Immunoglobulin Light Chain Amyloidosis: Diagnosis and Risk Assessment

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Saurabh ZanwarDivision of Hematology, Mayo Clinic, Rochester, Minnesota

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Morie A. GertzDivision of Hematology, Mayo Clinic, Rochester, Minnesota

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Eli MuchtarDivision of Hematology, Mayo Clinic, Rochester, Minnesota

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Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder with multiple clinical presentations. The diagnosis of AL amyloidosis requires a high index of suspicion, making a delay in diagnosis common, which contributes to the high early mortality seen in this disease. Establishing the diagnosis of AL amyloidosis requires the demonstration of tissue deposition of amyloid fibrils. A bone marrow biopsy and fat pad aspirate performed concurrently have a high sensitivity for the diagnosis of AL amyloidosis and negate the need for organ biopsies in most patients. An accurate diagnosis requires amyloid typing via additional testing, including tissue mass spectrometry. Prognostication for AL amyloidosis is largely driven by the organs impacted. Cardiac involvement represents the single most important prognostic marker, and the existing staging systems are driven by cardiac biomarkers. Apart from organ involvement, plasma cell percentage on the bone marrow biopsy, specific fluorescence in situ hybridization findings, age at diagnosis, and performance status are important prognostic markers. This review elaborates on the diagnostic testing and prognostication for patients with newly diagnosed AL amyloidosis.

The term “amyloid” refers to extracellular deposition of protein fibrils, with upward of 30 different types of amyloid fibrils having been identified in humans.13 Some of these amyloid fibrils are deposited systemically, leading to organ damage, whereas other types of amyloidosis have localized deposition.4 Systemic immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder arising from tissue deposition of insoluble β-pleated sheets of misfolded immunoglobulin light chains. Despite being the most frequently encountered systemic amyloidosis, AL amyloidosis is an uncommon entity with an estimated incidence of approximately 1 patient per 100,000 person-years.5 This translates to 3,500 to 4,500 new patients with AL amyloidosis being diagnosed in the United States each year.5,6 Immunoglobulin heavy chain (AH) amyloidosis, a rare immunoglobulin amyloidosis, presents with the clinical features and treatment responses that largely parallel AL amyloidosis, and as such are included in the discussion.7,8 Prognostication tools for AL amyloidosis have evolved over the past 2 decades. The heart is the most involved organ and is the most important determinant of outcome. This review addresses disease manifestations, diagnostic testing, and prognostic tools to aid clinicians in the initial steps of diagnosis.

Clinical Presentation of AL Amyloidosis

Establishing a diagnosis of AL amyloidosis is often challenging because there is no single test that conclusively establishes the diagnosis, but testing performed in the correct clinical context is needed. Delay in arriving at a diagnosis has been reported to range from 6 months to ≥2 years from time of symptom onset.9,10 The heterogenous clinical phenotype for AL amyloidosis often leads to patients presenting with advanced disease after being evaluated in various specialties without a diagnosis.10 This delay in diagnosis is true even in patients with preexisting plasma cell disorders, who are known to be at risk for AL amyloidosis.11 Fatigue is the commonest symptom in AL amyloidosis. In patients with coexisting/preexisting multiple myeloma or Waldenström’s macroglobulinemia, fatigue is often attributed to anemia or ongoing systemic therapy for these disorders.11,12

Amyloid deposition can affect any organ system, and the presenting symptoms are largely driven by the organ dysfunction caused by the amyloid deposition. Cardiac amyloidosis presents with signs and symptoms of heart failure and the initial suspicion is commonly raised by cardiologists during echocardiographic evaluation with findings suggesting infiltrative cardiomyopathy.13 A combination of concentric cardiac hypertrophy, increase in interventricular septal thickness, and normal-to-low voltage on electrocardiogram (ECG) has been classically described in AL amyloidosis, but multiple confounders limit the sensitivity of these findings.14 The cardiac hypertrophy tends to be biventricular, unlike in systemic hypertension in which it is commonly left-sided. More specific abnormalities on echocardiogram for cardiac amyloidosis include an abnormal strain pattern with a base-to-apex gradient.13 Cardiac MRI in amyloidosis demonstrates late gadolinium enhancement (LGE), which occurs due to the disruption of the tight junctions in between the myocytes from the expanding interstitial amyloid. Transmural LGE correlates to an advanced cardiac involvement.15 Apart from heart failure, electromechanical dissociation and ventricular arrythmias are a common cause of cardiac mortality in patients with AL amyloidosis, especially sudden cardiac death.16 Nephrotic range proteinuria without an obvious etiology merits evaluation for AL amyloidosis.9 Patients presenting with a symmetric distal painful peripheral neuropathy with or without an autonomic component often have an extensive neurologic evaluation performed before ultimately being diagnosed with AL amyloidosis.17 In a study of peripheral neuropathy as the first manifestation of AL amyloidosis, a median delay of 21 months from symptom onset to diagnosis of AL amyloidosis was reported.18 It is important to recognize other causes of peripheral neuropathy that may be associated with a monoclonal protein (eg, cryoglobulinemia, POEMS syndrome, IgM neuropathy) as well as common causes of peripheral neuropathy that can have an incidental presence of a monoclonal protein (eg, chronic inflammatory demyelinating polyneuropathy). Presentation with other organ involvement, including liver (eg, hepatomegaly, elevated alkaline phosphatase) and gastrointestinal tract (eg, diarrhea from malabsorption, constipation, early satiety, weight loss), and other manifestations such as musculoskeletal pathologies (eg, arthralgias/arthritis, myopathy), endocrinopathies (eg, hypothyroidism, hypogonadism), and coagulopathy (eg, bleeding diathesis), tend to be nonspecific and require a high index of suspicion. Other classic clinical findings, including macroglossia, bilateral carpel tunnel syndrome, and periorbital ecchymoses (“raccoon eyes”), may trigger an evaluation for systemic amyloidosis, but are uncommon.19 Incidental detection of amyloid deposits on bone marrow or fat specimens without a clinical syndrome has a low risk of progression to systemic amyloidosis with organ involvement (2.7%) and does not require treatment.20 Common signs and symptoms that should raise suspicion for AL amyloidosis are depicted in Figure 1.

Figure 1.
Figure 1.

Common presenting signs and symptoms that should raise clinical suspicion for immunoglobulin light chain amyloidosis.

Citation: Journal of the National Comprehensive Cancer Network 21, 1; 10.6004/jnccn.2022.7077

Diagnostic Testing for AL Amyloidosis

The first step in diagnosing AL amyloidosis is to establish the presence of a monoclonal protein, because the absence of a monoclonal protein makes the diagnosis of AL amyloidosis extremely unlikely. In a Mayo Clinic study, among 522 evaluable patients, only 1 (0.2%) had AL amyloidosis with normal results of all monoclonal protein studies.21 For full evaluation, serum electrophoresis and immunofixation, 24-hour urine protein collection for electrophoresis/immunofixation, and serum free light chain assay should be ordered. Once a suspicion of AL amyloidosis is entertained, a biopsy demonstration of Congo red–positive amorphous deposits with apple green birefringence on polarized light microscopy is necessary.22 Alternate stains, including thioflavin T or sulfated alcian blue, can be used in place of Congo red staining to demonstrate the amyloid fibrils. A bone marrow biopsy is typically the most common source for tissue specimen evaluation, but has a sensitivity of only 56% to 70% for establishing a diagnosis.23,24 The next most used biopsy is a fat pad aspiration, which when performed alone has a diagnostic sensitivity for AL amyloidosis of 70% to 80%.25,26 When a bone marrow biopsy and a fat pad aspiration are performed concurrently, the diagnostic sensitivity for AL amyloidosis reaches 80% to 90%.27,28 Thus, an organ biopsy is unnecessary in most patients. For example, although renal biopsy is the gold standard for confirming renal involvement, nonselective proteinuria (>0.5 g/24 h) and documented extrarenal amyloid deposits eliminate the need for a renal biopsy.29 Approximately 10% to 20% patients can have a negative fat pad aspirate and bone marrow study. If the clinical suspicion for amyloidosis remains elevated, biopsy of the suspected involved organ should be considered, with careful attention paid to the adequacy of the specimen to avoid false-negative results.27 Apart from providing tissue for Congo red staining, a bone marrow biopsy is needed to assess the underlying B-cell disease (typically pure plasma cell clone, as well as occasionally other monoclonal protein–secreting disorders, such as Waldenström macroglobulinemia).19,30 Fluorescence in situ hybridization (FISH) testing can have important prognostic and therapeutic implications, as discussed later, and should be performed on the bone marrow specimen at diagnosis.22

Amyloid Typing

The importance of typing the amyloid fibrils cannot be overstated. This is true even when there is evidence of a monoclonal protein in the serum, because a monoclonal gammopathy may be unrelated to the amyloid process. Mass spectrometry–based proteomic assay is considered the gold standard testing to establish the type of amyloid fibril.31 A major advantage of mass spectrometry is the high sensitivity/specificity for all types of amyloidosis with a single test, even with a small amount of tissue. Other techniques used for typing of amyloidosis include immunohistochemistry, immunofluorescence, and immunogold electron microscopy (IEM). These typing techniques, however, are less accurate, because antibodies are available only for common amyloid types, the antigen–antibody chemistry is nonspecific, and IEM is not readily available.22,32 In a study of 320 specimens that were Congo red–positive and –negative by immunohistochemistry testing, mass spectrometry was able to detect the amyloid protein in 255 (80%).32

Assessing Organ Involvement

Given that the heart is the most common organ involved in AL amyloidosis and cardiac involvement is the most important prognostic marker, assessing for heart involvement is crucial. Echocardiographic findings of concentric hypertrophy with a restrictive filling pattern and abnormal base-to-apex strain gradient are consistent with cardiac amyloidosis in the right clinical context (ie, compatible clinical syndrome with biopsy proof of AL amyloid from a different site) and negate the need for endomyocardial biopsy.13 Artificial intelligence–based ECG assessment can aid in diagnosing cardiac amyloidosis and may improve the rate of early diagnosis, based on the findings of a single-center study.33 Its impact on early diagnosis of cardiac amyloidosis is being explored, and it currently has limited access in clinical practice. The role of nuclear imaging of the heart is primarily reserved for identifying transthyretin (TTR) cardiac amyloidosis, an amyloid entity not related to a clonal plasma cell disorder. The technetium-99m pyrophosphate (PYP) single-photon emission CT (SPECT) scan has demonstrated excellent sensitivity (85%–97%) and specificity (97%–100%) in the diagnosis of TTR amyloidosis, and is used as a confirmatory study for cardiac TTR amyloidosis without the need for biopsy confirmation.34 However, PYP-SPECT can also be positive in AL cardiac amyloidosis. Therefore, in the presence of a monoclonal protein, this nuclear imaging test cannot be used to validate typing, and tissue-based typing should be pursued.35,36 Because the most commonly involved organs are the heart and kidneys, followed by the nerves, liver, and gastrointestinal tract, the minimal evaluation for organ involvement in patients with AL amyloidosis should include ECG, echocardiogram, cardiac biomarkers (as will be discussed later), serum creatinine, albumin, and alkaline phosphatase.22 If suspicion exists for nerve involvement, then nerve conduction studies, electromyography, and autonomic nerve studies should be performed. Gastrointestinal involvement can only be ascertained by biopsy confirmation and should be considered in the right clinical context. Screening for coagulopathy can be performed using prothrombin time and partial thromboplastin time and by directly measuring factor X level. In patients with AL amyloidosis and a bleeding disorder, acquired von Willebrand disease should also be ruled out, especially if prothrombin time and factor X level are normal.37

Prognostic Markers for AL Amyloidosis

Advances in plasma cell–directed therapies and improved supportive care have resulted in an improvement in overall survival (OS) for patients with AL amyloidosis over the past 2 decades.38,39 However, despite a reduction in early mortality rate, up to 30% patients die within 6 months of diagnosis.28,40 Much of the early mortality is driven by cardiac amyloidosis, whereas the long-term prognosis is determined by organ involvement and characteristics of the underlying plasma cell clone.22,39,41,42

Cardiac Prognostication

Cardiac biomarkers, troponin and natriuretic peptide, have been incorporated into well-validated prognostic models. The Mayo 2004 prognostic model for AL amyloidosis incorporates NT-proBNP (N-terminal pro–B-type natriuretic peptide; ≥332 ng/L) and cardiac troponin T (cTnT; ≥0.035 µg/L), with 1 point for each biomarker above the mentioned thresholds (Table 1).43 The European modification of the Mayo 2004 model further stratifies Mayo 2004 stage III into stages IIIa and IIIb based on NT-proBNP levels >8,500 ng/L (stage IIIb), which identifies patients with poorest outcomes with median OS of <6 months.44 The serum light chain burden has been incorporated with the cardiac biomarkers into the revised Mayo 2012 model.45 Work by researchers at Boston University established a BNP of 81 ng/L to be most closely comparable to the cutoff of 332 ng/L for NT-proBNP used in the Mayo 2004 model.46 Although there are limited head-to-head comparison data for BNP and NT-proBNP, the longer half-life, greater stability (even on frozen samples), and less stringent preanalytical requirements for NT-proBNP make it the routine choice of biomarker in clinical practice.47 The commonly used prognostic staging systems for AL amyloidosis and the expected survival with staging are depicted in Table 1. High-sensitivity cTnT (hs-cTnT) is now the cardiac biomarker of choice. To harmonize the previously used 4th generation troponin T assay used for modeling with the currently used hs-cTnT, a conversion tool has been developed (Table 2).48

Table 1.

Prognostic Models in AL Amyloidosis

Table 1.
Table 2.

Comparable Threshold for Cardiac Biomarkers Used in AL Amyloidosis Prognostic Systems

Table 2.

Renal Prognostication

Kidneys are involved in 50% to 70% of patients with AL amyloidosis, and end-organ damage is a major source of morbidity.49 In patients with coexistent cardiac and renal AL amyloidosis, OS is largely dictated by the cardiac involvement, and most patients succumb to the disease before end-stage renal disease ensues.43,49 Single-organ renal involvement has a favorable outcome, with 8-year OS of 80%.21 Palladini et al50 proposed a renal staging system for predicting progression to dialysis, the more pertinent endpoint for renal amyloidosis. In this staging system, proteinuria >5 g/24 hours and estimated glomerular filtration rate (eGFR) <50 mL/min per 1.73 m2 were identified as independent predictors of progression to dialysis. Patients with both of these risk factors were demonstrated to have a risk of progression to dialysis of 60% to 85%, compared with 0% to 4% among patients with proteinuria ≤5 g/24 hours and eGFR ≥50 mL/min per 1.73 m2 (Table 3).50

Table 3.

Renal Staging in AL Amyloidosis

Table 3.

Plasma Cell Burden and Interphase FISH

Average bone marrow plasma cell (BMPC) involvement in AL amyloidosis on bone marrow biopsy is approximately 10%, and although multiple studies have demonstrated that patients with a higher BMPC (>10%) have adverse outcomes, this is not universal.5153 More recently, a Mayo Clinic study demonstrated that coexistent plasma cell burden of ≥20% at diagnosis had a markedly inferior median OS of 12 months compared with 33 months in patients with 5% to 19% BMPCs and 81 months in patients with <5% BMPCs.54 A higher BMPC percentage was associated with increased cardiac involvement, and the prognostic impact of ≥20% BMPCs was independent of other commonly used prognostic markers.54 The frequency of high-risk FISH [eg, del(17p), t(4;14), and t(14;16)] as well as myeloma CRAB features was also more prevalent in patients with a higher BMPC percentage. Compared with multiple myeloma, the presence of clonal heterogeneity is much lower in AL amyloidosis. This is likely due to the high prevalence of t(11;14) in AL amyloidosis (seen in 40%–60% of AL), which can suppress subclonal disease, rather than an effect of the disease itself.55

Translocation t(11;14) is present in 40% to 60% of patients with AL amyloidosis and is associated with inferior response and survival in patients treated with bortezomib-based therapy.5659 This treatment-dependent adverse marker can be overcome with autologous transplant and daratumumab-based treatments.19 In addition, t(11;14) serves as a predictive marker for response to BCL-2 inhibition with venetoclax, although venetoclax is currently not FDA-approved for this indication.60 Patients with trisomies (identified in up to 30% of patients with AL amyloidosis) and those with high-risk FISH cytogenetics have poor outcomes, but the latter are infrequently encountered in patients with AL amyloidosis.56,61

Depth of Response and Prognosis

Serum free light chains are the primary assay used for assessment of hematologic response to therapy in AL amyloidosis.6264 The greater the reduction in the amyloidogenic light chain supply, the better the survival. Greater than 50% reduction in dFLC (difference between involved and uninvolved free light chains) is consistent with partial response, whereas dFLC <40 mg/L qualifies as a very good partial response (VGPR).62 Hematologic complete response, defined as a negative serum and urine immunofixation with a normal free light chain ratio, is the level of response that is consistently associated with superior outcomes, and should be the target goal if it can be safely achieved.6266 Hematologic VGPR is an acceptable response. Together, hematologic complete response and VGPR can be achieved with first-line therapy in approximately 65% to 80% of patients.67 Patients with a baseline dFLC of <50 mg/L are considered nonevaluable for hematologic response. In these patients, achievement of dFLC <10 mg/L after treatment has been demonstrated to be of prognostic value in multiple studies, and is termed low-dFLC partial response.68,69 Hematologic response should be achieved as early as possible to improve chances of organ response and survival. Multiparameter flow cytometry–based minimal residual disease negativity at the end of treatment is associated with improved progression-free survival, and additional studies are needed to better define its role in response assessment and management.70,71

Organ response, the ultimate goal of therapy, is typically delayed, occurring 6 to 12 months from the start of therapy. This is a limitation in its utility for early prognostication.72 Depth of organ response is also prognostic, and deeper responses are associated with improved OS for both cardiac and renal responses.7274 Other important prognostic parameters include advanced physiologic age at diagnosis (>65 to 70 years), poor performance status (ECOG performance status >2), and autonomic involvement.38,7577

Summary

Patients with systemic AL amyloidosis present with a varied constellation of symptoms driven by the underlying organ involvement. Establishing the diagnosis requires a high index of suspicion. Diagnosis confirmation requires biopsy-proven Congo red–positive material followed by accurate typing of the amyloid fibril. Prognosis in AL amyloidosis is driven by organ involvement, with the currently prevalent staging systems relying heavily on the baseline cardiac biomarkers. Apart from organ involvement, plasma cell burden and FISH findings carry prognostic value. Even with advances in treatment, high early mortality rates remain a major hurdle, further underscoring the need for early diagnosis.

References

  • 1.

    Gertz MA, Benson MD, Dyck PJ, et al. Diagnosis, prognosis, and therapy of transthyretin amyloidosis. J Am Coll Cardiol 2015;66:24512466.

  • 2.

    Benson MD, Buxbaum JN, Eisenberg DS, et al. Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee. Amyloid 2018;25:215219.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Muchtar E, Dispenzieri A, Magen H, et al. Systemic amyloidosis from A (AA) to T (ATTR): a review. J Intern Med 2021;289:268292.

  • 4.

    Wechalekar AD, Gillmore JD, Hawkins PN. Systemic amyloidosis. Lancet 2016;387:26412654.

  • 5.

    Kyle RA, Larson DR, Kurtin PJ, et al. Incidence of AL amyloidosis in Olmsted County, Minnesota, 1990 through 2015. Mayo Clin Proc 2019;94:465471.

  • 6.

    Quock TP, Yan T, Chang E, et al. Epidemiology of AL amyloidosis: a real-world study using US claims data. Blood Adv 2018;2:10461053.

  • 7.

    Nasr SH, Said SM, Valeri AM, et al. The diagnosis and characteristics of renal heavy-chain and heavy/light-chain amyloidosis and their comparison with renal light-chain amyloidosis. Kidney Int 2013;83:463470.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Chaulagain CP, Herlitz LC, Fu J, et al. How we manage systemic immunoglobulin heavy chain amyloidosis (AH amyloidosis) and immunoglobulin heavy-and-light-chain amyloidosis (AH/AL amyloidosis). Clin Lymphoma Myeloma Leuk 2020;20:e826831.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Hester LL, Gifkins DM, Bellew K, et al. Diagnostic delay and characterization of the clinical prodrome in AL amyloidosis among 1523 US adults diagnosed between 2001 and 2019. Eur J Haematol 2021;107:428435.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    McCausland KL, White MK, Guthrie SD, et al. Light chain (AL) amyloidosis: the journey to diagnosis. Patient 2018;11:207216.

  • 11.

    Kourelis TV, Kumar SK, Go RS, et al. Immunoglobulin light chain amyloidosis is diagnosed late in patients with preexisting plasma cell dyscrasias. Am J Hematol 2014;89:10511054.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Zanwar S, Abeykoon JP, Ansell SM, et al. Primary systemic amyloidosis in patients with Waldenström macroglobulinemia. Leukemia 2019;33:790794.

  • 13.

    Pagourelias ED, Mirea O, Duchenne J, et al. Echo parameters for differential diagnosis in cardiac amyloidosis: a head-to-head comparison of deformation and nondeformation parameters. Circ Cardiovasc Imaging 2017;10:e005588.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Selvanayagam JB, Hawkins PN, Paul B, et al. Evaluation and management of the cardiac amyloidosis. J Am Coll Cardiol 2007;50:21012110.

  • 15.

    Fontana M, Pica S, Reant P, et al. Prognostic value of late gadolinium enhancement cardiovascular magnetic resonance in cardiac amyloidosis. Circulation 2015;132:15701579.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Kristen AV, Dengler TJ, Hegenbart U, et al. Prophylactic implantation of cardioverter-defibrillator in patients with severe cardiac amyloidosis and high risk for sudden cardiac death. Heart Rhythm 2008;5:235240.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Adams D, Lozeron P, Theaudin M, et al. Varied patterns of inaugural light-chain (AL) amyloid polyneuropathy: a monocentric study of 24 patients. Amyloid 2011;18(Suppl 1):98100.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Qian M, Qin L, Shen K, et al. Light-chain amyloidosis with peripheral neuropathy as an initial presentation. Front Neurol 2021;12:707134.

  • 19.

    Gertz MA. Immunoglobulin light chain amyloidosis: 2022 update on diagnosis, prognosis, and treatment. Am J Hematol 2022;97:818829.

  • 20.

    Chakraborty R, Gertz MA, Dispenzieri A, et al. Natural history of amyloidosis isolated to fat and bone marrow aspirate. Br J Haematol 2017;179:170172.

  • 21.

    Muchtar E, Gertz MA, Kyle RA, et al. A modern primer on light chain amyloidosis in 592 patients with mass spectrometry-verified typing. Mayo Clin Proc 2019;94:472483.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Muchtar E, Dispenzieri A, Gertz MA, et al. Treatment of AL amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus statement 2020 update. Mayo Clin Proc 2021;96:15461577.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995;32:4559.

  • 24.

    Gertz MA, Dispenzieri A. Systemic amyloidosis recognition, prognosis, and therapy: a systematic review. JAMA 2020;324:7989.

  • 25.

    van Gameren II, Hazenberg BP, Bijzet J, et al. Diagnostic accuracy of subcutaneous abdominal fat tissue aspiration for detecting systemic amyloidosis and its utility in clinical practice. Arthritis Rheum 2006;54:20152021.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Hansen CT, Møller HEH, Rojek AM, et al. Combined subcutaneous fat aspirate and skin tru-cut biopsy for amyloid screening in patients with suspected systemic amyloidosis. Molecules 2021;26:3649.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Muchtar E, Dispenzieri A, Lacy MQ, et al. Overuse of organ biopsies in immunoglobulin light chain amyloidosis (AL): the consequence of failure of early recognition. Ann Med 2017;49:545551.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Palladini G, Milani P, Merlini G. Management of AL amyloidosis in 2020. Blood 2020;136:26202627.

  • 29.

    Comenzo RL, Reece D, Palladini G, et al. Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis. Leukemia 2012;26:23172325.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Zanwar S, Abeykoon JP. Treatment paradigm in Waldenström macroglobulinemia: frontline therapy and beyond. Ther Adv Hematol 2022;13:20406207221093962.

  • 31.

    Dasari S, Theis JD, Vrana JA, et al. Amyloid typing by mass spectrometry in clinical practice: a comprehensive review of 16,175 samples. Mayo Clin Proc 2020;95:18521864.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Rezk T, Gilbertson JA, Mangione PP, et al. The complementary role of histology and proteomics for diagnosis and typing of systemic amyloidosis. J Pathol Clin Res 2019;5:145153.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Grogan M, Lopez-Jimenez F, Cohen-Shelly M, et al. Artificial intelligence-enhanced electrocardiogram for the early detection of cardiac amyloidosis. Mayo Clin Proc 2021;96:27682778.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation 2016;133:24042412.

  • 35.

    Ren C, Ren J, Tian Z, et al. Assessment of cardiac amyloidosis with 99mTc-pyrophosphate (PYP) quantitative SPECT. EJNMMI Phys 2021;8:3.

  • 36.

    Zeng Y, Poterucha TJ, Einstein AJ, et al. False positive technetium-99m pyrophosphate scintigraphy in a patient with cardiac amyloidosis light chain: case report. Medicine (Baltimore) 2021;100:e25582.

    • Search Google Scholar
    • Export Citation
  • 37.

    Kos CA, Ward JE, Malek K, et al. Association of acquired von Willebrand syndrome with AL amyloidosis. Am J Hematol 2007;82:363367.

  • 38.

    Muchtar E, Gertz MA, Kumar SK, et al. Improved outcomes for newly diagnosed AL amyloidosis between 2000 and 2014: cracking the glass ceiling of early death. Blood 2017;129:21112119.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Staron A, Zheng L, Doros G, et al. Marked progress in AL amyloidosis survival: a 40-year longitudinal natural history study. Blood Cancer J 2021;11:139.

  • 40.

    Barrett CD, Dobos K, Liedtke M, et al. A changing landscape of mortality for systemic light chain amyloidosis. JACC Heart Fail 2019;7:958966.

  • 41.

    Ravichandran S, Lachmann HJ, Wechalekar AD. Epidemiologic and survival trends in amyloidosis, 1987-2019. N Engl J Med 2020;382:15671568.

  • 42.

    Muchtar E, Gertz MA, Lacy MQ, et al. Ten-year survivors in AL amyloidosis: characteristics and treatment pattern. Br J Haematol 2019;187:588594.

  • 43.

    Dispenzieri A, Gertz MA, Kyle RA, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol 2004;22:37513757.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Wechalekar AD, Schonland SO, Kastritis E, et al. A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood 2013;121:34203427.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Kumar S, Dispenzieri A, Lacy MQ, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol 2012;30:989995.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    Lilleness B, Ruberg FL, Mussinelli R, et al. Development and validation of a survival staging system incorporating BNP in patients with light chain amyloidosis. Blood 2019;133:215223.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    Merlini G, Lousada I, Ando Y, et al. Rationale, application and clinical qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in patients with AL amyloidosis. Leukemia 2016;30:19791986.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    Muchtar E, Kumar SK, Gertz MA, et al. Staging systems use for risk stratification of systemic amyloidosis in the era of high-sensitivity troponin T assay. Blood 2019;133:763766.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49.

    Palladini G, Comenzo RL. The challenge of systemic immunoglobulin light-chain amyloidosis (AL). Subcell Biochem 2012;65:609642.

  • 50.

    Palladini G, Hegenbart U, Milani P, et al. A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. Blood 2014;124:23252332.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Kourelis TV, Kumar SK, Gertz MA, et al. Coexistent multiple myeloma or increased bone marrow plasma cells define equally high-risk populations in patients with immunoglobulin light chain amyloidosis. J Clin Oncol 2013;31:43194324.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52.

    Tovar N, Rodríguez-Lobato LG, Cibeira MT, et al. Bone marrow plasma cell infiltration in light chain amyloidosis: impact on organ involvement and outcome. Amyloid 2018;25:7985.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Dittus C, Uwumugambi N, Sun F, et al. The effect of bone marrow plasma cell burden on survival in patients with light chain amyloidosis undergoing high-dose melphalan and autologous stem cell transplantation. Biol Blood Marrow Transplant 2016;22:17291732.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54.

    Muchtar E, Gertz MA, Kourelis TV, et al. Bone marrow plasma cells 20% or greater discriminate presentation, response, and survival in AL amyloidosis. Leukemia 2020;34:11351143.

    • Search Google Scholar
    • Export Citation
  • 55.

    Bochtler T, Merz M, Hielscher T, et al. Cytogenetic intraclonal heterogeneity of plasma cell dyscrasia in AL amyloidosis as compared with multiple myeloma. Blood Adv 2018;2:26072618.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56.

    Bryce AH, Ketterling RP, Gertz MA, et al. Translocation t(11;14) and survival of patients with light chain (AL) amyloidosis. Haematologica 2009;94:380386.

    • Search Google Scholar
    • Export Citation
  • 57.

    Bochtler T, Hegenbart U, Kunz C, et al. Translocation t(11;14) is associated with adverse outcome in patients with newly diagnosed AL amyloidosis when treated with bortezomib-based regimens. J Clin Oncol 2015;33:13711378.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58.

    Ozga M, Zhao Q, Benson D Jr, et al. AL amyloidosis: the effect of fluorescent in situ hybridization abnormalities on organ involvement and survival. Cancer Med 2021;10:965973.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59.

    Dumas B, Yameen H, Sarosiek S, et al. Presence of t(11;14) in AL amyloidosis as a marker of response when treated with a bortezomib-based regimen. Amyloid 2020;27:244249.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60.

    Sidiqi MH, Al Saleh AS, Leung N, et al. Venetoclax for the treatment of translocation (11;14) AL amyloidosis. Blood Cancer J 2020;10:55.

  • 61.

    Muchtar E, Dispenzieri A, Kumar SK, et al. Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category. Leukemia 2017;31:15621569.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62.

    Palladini G, Dispenzieri A, Gertz MA, et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol 2012;30:45414549.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63.

    Milani P, Basset M, Nuvolone M, et al. Indicators of profound hematologic response in AL amyloidosis: complete response remains the goal of therapy. Blood Cancer J 2020;10:90.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 64.

    Muchtar E, Dispenzieri A, Leung N, et al. Optimizing deep response assessment for AL amyloidosis using involved free light chain level at end of therapy: failure of the serum free light chain ratio. Leukemia 2019;33:527531.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 65.

    Cohen OC, Law S, Lachmann HJ, et al. The impact and importance of achieving a complete haematological response prior to renal transplantation in AL amyloidosis. Blood Cancer J 2020; 10:60.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 66.

    Sarosiek S, Zheng L, Sloan JM, et al. Comparing measures of hematologic response after high-dose melphalan and stem cell transplantation in AL amyloidosis. Blood Cancer J 2020;10:88.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67.

    Kastritis E, Palladini G, Minnema MC, et al. Daratumumab-based treatment for immunoglobulin light-chain amyloidosis. N Engl J Med 2021;385:4658.

  • 68.

    Milani P, Basset M, Russo F, et al. Patients with light-chain amyloidosis and low free light-chain burden have distinct clinical features and outcome. Blood 2017;130:625631.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 69.

    Dittrich T, Bochtler T, Kimmich C, et al. AL amyloidosis patients with low amyloidogenic free light chain levels at first diagnosis have an excellent prognosis. Blood 2017;130:632642.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 70.

    Muchtar E, Dispenzieri A, Jevremovic D, et al. Survival impact of achieving minimal residual negativity by multi-parametric flow cytometry in AL amyloidosis. Amyloid 2020;27:1316.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 71.

    Palladini G, Paiva B, Wechalekar A, et al. Minimal residual disease negativity by next-generation flow cytometry is associated with improved organ response in AL amyloidosis. Blood Cancer J 2021; 11:34.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 72.

    Muchtar E, Dispenzieri A, Leung N, et al. Depth of organ response in AL amyloidosis is associated with improved survival: grading the organ response criteria. Leukemia 2018;32:22402249.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 73.

    Muchtar E, Wisniowski B, Palladini G, et al. Graded renal response criteria for light chain (AL) amyloidosis. Blood 2021;138(Suppl 1):2724.

  • 74.

    Muchtar E, Dispenzieri A, Wisniowski B, et al. Graded cardiac response criteria for AL amyloidosis: the impact of depth of cardiac response on survival. Blood 2021;138(Suppl 1):2720.

    • Search Google Scholar
    • Export Citation
  • 75.

    Muchtar E, Therneau TM, Larson DR, et al. Comparative analysis of staging systems in AL amyloidosis. Leukemia 2019;33:811814.

  • 76.

    Sachchithanantham S, Offer M, Venner C, et al. Clinical profile and treatment outcome of older (>75 years) patients with systemic AL amyloidosis. Haematologica 2015;100:14691476.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 77.

    Berg AM, Anderson JJ, Chipkin SR, et al. Autonomic neuropathy in AL (primary) amyloidosis and its effect on survival. Amyloid 1994; 1:3946.

Submitted June 21, 2022; final revision received September 12, 2022; accepted for publication September 22, 2022.

Funding: Grant funding was received from the Amyloidosis Foundation and the International Waldenstrom’s Macroglobulinemia Foundation (NCI SPORE MM SPORE 5P50 CA186781-04).

Disclosures: Dr. Gertz has disclosed receiving personal fees from Ionis/Akcea, Prothena, Sanofi, Janssen, Aptitude Health, Ashfield, Juno, Physicians Education Resource, Johnson & Johnson, Celgene, Research to Practice, and Sorrento; developing educational materials of i3Health; receiving grant/research support from Ashfield; and serving on a data safety monitoring board for Abbvie. Dr. Muchtar has disclosed receiving honoraria from Janssen, and receiving consulting fees from Protego. Dr. Zanwar has disclosed having no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.

Funding: Grant funding was received from the Amyloidosis Foundation and the International Waldenstrom’s Macroglobulinemia Foundation (NCI SPORE MM SPORE 5P50 CA186781-04).

Correspondence: Eli Muchtar, MD, Division of Hematology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905. Email: muchtar.eli@mayo.edu
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    Figure 1.

    Common presenting signs and symptoms that should raise clinical suspicion for immunoglobulin light chain amyloidosis.

  • 1.

    Gertz MA, Benson MD, Dyck PJ, et al. Diagnosis, prognosis, and therapy of transthyretin amyloidosis. J Am Coll Cardiol 2015;66:24512466.

  • 2.

    Benson MD, Buxbaum JN, Eisenberg DS, et al. Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee. Amyloid 2018;25:215219.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Muchtar E, Dispenzieri A, Magen H, et al. Systemic amyloidosis from A (AA) to T (ATTR): a review. J Intern Med 2021;289:268292.

  • 4.

    Wechalekar AD, Gillmore JD, Hawkins PN. Systemic amyloidosis. Lancet 2016;387:26412654.

  • 5.

    Kyle RA, Larson DR, Kurtin PJ, et al. Incidence of AL amyloidosis in Olmsted County, Minnesota, 1990 through 2015. Mayo Clin Proc 2019;94:465471.

  • 6.

    Quock TP, Yan T, Chang E, et al. Epidemiology of AL amyloidosis: a real-world study using US claims data. Blood Adv 2018;2:10461053.

  • 7.

    Nasr SH, Said SM, Valeri AM, et al. The diagnosis and characteristics of renal heavy-chain and heavy/light-chain amyloidosis and their comparison with renal light-chain amyloidosis. Kidney Int 2013;83:463470.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Chaulagain CP, Herlitz LC, Fu J, et al. How we manage systemic immunoglobulin heavy chain amyloidosis (AH amyloidosis) and immunoglobulin heavy-and-light-chain amyloidosis (AH/AL amyloidosis). Clin Lymphoma Myeloma Leuk 2020;20:e826831.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Hester LL, Gifkins DM, Bellew K, et al. Diagnostic delay and characterization of the clinical prodrome in AL amyloidosis among 1523 US adults diagnosed between 2001 and 2019. Eur J Haematol 2021;107:428435.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    McCausland KL, White MK, Guthrie SD, et al. Light chain (AL) amyloidosis: the journey to diagnosis. Patient 2018;11:207216.

  • 11.

    Kourelis TV, Kumar SK, Go RS, et al. Immunoglobulin light chain amyloidosis is diagnosed late in patients with preexisting plasma cell dyscrasias. Am J Hematol 2014;89:10511054.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Zanwar S, Abeykoon JP, Ansell SM, et al. Primary systemic amyloidosis in patients with Waldenström macroglobulinemia. Leukemia 2019;33:790794.

  • 13.

    Pagourelias ED, Mirea O, Duchenne J, et al. Echo parameters for differential diagnosis in cardiac amyloidosis: a head-to-head comparison of deformation and nondeformation parameters. Circ Cardiovasc Imaging 2017;10:e005588.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Selvanayagam JB, Hawkins PN, Paul B, et al. Evaluation and management of the cardiac amyloidosis. J Am Coll Cardiol 2007;50:21012110.

  • 15.

    Fontana M, Pica S, Reant P, et al. Prognostic value of late gadolinium enhancement cardiovascular magnetic resonance in cardiac amyloidosis. Circulation 2015;132:15701579.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Kristen AV, Dengler TJ, Hegenbart U, et al. Prophylactic implantation of cardioverter-defibrillator in patients with severe cardiac amyloidosis and high risk for sudden cardiac death. Heart Rhythm 2008;5:235240.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Adams D, Lozeron P, Theaudin M, et al. Varied patterns of inaugural light-chain (AL) amyloid polyneuropathy: a monocentric study of 24 patients. Amyloid 2011;18(Suppl 1):98100.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Qian M, Qin L, Shen K, et al. Light-chain amyloidosis with peripheral neuropathy as an initial presentation. Front Neurol 2021;12:707134.

  • 19.

    Gertz MA. Immunoglobulin light chain amyloidosis: 2022 update on diagnosis, prognosis, and treatment. Am J Hematol 2022;97:818829.

  • 20.

    Chakraborty R, Gertz MA, Dispenzieri A, et al. Natural history of amyloidosis isolated to fat and bone marrow aspirate. Br J Haematol 2017;179:170172.

  • 21.

    Muchtar E, Gertz MA, Kyle RA, et al. A modern primer on light chain amyloidosis in 592 patients with mass spectrometry-verified typing. Mayo Clin Proc 2019;94:472483.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Muchtar E, Dispenzieri A, Gertz MA, et al. Treatment of AL amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus statement 2020 update. Mayo Clin Proc 2021;96:15461577.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995;32:4559.

  • 24.

    Gertz MA, Dispenzieri A. Systemic amyloidosis recognition, prognosis, and therapy: a systematic review. JAMA 2020;324:7989.

  • 25.

    van Gameren II, Hazenberg BP, Bijzet J, et al. Diagnostic accuracy of subcutaneous abdominal fat tissue aspiration for detecting systemic amyloidosis and its utility in clinical practice. Arthritis Rheum 2006;54:20152021.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Hansen CT, Møller HEH, Rojek AM, et al. Combined subcutaneous fat aspirate and skin tru-cut biopsy for amyloid screening in patients with suspected systemic amyloidosis. Molecules 2021;26:3649.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Muchtar E, Dispenzieri A, Lacy MQ, et al. Overuse of organ biopsies in immunoglobulin light chain amyloidosis (AL): the consequence of failure of early recognition. Ann Med 2017;49:545551.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Palladini G, Milani P, Merlini G. Management of AL amyloidosis in 2020. Blood 2020;136:26202627.

  • 29.

    Comenzo RL, Reece D, Palladini G, et al. Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis. Leukemia 2012;26:23172325.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Zanwar S, Abeykoon JP. Treatment paradigm in Waldenström macroglobulinemia: frontline therapy and beyond. Ther Adv Hematol 2022;13:20406207221093962.

  • 31.

    Dasari S, Theis JD, Vrana JA, et al. Amyloid typing by mass spectrometry in clinical practice: a comprehensive review of 16,175 samples. Mayo Clin Proc 2020;95:18521864.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Rezk T, Gilbertson JA, Mangione PP, et al. The complementary role of histology and proteomics for diagnosis and typing of systemic amyloidosis. J Pathol Clin Res 2019;5:145153.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Grogan M, Lopez-Jimenez F, Cohen-Shelly M, et al. Artificial intelligence-enhanced electrocardiogram for the early detection of cardiac amyloidosis. Mayo Clin Proc 2021;96:27682778.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation 2016;133:24042412.

  • 35.

    Ren C, Ren J, Tian Z, et al. Assessment of cardiac amyloidosis with 99mTc-pyrophosphate (PYP) quantitative SPECT. EJNMMI Phys 2021;8:3.

  • 36.

    Zeng Y, Poterucha TJ, Einstein AJ, et al. False positive technetium-99m pyrophosphate scintigraphy in a patient with cardiac amyloidosis light chain: case report. Medicine (Baltimore) 2021;100:e25582.

    • Search Google Scholar
    • Export Citation
  • 37.

    Kos CA, Ward JE, Malek K, et al. Association of acquired von Willebrand syndrome with AL amyloidosis. Am J Hematol 2007;82:363367.

  • 38.

    Muchtar E, Gertz MA, Kumar SK, et al. Improved outcomes for newly diagnosed AL amyloidosis between 2000 and 2014: cracking the glass ceiling of early death. Blood 2017;129:21112119.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Staron A, Zheng L, Doros G, et al. Marked progress in AL amyloidosis survival: a 40-year longitudinal natural history study. Blood Cancer J 2021;11:139.

  • 40.

    Barrett CD, Dobos K, Liedtke M, et al. A changing landscape of mortality for systemic light chain amyloidosis. JACC Heart Fail 2019;7:958966.

  • 41.

    Ravichandran S, Lachmann HJ, Wechalekar AD. Epidemiologic and survival trends in amyloidosis, 1987-2019. N Engl J Med 2020;382:15671568.

  • 42.

    Muchtar E, Gertz MA, Lacy MQ, et al. Ten-year survivors in AL amyloidosis: characteristics and treatment pattern. Br J Haematol 2019;187:588594.

  • 43.

    Dispenzieri A, Gertz MA, Kyle RA, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol 2004;22:37513757.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Wechalekar AD, Schonland SO, Kastritis E, et al. A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood 2013;121:34203427.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Kumar S, Dispenzieri A, Lacy MQ, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol 2012;30:989995.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    Lilleness B, Ruberg FL, Mussinelli R, et al. Development and validation of a survival staging system incorporating BNP in patients with light chain amyloidosis. Blood 2019;133:215223.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    Merlini G, Lousada I, Ando Y, et al. Rationale, application and clinical qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in patients with AL amyloidosis. Leukemia 2016;30:19791986.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    Muchtar E, Kumar SK, Gertz MA, et al. Staging systems use for risk stratification of systemic amyloidosis in the era of high-sensitivity troponin T assay. Blood 2019;133:763766.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49.

    Palladini G, Comenzo RL. The challenge of systemic immunoglobulin light-chain amyloidosis (AL). Subcell Biochem 2012;65:609642.

  • 50.

    Palladini G, Hegenbart U, Milani P, et al. A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. Blood 2014;124:23252332.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Kourelis TV, Kumar SK, Gertz MA, et al. Coexistent multiple myeloma or increased bone marrow plasma cells define equally high-risk populations in patients with immunoglobulin light chain amyloidosis. J Clin Oncol 2013;31:43194324.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52.

    Tovar N, Rodríguez-Lobato LG, Cibeira MT, et al. Bone marrow plasma cell infiltration in light chain amyloidosis: impact on organ involvement and outcome. Amyloid 2018;25:7985.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Dittus C, Uwumugambi N, Sun F, et al. The effect of bone marrow plasma cell burden on survival in patients with light chain amyloidosis undergoing high-dose melphalan and autologous stem cell transplantation. Biol Blood Marrow Transplant 2016;22:17291732.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54.

    Muchtar E, Gertz MA, Kourelis TV, et al. Bone marrow plasma cells 20% or greater discriminate presentation, response, and survival in AL amyloidosis. Leukemia 2020;34:11351143.

    • Search Google Scholar
    • Export Citation
  • 55.

    Bochtler T, Merz M, Hielscher T, et al. Cytogenetic intraclonal heterogeneity of plasma cell dyscrasia in AL amyloidosis as compared with multiple myeloma. Blood Adv 2018;2:26072618.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56.

    Bryce AH, Ketterling RP, Gertz MA, et al. Translocation t(11;14) and survival of patients with light chain (AL) amyloidosis. Haematologica 2009;94:380386.

    • Search Google Scholar
    • Export Citation
  • 57.

    Bochtler T, Hegenbart U, Kunz C, et al. Translocation t(11;14) is associated with adverse outcome in patients with newly diagnosed AL amyloidosis when treated with bortezomib-based regimens. J Clin Oncol 2015;33:13711378.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58.

    Ozga M, Zhao Q, Benson D Jr, et al. AL amyloidosis: the effect of fluorescent in situ hybridization abnormalities on organ involvement and survival. Cancer Med 2021;10:965973.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59.

    Dumas B, Yameen H, Sarosiek S, et al. Presence of t(11;14) in AL amyloidosis as a marker of response when treated with a bortezomib-based regimen. Amyloid 2020;27:244249.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60.

    Sidiqi MH, Al Saleh AS, Leung N, et al. Venetoclax for the treatment of translocation (11;14) AL amyloidosis. Blood Cancer J 2020;10:55.

  • 61.

    Muchtar E, Dispenzieri A, Kumar SK, et al. Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category. Leukemia 2017;31:15621569.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62.

    Palladini G, Dispenzieri A, Gertz MA, et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol 2012;30:45414549.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63.

    Milani P, Basset M, Nuvolone M, et al. Indicators of profound hematologic response in AL amyloidosis: complete response remains the goal of therapy. Blood Cancer J 2020;10:90.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 64.

    Muchtar E, Dispenzieri A, Leung N, et al. Optimizing deep response assessment for AL amyloidosis using involved free light chain level at end of therapy: failure of the serum free light chain ratio. Leukemia 2019;33:527531.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 65.

    Cohen OC, Law S, Lachmann HJ, et al. The impact and importance of achieving a complete haematological response prior to renal transplantation in AL amyloidosis. Blood Cancer J 2020; 10:60.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 66.

    Sarosiek S, Zheng L, Sloan JM, et al. Comparing measures of hematologic response after high-dose melphalan and stem cell transplantation in AL amyloidosis. Blood Cancer J 2020;10:88.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67.

    Kastritis E, Palladini G, Minnema MC, et al. Daratumumab-based treatment for immunoglobulin light-chain amyloidosis. N Engl J Med 2021;385:4658.

  • 68.

    Milani P, Basset M, Russo F, et al. Patients with light-chain amyloidosis and low free light-chain burden have distinct clinical features and outcome. Blood 2017;130:625631.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 69.

    Dittrich T, Bochtler T, Kimmich C, et al. AL amyloidosis patients with low amyloidogenic free light chain levels at first diagnosis have an excellent prognosis. Blood 2017;130:632642.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 70.

    Muchtar E, Dispenzieri A, Jevremovic D, et al. Survival impact of achieving minimal residual negativity by multi-parametric flow cytometry in AL amyloidosis. Amyloid 2020;27:1316.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 71.

    Palladini G, Paiva B, Wechalekar A, et al. Minimal residual disease negativity by next-generation flow cytometry is associated with improved organ response in AL amyloidosis. Blood Cancer J 2021; 11:34.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 72.

    Muchtar E, Dispenzieri A, Leung N, et al. Depth of organ response in AL amyloidosis is associated with improved survival: grading the organ response criteria. Leukemia 2018;32:22402249.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 73.

    Muchtar E, Wisniowski B, Palladini G, et al. Graded renal response criteria for light chain (AL) amyloidosis. Blood 2021;138(Suppl 1):2724.

  • 74.

    Muchtar E, Dispenzieri A, Wisniowski B, et al. Graded cardiac response criteria for AL amyloidosis: the impact of depth of cardiac response on survival. Blood 2021;138(Suppl 1):2720.

    • Search Google Scholar
    • Export Citation
  • 75.

    Muchtar E, Therneau TM, Larson DR, et al. Comparative analysis of staging systems in AL amyloidosis. Leukemia 2019;33:811814.

  • 76.

    Sachchithanantham S, Offer M, Venner C, et al. Clinical profile and treatment outcome of older (>75 years) patients with systemic AL amyloidosis. Haematologica 2015;100:14691476.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 77.

    Berg AM, Anderson JJ, Chipkin SR, et al. Autonomic neuropathy in AL (primary) amyloidosis and its effect on survival. Amyloid 1994; 1:3946.

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