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Adding the anti-CD38 agent daratumumab (Darzalex) to cyclophosphamide, bortezomib, and dexamethasone (D-CyBorD) improved the rate of hematologic complete response and delayed the time to major organ deterioration progression-free survival (MOD-PFS) compared with CyBorD in patients with newly diagnosed light chain (AL) amyloidosis who were enrolled in the .

The primary endpoint, hematologic complete response rate as assessed by a blinded review committee, was achieved by 53% of patients randomized to the D-CyBorD regimen compared with 18% of those assigned to CyBorD without daratumumab (OR 5.1, 95% CI 3.2-8.2, P<0.0001), with a median duration of follow-up of 11.4 months, reported Efstathios Kastritis, MD, during the .

"D-CyBorD significantly improved outcomes for patients with AL amyloidosis, and will become a new standard of care," said Kastritis, from the National and Kapodistrian University in Athens.

Significantly delayed major organ deterioration and hematologic progression or death and improved EFS were demonstrated with the D-CyBorD regimen. The MOD-PFS rate, defined as hematologic progression, end-stage cardiac or renal disease, or death, favored D-CyBorD over CyBorD (HR 0.58, 95% CI 0.37-0.93, P=0.0230), as did the MOD-EFS rate, which adds the use of subsequent therapy to the MOD-PFS endpoint (HR 0.40, 95% CI 0.28-0.57, P<0.0001).

"The prognosis [of systemic AL amyloidosis] is poor due to advanced, multiorgan [especially cardiac] involvement, so that approximately 30% of the patients die within the first year from diagnosis," said Kastritis, with no therapies currently approved for this indication amyloidosis. Although outcomes have improved with the use of bortezomib-based therapies, more effective therapies are still needed to produce rapid, deep, and sustained hematologic responses to reverse amyloid-mediated organ dysfunction, he said.

Daratumumab previously showed promising single-agent activity in relapsed/refractory AL amyloidosis, leading to examination of its use in combination in ANDROMEDA, said Kastritis. A total of 388 patients with AL amyloidosis with at least one organ involved were randomized to D-CyBorD or CyBorD. Eligibility criteria included no prior therapy for AL amyloidosis or multiple myeloma, cardiac stage I to IIIA disease, and an estimated glomerular filtration rate ≥20 mL/min.

Patients randomized to D-CyBorD received 1,800 mg of daratumumab subcutaneously followed by cyclophosphamide (300 mg/m² orally or IV weekly) and bortezomib (1.3 mg/m² subcutaneous injection weekly) on days 1, 8, 15, and 22 in every 28-day cycle for a maximum of 6 cycles. Daratumumab was administered weekly for the first two cycles, then every 2 weeks for four cycles (cycles 3-6), and then every 4 weeks until disease progression or subsequent therapy, for a maximum of 24 cycles. Those assigned to CyBorD alone received treatment on days 1, 8, 15, and 22 in every 28-day cycle for a maximum of six cycles.

At baseline, two-thirds of patients had at least two organs involved; about 70% had cardiac involvement and 59% had kidney involvement. About one-third of patients in both arms had cardiac stage III disease.

Median duration of study treatment was 9.6 months in the D-CyBorD arm versus 5.3 months in the CyBorD arm. Some 72% of patients in the D-CyBorD continue to receive daratumumab monotherapy maintenance. Subsequent therapy has been started in 42% of the CyBorD arm compared with only 10% in the D-CyBorD arm.

The complete response rate at 6 months -- 50% in the D-CyBorD arm versus 14% in the CyBorD arm -- was consistent with the overall complete response rate (OR 6.1, P<0.0001).

The improvement in the hematologic complete response rate with D-CyBorD was consistent across subgroups, and the OR favoring D-CyBorD was even greater in patients with more advanced baseline cardiac disease stage. "Importantly, patients with t(11;14), which tends to have lower response rates with bortezomib therapy, seemed to have a major benefit with the addition of daratumumab to CyBorD," said Kastritis. In this subgroup, the odds ratio favoring D-CyBorD was 8.35 (95% CI 3.18-21.93).

Hematologic overall response rates were 92% and 77% in the D-CyBorD and CyBorD arms, respectively, and rates of very good partial response were 79% versus 49% (OR 3.8, P<0.0001), respectively.

Blinded organ response rate at 6 months was approximately doubled in patients assigned to D-CyBorD versus CyBorD, for both cardiac (42 vs 22%, P=0.0029) and renal (54 vs 27%, P<0.0001) responses.

Safety was consistent with previous observations for daratumumab subcutaneous or CyBorD alone. The rate of grade 3 or 4 treatment-emergent adverse events was 59% in the D-CyBorD arm versus 57% in the CyBorD alone arm. The rate of discontinuation due to TEAEs was 4% in each arm. The rate of infections was 12% in patients assigned to D-CyBorD and 9% in those randomized to CyBorD. In the first 6 months, there were 25 deaths in the D-CyBorD arm and 20 in the CyBorD arm, with >90% of deaths related to underlying AL amyloidosis.

Twenty-one (11%) patients in the D-CyBorD arm experienced injection site reactions related to daratumumab; all were grade 1 or 2.

"My experience with this drug [daratumumab] is very positive and it has become our standard of care for newly diagnosed patients," commented Mathew Maurer, MD, from Columbia University, New York City, who was not involved in the study.

"The reported results of the ANDROMEDA study [are] a breakthrough for patients with AL cardiac amyloidosis," he added. "We need to identify patients early in the course of their disease to best leverage this impressive new anti-plasma cell therapy."

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