Minimal residual disease negativity by next-generation flow cytometry is associated with improved organ response in AL amyloidosis

Giovanni Palladini,Ramón Lecumberri,Margherita Massa,Leire Burgos,Ashutosh D Wechalekar ,Jesús F San Miguel ,P Berti ,Alberto Órfão ,Alice Nevone,Andrea Foli,Ombretta Annibali,Jessica Ripepi,Noemí Puig ,Pasquale Cascino,Marco Basset,Simona Casarini,Mario Nuvolone,Margherita Bozzola,Melania Antonietta Sesta,Isabel Krsnik,Sriram Ravichandran,Bruno Paiva,Paolo Milani,Marta Lasa,Giampaolo Merlini

doi:10.1038/s41408-021-00428-0

Abstract

Light chain (AL) amyloidosis is caused by a small B-cell clone producing light chains that form amyloid deposits and cause organ dysfunction. Chemotherapy aims at suppressing the production of the toxic light chain (LC) and restore organ function. However, even complete hematologic response (CR), defined as negative serum and urine immunofixation and normalized free LC ratio, does not always translate into organ response. Next-generation flow (NGF) cytometry is used to detect minimal residual disease (MRD) in multiple myeloma. We evaluated MRD by NGF in 92 AL amyloidosis patients in CR. Fifty-four percent had persistent MRD (median 0.03% abnormal plasma cells). There were no differences in baseline clinical variables in patients with or without detectable MRD. Undetectable MRD was associated with higher rates of renal (90% vs 62%, p = 0.006) and cardiac response (95% vs 75%, p = 0.023). Hematologic progression was more frequent in MRD positive (0 vs 25% at 1 year, p = 0.001). Altogether, NGF can detect MRD in approximately half the AL amyloidosis patients in CR, and persistent MRD can explain persistent organ dysfunction. Thus, this study supports testing MRD in CR patients, especially if not accompanied by organ response. In case MRD persists, further treatment could be considered, carefully balancing residual organ damage, patient frailty, and possible toxicity.

Highlights

Light chain (AL) amyloidosis is caused by a small B-cell clone, more commonly a plasma cell (PC) clone with shared genetic features with multiple myeloma (MM) and monoclonal gammopathy of undetermined significance, producing light chains (LCs) that form amyloid deposits and exert toxicity on target organs1–3.Lymphoplasmacytic clones sustain the disease in a minority of patients4
A total of 108 patients with AL amyloidosis who were known to be in Amyloid complete response (aCR) at least 6 months after treatment discontinuation, underwent Next-generation flow (NGF)-based minimal residual disease (MRD) assessment
We report here on the largest population of patients with AL amyloidosis with sustained complete hematologic response (CR) undergoing MRD assessment with NGF

Summary

Introduction

Light chain (AL) amyloidosis is caused by a small B-cell clone, more commonly a plasma cell (PC) clone with shared genetic features with multiple myeloma (MM) and monoclonal gammopathy of undetermined significance, producing light chains (LCs) that form amyloid deposits and exert toxicity on target organs. Lymphoplasmacytic clones sustain the disease in a minority of patients. The size of the underlying PC clone at baseline affects prognosis. Profound decreases of LC levels through PC-targeting chemotherapy can result in the improved organ dysfunction and arrest the otherwise inexorable progression of the disease. Even small increases in amyloid LCs can cause organ progression and reduced survival. Current hematologic and organ response criteria are based on M protein studies and on changes in the difference between amyloidogenic (involved; iFLC) and uninvolved free LC (dFLC) and in markers of organ dysfunction. Amyloid complete response (aCR) is defined by normal FLC ratio plus

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