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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Disease Overview
  5. Prognosis
  6. Therapy
  7. Conventional Treatment of Amyloidosis
  8. Novel Agents in the Treatment of Amyloidosis
  9. Conclusion
  10. APPENDIX
  11. References

Disease Overview

Immunoglobulin (Ig) light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of Ig light chain are deposited in tissues. Clinical features depend on organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, peripheral/autonomic neuropathy, and atypical multiple myeloma.

Diagnosis

Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required for diagnosis. Invasive organ biopsy is not required because amyloid deposits can be found in bone marrow biopsy or subcutaneous fat aspirate in 85% of patients. Verification that amyloid is of immunoglobulin origin is mandatory.

Prognosis

N-terminal pro–brain natriuretic peptide (NT-proBNP), serum troponin T, and immunoglobulin free light chain values are used to classify patients into four groups of similar size; median survivals are 94.1, 40.3, 14.0, and 5.8 months.

Therapy

All patients with a visceral amyloid syndrome require therapy to prevent deposition of amyloid in other viscera and prevent progressive organ failure of involved sites. Stem cell transplant (SCT) is preferred, but only 20% of patients are eligible. Requirements for safe SCT include NT-proBNP <5,000 ng/mL, troponin T < 0.06 ng/mL, age <70 years, <3 organs involved, and serum creatinine ≤1.7 mg/dL. Nontransplant candidates can be offered melphalan-dexamethasone. Pomalidomide appears to have activity, as do other combinations of chemotherapy with agents such as cyclophosphamide-thalidomide (or lenalidomide or bortezomib)-dexamethasone, bortezomib-dexamethasone, and melphalan-prednisone-lenalidomide.

Future Challenges

Late diagnosis remains a major obstacle to initiating effective therapy when organ dysfunction is still recoverable. Recognizing the presenting syndromes is necessary for improving survival. Am. J. Hematol. 88:417–425, 2013. © 2013 Wiley Periodicals, Inc.


Abbreviations
AL amyloidosis

immunoglobulin light chain amyloidosis

dFLC

difference between involved and uninvolved serum free light chain levels

FLC

free light chain

Ig

immunoglobulin

NT-proBNP

N-terminal pro–brain natriuretic peptide

SCT

stem cell transplant

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Disease Overview
  5. Prognosis
  6. Therapy
  7. Conventional Treatment of Amyloidosis
  8. Novel Agents in the Treatment of Amyloidosis
  9. Conclusion
  10. APPENDIX
  11. References

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 [1]. The light chain protein, instead of conforming to the α-helical configuration of most proteins, misfolds and forms a β-pleated sheet [2]. 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 [3]. In Sweden, the median survival after diagnosis of AL is 3 years [4].

Disease Overview

  1. Top of page
  2. Abstract
  3. Introduction
  4. Disease Overview
  5. Prognosis
  6. Therapy
  7. Conventional Treatment of Amyloidosis
  8. Novel Agents in the Treatment of Amyloidosis
  9. Conclusion
  10. APPENDIX
  11. References

Amyloidosis is particularly difficult to diagnose because no single imaging, blood, or urine test is diagnostic for this disorder [5]. The positron emission tomography imaging agent 18F-florbetapir, approved for imaging amyloid beta of Alzheimer disease, is under investigation as a potential imaging agent for systemic amyloid deposits [6]. 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 [7]; 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 [8]. The presence of proteinuria in a patient with a monoclonal gammopathy may be mistaken for multiple myeloma with cast nephropathy [9]. If a 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 [10]. 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 [11]. 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 [12], and the ventricular thickening is interpreted as hypertrophy rather than infiltration [13]. Patients with monoclonal gammopathy of undetermined significance who present unwell, with weight loss or fatigue, should raise clinical suspicion of amyloidosis. Routine amyloid staining is not indicated in a typical patient with multiple myeloma [14].

Appropriate screening of a patient with a clinical syndrome compatible with AL amyloidosis would include immunofixation of the serum [15], immunofixation of the urine [16], and an Ig free light chain (FLC) assay [17]. 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 FLC (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 [21]. An algorithm for the evaluation of a patient with suspected amyloidosis is given in Fig. 2.

image

Figure 1. Types of Serum M Proteins Found on Immunofixation Results. The percentage of each type of M protein is shown in samples from patients with monoclonal gammopathy of undetermined significance (MGUS) [18], myeloma [19], and light chain amyloidosis (AL) [20]. The ratio of λ:κ light chain in patients with AL amyloidosis is 3.8.

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image

Figure 2. Algorithm for evaluating patients with suspected amyloidosis.

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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 [22], endomyocardial biopsy [23], and liver biopsy are expensive, invasive, and increase the risk of postbiopsy hemorrhage. Biopsy of the iliac crest bone marrow [24] combined with abdominal subcutaneous fat aspiration [25] will identify amyloid deposits in 85% of patients (Table 1). 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 [26] (CME question 1), larynx [27], or urinary tract [28], which can include the renal pelvis, ureter, bladder, and urethra. Pulmonary nodules are frequently localized deposits of amyloid composed of light chains or transthyretin [29]. 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 [30].

Table 1. Agreement of Results of Fat Aspiration and Bone Marrow Biopsy in 378 Patients With a Diagnosis of AL Amyloidosisa
 Fat aspiration
Bone Marrow BiopsyPositiveNegativeEquivocal
  1. a

    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).

  2. Adapted from Gertz et al. [20]. Used with permission.

Positive2025910
Negative49449
Equivocal320

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 [31]. The light chain origin of an amyloid deposit can be confirmed with immunohistochemistry [32] or immunogold assay [33]. Mass spectrometry can confirm the amyloid protein composition and is considered the standard for typing the protein subunit in amyloid deposits [34] (CME question 2). The technique can be applied to almost any tissue source, including nerve and fat [35, 36], and it can identify heavy chain as well as light chain amyloidosis [37]. Even in the presence of a monoclonal protein, the type of amyloidosis is uncertain without further testing. Twenty of 81 patients with proven transthyretin amyloidosis had a monoclonal protein, for a positive predictive value of only 74% [38] (CME question 3). This may relate to the high incidence of senile cardiac amyloidosis and monoclonal gammopathy of undetermined significance in the elderly. If systemic AL amyloidosis is confirmed, prognosis must be assessed. A required test panel for patients after histologic diagnosis of AL amyloidosis is given in the Box.

Box. Required Diagnostic Evaluation After Amyloidosis is Established

  • Pathologic confirmation that amyloid deposits are of immunoglobulin origin
  • Immunoglobulin-free light chain κ and λ testing
  • Bone marrow biopsy
  • Serum and urine immunofixation
  • Echocardiography
  • 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 immunoglobulin measurement

Prognosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Disease Overview
  5. Prognosis
  6. Therapy
  7. Conventional Treatment of Amyloidosis
  8. Novel Agents in the Treatment of Amyloidosis
  9. Conclusion
  10. APPENDIX
  11. References

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 [39]. 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 [40]. In the past 8 years, serum cardiac biomarkers have been introduced. Tests for serum troponin T and N-terminal pro–brain natriuretic peptide (NT-proBNP) are widely available. Outcome is also dependent on the plasma cell clone. Assigning 1 point for a difference between involved and uninvolved serum free light chain levels (dFLC) >18 mg/dL, troponin T > 0.025 ng/mL, and NT-proBNP >1,800 pg/mL produces four stages (0–3 points). The median survivals are 94.1, 40.3, 14.0, and 5.8 months, respectively, for stages I, II, III, and IV [41] (CME question 4). The value of cardiac biomarkers has been validated in patients treated conventionally and those treated with stem cell transplant (SCT) [42] (CME question 5). Several studies have demonstrated that advanced cardiac patients should be excluded from SCT studies [43]. High troponin T level predicts early mortality from SCT and can be used as an exclusion criterion for this therapy [44]. Advanced heart failure patients also are poor candidates for clinical trials of standard agents [45]. High-sensitivity cardiac troponin T assays at presentation (median survival is 10.6 months if troponin T levels >77 ng/L) and changes in NT-proBNP levels after chemotherapy are reported to be the best predictors of long-term outcome [46].

An excess of early deaths occur in AL amyloidosis for patients with 10% or fewer plasma cells at diagnosis [47]. The Ig FLC level at diagnosis [48], the number of organs involved [49], and the serum uric acid level [50] have all been associated with prognosis.

For the purpose of uniform reporting, new response criteria were developed for hematologic and organ response. Complete response was defined as negative serum and urine immunofixation results, normal FLC ratio, and normal bone marrow. A partial response was defined as a 50% reduction in dFLC. A very good partial response was defined as dFLC less than 40 mg/L. Cardiac response and progression were defined as an increase or decrease of NT-proBNP of 30% and at least 300 ng/L. To qualify as evaluable for response, NT-proBNP levels must be greater than 650 ng/L [51].

Therapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Disease Overview
  5. Prognosis
  6. Therapy
  7. Conventional Treatment of Amyloidosis
  8. Novel Agents in the Treatment of Amyloidosis
  9. Conclusion
  10. APPENDIX
  11. References

Chemotherapy for the treatment of amyloidosis was introduced in 1972 in the form of melphalan and prednisone [52]. Only a minority of patients responded, and the median survival was 12–18 months [53]. 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 [54]. Organ response rates of up to 65% have been reported [55]. A prospective randomized study did not demonstrate a survival advantage for patients treated with SCT [56], and a meta-analysis also questioned the value of SCT for amyloidosis [57]. 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 [58]. The transplant-related mortality rate has fallen to 7% since 2006 [59]. Survival in AL amyloidosis has improved over time, reflecting improvements in therapy. However, the 1-year mortality rate has remained at 30% since 1966; this likely reflects patients who are diagnosed late in the disease course, when no therapy can affect outcome [60]. Good outcomes with SCT have been reported for patients with cardiac amyloidosis diagnosed before the onset of advanced congestive heart failure. The hematologic and cardiac response rates were 66 and 41%, respectively, and hematologic response predicted survival [61].

One 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 [62]. Ten-year survival of all patients at our center is 43% [63]. Transplant-related mortality rates have decreased from as high as 40%, to 7% in current studies [64]. Excluding patients from SCT whose NT-proBNP levels are >5,000 pg/mL can reduce therapy-related mortality rates to 1% [65]. Renal and cardiac organ responses and high complete hematologic response rates have been reported after SCT [66]. The major limitation to wider application of SCT is that no more than 20–25% of patients are eligible for transplant. Currently, a hematologic response is achievable in 76% of eligible patients, which is complete in 39% [67]. At Mayo Clinic, organ responses have been recorded in 47% of patients [67]. In multivariate survival analysis, the most important predictor of outcome is stage. The median survival was not reached in stage I disease; for stages II through IV, median survival was 96.5, 58.2, and 22.2 months, respectively [41]. Post-hoc, hematologic response is the strongest predictor of outcome [66]. In an analysis that excluded both early deaths and patients inevaluable for response at 6 months [20], the significance of depth of hematologic response for predicting survival persisted. SCT should remain an important consideration for patients who are eligible to undergo this therapy.

For patients with durable responses, a second course of high-dose therapy at progression can produce a second complete response [68]. There is no evidence, given the small number of plasma cells seen in these patients, that induction before SCT improves outcomes [69]. Changes in light chain levels are a better predictor of outcome than changes in the intact immunoglobulin levels [70].

Conventional Treatment of Amyloidosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Disease Overview
  5. Prognosis
  6. Therapy
  7. Conventional Treatment of Amyloidosis
  8. Novel Agents in the Treatment of Amyloidosis
  9. Conclusion
  10. APPENDIX
  11. References

Melphalan and prednisone have been demonstrated to be superior therapy to colchicine in two randomized phase III studies [71, 72]. Even in patients with severe cardiac failure, continuous, oral, daily melphalan has been used and can provide palliation [73]. 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 [74, 75] 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 6 years, the actuarial survival was approximately 50% and the progression-free survival was 40% [75]. Alkylator-based chemotherapy has been reported to be effective in almost two-thirds of patients [76]. However, two other reports using the identical regimen used by Palladini et al [74, 75] have shown median survivals of less than 1.5 years [77, 78]. 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 [77, 78].

The difference in results among these 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 [79].

Melphalan with 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 [79]. A summary of regimens used in the treatment of amyloidosis is given in Table 2.

Table 2. Conventional Systemic Chemotherapy Options for AL Amyloidosis
TherapyComment
Melphalan-dexamethasoneReported outcome dependent on proportion of cardiac patients
Cyclophosphamide-thalidomide-dexamethasoneAll oral regimen thalidomide dose begins at 100 mg/d
Melphalan-lenalidomide-dexamethasoneLenalidomide dose 15 mg, 21 of 28 days
Bortezomib-dexamethasoneWeekly dosing better tolerated, less neurotoxicity
Lenalidomide-cyclophosphamide-dexamethasoneLenalidomide (15 mg), days 1–21; cyclophosphamide (300 mg/m2; orally), weekly on days 1, 8, 15; every 28 days
Cyclophosphamide-bortezomib-dexamethasoneResponse rates of 94 and 81% [80, 81]

Novel Agents in the Treatment of Amyloidosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Disease Overview
  5. Prognosis
  6. Therapy
  7. Conventional Treatment of Amyloidosis
  8. Novel Agents in the Treatment of Amyloidosis
  9. Conclusion
  10. APPENDIX
  11. References

Thalidomide

In the first study of thalidomide therapy for AL amyloidosis, 16 patients were treated, and no organ responses were seen [82]. 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 [83]. Thalidomide has been combined with melphalan and dexamethasone in 22 patients, resulting in eight hematologic and four organ responses [84]. Thalidomide has also been combined with cyclophosphamide and dexamethasone, with a hematologic response rate of 74% and complete response in 21% of the patients [85]. 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 [49].

Lenalidomide

Lenalidomide has been combined with dexamethasone in the treatment of AL amyloidosis. Toxicities include cytopenias, rash, fatigue, and cramps [86]. 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 [45]. In the second study, the response rate was 67% [87]. 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 [87]. 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 [88]. Hematologic responses were seen in 58% and were complete in 42%. The 2-year event-free and overall survivals were 54 and 81%, respectively [88]. In a phase II study, melphalan, lenalidomide, and dexamethasone produced a 50% response rate, with 7% having a complete response, but the regimen was associated with significant myelosuppression [89]. Lenalidomide has been combined with cyclophosphamide and dexamethasone in 35 patients [90]. 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 37.8 months, and similar results were reported with the use of lenalidomide, cyclophosphamide, and dexamethasone, with an 8% complete response rate and a 2-year survival rate of 41%. As salvage therapy in relapsing disease, cyclophosphamide, lenalidomide, and dexamethasone can produce a 62% response rate [90-92]. In patients with amyloidosis, lenalidomide can frequently worsen kidney function, even for patients whose amyloidosis spares the kidney. Recovery was reported in only 44% [93]. Lenalidomide-treated patients had a higher risk of rising NT-proBNP levels. It is unclear whether this is indicative of cardiac toxicity or whether this biomarker is not a reliable measure of cardiac function in lenalidomide-treated patients [94]. Lenalidomide salvage therapy after bortezomib or melphalan treatment failures has been reported to achieve a hematologic response rate of 41% [95].

Pomalidomide

Pomalidomide, a derivative of thalidomide with structural similarity to both thalidomide and lenalidomide, was administered to 29 patients [96]. Twenty-eight had previously received alkylating agents, as well as autologous SCT in 13, prior lenalidomide or thalidomide in 15, and prior bortezomib in 12. All patients were evaluable for hematologic response, with a response rate of 38%; three patients had very good partial responses, and three and four patients had confirmed and unconfirmed organ responses, respectively [96]. One-year progression-free survival and overall survival rates were 59 and 76%, respectively. Pomalidomide and dexamethasone is a promising therapy for AL amyloidosis.

Bortezomib

In an early study of bortezomib, 80% of evaluable patients had a hematologic response [97]. A subsequent study of 18 patients demonstrated a hematologic response in 77, with 16% complete responses [98]. A phase I dose-escalation study of bortezomib that specifically excluded use of corticosteroids used two 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 [99]. Patients with New York Heart Association class 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. Bortezomib has been reported to successfully improve cardiac function in AL amyloidosis [100]. Combination bortezomib and dexamethasone has been used after SCT to improve the depth of response [101]. Nineteen patients received posttransplant bortezomib and dexamethasone, and 67% achieved a complete response, with organ responses in 60%. Data from 33 national centers were combined in another study, reporting on 94 patients receiving bortezomib with or without dexamethasone [102]. 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 [103]. The overall response rate was 54%, with 31% complete responses. The median time to response was 7.5 weeks [103]. A survey of European centers, with 428 evaluable patients, reported that bortezomib therapy achieved a lower dFLC at completion of therapy compared with treatment with cyclophosphamide-thalidomide-dexamethasone, melphalan and dexamethasone, SCT, and cyclophosphamide-lenalidomide-dexamethasone [104].

Bortezomib has been combined with cyclophosphamide and dexamethasone. In one study [80], 17 patients (10 therapy naïve) achieved a response rate of 94%, with 71% achieving a complete response. Three subsequently became transplant eligible. A second cohort of 43 patients achieved a hematologic response rate of 81%, with 42% achieving a complete response [81]. Two-year progression-free survival was 67% for newly diagnosed patients. Combinations of novel agents are being reported. In one study, seven of nine in a case series received bortezomib, cyclophosphamide or lenalidomide/thalidomide, and dexamethasone. Hematologic and organ response was seen in 89 and 78% of patients, respectively. Unfortunately, neuropathy was reported in 44% [105].

Figure 3 shows chemotherapy algorithms recommended for patients with newly diagnosed AL amyloidosis (stratified by transplant eligibility). For patients who achieve a complete hematologic response, kidney transplantation can be successful (80% graft survival at 42 months) [106]. Renal transplantation is feasible in AL [107]. Selection should exclude patients with extrarenal amyloid deposition, and the underlying clonal plasma cell disorder ideally should be controlled [108]. Median graft survival of 8.9 years is reported when amyloid precursor protein production is reduced. In a registry series [109], 0.8% of end-stage renal disease was due to amyloidosis. Forty-six patients received renal allografts. Five- and 10-year graft survival rates were 45 and 26%, respectively. Amyloid recurrence was proven in 16%.

image

Figure 3. mSMART.org Guidelines for Treatment of Newly Diagnosed AL Amyloidosis (Off-Study). A: Transplant-eligible patients. B: Transplant-ineligible patients. AL indicates light chain amyloidosis; cTnT, cardiac troponin T; Dex, dexamethasone; dFLC, difference between involved and uninvolved serum free light chain levels; Mel, melphalan; NT-proBNP, N-terminal pro-brain natriuretic peptide; SCT, stem cell transplant; Std, standard. Adapted from: http://msmart.org/amyloid.pdf.

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Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Disease Overview
  5. Prognosis
  6. Therapy
  7. Conventional Treatment of Amyloidosis
  8. Novel Agents in the Treatment of Amyloidosis
  9. Conclusion
  10. APPENDIX
  11. References

When AL amyloidosis is diagnosed before the development of advanced cardiomyopathy, patients typically have both hematologic and organ responses after chemotherapy, which translates into prolonged survival. The best predictor of organ response is a deep hematologic response [110]. A patient with a compatible syndrome that suggests amyloidosis should have testing with immunofixation and FLC 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).

APPENDIX

  1. Top of page
  2. Abstract
  3. Introduction
  4. Disease Overview
  5. Prognosis
  6. Therapy
  7. Conventional Treatment of Amyloidosis
  8. Novel Agents in the Treatment of Amyloidosis
  9. Conclusion
  10. APPENDIX
  11. References

Immunoglobulin Light Chain Amyloidosis: 2013 Update on Diagnosis, Prognosis, and Treatment

CME Questions

1. A 61-year-old presents to an otorhinolaryngologist with hoarseness. During laryngoscopy, a mass is found on the left vocal cord. A biopsy shows dense deposits of amyloid. The patient is referred to you for subsequent evaluation. What is the most likely next step?

  1. Cardiac biopsy to assess suitability for high-dose chemotherapy and stem cell transplantation.
  2. Initiation of bortezomib-based chemotherapy.
  3. Bone marrow biopsy to determine whether this represents coexistent multiple myeloma.
  4. Referral back to the otorhinolaryngologist for therapy.
  5. Bronchoscopy to assess status of main stem bronchi.

ANSWER: D

Laryngeal and vocal cord amyloid is always localized (not associated with systemic amyloid). Therefore, the treatment is local and usually involves endoscopic laser therapy of the deposits. Recurrence is common, and the patient likely will require ongoing monitoring. Pulmonary function testing would be reasonable to detect flow obstruction. Computed tomographic imaging would not add value to the evaluation.

2. A 76-year-old black man is referred to you by a cardiologist after an endomyocardial biopsy showed amyloid deposits. The patient was seen for dyspnea on exertion that evolved over 24 months. The echocardiogram was clinically suspicious for infiltrative cardiomyopathy. The patient has congestive heart failure. Serum and urine immunofixation assays were negative, and a free light chain assay showed a normal ratio. What should be your next step in the evaluation?

  1. Mass spectroscopy to classify the amyloid.
  2. Chemotherapy is urgent in the presence of progressive congestive heart failure.
  3. If a bone marrow assay is negative for amyloid deposits, the patient is eligible for cardiac transplantation.
  4. Computed tomographic imaging of the chest, abdomen, and pelvis should be performed to screen for occult amyloid deposits.

ANSWER: A

The absence of serum and urine light chains and a normal light chain ratio makes light chain amyloidosis highly unlikely. This patient is more likely to have non–immunoglobulin-related amyloidosis. Three percent of black males have a mutation in transthyretin, which causes late-onset familial amyloid cardiomyopathy. At 76 years of age, senile cardiac (systemic) amyloidosis is a definite possibility. There is a 1% possibility that this is AL. The evaluation cannot move forward until the type of amyloid is identified. Mass spectroscopy is the method most likely to provide this information.

3. Your patient with renal amyloidosis read that cerebral amyloid angiopathy is found in most patients with Alzheimer disease. The patient is concerned that dementia will soon follow. Your next step is:

  1. Referral to a neurologist for neurocognitive studies.
  2. Magnetic resonance imaging to look for cerebral amyloid angiopathy.
  3. Place the patient on aspirin therapy to prevent subcortical infarcts.
  4. Tell the patient not to worry.

ANSWER: D

The amyloid in Alzheimer disease is composed of amyloid-β protein, which is chemically unrelated to immunoglobulin light chains. The risk of Alzheimer disease in the patient is the same as the risk of dementia in the patient's attending physician (you).

4. A 58-year-old man is referred to you with endomyocardial biopsy–proven amyloidosis. The λ monoclonal protein in the serum is 0.6 mg/dL. The κ/λ free light chain ratio is 0.01. You perform a bone marrow biopsy that shows 7% plasma cells. The serum troponin level is 0.08 ng/mL. The NT-proBNP is 7,800 pg/mL. What is your recommendation?

  1. Referral to a transplant center for high-dose therapy.
  2. Referral for cardiac transplantation.
  3. Initiation of conventional chemotherapy.
  4. Initiation of digoxin to prevent atrial fibrillation.
  5. Referral for consultation in palliative care.

ANSWER: C

This patient's cardiac biomarkers suggest a degree of cardiac dysfunction that is associated with an excessive risk of death during transplant. This patient cannot be considered for cardiac transplantation until the underlying hematologic disorder is under control. Even patients with advanced cardiac failure can have improvement of cardiac function with appropriate systemic chemotherapy. Initiation of any of the regimens in Table 2 are reasonable next steps. Digoxin is contraindicated in cardiac amyloidosis.

5. Which is (are) the most important test(s) for assessing prognosis in a patient with light chain amyloidosis?

  1. Troponin.
  2. Albumin.
  3. NT-proBNP.
  4. β-2 microglobulin.
  5. Fluorescence in situ hybridization (genetic test).
  6. A and C.
  7. B and D.
  8. A through C.
  9. A through D.
  10. A through E.

ANSWER: F

The cardiac biomarkers (troponin and NT-proBNP) determine the prognosis in this disease and are the most important tests to perform. The dFLC would complete the evaluation of prognosis. β-2 microglobulin and albumin are not important markers for light chain amyloidosis, although they are important in multiple myeloma. The role of genetics is yet undefined in amyloidosis, and very few patients carry the adverse t(4;14) and –17p chromosomal abnormalities seen in myeloma.

Educational Objectives

Upon completion of this educational activity, participants will be better able to:

  • Master recognition of clinical presentations that should trigger suspicion of amyloidosis
  • Recognize that a tissue diagnosis of amyloidosis does not provide information on amyloid protein type
  • Understand the roles of the newly introduced chemotherapeutic regimens for the therapy of light chain amyloidosis

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Disease Overview
  5. Prognosis
  6. Therapy
  7. Conventional Treatment of Amyloidosis
  8. Novel Agents in the Treatment of Amyloidosis
  9. Conclusion
  10. APPENDIX
  11. References
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