Benefit of Daratumumab-VCd Outcomes According to Cardiac Stage in Patients with Newly Diagnosed Light Chain Amyloidosis: Results from ANDROMEDA

In patients with newly diagnosed light chain amyloidosis (AL), the degree of cardiac involvement plays a key role in clinical outcomes. Monique Minnema, MD, PhD, of UMC Utrecht, Utrecht, Netherlands, and colleagues studied the impact on major organ deterioration progression-free survival (MOD-PFS), hematologic responses, major organ deterioration event-free survival (MOD-EFS), and organ responses by cardiac stage in patients with newly diagnosed AL treated with bortezomib, cyclophosphamide, and dexamethasone (VCd) with or without daratumumab subcutaneous (SC) in the ANDROMEDA trial.

Patients were able to enroll in the study if they met specific eligibility criteria, including ≥1 involved organs, estimated glomerular filtration rate ≥20 mL/min, cardiac stage I-IIIA (based on the European Modification of the Mayo staging system), newly diagnosed AL with measurable hematologic disease, and absence of symptomatic multiple myeloma. Randomization (1:1) of patients to receive daratumumab-VCd or VCd alone was performed.

All patients included in the study were prescribed cyclophosphamide (300 mg/m2 oral [PO] or intravenous [IV] weekly [500 mg maximum]), bortezomib (1.3 mg/m2 SC weekly), and dexamethasone (20-40 mg PO or IV weekly) for six 28-day cycles. In cycles 1 and 2, every 2 weeks in cycles 3 to 6, and every 4 weeks thereafter for up to 24 cycles, patients received weekly injections of daratumumab SC (1800 mg, coformulated with recombinant human hyaluronidase PH20 in 15 mL). Patients were evaluated every 4 weeks (cycles 1-6) and every 8 weeks (after cycle 7) until end of study, or withdrawal, major organ deterioration, hematologic progression, or death. In this study, the primary end point was defined as overall hematologic complete response rate.

The secondary end points consisted of organ response rate, time to hematologic response, survival, safety, time to MOD-PFS, and MOD-EFS.

Evaluation of MOD-PFS and hematologic complete response were performed on the intent-to-treat analysis set; cardiac response analyses were performed on patients with baseline NT-proBNP ≥650 ng/L or baseline New York Heart Association (NYHA) class 3 or 4 and who received at least 1 administration of study treatment.

In total, 388 patients were randomized to receive VCd alone (n = 193) or daratumumab-VCd (n = 195). Between treatment groups, baseline characteristics were well-balanced; 64 years was the median age, and the percentages of patients with cardiac stages I, II, and III were 23%, 40%, and 37%, respectively.

The median duration of treatment was 5.3 months for VCd and 9.6 months for daratumumab-VCd; 11.4 months (range, 0.03-21.3+ months) was the median follow-up.

Across cardiac stages, baseline characteristics were generally balanced, except increasing cardiac stage that was associated with worse Eastern Cooperative Oncology Group performance status, older age (≥65 years), functionally worse heart failure (NYHA IIIA), and more advanced renal failure (creatinine clearance ≤30). Hematologic complete response rates were higher in the daratumumab-VCd group than in the VCd group in patients with cardiac stages I, II, and III at baseline. At 6 months, cardiac and renal response rates were also higher in the daratumumab-VCd group, irrespective of cardiac stage at baseline.

The MOD-PFS were 0.33, 0.55, and 0.66 for cardiac stages I, II, and III, respectively, and the hazard ratios favored daratumumab-VCd. For MOD-EFS, corresponding hazard ratios were 0.24, 0.39, and 0.48, respectively.

There was a similar number of patients with and without cardiac involvement at baseline to experience any grade of adverse events. However, rates of serious treatment-emergent adverse events were higher in patients with cardiac involvement at baseline than in those without, across both treatment arms.

The authors concluded that, compared with VCd alone, the benefit of daratumumab-VCd was maintained through cardiac stages for hematologic complete response, organ responses, MOD-PFS, and MOD-EFS.

Reference

Minnema NC, Dispenzieri A, Merlini G, et al. Outcomes by cardiac stage in newly diagnosed AL amyloidosis: results from ANDROMEDA. Presented at: 2020 American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020. Abstract 1392.

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