Novel challenges in the management of immunoglobulin light chain amyloidosis: from the bench to the bedside

ABSTRACT

Introduction

Immunoglobulin light chain (AL) amyloidosis is one of the most frequent systemic amyloidosis in Western countries. It is caused by a B-cell clone producing a misfolded light chain (LC) that deposits in organs.

Areas covered

The review examines recent findings on pathophysiology and clinical management of AL amyloidosis. It contains an update on the recent hot topics as novel therapeutic approaches, definition of relapse, and hematologic response assessment. To review literature on AL amyloidosis, a bibliographic search was performed using PubMed.

Expert opinion

Due to the proteotoxicity of amyloidogenic LCs, the therapeutic goal is a rapid and profound decrease in their concentration. The standard treatment is a risk-adapted chemotherapy targeting the B-cell clone. Novel, promising drugs, as daratumumab, are currently under evaluation in newly-diagnosed and relapsed/refractory patients. New sensitive techniques, as mass spectrometry approach and bone marrow minimal residual disease assessment, are available to evaluate depth of response. After first-line therapy, increase in LC concentration may precede worsening of organ dysfunction and should be considered carefully. Further clarification of molecular mechanisms of the disease are shedding light on new possible therapeutic targets. Innovative treatment strategies and novel technologies will improve our ability to treat AL amyloidosis, preventing organ deterioration.

KEYWORDS:

• Amyloidosis
• light chains
• diagnosis
• prognosis
• therapy

Article highlights

• Organ biomarkers allow diagnosis of cardiac and renal involvement at a pre-symptomatic (low-risk stage) stage, in which organ dysfunction is still reversible and has a minor impact on the therapeutic strategy

• Amyloid typing with adequate techniques is mandatory to rule out non-AL systemic amyloidosis (e.g. ATTRwt and hereditary amyloidoses) and to avoid the risk of unnecessary chemotherapy

• Treatment should be risk-adapted and some clonal features, as translocation t(11;14) and gain 1q21, may orient/guide therapeutic choices

• Response to treatment should be early and frequently evaluated by close monitoring of FLC concentration and MRD assessment should be considered in patients who achieved a CR

• Novel effective treatments in newly diagnosed and relapsed/refractory AL amyloidosis are already under evaluation in clinical trials

• New possible therapeutic targets in the amyloidogenic process have been identified and novel treatment approaches that may be used in combination with chemotherapy are currently under study.

Declaration of interest

G Palladini receives honoraria from Janssen and Prothena and travel support from Prothena and Celgene; M Nuvolone receives from honoraria from Janssen; G Merlini is a consultant for Millennium Pharmaceuticals, Pfizer, and Janssen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by Agenzia Italiana del Farmaco, Ministero della Salute [grant AIFA-2016-02364602]; Amyloidosis Foundation; Associazione Italiana per la Ricerca sul Cancro [9965]; E-Rare JTC 2016 x [Grant ReDox]; Fondazione Cariplo [2014-0700;2015-0591; 2016-0489; 2018-0257]; International Myeloma Society x Bart Barlogie Young Investigator Award and Ministero della Salute [RF-2013-02355259; RF-2016-02361756; GR-2018-12368387] and by an Accelerator Award from the Cancer Research UK, the Fundación Científica – Asociación Española Contra el Cáncer and the Associazione Italiana Ricerca sul Cancro.