Introduction In light chain (AL) amyloidosis, patients achieving hematologic complete response (hemCR) may still harbor residual clonal plasma cell disease that is undetectable by conventional testing. Measurable residual disease (MRD) assessment by multiparametric flow cytometry provides a more sensitive measure of disease control. While single-timepoint MRD negativity has been associated with improved outcomes in AL amyloidosis, the added benefit of sustained MRD negativity remains underexplored.

Given the dynamic nature of MRD status, serial assessments may better capture disease trajectory and progression risk. We aimed to evaluate the clinical significance of sustained MRD negativity in a real-world cohort of patients with AL amyloidosis in hemCR during longitudinal post-treatment surveillance.

Methods At the Boston University Amyloidosis Center, serial flow-based MRD testing of bone marrow aspirates (sensitivity ≥10-5; PhenoPath, Seattle) was implemented in 2019 for patients in hemCR. We analyzed outcomes in patients with ≥2 MRD assessments ≥12 months apart through the end of 2024. Sustained MRD negativity was defined as ≥2 consecutive negative results without subsequent MRD positivity. Outcomes includedhematologic progression (based on serum free light chain and serum/urine immunofixation electrophoresis findings as per consensus criteria [1] with or without accompanying organ deterioration), clinical progression (organ deterioration without hematologic relapse), and survival. Patients with end-stage organ failure prior to hemCR achievement were considered unevaluable for clinical progression.

Results A total of 106 patients with AL amyloidosis in hemCR underwent serial MRD assessments: 39 had 2 tests, 39 had 3, and 28 had ≥4. Median age was 58.5 years (IQR, 51.3–64.8); 65% were male, 85% White, and 77% had lambda light chain involvement. Fifty-seven percent were newly diagnosed (ND), while 43% were relapsed/refractory (R/R) with a median of 2 prior lines of therapy (range 2–5).

Sustained MRD negativity was achieved by 42 patients (40%) at any point in the disease course: 22/60 (37%) in the ND setting and 20/46 (43%) in the R/R setting. Within this hemCR-achieving study population, rates of sustained MRD negativity by treatment group were:

• ND cohort: Dara-CyBorD 50% (5/10), HDM/SCT 40% (14/35), other regimens 23% (3/13)

• R/R cohort: HDM/SCT 57% (4/7), daratumumab monotherapy 48% (11/23), other regimens 31% (5/16)

At a median follow-up of 53 months from hemCR achievement, no patients with sustained MRD negativity developed hematologic progression; 4 had organ-related clinical progression and 2 died of unrelated causes. In contrast, among 52 patients with MRD positivity, 25 (48%) progressed: 18 (35%) hematologically and 7 (13%) clinically; and 4 patients died (3 due to disease-related progression). Twelve patients converted from MRD-negative to MRD-positive status (MRD resurgence) at a median of 47.5 months post-hemCR achievement, with 5 (42%) subsequently progressing, including 3 (25%) hematologically within 11–23 of MRD resurgence.

Conclusions Sustained MRD negativity lasting ≥12 months was strongly associated with freedom from hematologic progression, regardless of the treatment approach, and therefore may serve as a meaningful marker of long-term disease control in AL amyloidosis. Both HDM/SCT and daratumumab-based regimens achieved high rates of durable MRD negativity. Additionally, MRD resurgence preceded hematologic progression in a subset of patients, supporting the value of serial MRD monitoring over single-timepoint assessments. These findings underscore the importance of MRD dynamics as a prognostic tool in post-treatment surveillance for AL amyloidosis.

Reference

  • Gertz et al, Am J Hematol, 79:319–328, 2005.

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2025
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