Factors Underlying Impaired Organ Recovery Despite a Deep Hematologic Response in Patients with Systemic AL Amyloidosis

Background: Amyloid-mediated organ dysfunction is the main determinant of survival for patients with light chain (AL) amyloidosis. Reducing the production of amyloidogenic light chains with plasma cell-directed therapy is a prerequisite for organ response. Despite achieving a hematologic complete response (hemCR), some patients have enduring organ dysfunction. A better grasp of the mechanisms underlying organ recovery is needed, especially as attention moves to novel therapeutics that trigger removal of existing amyloid deposits, and as graded organ response criteria to gauge improvement more precisely than traditional binary systems are adopted. Aims: We designed this study to identify the (1) rates of organ non-response and (2) possible reasons for impaired organ recovery in patients with AL amyloidosis with hemCR after treatment. Methods: Patients with biopsy confirmed AL amyloidosis who presented to our center for post-treatment assessment between February 2019 and June 2023 were included if they had major organ involvement (heart, kidney and/or liver) and were evaluable for organ response (Palladini, 2012). Graded cardiac response was assessed by validated criteria (Muchtar, 2022). We excluded patients who received amyloid fibril-targeted antibody therapies. To eliminate the possibility of insufficient hematologic response as a confounder for organ non-response, we focused only on patients with hemCR. Organ response was measured as best response >3 months from hemCR achievement. Reasons for organ non-response were postulated by our multidisciplinary team after extensive workup and review of clinical data. Results: Among 143 patients with hemCR, the median age at diagnosis was 58 years (range 30-78); 94 (66%) were male; and 24 (17%) identified as non-white race. Kidney, heart and liver involvement was present in 117 (82%), 68 (48%) and 17 (12%) patients, respectively; 54 (38%) had ≥2 major organs affected. Final treatment granting hemCR was high-dose melphalan and stem cell transplantation for 49 (34%); bortezomib-based for 37 (26%); daratumumab monotherapy for 31 (22%); daratumumab-CyBorD for 18 (13%); and an immunomodulatory drug for 8 (6%) patients; 58 (41%) required ≥2 lines of therapy to achieve hemCR. Failure to attain organ response was observed in 40/117 (34%), 19/68 (28%) and 3/17 (18%) of patients with kidney, heart and liver involvement, respectively. Of 42 patients with both kidney and heart involvement, 21 (50%) had concordant responses of