaluated whether this is a reasonable approach to improve outcomes for a disease with no approved therapeutic options.

In the ANDROMEDA trial, patients with newly diagnosed AL were randomized to receive CyBorD with or without subcutaneous (SC) daratumumab; this open-label, active-controlled phase 3 study included patients who met the key eligibility criteria of newly diagnosed AL with measurable hematologic disease, at least ≥1 involved organs, absence of symptomatic multiple myeloma, estimated glomerular filtration rate ≥20 mL/min, and cardiac stage (Mayo 2004) I-IIIA.

Patients were randomized 1:1 to receive CyBorD with or without daratumumab. All received cyclophosphamide (300 mg/m2 oral [PO] or intravenous [IV] weekly), bortezomib (1.3 mg/m2 SC weekly), and dexamethasone (20-40 mg PO or IV weekly) for six 28-day cycles. All patients receiving daratumumab SC (1800 mg, coformulated with recombinant human hyaluronidase PH20 in 15 mL) had it administered by injection once weekly in cycles 1 and 2, every 2 weeks in cycles 3 to 6, and every 4 weeks thereafter for up to 24 cycles (28-day cycles).

An evaluation of disease status was conducted at every 4 weeks in cycles 1 to 6 and every 8 weeks after cycle 7 until major organ deterioration, withdrawal, end of study, or death. Overall hematologic complete response rate (CR) was the primary end point. Major organ deterioration progression-free survival (MOD-PFS), time to hematologic response, organ response rate, survival, and safety were included as the secondary end points.

In total, 388 patients received daratumumab-CyBorD (N = 195) or CyBorD (N = 193) according to the 1:1 randomization protocol. The arms were well-balanced between baseline characteristics. The median age of participants was 64 years; 71% and 59% had heart and kidney involvement, respectively; and 65% had ≥2 organs involved. Twenty-three percent of the group had cardiac stage I, 40% had cardiac stage II, and 37% had cardiac stage III. For the daratumumab-CyBorD group, the median duration of treatment was 9.6 months, and for the CyBorD group, the median duration of treatment was 5.3 months.

Subsequent therapy was administered to 19 patients treated with daratumumab-CyBorD and 79 patients with CyBorD; some patients (N = 48) who were treated with CyBorD received subsequent daratumumab. The median follow-up was 11.4 months (range, 0.03-21.3+ months). For daratumumab-CyBorD, the CR rate was 53%; it was 18% for CyBorD (odds ratio, 5.1; 95% confidence interval [CI], 3.2-8.2; P <.0001). There was a higher level of overall hematologic response in the daratumumab-CyBorD group (92% compared with 77%) and very good partial response or better (≥VGPR; 79% vs 49%).

Median time to ≥VGPR/CR was 17/60 days for the daratumumab-CyBorD group compared with 25/85 days for CyBorD, among the responders. MOD-PFS favored patients treated with daratumumab-CyBorD (hazard ratio, 0.58; 95% CI, 0.36-0.93; P = .0224).

For daratumumab-CyBorD, the 6-month cardiac response rate was 42% and for CyBorD it was 22% (P = .0029); 6-month renal response rate was 54% and 27%, respectively (P <.0001). Fifty-six deaths occurred in total (daratumumab-CyBorD, N = 27; CyBorD, N = 29). The most common grade 3/4 treatment-emergent adverse events occurring in >5% were lymphopenia (daratumumab-CyBorD 13%/CyBorD 10%), syncope (5%/6%), diarrhea (6%/4%), cardiac failure (congestive; 6%/5%), neutropenia (5%/3%), pneumonia (8%/4%), and peripheral edema (3%/6%). Systemic administration-related reactions occurred in 14 (7%) patients, and all were grade 1/2, with first infusion occurrence being the most common.

The authors concluded that a superior, deeper, and faster hematologic response was experienced when supplementing CyBorD with daratumumab; improved clinical outcomes were evident, and an acceptable safety profile was maintained. The substantially higher response in organs in newly diagnosed patients and enhancement in MOD-PFS suggests the positive impact of the combination of daratumumab-CyBorD therapy.

Reference

Kastritis E, Palladini G, Minnema NC, 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: 2020 Annual Congress of the European Hematology Association; June 11-21, 2020. Abstract LB2604.

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