ASH 2025 | Cardiac safety of two Dara-VCd dosing schedules in newly diagnosed AL amyloidosis: AQUARIUS trial

I presented the phase 2 data of the AQUARIUS study on Sunday evening session in the AL amyloidosis session. The Phase 2 AQUARIUS study was designed to evaluate cardiac safety and characterize cardiac events in patients with cardiac involvement from AL amyloidosis, in a newly diagnosed setting. And this is a follow-up study to the ANDROMEDA clinical trial, which is a study, as a reminder, of daratumumab, cyclophosphamide, bortezomib, and dexamethasone, or Dara-VCd, which led to significantly higher hematologic responses, organ responses, major organ deterioration, progression-free survival, and overall survival in comparison with VCd alone, leading to its approval by the regulatory agencies in the treatment of AL amyloidosis. 

So, in the Phase II AQUARIUS study, the primary objectives were to assess and characterize cardiac events with two different treatment schedules of Dara-VCd and also to look at the pharmacokinetics of this particular regimen in minority patients. And patients with newly diagnosed AL amyloidosis were enrolled on this clinical trial. In cohort one of the clinical trial, all patients had to have cardiac involvement and they were randomized to two to one. The arm A of cohort one was the standard treatment, just exactly the same as ANDROMEDA, the treatment regimen, treatment schedule. VCd was administered concurrently with Daratumumab and this is referred to as Dara-immediate VCd. The intervention arm was arm B of cohort 1 in which VCd was administered after three cycles of Daratumumab and this was called Dara-deferred VCD. In cohort 2, patients with minority were enrolled and they received Dara-immediate VCD. Overall, 142 patients with cardiac involvement were analyzed in this clinical trial, enrolled in this clinical trial. 

And again, you know, the median treatment duration was equal in both groups, Dara-immediate VCd as well as Dara-deferred VCd group at 10.4 cycles. And there were similar amounts of patients, approximately 10%, which discontinued the study in both treatment groups, and the majority of the reasons were predominantly due to death. There were nine treatment-emergent deaths. Two of these deaths occurred within 60 days. And they were both in the Dara-immediate VCd group. However, they were attributed not to be related to the study treatment, but to cardiac amyloidosis. Now, going on to cardiac events, the cardiac safety events, treatment-emergent adverse events were approximately 46% for patients who were treated with Dara- immediate VCd and they occurred more frequently in cycles 1 to 3. Whereas in contrast, cardiac events occurred at 61% in the Dara-deferred VCd group and they predominantly occurred in cycles 4 to 6. Again, as a reminder, VCd was added at cycle 4 in the Dara-deferred VCd group. Most of these adverse events were related to patients who had higher baseline Mayo stage 3 disease, regardless of the treatment group. And furthermore, there was an adjudication committee, which was an independent adjudication committee that looked at about 38 events in 20 patients, and most of these events were related to underlying cardiac amyloidosis. 

We also noted that patients who developed major cardiac events had worse baseline cardiac risk profiles than those who did not develop major cardiac events. Hematologic complete response was 59% in patients who were treated on Dara-deferred VCd versus 62% for patients treated with Dara-immediate VCd. However, time to hematologic complete response was approximately two months for Dara-immediate VCd and three months for Dara-deferred VCd. So, the median time to response to complete hematologic response was longer for patients on Dara-deferred VCd. 

So, again, we demonstrated that Dara-VCd, whether immediate or deferred, had a good safety profile for cardiac involvement patients, cardiac safety was not a major issue, and also this led to very high hematologic efficacy. So this really corroborates our prior results of ANDROMEDA that this regimen remains a standard of care for newly diagnosed patients with AL amyloidosis who also have cardiac involvement.

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