Elsevier

Mayo Clinic Proceedings

Volume 90, Issue 8, August 2015, Pages 1054-1081
Mayo Clinic Proceedings

Diagnosis and treatment guidelines
Treatment of Immunoglobulin Light Chain Amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Statement

https://doi.org/10.1016/j.mayocp.2015.06.009Get rights and content

Abstract

Immunoglobulin light chain amyloidosis (AL amyloidosis) has an incidence of approximately 1 case per 100,000 person-years in Western countries. The rarity of the condition not only poses a challenge for making a prompt diagnosis but also makes evidenced decision making about treatment even more challenging. Physicians caring for patients with AL amyloidosis have been borrowing and customizing the therapies used for patients with multiple myeloma with varying degrees of success. One of the biggest failings in the science of the treatment of AL amyloidosis is the paucity of prospective trials, especially phase 3 trials. Herein, we present an extensive review of the literature with an aim of making recommendations in the context of the best evidence and expert opinion.

Section snippets

Diagnosis of AL Amyloidosis

The diagnostic biopsy sample may be from the tissue causing symptoms—eg, heart or kidney—or from a more accessible tissue, such as subcutaneous fat or bone marrow. The sensitivity of a biopsy sample from a symptomatic organ is higher than that from the more accessible tissues, ie, more than 95% for a symptomatic organ, 75% to 80% for fat, and 50% to 65% for bone marrow.10 Special stains, such as Congo red, thioflavin T, and sulfated alcian blue, are required to recognize amyloidosis. The gold

Tumor/Precursor Protein Burden

Screening for a monoclonal protein is done by serum immunoglobulin free light chain measurement and immunofixation studies of the serum and urine.17 The distribution of immunoglobulin light chain variable gene use by bone marrow plasma cells is expected to be 2 to 1 κ to λ in the healthy population. Despite this, the number of AL amyloidosis cases favors λ to κ by 2 to 1, which supports the concept that germline λ is intrinsically more amyloidogenic than κ. A bone marrow aspirate to determine

Prognosis of AL Amyloidosis

The prognosis of patients with AL amyloidosis depends on the burden of the amyloid in the tissues (especially the heart) and the size of the plasma cell clone and its biology, which predict the ability to achieve a hematologic and organ response (Table 2).41, 42 Cardiac involvement predicts most early deaths. Plasma cell biology predicts deaths occurring after the first year. During the past 40 years, the proportion of patients dying within 12 months of diagnosis remains fixed at approximately

Prognostic Impact of Cardiac Involvement

The extent of cardiac involvement drives prognosis more than any other organ involvement, although symptomatic hepatic involvement and autonomic involvement also influence survival.54 Soluble cardiac biomarkers have been accepted by the amyloid community as the best means by which to stage patients with AL amyloidosis; the most commonly used biomarkers include troponin T and NT-proBNP (Table 3).26, 27, 28, 29, 30, 31, 32, 33, 34, 35 Potential advantages of blood tests for assessing cardiac

Rationale for the Recommendations

Any recommendation for the treatment of AL amyloidosis is confounded by the disease’s intrinsic heterogeneity, its rarity, and the paucity of randomized clinical trials. Despite these challenges, we believe that the combination of the literature and the experience of the authors, who are experts in the field, make these recommendations sound. Clinical trials should always be considered the first choice when available. In the absence of clinical trials, recommendations are as discussed herein (

Guideline

Treatment should be initiated immediately in virtually all patients with systemic AL amyloidosis.

Initial Therapy for Patients With Systemic AL Amyloidosis

Clinical trials should always be considered in the frontline setting if available. In the absence of clinical trials, recommendations are as discussed herein.

Initial Therapy for Patients Ineligible for SCT

Clinical trials are again the preferred strategy; however, in the absence of a trial, a variety of options can be considered.

Regimen

Rituxan, bortezomib, and dexamethasone.

Guideline

Potential benefit as first line therapy.

Grade of Recommendation

B

Regimen

CyBorD as first line

Guideline

Potential benefit as first line therapy.

Grade of Recommendation

B

IgM-associated AL amyloidosis is a rare clinical entity with distinctive clinical characteristics. Many cases may be localized forms, in which there is only nodal or soft-tissue involvement without visceral involvement. Many of these cases can merely be observed, but observed more aggressively if there is a circulating monoclonal protein and especially

Guideline

Base salvage therapies on previous therapies, with the aim of introducing drugs with other mechanisms of action to treat relapsed or refractory AL amyloidosis.

Guideline

Diuretics are the mainstay of supportive care for cardiac AL amyloidosis.

Guideline

β-Blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and calcium channel blockers should be used with great caution (or not at all) in cardiac AL amyloidosis.

Organ Transplant

Solid organ transplant is a controversial intervention in patients with AL amyloidosis. Because the disease is systemic and presumably incurable, there is concern that the amyloid will either reoccur in the transplanted organ or progress in another organ, resulting in a poor outcome. The best outcomes have occurred in the setting of careful patient selection, excluding patients with clinically evident multiorgan involvement, and in those who received chemotherapy to eradicate the clone either

Treating Localized Amyloidosis

The location of the amyloid is an important clue in recognizing the amyloid as being localized. The most frequent sites of localized amyloid are the respiratory tract, genitourinary tract, and skin.13 Pulmonary amyloid can be subdivided into nodular, laryngeal/tracheobronchial, and diffuse interstitial. Only the third type represents a manifestation of systemic AL amyloidosis.196, 197 The nodular form of amyloid presents as solitary pulmonary nodules or multiple nodules. This does not represent

Future Directions

There is unprecedented interest in AL amyloidosis, which has resulted in improved outcomes for these patients. Clearly, more work needs to be done, especially in the realms of earlier diagnosis, salvaging the 35% of patients who seem destined to die within the first 6 months of diagnosis, and more innovative therapies. Physicians caring for patients with AL amyloidosis have been borrowing and customizing therapies used for patients with MM with varying degrees of success. One of the biggest

References (202)

  • A. Dispenzieri et al.

    Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation

    Blood

    (2004)
  • G. Palladini et al.

    Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL

    Blood

    (2006)
  • F.L. Ruberg et al.

    Diagnostic and prognostic utility of cardiovascular magnetic resonance imaging in light-chain cardiac amyloidosis

    Am J Cardiol

    (2009)
  • G. Palladini et al.

    The combination of high-sensitivity cardiac troponin T (hs-cTnT) at presentation and changes in N-terminal natriuretic peptide type B (NT-proBNP) after chemotherapy best predicts survival in AL amyloidosis

    Blood

    (2010)
  • A.V. Kristen et al.

    Assessment of disease severity and outcome in patients with systemic light-chain amyloidosis by the high-sensitivity troponin T assay

    Blood

    (2010)
  • A.D. Wechalekar et al.

    A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis

    Blood

    (2013)
  • M.A. Gertz et al.

    Hepatic amyloidosis: clinical appraisal in 77 patients

    Hepatology

    (1997)
  • S.R. Hayman et al.

    Primary systemic amyloidosis: a cause of malabsorption syndrome

    Am J Med

    (2001)
  • G. Palladini et al.

    A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis

    Blood

    (2014)
  • M.A. Gertz et al.

    Amyloidosis: prognosis and treatment

    Semin Arthritis Rheum

    (1994)
  • M.A. Gertz et al.

    Amyloidosis: recognition, confirmation, prognosis, and therapy

    Mayo Clin Proc

    (1999)
  • M.T. Cibeira et al.

    Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients

    Blood

    (2011)
  • G. Palladini et al.

    Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation

    Blood

    (2004)
  • S.K. Kumar et al.

    Recent improvements in survival in primary systemic amyloidosis and the importance of an early mortality risk score

    Mayo Clin Proc

    (2011)
  • R.A. Kyle et al.

    Primary systemic amyloidosis: multivariate analysis for prognostic factors in 168 cases

    Blood

    (1986)
  • H.J. Park et al.

    Direct comparison of B-type natriuretic peptide and N-terminal pro-BNP for assessment of cardiac function in a large population of symptomatic patients

    Int J Cardiol

    (2010)
  • V. Trinkaus-Randall et al.

    Cellular response of cardiac fibroblasts to amyloidogenic light chains

    Am J Pathol

    (2005)
  • J.S. Wall et al.

    Radioimmunodetection of amyloid deposits in patients with AL amyloidosis

    Blood

    (2010)
  • V. Sanchorawala et al.

    Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem-cell transplantation

    Blood

    (2007)
  • G. Palladini et al.

    Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis

    Blood

    (2007)
  • V. Perfetti et al.

    Analysis of V(λ)-J(λ) expression in plasma cells from primary (AL) amyloidosis and normal bone marrow identifies 3r (λIII) as a new amyloid-associated germline gene segment

    Blood

    (2002)
  • E.G. Randles et al.

    Structural alterations within native amyloidogenic immunoglobulin light chains

    J Mol Biol

    (2009)
  • R.A. Kyle et al.

    Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo

    Blood

    (1978)
  • R.A. Kyle et al.

    Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine

    Am J Med

    (1985)
  • M. Skinner et al.

    Treatment of 100 patients with primary amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine only

    Am J Med

    (1996)
  • R.L. Comenzo et al.

    Autologous stem cell transplantation for primary systemic amyloidosis

    Blood

    (2002)
  • D.H. Vesole et al.

    High-dose therapy and autologous hematopoietic stem cell transplantation for patients with primary systemic amyloidosis: a Center for International Blood and Marrow Transplant Research study

    Mayo Clin Proc

    (2006)
  • R.L. Comenzo et al.

    Dose-intensive melphalan with blood stem-cell support for the treatment of AL (amyloid light-chain) amyloidosis: survival and responses in 25 patients

    Blood

    (1998)
  • J.D. Sipe et al.

    Nomenclature 2014: amyloid fibril proteins and clinical classification of the amyloidosis

    Amyloid

    (2014)
  • J.D. Sipe et al.

    Amyloid fibril protein nomenclature: 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis

    Amyloid

    (2010)
  • J.A. Vrana et al.

    A clinical test for the identification of amyloid proteins in biopsy specimens by a novel method based on laser microdissection and mass spectrometry

    Blood

    (2007)
  • N. Sakata et al.

    Colocalization of apolipoprotein AI in various kinds of systemic amyloidosis

    J Histochem Cytochem

    (2005)
  • R.A. Kyle et al.

    Primary systemic amyloidosis: clinical and laboratory features in 474 cases

    Semin Hematol

    (1995)
  • H.J. Lachmann et al.

    Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis

    N Engl J Med

    (2002)
  • M.L. Biewend et al.

    The spectrum of localized amyloidosis: a case series of 20 patients and review of the literature

    Amyloid

    (2006)
  • K. Hamidi Asl et al.

    Organ-specific (localized) synthesis of Ig light chain amyloid

    J Immunol

    (1999)
  • M. Paccalin et al.

    Localized amyloidosis: a survey of 35 French cases

    Amyloid

    (2005)
  • J.A. Katzmann et al.

    Screening panels for detection of monoclonal gammopathies

    Clin Chem

    (2009)
  • A.D. Wechalekar et al.

    A new staging system for AL amyloidosis incorporating serum free light chains, cardiac troponin-T and NT-ProBNP

    Blood

    (2009)
  • H.J. Lachmann et al.

    Outcome in systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light chains following chemotherapy

    Br J Haematol

    (2003)
  • Cited by (0)

    Grant Support: This work was supported in part by the Robert A. Kyle Hematologic Malignancies Program, the Jabbs Foundation, and the Predolin Foundation.

    Potential Competing Interests: Dr Dispenzieri has received research support from Celgene, Millenium, Pfizer, Jannsen, and Alnylam. Dr Kumar as received research support from Celgene, Novartis, Onyx, Millennium, Sanofi, and Janssen. Dr Reeder has received research support from Celgene, Novartis, and Millennium. Dr Mikhael has received research support from Celgene, Onyx, Abbvie, and Sanofi. Dr Grogan has received research support from Pfizer; and consulting fees from Prothena. Dr Fonseca has a patent for the prognostication of multiple myeloma based on genetic categorization of the disease; has received consulting fees from Celgene, Genzyme, BMS, Bayer, Lilly, Onyx, Binding Site, Novartis, Sanofi, Millennium, and AMGEN; has sponsored research from Onyx; and is a member of the scientific advisory board of Applied Biosciences. Dr Ailawadhi has received honoraria from Millennium and Amgen. Dr Bergsagel has received research support from Novartis and Constellation Pharmaceuticals; and consultant fees from Amgen, Janssen, Sanofi-Aventis, Mundipharma, and BMS. Dr Stewart has received research support from Celgene and Millennium Pharmaceuticals; and consulting fees from Novartis and Millennium Pharmaceuticals. Dr Gertz has received research support from ISIS and Prothena; and honoraria from Celgene, Millennium Pharmaceuticals, and Novartis.

    View full text