A safety review of drug treatments for patients with systemic immunoglobulin light chain (AL) amyloidosis

ABSTRACT

Introduction

In AL amyloidosis, a usually small plasma cell clone secretes unstable, amyloid-forming light chains, causing cytotoxicity and progressive (multi)organ function deterioration. Treatment aims at reducing/eradicating the underlying clone, to reduce/zero the supply of the amyloidogenic protein and halt the amyloidogenic cascade.

Areas covered

Safety data of alkylating agents, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies from clinical trials are reviewed.

Expert opinion

Drugs used to treat AL amyloidosis are derived from experience with multiple myeloma or other B cell malignancies. However, treating AL amyloidosis is particularly challenging, as it implies delivering anti-neoplastic therapy to a hematologic malignancy directly causing (multi)organ function deterioration, often in elderly subjects with other comorbidities and polypharmacotherapy. This unique combination translates in increased patients’ frailty and higher sensitivity toward treatment-related toxicities. Therefore, dose/schedule adjustments and special precautions are needed when translating treatment experience from multiple myeloma or other B cell malignancies to AL amyloidosis. Treatment of patients with AL amyloidosis should be risk adapted, tailored to individual patients’ risk profile, considering the type and extent of organ involvement, and eventual comorbidity. As several classes of effective anti-plasma cell or B cell drugs are available, therapeutic choices are also influenced by individual drug’s safety profile.

KEYWORDS:

• AL amyloidosis
• plasma cell dyscrasia
• monoclonal gammopathies
• targeted therapies
• toxicity
• chemotherapy
• immunotherapy
• novel agents

Article highlights

• In AL amyloidosis, a hematologic malignancy directly causes (multi)organ function deterioration, often in the context of elderly subjects with other comorbidities and polypharmacotherapy.

• Translating treatment experience from multiple myeloma or other B cell malignancies to AL amyloidosis requires dose and schedule adjustments and special precautions due to increased patients’ frailty and higher sensitivity toward treatment-related toxicities.

• Treatment of AL amyloidosis should be patient-tailored, guided by individual patients’ risk, type and extent of amyloid organ involvement, other possible comorbidities, safety profile of available treatments, and prior experienced toxicity in the case of non-frontline therapies.

• Supportive therapy, close monitoring of response to therapy and rapid therapy switching if deep responses are not achieved can help minimizing treatment-related toxicity while increasing chances of obtaining a clinically relevant hematologic and organ responses.

Declaration of interest

M Nuvolone received honoraria from Jannsen. G Palladini received honoraria from Jannsen, Pfizer and Siemens and is member of the advisory board of Jannsen. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

This study was supported by a grant from CARIPLO “Harnessing the plasma cell secretory capacity against systemic light chain amyloidosis” (n. 2018-0257), by a grant from the Italian Ministry of Health “Towards effective, patient-tailored anti-plasma cell therapies in AL amyloidosis: Predicting drug response and overcoming drug resistance” (GR-2018-12368387), and by a grant from Cancer Research UK, FCAECC and AIRC under the Accelerator Award 2017 Program “Early detection and intervention: Understanding the mechanisms of transformation and hidden resistance of incurable haematological malignancies”.