Efficacy and Safety of Daratumumab Monotherapy in Newly Diagnosed Patients with Stage 3B Light-Chain Amyloidosis: A Phase 2 Study By the European Myeloma Network
Authors: Kastritis Efstathios , Minnema Monique C , Dimopoulos Meletios A. , Merlini Giampaolo , Theodorakakou Foteini , Fotiou Despina , Huart Antoine , Belhadj Merzoug Karim , Papachristou Elena , Manousou Kyriaki , Sonneveld Pieter , Palladini Giovanni 
Published: December 2023

Introduction
Patients (pts) with Mayo stage 3B light-chain (AL) amyloidosis have high risk of early death, mainly due to severe cardiac dysfunction. The ANDROMEDA study showed that pts with newly diagnosed (ND) AL amyloidosis, daratumumab (dara) combined with bortezomib-cyclophosphamide-dexamethasone (D-VCd) induced high rates of hematologic complete response (CR); however, pts with Mayo stage 3B were excluded. Dara's high single agent activity and favorable toxicity profile makes it an attractive option for stage 3B AL amyloidosis pts. This prospective study evaluated the efficacy and safety of dara monotherapy in stage 3B NDAL pts.
Methods
EMN22, a phase 2, open-label, multinational study (NCT04131309) enrolled 40 NDAL pts with stage 3B disease. Eligible adult pts had serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥8500 pg/mL and high-sensitivity troponin T (hsTnT) &gt;54 pg/mL. Dara monotherapy was initially administered intravenously (16 mg/mL), and after February 2020 subcutaneously as a fixed dose of 1800 mg weekly (QW) during cycles (C)1-2, Q2W for C3-6, and Q4W thereafter. Pts not achieving ≥hematological very good partial response (VGPR) by C4 could receive additional bortezomib QW and low-dose dexamethasone (Vd). Treatment continues for up to 2 years from initiation or until progressive disease (PD) or initiation of new therapy. The primary endpoint was the overall survival (OS) rate at 6 months, aiming for a 6-month OS rate of ≥50%.
Results
The study completed accrual and 40 pts were enrolled (median age: 70.5 years [range 45.0-86.0]; male: 22 [55.0%]). At cut-off (31/05/2023), 6 (15.0%) pts continued treatment, 26 (65.0%) had discontinued, and 8 (20.0%) had completed treatment. At screening, 25 (62.5%) pts had ECOG status ≥2, and 16 (40.0%) and 24 (60.0%) pts had New York Heart Association class II and IIIA symptoms, respectively. The median (range) NT-proBNP, hsTnT and difference of involved to uninvolved free light chains were 14,353 (8,516-72,522) pg/mL, 136 pg/mL (55-692), and 430 mg/L (40-2820) respectively. At baseline (C1, day 1), besides the heart, 33 (82.5%) pts had ≥1 organs involved, most frequently the kidneys (20/40 pts, 50%) and peripheral nerves (12/40 pts, 30%).
At a median (range) follow-up of 10.1 months (&lt;0.1-43.6), the median (range) number of dara administrations was 18 (1-36) and treatment duration was 6.6 months (&lt;0.1-25.3). Ten (25.0%) pts received additional Vd treatment. The 6-month OS rate (primary end point) was 65.0% (95% CI) (48.2-77.6); the 3-month OS was 72.5% (55.9-83.7) and median OS was 10.3 months (4.1-32.1) ( Figure).
At 6 months, a hematologic response (≥partial response [PR]) was achieved by 31 (77.50%) pts (CR: 5 [12.5%]; VGPR: 15 [37.5%]; PR: 11 [27.5%]) ( Table). Within 3 months of treatment initiation 28 (70.0%) pts had achieved a response. Median duration of hematologic response was not reached. Pts achieving ≥PR at 3 months had a higher post-3-months median (95% CI) OS compared to pts with &lt;PR (29.10 [8.34-NR]; 5.8 [0.38-NR], respectively). Any organ response at 3 or 6 months was achieved by 10 (25.0%) and 13 (32.5%) pts, respectively; a cardiac response at 3- and 6-months was achieved by 9 (22.5%) and 11 (27.5%) pts, respectively ( Table).
All pts experienced ≥1 adverse event, either serious (SAE) or non-serious (NSAE). Thirty-eight (95.0%) pts had ≥1 NSAE. Grade (Gr) 3/4 NSAEs occurred in 21 (52.5%) pts, commonly dyspnea and peripheral edema (4 [10.0%] pts each). Of all pts, six (15.0%) experienced treatment related Gr3/4 NSAEs, including Gr3 neutropenia and lymphopenia (1 [2.5%] each) related to dara and a Gr3 troponin increase (1 [2.5%]) related to bortezomib. Thirty-one (77.5%) pts had ≥1 SAE, including 17 (42.5%) pts with cardiac disorders. Seventeen (42.5%) pts had fatal SAEs, mostly to cardiac disorders (9 [22.5%]); 14 (35.0%) were ongoing and 3 (7.5%) had discontinued. Treatment-related SAEs occurred in 6 (15.0%) pts and dara-related SAEs in 4 (10.0%) pts.
Conclusions
In high-risk (stage 3B) AL amyloidosis pts, dara monotherapy induced early and profound hematologic responses over 6 months with 77.5% of pts achieving ≥PR and 50% VGPR/CR, and cardiac responses were seen in 27.5% of pts. No new safety (cardiac) concerns were observed and the primary objective of the study was met. Based on these results, dara monotherapy should be considered as an active and relatively non-toxic treatment option for stage 3B pts with AL amyloidosis.