Systemic AL Amyloidosis: Current Approaches to Diagnosis and Management

Abstract

AL amyloidosis is characterized by a low-level expansion of an indolent, small plasma cell clone that produces amyloidogenic light chains. Amyloid aggregates or preceding intermediaries cause direct cell damage through their proteotoxicity, and amyloid deposits distort tissue architecture, and, eventually, lead to organ impairment. It is a rare, underdiagnosed disease with a diverse clinical presentation depending on the organ tropism of the amyloid fibrils; cardiac and renal involvement is most common, but any organ can be affected, excluding the central nervous system. A high level of awareness and a systematic approach using newly emerging screening biomarkers is required to achieve early diagnosis. Management should be multidisciplinary as supportive management tailored to management of organ dysfunction is paramount to survival and minimization of treatment-associated toxicity. The initial therapeutic aim is to rapidly eliminate the clonal plasma cell that produces the circulating amyloid precursor and achieve a complete hematologic response, and if possible with undetectable minimal residual disease as assessed by next-generation methods (flow and sequencing), with minimal toxicity. Treatment is tailored to the initial risk assessment of the patients. Treatments are based on regimens adapted from the expanding options that are available for multiple myeloma patients and hematological response rates have improved. Organ response rates are strongly associated with deeper hematologic response but usually lag behind hematological response and are also dependent on the initial organ function reserve. Agents directed against the amyloid deposits have been explored to aid amyloid clearance and improve organ function, but data are still negative.

Daratumumab for relapsed AL amyloidosis—When cumulative real‐world data precedes clinical trials: A multisite study and systematic literature review

“…Thus, the outcomes of DARA for treatment of RRAL reported in our series as well as other series supersede the benchmark set by IMiD and bortezomib combinations, which have been the accepted standard therapy for RRAL until recently. 35 Our series, like others, suffers limitations due to its retrospective nature. Thus, data reporting may be incomplete, in particular that assessing organ responses and toxicity.…”

“…Hematologic, renal and cardiac response for the entire cohort (n = 101, including also newly diagnosed patients) were 62%, 50%, and 8%, respectively 34 . Bortezomib‐based regimens have become a standard part of the initial treatment of AL amyloidosis in the majority of centers; however, it may also be considered for treatment of relapsed patients 35 . Proteasome inhibitors treatment for AL amyloidosis was recently reviewed, 36 and hematologic response in relapsed patients treated with bortezomib‐based regimens was reported between 69% and 78%, median PFS of 25.5 months, and a variable organ response rate ranging from 13% to 50% for cardiac and 18%‐29% for renal responses.…”

“…34 Bortezomib-based regimens have become a standard part of the initial treatment of AL amyloidosis in the majority of centers; however, it may also be considered for treatment of relapsed patients. 35 Proteasome inhibitors treatment for AL amyloidosis was recently reviewed, 36 and hematologic response in relapsed patients treated with bortezomib-based regimens was reported between 69% and 78%, median PFS of 25.5 months, and a variable organ response rate ranging from 13% to 50% for cardiac and 18%-29% for renal responses. Thus, the outcomes of DARA for treatment of RRAL reported in our series as well as other series supersede the benchmark set by IMiD and bortezomib combinations, which have been the accepted standard therapy for RRAL until recently.…”

Immunoglobulin light chain amyloidosis

“…It is important to keep in mind that false-positive staining results of deep abdominal fat aspirates from diabetic patients (localized AL amyloidosis from frequent subcutaneous insulin administration) might occur [14]. On the other hand as mentioned above, Congo red negativity is not uncommon in abdominal fat aspirations or silent site biopsies and does not exclude systemic AL [15].…”

“…Similar to multiple myeloma, genetic abnormalities are of high importance [29] Translocation t [12,15] is detected in > 50% of AL.…”