Background: Cardiac involvement and severity of cardiac dysfunction in light chain (AL) amyloidosis is a critical prognostic factor. Patients (pts) at Mayo cardiac stage 3b have a poor prognosis with a median overall survival (OS) of just 4 months and high rates of early death with current therapies; thus, there is a need for novel, non-toxic, effective treatments for these pts. Daratumumab (DARA), a human anti-CD38 antibody, has shown efficacy and tolerability in pts with AL amyloidosis.
Aims: To evaluate the efficacy and safety of DARA monotherapy used off-label in newly diagnosed pts with stage 3b AL amyloidosis.
Methods: The ongoing EMN22 phase 2, multinational, open-label study (NCT04131309) aims to enroll 40 newly diagnosed pts with stage 3b AL amyloidosis. Eligible adult pts have high-sensitivity troponin T (hsTnT) >54 pg/mL and N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥8,500 pg/mL. DARA monotherapy, 16 mg/mL by intravenous infusion (09/2019–01/2020) and 1,800 mg by subcutaneous injection (01/2020 and thereafter), is administered weekly during cycles (C)1 and 2, every 2 weeks for C3–6, and every 4 weeks thereafter. Pts not achieving a hematological very good partial response (VGPR) or better by the end of C3 can receive additional weekly bortezomib and low dose dexamethasone (Vd). Treatment continues up to 2 years from initiation or until disease progression or initiation of a new therapy. Primary endpoint is OS rate at 6 months. This descriptive analysis included pts initiating treatment ≥6 months before the cut-off date (14/01/2022); the median (95% confidence interval [CI]) OS was obtained by Kaplan-Meier analysis.
Results: Of 27 pts included, 8 (30%) continued study treatment by the cut-off date and 19 (70%) had discontinued. The pts median age was 68 (range 45–84) years, and most were male (16, 59%). At screening, 10 (37%) and 17 (63%) pts had New York Heart Association class II and IIIA symptoms, respectively; the median NT-proBNP was 15,512 pg/mL (range 8,816–72,522), hsTnT was 133 pg/mL (range 60–692), and the difference of involved to uninvolved free light chains was 406 mg/l (range 24–3,377). Beyond the heart, the median number of other organs involved was 2 (range 0–5), most commonly kidneys (14 pts, 52%) and peripheral nerves (11 pts, 41%). The median duration of DARA therapy was 7 months (range <1–24); seven (26%) pts received additional Vd. At a median observation time of 8 months (range <1–11), the overall response rate (ORR) was 67% (18 pts; complete response [CR]:19.0% [5 pts], VGPR:37% [10 pts], partial response:11% [3 pts]). The ORRs at 1, 2, and 3 months were 59% (16 pts), 63% (17 pts), and 63% (17 pts), respectively. Median time to first response was 7 days (range 6–114), and to VGPR or better 54 days (range 6–219). Median OS was 9 months (95% CI, 3–not reached). The 6- and 12-month median (95% CI) OS rates were 63% (42–78) and 49% (28–67), respectively. Twenty-five (93%) pts had ≥1 non-serious adverse event. Twenty (74%) pts had ≥1 serious adverse event (SAE), comprising 15 (56%) pts with ≥1 cardiac-related SAE and 11 (41%) pts with a fatal SAE. Six SAEs were treatment-related: 2 with DARA (grade 3 pneumonia, grade 5 sepsis); 3 with bortezomib (grade 2 fatigue, grade 2 fall, and grade 3 troponin I increase); and 1 with dexamethasone (grade 3 cardiac failure).
Summary/Conclusion: Among pts with Mayo stage 3b AL amyloidosis, a subgroup with poor prognosis, DARA monotherapy induced rapid and deep hematological responses and no new safety signals; the median OS surpassed that reported previously.