Minimal Residual Disease Testing in Relapsed Systemic AL Amyloidosis

Background

The only FDA-approved therapy for systemic light chain (AL) amyloidosis is daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (i.e., Dara-CyBorD). There are no standard therapies for the second or third line of treatment after relapses. The primary endpoint for the Dara-CyBorD trial ANDROMEDA was hematologic response and a critical secondary endpoint was a composite of major organ dysfunction (cardiac, renal) and progression of hematologic disease. Given the improved survival of AL patients and the frequent need for second- and third-line therapies for progression of hematologic disease, often in the context of progressive renal dysfunction, the use of serologic criteria of response such as free light chain measurements becomes problematic. Additional endpoints may be useful in trials for relapsed AL patients forgoing a need for restricting the study population based on chronic kidney disease status. The application of minimal residual disease (MRD) testing in AL is attractive because the clonal plasma cell disease is marrow-based, and the pathological light chains produced by the clone can propagate organ damage even at low levels. The question of correlation between MRD status and hematologic response in patients relapsing after second- or third-line therapy remains an open one. Our study aimed to assess the application of MRD and its correlation with hematological and organ responses in AL patients, particularly those with relapsed disease.

Methods

We performed a retrospective single-center study at Tufts Medical Center that included patients diagnosed with systemic AL between September 2016 and June 2024. For MRD assessment, bone marrow aspirate samples were sent to Adaptive Biotechnologies Inc. (Seattle, WA) for initial clone identification and tracking clonotypic sequences using the clonoSEQ Assay or to Mayo Labs for next-generation flow (NGF) cytometry. MRD negativity was defined as less than 1 cell in 10⁵ marrow aspirate cells (< 10^-5). Clinical data, including demographic characteristics, organ involvement, lines and regimens of treatment, and hematological and organ responses, were collected.

Results

Fifty-one patients with MRD testing data were identified. Among them 34 (66.7%) had cardiac and 39 (76.5%) had renal involvement. Sixteen (31.4%) achieved MRD negative status. Of the 51 patients, 25 (49.5%) had received one line of treatment at the time of the MRD test, 10 (19.6%) had received two lines, and 16 (31.4%) had received three or more lines. Twenty-five (49.0%) patients received an autologous stem cell transplant (ASCT) and two (3.9%) received ASCT twice. Thirty-nine (76.5%) received a daratumumab-based regimen and 18 (35.3%) venetoclax. At the time of the MRD test, 30 (58.8%) patients were on active surveillance, 10 (19.6%) were on daratumumab and 9 (17.6%) on venetoclax. MRD negative rates were associated with lines of treatment (one, two, three or more lines: 20%, 70%, 25%, respectively, P < 0.05). In the 26 patients with relapsed AL amyloidosis, MRD negativity was associated with a better hematological response (P < 0.01). MRD-negative patients had significantly better hematological responses (CR+VGPR) compared to the MRD-positive group (15/16 vs. 27/35, P < 0.01). Cardiac response was achieved in 6 of 9 MRD-negative patients and 17 of 22 MRD-positive patients (P = 0.91). Renal response was achieved in 9 of 11 MRD-negative patients and 20 of 23 MRD-positive patients (P = 0.18). Compared to MRD-positive patients, MRD-negative patients were less likely male (37.5% vs. 77.8%, P < 0.01). Gender was an independent predictor for MRD positivity by logistic regression (OR 13.13, 95% CI 2.12 – 81.07, P < 0.01).

After a median follow-up of 69.6 months, one patient in the MRD positive group had died due to treatment-related side effects, with the median overall survival not achieved in both MRD positive and negative groups.

Conclusion

MRD analysis may be a useful endpoint for monitoring treatment responses in patients with relapsed AL amyloidosis. If MRD persists, further treatment may be considered to achieve MRD negativity. In patients with relapsed AL, MRD negativity is correlated with a better hematological response and could potentially play a role in clinical trial design. The impact of gender on MRD status remains an important area for further study.