Immunoglobulin light chain (AL) amyloidosis is characterized by a clonal population of bone marrow plasma cells that produces a monoclonal light chain of κ or λ type as either an intact molecule or a fragment . The light chain protein, instead of conforming to the α-helical configuration of most proteins, misfolds and forms a β-pleated sheet . This insoluble protein deposits in tissues and interferes with organ function. The β-pleated sheet configuration is responsible for positive staining with Congo red when viewed under polarized light; this staining is required for the diagnosis of AL amyloidosis .
Amyloidosis is particularly difficult to diagnose because no single imaging, blood, or urine test is diagnostic for this disorder . The presenting symptoms can be very broad and are often mimicked by more common disorders. The diagnosis of AL amyloidosis should be suspected in any patient with nondiabetic nephrotic syndrome; nonischemic cardiomyopathy with “hypertrophy” on echocardiography ; hepatomegaly or increased alkaline phosphatase value with no imaging abnormalities of the liver; chronic inflammatory demyelinating polyneuropathy with a monoclonal protein; or the presence of a monoclonal gammopathy in a patient with unexplained fatigue, edema, weight loss, or paresthesias . The presence of proteinuria in a patient with a monoclonal gammopathy may be mistaken for multiple myeloma with cast nephropathy . If specific diagnostic evaluation for amyloidosis is not performed, patients with sensory neuropathy may instead undergo treatment for a chronic inflammatory demyelinating polyneuropathy with a monoclonal protein, receiving plasma exchange and immunoglobulin (Ig) infusions . Some patients with unrecognized cardiac amyloidosis and a bone marrow plasma cell percentage less than 10% are referred to hematologists with a diagnosis of atypical multiple myeloma . The associated fatigue may be incorrectly ascribed to the mild anemia, and the cardiac infiltration goes unrecognized because the patient's ejection fraction is well preserved, the cardiac silhouette is normal in size , and the ventricular thickening is interpreted as hypertrophy rather than infiltration .
Appropriate screening of a patient with a clinical syndrome compatible with AL amyloidosis would include immunofixation of the serum , immunofixation of the urine , and an Ig free light chain assay . The amyloidogenicity of λ Ig light chains is shown in Fig. 1, which compares the findings of serum immunofixation in patients with monoclonal gammopathy of undetermined significance, myeloma, and amyloidosis. The high frequency of λ light chain proteinemia is a hallmark of AL amyloidosis. If immunofixation of serum and urine is negative and the Ig free light chain (κ:λ) ratio is normal (0.26–1.65), AL amyloidosis is unlikely and further evaluation should not be undertaken, unless the clinical index of suspicion is very high . An algorithm for the evaluation of a patient with suspected amyloidosis is given in Fig. 2.
If the patient has a compatible clinical syndrome and a light chain abnormality is found, biopsy is required to establish the diagnosis. Biopsy of the clinically involved organ is generally unnecessary. Renal biopsy , endomyocardial biopsy , and liver biopsy are expensive, invasive, and increase the risk of postbiopsy hemorrhage. Biopsy of the iliac crest bone marrow  combined with abdominal subcutaneous fat aspiration  will identify amyloid deposits in 85% of patients (Table I). If both the fat and the bone marrow stain negative for amyloid, there is still a 15% chance that amyloidosis is present, and the appropriate organs should be biopsied if the index of suspicion is high. If amyloid deposits are seen, it is important to investigate whether the amyloidosis is localized or systemic. Typical sites for localized amyloidosis include the skin , larynx , or urinary tract , which can include renal pelvis, ureter, bladder, and urethra. Pulmonary nodules are frequently localized deposits of amyloid composed of light chains or transthyretin . Deposits found in the colon or stomach, particularly in a polyp or at the edge of an ulcer, can represent degenerative amyloid and may be an incidental endoscopic finding and not reflect systemic AL amyloidosis .
Table I. Agreement of Results of Fat Aspiration and Bone Marrow Biopsy in 378 Patients With a Diagnosis of AL Amyloidosisa
Results are both positive in 53.4% (202/378), one positive in 32.0% (121/378), and both negative or equivocal in 14.6% (55/378).
If a patient has a visceral amyloid syndrome, even if an Ig abnormality is present, it is important to address the possibility that the amyloidosis may be secondary or familial with an incidental monoclonal gammopathy of undetermined significance . The light chain origin of an amyloid deposit can be confirmed with immunohistochemistry  or immunogold assay . Mass spectrometry can confirm the amyloid protein composition and is considered the standard for typing the protein subunit in amyloid deposits . If systemic light chain amyloidosis is confirmed, prognosis must be assessed. A required test panel for patients after histologic diagnosis of AL amyloidosis includes the following:
Pathologic confirmation that amyloid deposits are of Ig origin
Ig-free light chain κ and λ testing
Bone marrow biopsy
Serum and urine immunofixation
24-hour urine total protein measurement
Measurement of complete blood count, creatinine level, alkaline phosphatase level
Measurement of troponin, brain natriuretic peptide, or N-terminal pro–brain natriuretic peptide levels
Quantitative Ig measurement
The major determinant of outcome in amyloidosis is the extent of cardiac involvement. The accurate definition of cardiac involvement has evolved over the past three decades. Initially, cardiac involvement meant cardiac failure with cardiomegaly, pleural effusions, and Kerley B lines on the chest radiograph . Clinical cardiac assessment has been supplanted by echocardiography. Wall thickening, a granular sparkling appearance, diastolic relaxation abnormalities, right ventricular dysfunction with valvular thickening, and abnormal echocardiographic strain have all been shown to be associated with prognosis . In the past five years, serum cardiac biomarkers have been introduced. Tests for serum troponin T and N-terminal pro–brain natriuretic peptide (NT-proBNP) are widely available. Using cutoff values of 0.035 mcg/L troponin T and 332 pg/mL NT-proBNP, patients can be classified into three stages: Stage I, both biomarkers low (33% incidence); Stage III, both values high (30% incidence); or Stage II, only 1 marker high (37% incidence). The reported median survivals are 26.4, 10.5, and 3.5 months, respectively, for Stages I, II, and III . The value of cardiac biomarkers has been validated in patients treated conventionally and those treated with stem cell transplant (SCT) . Several studies have demonstrated that Stage III patients should be excluded from SCT studies . High troponin T level predicts early mortality from SCT and can be used as an exclusion criterion for this therapy . Stage III patients also are poor candidates for clinical trials of standard agents .
The percentage of bone marrow plasma cells , the Ig free light chain level at diagnosis , the number of organs involved , and the serum uric acid level  have all been associated with prognosis but have not been integrated into a staging system as has been defined for cardiac biomarkers.
Chemotherapy for the treatment of amyloidosis was introduced in 1972 in the form of melphalan and prednisone . Only a minority of patients responded, and the median survival was 12 to 18 months . Therapy remained unchanged until the introduction of SCT. The use of SCT in the management of amyloidosis was logical because it could rapidly eradicate the amyloidogenic light chain produced by the clonal plasma cell populations . Organ response rates of up to 65% have been reported . A prospective randomized study did not demonstrate a survival advantage for patients treated with SCT , and a meta-analysis also questioned the value of SCT for amyloidosis . A weakness of these assessments, however, is the high rate of treatment-related mortality, which suggests that patients in these studies were not risk-stratified and some may not have been suitable candidates for transplant .
A recent report has described 10-year survivors after SCT; 25% of patients receiving SCT survived 10 years, and the 10-year survival was 53% for patients with complete response to treatment . Transplant-related mortality rates have decreased from as high as 40%, to 7% in current studies . Renal and cardiac organ responses and high complete hematologic response rates have been reported after SCT . The major limitation to wider application of SCT is that no more than 20% to 25% of patients are eligible for transplant. Currently, a hematologic response is achievable in 76% of eligible patients, which is complete in 39% . At Mayo Clinic, organ responses have been recorded in 47% of patients . In multivariate survival analysis, the most important predictor of outcome is stage. For transplant-eligible patients with Stages I and II disease, median survival has not been reached; median survival is 58 months for patients with Stage III disease. Post-hoc hematologic response is the strongest predictor of outcome . Median survival was not reached for patients who achieved a complete response, 107 months for those with a partial response, and 32 months for nonresponders. In an analysis that excluded both early deaths and patients inevaluable for response at six months , the significance of hematologic response for prognosis persisted. SCT should remain an important consideration for patients who are deemed eligible to undergo this technique.
Conventional Treatment of Amyloidosis
Melphalan and prednisone have been demonstrated to be superior therapy to colchicine in two randomized Phase III studies [54, 55]. Even in patients with severe cardiac failure, continuous, oral, daily melphalan has been used and can provide palliation . On the basis of these studies and because dexamethasone as a single agent was reported to produce hematologic and organ responses, melphalan and dexamethasone have been combined in the treatment of AL amyloidosis. In a study by Palladini et al. [57, 58] of 46 patients who were ineligible for SCT, organ response after treatment with melphalan and dexamethasone was seen in 48% of patients, with a low treatment-related mortality of only 4%. At six years, the actuarial survival was ∼50% and the progression-free survival was 40% . Recently, however, two other reports using the identical regimen used by Palladini et al. [57, 58] have shown median survivals of less than 1.5 years [59, 60]. All of these studies had different patient compositions and had different percentages of patients with advanced disease. In the latter two studies, a high proportion of patients with advanced cardiac amyloid involvement were entered, and these patients were nonresponders with early death [59, 60].
The difference in results among these four reports, therefore, reflects the importance of stratifying patients by disease stage when interpreting results. Populations of patients with AL amyloidosis are heterogeneous from center to center, with resultant disparate outcomes despite use of the same chemotherapy protocol. Thus, comparison of outcomes across Phase II studies is fraught with risks of misinterpretation of data. Outcomes appear to be strongly linked to the proportion of patients with cardiac amyloidosis. It is dangerous to make treatment-based decisions solely on the basis of the outcomes of single-institution Phase II trials, because patient selection has as much a role in outcomes as the specifics of therapy .
Melphalan and dexamethasone is still considered a standard for nonstudy, nontransplant intervention because of its low toxicity profile, its demonstrated ability to produce hematologic responses even in the presence of advanced disease, and the orally available formulations of both agents . A summary of regimens used in the treatment of amyloidosis is given in Table II.
Table II. Conventional Systemic Chemotherapy Options for AL Amyloidosis
Reported outcome dependent on proportion of cardiac patients
All oral regimen thalidomide dose 50 mg daily
Lenalidomide dose 15 mg, 21 of 28 days
Weekly dosing better tolerated, less neurotoxicity
Novel Agents in the Treatment of Amyloidosis
In the first study of thalidomide therapy for AL amyloidosis, 16 patients were treated, and no organ responses were seen . In a subsequent study, hematologic responses were reported in 48% of patients, with 19% having complete hematologic responses, but treatment-related toxicity was frequent, and the agent was poorly tolerated . Thalidomide has been combined with melphalan and dexamethasone in 22 patients, resulting in eight hematologic and four organ responses . Thalidomide has also been combined with cyclophosphamide and dexamethasone, with a hematologic response rate of 74% and complete response in 21% of the patients . The median overall survival from the start of therapy was 41 months, median progression-free survival was 32 months, and treatment-related mortality was 3%. Current recommendations suggest that thalidomide be started at a dose not higher than 50 mg. Dose can be increased if tolerated .
Lenalidomide has been combined with dexamethasone in the treatment of AL amyloidosis. Toxicities include cytopenias, rash, fatigue, and cramps . In the first of two published studies, the hematologic response rate was 41% and the median response duration and overall survival were 19.2 and 31 months, respectively . In the second study, the response rate was 67% . Of the patients with renal involvement, 41% had a decrease in urinary protein excretion of more than 50% with no decrease in renal function. Response duration and overall survival were not reported . High-risk patients were less likely to respond to lenalidomide.
Lenalidomide has been combined with melphalan and dexamethasone for patients with newly diagnosed AL amyloidosis. In a phase I-II dose-escalation study, the maximum tolerated dose of lenalidomide was 15 mg when combined with melphalan and dexamethasone . Hematologic responses were seen in 58% and were complete in 42%. The two-year event-free and overall survivals were 54% and 81%, respectively . Lenalidomide has been combined with cyclophosphamide and dexamethasone in 35 patients . The median number of treatment cycles was six. The hematologic response rate was 60%, and in those receiving at least four cycles, the response rate was 87%. The median overall survival was 16.1 months, and similar results were reported with the use of lenalidomide, cyclophosphamide, and dexamethasone, with an 80% complete response rate [69, 70].
Pomalidomide, a derivative of thalidomide with structural similarity to both thalidomide and lenalidomide, was administered to 26 patients enrolled over a 12-month period in one study . All had previously received alkylating agents, as well as autologous SCT in 13, prior lenalidomide or thalidomide in 12, and prior bortezomib in 9. Nineteen patients evaluable for hematologic response had a response rate of 35%, with two very good partial responses and two confirmed and four unconfirmed organ responses . Pomalidomide and dexamethasone is a promising therapy for AL amyloidosis.
In an early study of bortezomib, 80% of evaluable patients had a hematologic response . A subsequent study of 18 patients demonstrated a hematologic response in 77%, with 16% complete responses . A phase I dose-escalation study of bortezomib that specifically excluded use of corticosteroids used 2 different bortezomib administration schedules: bortezomib administration either (1) on Days 1, 4, 8, and 11 every 21 days or (2) on days 1, 8, 15, and 22 every 35 days . Patients with New York Heart Association Classes III–IV heart disease were excluded. There were no treatment-related deaths. Hematologic responses were seen in 50% of patients, 20% of which were complete responses; median time to response was 1.2 months. The weekly bortezomib regimen in patients with multiple myeloma is associated with lower neurotoxicity. Combination bortezomib and dexamethasone has been used after SCT to improve the depth of response . Seventeen of 23 patients received posttransplant bortezomib and dexamethasone, and 74% achieved a complete response, with organ responses in 58%. Data from 33 national centers were combined in another study, reporting on 94 patients receiving bortezomib with or without dexamethasone . Hematologic responses were seen in 71%, 25% complete. A cardiac response was seen in 29% of patients. The NT-proBNP level predicted survival. In another study, the combination of bortezomib-dexamethasone was given to 26 patients; 18 received this as first-line therapy . The overall response rate was 54%, with 31% complete responses. The median time to response was 7.5 weeks . Currently, two studies are under way, one in Europe and one in the United States, randomly assigning patients with newly diagnosed AL amyloidosis to melphalan-dexamethasone or melphalan-dexamethasone-bortezomib.
Figure 3 shows an algorithm for the recommended management of newly diagnosed AL amyloidosis using chemotherapy.
When AL amyloidosis is diagnosed before the development of advanced cardiomyopathy, patients typically have both hematologic and organ responses after chemotherapy. This translates into prolonged survival. A patient with a compatible syndrome that suggests amyloidosis should have testing with immunofixation and free light chain assessment followed by bone marrow and fat biopsies to establish the diagnosis. Once the amyloidosis is confirmed to be of light chain origin, patients should be considered for SCT (only a minority are eligible) or trials of systemic chemotherapy. Active agents include corticosteroids (dexamethasone, prednisone), alkylating agents (melphalan, cyclophosphamide), immunomodulatory drugs (thalidomide, lenalidomide), and proteasome inhibitors (bortezomib).