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

Introduction Patients (pts) with stage IIIB light-chain (AL) amyloidosis have high risk of early death (historical median overall survival [OS] reported from 2 to 7 months), mainly due to severe cardiac dysfunction, being also frail and sensitive to treatment related toxicities. Identifying the optimal treatment strategy for this subgroup is a high unmet need. Single agent Daratumumab (Dara) has shown high efficacy & rapid hematologic responses with a favorable toxicity profile in pts with AL amyloidosis. ANDROMEDA study showed that in pts with newly diagnosed AL (NDAL) amyloidosis, the combination of Dara with Bortezomib, Cyclophosphamide & dexamethasone (VCd) induces high rates of hematologic complete response (CR) across cardiac stages I-IIIA; yet, pts with Mayo stage IIIB were excluded. This is an updated analysis of a prospective study evaluating the efficacy & safety of Dara monotherapy in stage IIIB NDAL pts. Methods EMN22, a phase 2, open-label, multinational study (NCT04131309) enrolled 40 NDAL pts with stage IIIB disease. Eligible adult pts had serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥8500 pg/mL & high-sensitivity troponin T (hsTnT) >54 pg/mL. Dara was initially administered intravenously (16 mg/mL), & after February 2020 subcutaneously as a fixed dose of 1800 mg weekly (QW) during cycles (C)1-2, Q2W for C3-6, & Q4W thereafter. Bortezomib QW & low-dose dexamethasone (Vd) could be added to pts not achieving ≥ very good partial hematological response (VGPR) by start of C4. Treatment continues for maximum 2 years from initiation or until progressive disease or initiation of new therapy. OS rate at 6 months was the primary endpoint. Key secondary endpoints were the hematologic response rate, the organ response rate & the proportion of patients that received Vd. Results Accrual was completed with 40 pts enrolled (median age: 70.5 years [range 45.0-86.0]; male: 22 [55%]). At cut-off of 31 May 2024, 1 (2.5%) pt was on treatment, 27 (67.5%) had discontinued before the end of protocol treatment & 12 (30%) had completed treatment as per protocol. At screening, 25 (62.5%) pts had ECOG status ≥2, and 16 (40%) & 24 (60%) pts had NYHA class II & IIIA symptoms, respectively. The median (range) NT-proBNP, hsTnT, difference of involved to uninvolved free light chains & left ventricular ejection fraction (LVEF) were 14,353 (8,516-72,522) pg/mL, 136 (55-692) pg/mL, 427 (36-2,823) mg/L, & 44.5% (26-68), respectively. At baseline, besides heart, 33 (82.5%) pts had ≥1 organ involved, most often kidney (20 pts, 50%) & peripheral nerves (12 pts, 30%). At a median (range) follow-up of 10.3 months (<0.1-55.6), the median number of Dara administrations was 18 (1-36) & median treatment duration was 6.6 months (<0.1-25.3). 10 (25%) pts received additional Vd treatment. The 6-month OS rate was 65% (95% CI: 48.2-77.6); the 3-month & the 12-month OS rates were 72.5% (55.9-83.7) & 45% (29.3-59.5), respectively; median OS was 10.3 months (4.1-32.1). A hematologic response (≥partial response [PR]) was achieved by 31 (77.5%) pts, ≥VGPR and CR rates were 55% & 27.5%, respectively. Median times (range) to 1st response ≥PR & 1st VGPR, were 0.2 months (0.2-4.1) & 1.8 months (0.2-7.3), respectively. Following Vd addition, responses deepened in 60% (6/10) of patients. Pts achieving ≥ PR at 1 month had a higher median (95% CI) OS compared to pts with <PR (31.2 months [8.4-NR] vs 3.1 months [1.2-9.4], respectively). A cardiac response at 3 & 6 months was achieved by 9 (22.5%) & 11 (27.5%) pts respectively & overall 20 (50%) pts achieved cardiac response (≥carPR), with 12 (30%) having achieved carVGPR, & 4 (10%) having achieved carCR. All pts experienced ≥1 adverse event (AE), either serious (SAE) or non-serious (NSAE). 38 (95%) pts had ≥1 NSAE and 32 (80%) pts had ≥1 SAE, including 17 (42.5%) pts with cardiac SAEs, while 17 (42.5%) pts had fatal SAEs, mostly related to cardiac AE (8 [20%]), such as sudden cardiac death & cardiac failure, Early mortality rate at 15-days, 1-month & 3-months was 7.5%, 10% & 27.5%, respectively. Conclusions Dara monotherapy resulted in improved 6-month and overall survival rates compared with historical data. Deep hematologic & cardiac responses were observed, in this population of patients with very advanced cardiac dysfunction, with no new safety signals. Addition of other established AL treatments could further improve outcomes, indicating Dara's potential to benefit this ultra-high-risk population.