How I Manage Systemic Light Chain Amyloidosis

Gregory P Kaufman,Claudio Cerchione

doi:10.4081/hr.2021.9383

Abstract

Light chain amyloidosis (AL) is a protein deposition disorder with a heterogenous pattern of organ involvement and dysfunction that varies by affected patient. Often diagnosed late after the onset of symptoms, appropriate and correct diagnosis, and prompt initial management, typically with anti-plasma cell therapy targeting the underlying cell producing the aberrant light chain protein, can lead to significant improvement in patient symptoms, organ function and lifespan. With recent publication of phase III studies focused on AL, and a changing regulatory landscape providing greater availability of novel therapies, the management of AL is in some ways more complex with greater options to consider. In this clinical review, a discussion of the diagnosis, staging, and goals of therapy transitions to a focus on contemporary management questions to outline our clinical approach to multi-disciplinary management and long term follow up for patients with suspected or confirmed AL.

Highlights

Amyloidosis caused by deposition of misfolded light chain fibrils, or AL amyloidosis, is often found with an underlying low-grade plasma cell population in the bone marrow, though occurs in a portion of patients with multiple myeloma, and less commonly other indolent hematolymphoid cancers
In a study of 117 patients with amyloid deposits fitting this criteria, 52 patients did not require systemic therapy for another plasma cell neoplasm indication and among these patients there was no progression over a median of 2.5 years to systemic AL with organ involvement requiring therapy.[11] while the subcutaneous fat and bone marrow are sites of interest for the diagnosis and typing of amyloid deposits, in and of themselves should not be seen as an indication for therapy for systemic AL
Several staging systems have been proposed for cardiac AL prognosis, though we find the European modification of the original Mayo staging system to be most useful in clinical practice.[14]. In the original analysis to develop this staging system it should be noted that only a minority of patients (

Summary

Introduction

Amyloidosis caused by deposition of misfolded light chain fibrils, or AL amyloidosis, is often found with an underlying low-grade plasma cell population in the bone marrow, though occurs in a portion of patients with multiple myeloma, and less commonly other indolent hematolymphoid cancers. A rapid and deep hematologic response as early as 1 month into treatment has been shown to carry a survival benefit with a landmark analysis carried out by a European consortium of AL patients treated primarily with bortezomib based therapy.[16] A comparison of prognostic models, using the original 2004 Mayo Staging system, 2012 revised Mayo Stage which introduced dFCL as a covariate with high dFLC being an adverse prognostic factor, and the European modification of the 2004 Mayo system showed general agreement, with the European model showing improved prediction of early 1-year mortality.[17] We find it clinically useful to identify patients who have stage IIIB cardiac AL as these patients have been excluded from some key prospective interventional studies, and are being evaluated as a separate population from the standpoint of clinical trial eligibility for targeted interventions given the poor prognosis and high risk of early death in this population.[18] In our practice we often use cardiac MRI at baseline for patients with suspected cardiac dysfunction, as T1 and T2 mapping combined with determinants of extracellular volume (ECV) are powerful predictors of outcomes, and can be followed serially to provide additional information on cardiac response beyond serum NT-proBNP and echocardiographic findings.[19]. Ongoing areas of interest include the incorporation of bone marrow and serum based minimal residual disease (MRD) techniques, and improving understanding of how obtaining MRD negativity may yield additional marginal benefit in patient outcomes.[25, 26]

What is the optimal frontline therapy for newly diagnosed systemic AL?

What may change in the future?

Findings

Conclusions