AL amyloidosis (amyloid light chain amyloidosis) is a monoclonal gammopathy
The symptoms are caused by the deposition of amyloid fibrils in tissues. The fibrils are formed from monoclonal light chains. Worldwide incidence is about 9 cases per million per year 1 with a prevalence of 58 cases per million 2.
Unlike multiple myeloma (MM), the morbidity and mortality associated with AL amyloidosis are due to the accumulation of FLC-derived amyloid fibrils in the organs, and not directly due to the proliferation of monoclonal plasma cells. This deposition may occur in a number of different organs including the heart, kidney, liver and nervous system 3.
The kidney is the organ most frequently involved, with 70-80% of AL amyloidosis patients having renal involvement 4. The heart is the next most common site of involvement, with 50-60% of patients having evidence of cardiac involvement by echocardiography 4, followed by liver involvement (25%) and involvement of the peripheral nervous system in 20% of AL amyloidosis patients 4. It is particularly important to identify cardiac involvement so treatment of the underlying monoclonal gammopathy can begin alongside supportive care for the cardiac dysfunction, as 75% of deaths in AL amyloidosis are due to heart failure or arrhythmia caused by the amyloid fibril deposits 5.
Diagnosis of AL amyloidosis is complicated in two ways:
For this reason, a variety of clinical and laboratory tests are used to diagnose or rule out AL amyloidosis 7.
- First, there must be evidence of an amyloid-related systemic syndrome.
- There must be evidence that the deposits in organs are due to amyloid proteins. This is normally identified by Congo red staining of the deposits obtained through biopsy. If the deposit is due to amyloid fibrils, the stain will demonstrate birefringence under polarised light.
- Then there must be evidence that the amyloid found in the organ is light chain related. This is determined by direct examination of the deposits in the biopsy by immunohistochemistry, or by mass spectrometry.
- There must also be evidence of a monoclonal plasma cell disorder. This can be confirmed by identification of a serum and/or urine monoclonal protein, an abnormal κ/λ sFLC ratio, or clonal plasma cells in the bone marrow. Even if all five techniques (SPE, sIFE, UPE, uIFE and sFLC testing) are used, 2-3% of AL patients will have no evidence of monoclonal protein production by these methods 8.
Once identified, a number of treatment options are available for AL amyloidosis patients - these can include drugs that target the underlying tumor (the source of the amyloidogenic FLC) and stem cell transplant.
Response to treatment in AL amyloidosis is assessed by organ response and hematological response. Hematological response is evaluated by measurement of free light chains 9.
In AL amyloidosis, the dFLC (difference between the involved FLC and uninvolved FLC) is used in response assessment.
It is very important to assess hematological response, because it begins to occur earlier than organ response, and can tell clinicians whether a treatment is working or whether it needs to be changed.
Around 10-15% of patients with multiple myeloma may develop concurrent AL amyloidosis 10. It’s important to be aware of this when managing patients with myeloma, and be alert for signs of amyloid deposit-related organ damage so supportive care given if needed.
| Haematological response and progression criteria 9 | ||||
|---|---|---|---|---|
| Complete response | Normal FLC ratio, and Negative IFE of serum and urine, and <5% plasma cells in bone marrow | |||
| Very good partial response | Reduction in dFLC to <40mg/L | |||
| Partial response | >50% decrease in dFLC | |||
| No response | Less than a PR | |||
| Progression | From CR | Detectable M-protein or abnormal sFLC ratio (FLC must double) | ||
| From PR | increase in urine M-protein to >200mg/day | |||
References
- Tosi P, et al. Serum free light-chain assay for the detection and monitoring of multiple myeloma and related conditions. Ther Adv Hematol 2013; 4:37-41
- Kumar S, et al. Serum immunoglobulin free light chain measurement in AL amyloidosis: prognostic value and correlations with clinical features. Blood 2010; 116:5126-5129
- Yang Y, et al. Comparison of two serum free light chain assays for the diagnosis of primary plasma cell malignant proliferative disease. Health Science Reports 2019; 2:e113
- Rajkumar SV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014; 15:e538-e548
- Kumar S, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 2016; 17:e328-46
- Rajkumar SV, et al. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Blood Rev 2007; 21:255-265
- Korde N, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies. Blood 2011; 117:5573-5581
- Bradwell AR, et al. Highly sensitive, automated immunoassay for immunoglobulin free light chains in serum and urine. Clin Chem 2001; 47:673-680
- Dejoie T, et al. Responses in multiple myeloma should be assigned according to serum, not urine, free light chain measurements. Leukemia 2019; 33:313-318
- Katzmann JA, et al. Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. Clin Chem 2002; 48:1437-1444
- Mollee P. Current trends in the diagnosis, therapy and monitoring of the monoclonal gammopathies. Clin Biochem Rev 2009; 30:93-103
- Rajkumar SV, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 2005; 106:812-817
- Comenzo RL, et al. Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis. Leukemia 2012; 26:2317-25
- Kyle RA & Rajkumar SV. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Curr Hematol Malig Rep 2010; 5:62-69