SUMMARY

• AQUARIUS is an ongoing, multicenter, multicohort, open-label, phase-2 study evaluating cardiac safety of 2 different treatment schedules of DARZALEX FASPRO in combination with bortezomib, cyclophosphamide and dexamethasone (D-VCd) in patients with newly diagnosed systemic light chain (AL) amyloidosis.¹
  • Sanchorawala et al (2025)² presented the results of the study. The best hematologic overall response rate was 93.2% for patients in the DARZALEX FASPRO + Immediate VCd arm vs 97.4% in the DARZALEX FASPRO + Deferred VCd arm. Serious cardiac treatment-emergent adverse events (TEAEs) occurred in 7.8% of patients in the immediate group vs 7.7% of patients in the deferred group, with higher rates of cardiac TEAEs correlating to initiation of VCd.

CLINICAL DATA

AQUARIUS (AMY2009; NCT05250973) is an ongoing, multicenter, multicohort, open-label, phase 2 study evaluating the cardiac safety of 2 different D-VCd treatment schedules in patients with newly diagnosed systemic AL amyloidosis.¹ Sanchorawala et al (2025) presented the results of this study.² 

Study Design/Methods

• Key eligibility criteria:
  • Cohort 1: newly diagnosed AL amyloidosis, no prior therapy for AL amyloidosis or multiple myelomas (MM), Mayo cardiac stage II-IIIA with or without other organ involvement.² 
  • Cohort 2: newly diagnosed AL amyloidosis with ≥1 impacted organ (cardiac safety analysis includes only patients with cardiac involvement), no prior therapy for AL amyloidosis or MM, self-identified racial and ethnic minorities.²
• Dosing schedules:
  • Cohort 1 Arm A and Cohort 2: DARZALEX FASPRO + immediate VCd (28-day cycles)
    • DARZALEX FASPRO: subcutaneously (SC) weekly (QW) for cycles 1-2, every 2 weeks (Q2W) for cycles 3-6, every 4 weeks (Q4W) for cycle 7 onwards until a maximum of 24 cycles of treatment or the start of subsequent therapy.^1,2 
    • VCd: V, 1.3 mg/m² QW SC; C, 300 mg/m² QW orally (PO) or intravenously (IV); d 40 mg QW PO or IV for cycles 1-6 for a maximum of 6 cycles.¹ 
  • Cohort 1 Arm B: DARZALEX FASPRO + deferred VCd (28-day cycles)
    • DARZALEX FASPRO: as described for Cohort 1 Arm A and Cohort 2.^1,2
    • VCd: doses as described for Cohort 1 Arm A and Cohort 2 for cycles 4-9 for a maximum of 6 cycles.¹
• Primary endpoints:
  • Cohort 1: safety (cardiac events)²
  • Cohort 2: daratumumab maximum trough concentration (cycle 3 day 1 pre-dose)²
• Key secondary endpoints: hematologic complete response (CR) and very good partial response or better (≥VGPR) rates, time to hematologic CR and ≥VGPR, duration of hematologic CR and ≥VGPR, organ response, clinical signs and symptoms of cardiac AL amyloidosis²

Results

Patient Characteristics and Treatment Disposition

• The baseline characteristics were well-balanced between the groups. See Table: Baseline Characteristics.²
• The median treatment duration was 10.4 months for both groups as summarized in Table: Treatment Disposition.²

Efficacy

• Hematologic CR rate was 62.1% (n=64) in the DARZALEX FASPRO + Immediate VCd group vs 59.0% (n=23) in the DARZALEX FASPRO + Deferred VCd group.²
  • The median time to CR was 63.5 days vs 113.0 days in the Immediate VCd vs Deferred VCd groups, respectively.
• In the DARZALEX FASPRO + Immediate VCd group, 87 patients achieved VGPR or better vs 36 patients in the DARZALEX FASPRO + Deferred VCd group.²
  • The median time to VGPR was 29.0 days vs 72.5 days in the Immediate VCd vs Deferred VCd groups, respectively.
• Best hematologic response rates are described in Table: Best Hematologic Responses.²
• Of the 85 patients in the DARZALEX FASPRO + Immediate VCd group that were cardiac response-evaluable, 47 patients (55.3%) achieved a cardiac response at 6 months (95% CI, 44.1-66.1) vs 20/34 patients (58.8%) in the DARZALEX FASPRO + Deferred VCd group (95% CI, 40.7-75.4).²
• N-terminal pro b-type natriuretic peptide (NT-proBNP) and high sensitivity (HS) troponin T levels improved across both groups.²
• Cardiac signs/symptoms and 6-minute walk test distance improved across both arms.²

Safety

• There were similar rates of serious cardiac TEAEs in both groups, see Table: Summary of Cardiac TEAEs.²
• Of the 30 major cardiac TEAEs (grade >3 or serious) that occurred in 20 patients, 28 events were attributed to underlying cardiac amyloid disease.²
  • Patients who experienced major cardiac TEAEs had more advanced cardiac disease at baseline.
• Cardiac TEAEs of any grade were more frequent in Mayo stage III vs Mayo stage II patients, independent of treatment schedule (DARZALEX FASPRO + Immediate VCd: 73.0% vs 35.9%; DARZAELX FASPRO + Deferred VCd: 68.8% vs 57.1%).²
• Most cardiac TEAEs emerged during cycles 1-6, with a higher rate correlating to the start of VCd, as summarized in Table: Emergence of Cardiac TEAEs.²

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 16 December 2025.