Hitting OS endpoint reaffirms frontline daratumumab-VCd as SoC for AL amyloidosis

The evidence supporting an upfront daratumumab-containing regimen as the standard of care (SoC) for systemic amyloid light chain (AL) amyloidosis is reaffirmed by the significant overall survival (OS) benefit demonstrated in the final analysis of the ANDROMEDA trial.

At a median follow-up of 61.4 months, the 5-year OS rate was 76.1 percent among patients randomized to receive bortezomib, cyclophosphamide, and dexamethasone (VCd) plus subcutaneous daratumumab (D-VCd) vs 64.7 percent among those randomized to receive VCd alone. The 38-percent reduction in the risk of death crossed the required significance level to establish superiority (hazard ratio [HR], 0.62, 95 percent confidence interval [CI], 0.42–0.90; p=0.0121 vs prespecified significance boundary of 0.0163).

“ANDROMEDA shows that the addition of daratumumab to VCd improves survival for patients with newly diagnosed AL amyloidosis and reaffirms that frontline D-VCd is the SoC in this difficult-to-treat population,” said lead author Dr Efstathios Kastritis from the Department of Clinical Therapeutics, National and Kapodistrian University of Athens in Greece, at ASH 2024.

Of note, 61.2 percent of patients in the VCd control arm received subsequent therapy, of which 71.3 percent received daratumumab-based treatment. [ASH 2024, abstract 891]

“The OS benefit occurred even though >70 percent of the patients in the VCd arm who received subsequent therapy were treated with a daratumumab-based regimen. This further emphasizes the importance of using daratumumab in the frontline setting,” added Kastritis.

Hierarchical testing

ANDROMEDA (n=388) utilized a hierarchical testing approach to perform hypothesis testing for three efficacy endpoints. OS was the third in the sequence to be tested after the primary endpoint of overall haematologic complete response (HaemCR) and the other major secondary endpoint of major organ deterioration–progression-free survival (MOD-PFS) were met. [N Engl J Med 2021;385:46-58]

The phase III trial met the study’s endpoint concerning deep haematologic responses since the time of primary analysis. [EHA 2020, abstract LB2604] The significant improvement in HaemCR rate provided the basis for the accelerated approval of subcutaneous daratumumab for AL amyloidosis by the FDA in January 2021.

The overall HaemCR rates for both arms in the current analysis remained unchanged from those in a prior analysis when the median follow-up was 25.8 months (59.5 percent vs 19.2 percent; odds ratio, 6.03, 95 percent CI, 3.80–9.58; p<0.0001). [ASH 2021, abstract 159]

MOD-PFS is a composite endpoint that captures end-stage cardiac or renal failure, haematologic progression per consensus guidelines, or death. In the primary analysis, the improvement in MOD-PFS shown in the D-VCd arm had not crossed the required significance level.

The current analysis served to provide the final MOD-PFS results. With 197 MOD-PFS events accrued, the median MOD-PFS at this 5-year follow-up was not reached for D-VCd vs 30.2 months for VCd (HR, 0.44, 95 percent CI, 0.31–0.63; p<0.0001 vs prespecified significance boundary of 0.0495).

Organ involvement

AL amyloidosis is an acquired plasma cell disorder in which a plasma cell clone grows and produces misfolded immunoglobulin light chains. While rare, it represents the most common form of systemic amyloidosis.

Because the amyloid fibrils formed can deposit in the tissues of any organ in the body except the brain, systemic AL amyloidosis is a multi-organ disease, with the heart and kidneys being the most frequently affected. [Nat Rev Dis Primers 2018;4:38] In natural history studies, the 5-year OS rates were <50 percent. [Orphanet J Rare Dis 2022;17:278]

Given the perceived risk of volume overload in a population prone to amyloid-induced cardiac or renal insufficiency, the subcutaneous formulation of daratumumab was employed in ANDROMEDA instead of IV daratumumab.