eMedicine Specialties > Hematology > Plasma Cell Disorders

Amyloidosis, Immunoglobulin-Related

Slavomir Urbancek, MD, PhD, Head, Department of Dermatology, FD Roosevelt Hospital, Slovakia; Scientific Secretary, Slovak Dermatovenereological Society
Pere Gascon, MD, PhD, Professor and Director, Division of Medical Oncology, Institute of Hematology and Medical Oncology, IDIBAPS, University of Barcelona Faculty of Medicine, Spain; Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School; Daniel R Jacobson, MD, Professor of Medicine, Boston University School of Medicine; Chief of Oncology, Veterans Affairs Boston Healthcare System; Joel Buxbaum, MD, Professor, Department of Molecular and Experimental Medicine, The Scripps Research Institute; Carol A Bogdan, MD, Consulting Staff, Coastal Cancer Center, Myrtle Beach, SC

Updated: Feb 12, 2009

Introduction

Background

Immunoglobulin-related amyloidosis is a monoclonal plasma cell disorder in which the secreted monoclonal immunoglobulin protein forms insoluble fibrillar deposits in 1 or more organs. In nearly all cases, the deposits contain immunoglobulin light (L) chains or L-chain fragments, termed L chain–type amyloidosis (AL). In a few reported patients, the amyloid deposits have contained immunoglobulin heavy (H) chains; these are termed H chain–type amyloidosis  AH). Before the discovery that the major fibril component in these patients was an immunoglobulin fragment, patients with light chain–type amyloidosis were described as having primary (in the sense of idiopathic) amyloidosis or, when the burden of monoclonal plasma cells was large, myeloma-associated amyloidosis.

Immunoglobulin L and H chains are 2 of 20 different fibril proteins that have been described in human amyloidosis. For a general discussion of the human amyloidoses, the types of human amyloidosis, and an approach to the diagnosis of amyloidosis, see Amyloidosis, Overview.

L chain–type amyloidosis (AL) is related to both multiple myeloma and monoclonal gammopathy of undetermined significance (MGUS). These monoclonal plasma cell disorders can be categorized according to the total body burden of monoclonal plasma cells. When this burden is large, the diagnostic criteria for multiple myeloma are fulfilled; when this burden is lower, MGUS is diagnosed. Multiple myeloma and MGUS fall on a continuum, with 20% of patients with MGUS progressing to multiple myeloma within 10 years.

In most patients with a monoclonal plasma cell disorder, whether multiple myeloma or MGUS, the monoclonal L chain secreted by the clone remains soluble in the bloodstream. However, in some patients, the physicochemical characteristics of the immunoglobulin L chain or L-chain fragment lead to its deposition as amyloid. Thus, some patients with light chain–type amyloidosis meet the diagnostic criteria of multiple myeloma, whereas other patients can be considered as having MGUS in which the clonal immunoglobulin product is amyloidogenic.

In addition to cases of monoclonal gammopathy in which the secreted clonal immunoglobulin remains in solution and those in which secreted clonal immunoglobulin forms amyloid deposits, a third group consists of cases in which the monoclonal proteins accumulate in various organs, but the deposits do not form fibrils. Patients with this form are described as having nonamyloid monoclonal immunoglobulin deposition disease (MIDD). The relationship among the plasma cell dyscrasias and the amyloidoses is depicted in Image 1 and below.

The relationship among light chain–type amyloidosis (AL), the other monoclonal plasma cell disorders, and the other amyloidoses. Ig = immunoglobulin; MGUS = monoclonal gammopathy of undetermined significance.

Pathophysiology

The most common light chain–type amyloidosis precursor proteins are L chains of the lambda (l) class. The lambda light chain–type amyloidosis is approximately twice as prevalent as the kappa (k) light chain–type amyloidosis, and L chains of the V_l 6 class are the most amyloidogenic. Clonal plasma cell proliferative diseases in which the V_l 6 gene is expressed are always associated with amyloid deposition. Among V_k genes, the V_k 1 subgroup is overrepresented among amyloid-forming L chains.

Within the V region families, certain amino acid residues occurring at particular positions in the L-chain sequence render those chains are more amyloidogenic, with a combination of such residues increasing the chances of a particular L-chain protein being associated with tissue amyloid deposition. Another structural feature that appears to predispose to L chain – type amyloid deposition is enzymatic glycosylation of the L chain. Although 15% of human L chains bear sugar residues, almost one third of amyloidogenic L chains are glycosylated. Why certain amino acid and glycosylation characteristics in L chains predispose to amyloid formation remains unknown.

L chain – type amyloid deposits contain intact L chains, L-chain fragments, or both (most patients). The fragments always include the amino terminus of the chain and range in mass from 5000 to 16,000 d. In 90% of patients, the deposited peptides include at least some constant region sequence; therefore, the peptides react with commercially available anti–L chain sera, which are specific for constant region determinants. These observations explain why 10% of deposits do not bind either commercial anti-k or anti-l antisera.

L chain – type amyloid deposits can develop in any organ system. The most common organs involved are the kidneys, the heart, the gastrointestinal (GI) tract, the peripheral nerves, and the liver. In most cases, the deposits affect multiple organ systems. Factors leading to the specific pattern of organ involvement in a particular patient are not understood.

In a minority of cases, localized amyloid deposits, including amyloid masses (amyloidomas), may be found in various sites, even in the absence of systemic disease. The pathogenesis of localized light chain–type amyloidosis is not well understood, but a small, localized clone of plasma cells apparently produces immunoglobulin, which forms deposits near the site of synthesis. In some patients, plasma cells have been demonstrated histologically, accompanying the localized amyloid deposits. In one patient, DNA sequencing revealed that local plasma cells were producing the locally deposited L chains.

Researchers from the University of Arkansas for Medical Sciences (UAMS) studied the gene profile of more than 500 patients treated for multiple myeloma at UAMS.¹ Of the about 25,000 genes in the body, the UAMS team found the expression of just 17 genes revealed which form of the disease the patients had.¹ A gene is expressed when its DNA is transcribed into RNA, which is later transcribed into protein. The expression level of those 17 genes becomes an overpowering and overriding predictor of outcome in therapy. It is questionable whether a drug that targets those genes will be developed.

Frequency

United States

Annually, 1-5 cases of immunoglobulin-related amyloidosis per 100,000 people occur.

The best available direct data on L chain–type amyloidosis prevalence in the United States come from Olmstead County, Minn, where the annual prevalence of L chain–type amyloidosis was calculated to be approximately 1 case per 100,000 people. The population in this location is primarily of northern European ancestry. Whether this prevalence applies to different populations is not known.

Based on indirect calculations, the prevalence may be higher. The annual incidence of multiple myeloma is approximately 5 cases per 100,000 people, and the prevalence of L chain–type amyloidosis in patients with myeloma is approximately 20-35%, producing an overall incidence of combined L chain–type amyloidosis and myeloma of 1-1.5 cases per 100,000 people. Only 1 in 5 patients with L chain–type amyloidosis has frank myeloma; therefore, the total number of patients with L chain–type amyloidosis type is 5 times the number of patients with L chain–type amyloidosis and myeloma, or at least 5 cases per 100,000 people.

International

The prevalence of L chain–type amyloidosis appears to be the same in all populations. The only population-based direct measurement comes from the United States.

Mortality/Morbidity

Symptoms of immunoglobulin-related amyloidosis reflect the organs containing amyloid deposits. Factors that cause deposits in different organs in different patients are unknown. Cardiac deposition is the most severe consequence of systemic L chain–type amyloidosis, eventually occurring in most patients. Cardiac L chain–type amyloidosis is the cause of death in most patients with systemic L chain–type amyloidosis.

Race

L chain–type amyloidosis affects people of all racial and ethnic groups. No data are available comparing the incidence of disease in different groups.

Sex

The male-to-female incidence ratio of L chain–type amyloidosis is 2:1.

Age

The median age at diagnosis of immunoglobulin-related amyloidosis in the largest published series (from the Mayo Clinic) was 64 years.²

Clinical

History

The most common presenting symptoms of immunoglobulin-related amyloidosis, including weakness and weight loss followed by purpura, particularly in loose facial tissue, are nonspecific. Other symptoms and physical findings vary widely, depending on which organs contain deposits. Amyloid deposition in a particular organ leads to similar clinical consequences and, therefore, similar complaints, regardless of the type of amyloid deposited. For example, cardiac L chain–type amyloidosis and cardiac transthyretin (TTR) amyloidosis cause similar symptoms.

Clinical features and management outcome were evaluated in a case series of 24 patients with periocular and orbital amyloidosis.³ Signs and symptoms included a visible or palpable periocular mass or tissue infiltration (95.8%), ptosis (54.2%), periocular discomfort or pain (25%), proptosis or globe displacement (21%), limitations in ocular motility (16.7%), recurrent periocular subcutaneous hemorrhages (12.5%), and diplopia (8.3%).³ Seven patients had B cells or plasma cells producing monoclonal immunoglobulin chains that were deposited as amyloid light chains.³

• Renal involvement
  • The kidneys are the most frequent sites of deposition, with nephrotic syndrome being common; therefore, complaints of peripheral edema are common.
  • Patients can present with renal failure.
• Cardiovascular involvement
  • Involvement of the heart and the peripheral vasculature often leads to postural hypotension, with patients complaining of lightheadedness.
  • Patients also develop weakness, palpitations, dyspnea, and peripheral edema due to congestive heart failure and arrhythmias.
  • Occasionally, deposits in the coronary arteries (usually the smaller intracardiac arterioles) may cause anginal symptoms similar to those typical of atherosclerotic coronary artery disease.
• Peripheral neuropathy
  • Patients whose disease involves the peripheral nerves often report dysesthesia, decreased sensation, and decreased strength.
  • Symptoms usually affect the lower extremities more severely than the upper extremities.
• Gastrointestinal (GI) involvement:
  • Most patients with L chain–type amyloidosis have histologic evidence of infiltration of the gut, particularly in the blood vessels. However, deposition is symptomatic in only a minority of patients.
  • The most common GI symptoms are constipation or alternating constipation and diarrhea. Gastric L chain–type amyloidosis can cause hematemesis, nausea, and vomiting. Intestinal L chain–type amyloidosis can impair motility and cause hemorrhage, obstruction, constipation, and diarrhea or alternating constipation and diarrhea.
  • Myeloma-associated amyloidosis may rarely be first evident as subacute liver failure.⁴
• Carpal tunnel syndrome: Approximately 20% of patients with L chain–type amyloidosis initially report weakness and paresthesia of one or both hands, suggesting carpal ligament involvement.

Physical

• General features
  • The most common initial physical findings in individuals with immunoglobulin-related amyloidosis include peripheral edema, hepatomegaly, purpura, orthostatic hypotension, peripheral neuropathy, carpal tunnel syndrome, and macroglossia.
  • Peripheral edema and hypotension result from congestive heart failure and nephrotic syndrome.
  • Purpura results from vascular fragility produced by amyloid deposition in the subendothelium of the small blood vessels.
• Cardiac involvement
  • Cardiac amyloidosis typically causes diastolic dysfunction; congestive heart failure; and arrhythmias, including heart block, premature ventricular contractions, and various tachyarrhythmias.
  • The physical findings observed are not specific for cardiac amyloidosis.
• Ecchymosis
  • Bleeding may be a severe manifestation of L chain–type amyloidosis or of any of the systemic amyloidoses.
  • Subendothelial deposition leads to capillary fragility and mucocutaneous bleeding.
  • A deficiency in coagulation factor X, resulting from its binding to L chain–type amyloid fibrils, can exacerbate bleeding.
• Neuropathy
  • In approximately 20% of people with L chain–type amyloidosis, deposition occurs in the peripheral nerves, causing sensorimotor peripheral neuropathy. Nerve deposition leads to symmetric sensory impairment and weakness, accompanied at times by painless ulcers similar to those of diabetic neuropathy. Cranial neuropathy is occasionally observed. Autonomic neuropathy may cause severe orthostatic hypotension, diarrhea, or impotence.
  • Patients with familial TTR amyloidosis commonly present with a combination of severe peripheral and autonomic neuropathy. Consider the alternative diagnosis of TTR amyloidosis in a young patient with severe amyloid neuropathy but no other severe organ involvement (see Amyloidosis, Transthyretin-Related and Amyloidosis, Overview).
• Orthostatic hypotension
  • L chain–type amyloidosis and other systemic amyloidoses can lead to severe orthostatic hypotension, to the point of producing syncope and preventing normal activity.
  • Poor cardiac contractility resulting from myocardial deposition, autonomic neuropathy resulting from amyloid deposits in the peripheral nerves, and impaired arteriolar responsiveness resulting from endothelial deposition may contribute to orthostatic hypotension.
  • Treating heart failure or the nephrotic syndrome with diuretics may exacerbate hypotension.
• Hepatosplenomegaly
  • Hepatic and splenic depositions causing hepatomegaly and/or splenomegaly are common and usually asymptomatic.
  • Rarely, spontaneous rupture of the liver or the spleen may present as a surgical emergency.
• Macroglossia
  • Macroglossia is present less frequently at diagnosis than was reported in earlier case series, probably because of earlier diagnosis.
  • When present, macroglossia can become severe enough to interfere with swallowing and breathing.
  • When it occurs, macroglossia highly suggests amyloidosis of the amyloid L-chain type, because this physical finding has apparently been described only in L chain–type amyloidosis and occasionally in β ₂ -microglobulin (B2M) amyloidosis.
• Musculoskeletal system
  • L chain–type amyloidosis deposits in the joints resembling seronegative rheumatoid arthritis may lead to a clinical examination.
  • Deposits in the glenohumeral articulation may cause localized pain and swelling ("shoulder pad" sign), whereas deposits in skeletal muscle may produce pseudohypertrophy.
• Localized L chain–type amyloidosis
  • For unknown reasons, localized L chain–type amyloidosis most commonly occurs in the respiratory tract.
  • Localized pulmonary L chain–type amyloidosis often remains localized (ie, does not progress to systemic disease).
  • Localized L chain–type amyloidosis may involve the ureter or the urinary bladder, causing hematuria.
  • Amyloidomas are often found in the soft tissues, including the mediastinum and the retroperitoneum.
  • Skin involvement can manifest as plaques and nodules.

Causes

No cause is known for any of the monoclonal plasma cell dyscrasias. Some evidence supports an etiologic role for human herpesvirus 8 (HHV-8), but this proposed etiology remains controversial.

Differential Diagnoses

Amyloidosis, AA (Inflammatory)
Amyloidosis, Beta2M (Dialysis-Related)
Amyloidosis, Familial Renal
Amyloidosis, Transthyretin-Related
Monoclonal Gammopathies of Uncertain Origin
Multiple Myeloma

Workup

Laboratory Studies

• Blood and urine tests: Once the diagnosis of L chain–type amyloidosis established (see Procedures), perform laboratory studies to observe for abnormalities, such as abnormal renal function or coagulation, commonly found in L chain–type amyloidosis and to evaluate for possible multiple myeloma.
  • Monoclonal immunoglobulin (serum protein electrophoresis, urine protein electrophoresis, serum and urine protein immunoelectrophoresis)
    • Monoclonal immunoglobulin L chain, the cardinal laboratory finding in L chain–type amyloidosis, is detected on routine clinical laboratory testing in the serum or the urine of 80-90% of patients. This percentage reflects the limit to the sensitivity of routine laboratory testing rather than the biology of L chain–type amyloidosis. Because plasma cells in bone marrow (or occasionally in other sites) synthesize immunoglobulin L chains, which are deposited in various organs, the L chains must travel through the bloodstream. Thus, in theory, if a sufficiently sensitive assay were used, monoclonal serum L chains or L-chain fragments would be detected in all patients.
    • The concentration of normal immunoglobulin is often decreased, such as in multiple myeloma. The combination of hypogammaglobulinemia and proteinuria should suggest a diagnosis of L chain–type amyloidosis or MIDD. In contrast, renal amyloid of the amyloid A type is usually associated with hypergammaglobulinemia related to persistent inflammation and interleukin (IL) 6 production.
    • A study by Dispenzieri et al showed that the absolute value of immunoglobulin free light chain (FLC) as a precursor protein of amyloid is prognostic in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation (PBSCT).⁵ There was a significantly higher risk of death in patients with higher baseline free light chains, and normalization of the free light chain level after PBSCT predicted for both organ response and complete hematologic response.  Blood counts: The complete blood cell count (CBC) is usually unremarkable. Functional asplenism may occur, leading to mild thrombocytosis and Howell-Jolly bodies in the peripheral blood.
  • Absolute lymphocyte count recovery at day 15 (ALC-15) after autologous stem cell transplantation seems to be a powerful prognostic indicator for overall survival and progression-free survival.⁶ An ALC-15 of 500 or greater is associated with significantly improved clinical outcomes.
  • Prothrombin time (PT) and activated partial thromboplastin time (aPTT)
    • Many clotting system abnormalities have been described in L chain–type amyloidosis. Occasionally, coagulopathy and prolongation of the PT or aPTT arise because of the binding of a clotting factor (most often factor X) to the amyloid deposits.
    • Acquired factor X deficiency is difficult to correct because infused factor X is cleared quickly from the circulation. Elevation in tissue and urine plasminogen activators and a decrease in tissue plasminogen activator inhibitor, leading to hyperfibrinolytic states, have also been reported.     
  • Urinary protein: When L chain–type amyloidosis involves the kidneys, proteinuria is invariably present. One third to one half of patients excrete at least 1 gram of protein per day in the urine, predominantly albumin. The 24-hour urinary protein level can be monitored serially to evaluate the response to chemotherapy. Improvement in response to treatment may be associated with a decrease in protein excretion.
  • Liver function studies: Liver function abnormalities are rare, even in cases with massive deposition. Rarely, extensive liver involvement can lead to decreased levels of vitamin K-dependent clotting factors.
  • Renal function studies: Severe azotemia is a late manifestation of renal L chain–type amyloidosis and is less common than proteinuria, although mild elevation of the serum creatinine level (at least 2 mg/dL) is often present.    
• Bone marrow examination: Approximately 40% of patients have more than 10% plasma cells in the bone marrow. L-chain immunophenotyping of the marrow, even in the absence of increased numbers of plasma cells, usually exhibits the distortion in the k:l ratio, reflecting the L-chain type of the amyloid precursor.

Imaging Studies

• Cardiac imaging: Cardiac deposition is the most serious complication of L chain–type amyloidosis. Cardiac involvement should be assessed and monitored by means of imaging studies. No noninvasive test is sufficiently sensitive or specific to definitively diagnose cardiac amyloidosis, although 2-dimensional echocardiography (2-D echo) and electrocardiography (ECG), particularly when combined, can strongly suggest cardiac amyloidosis.
  • Echocardiography
    • The most useful noninvasive diagnostic test for cardiac amyloidosis is echocardiography, which enables the visualization of increased ventricular wall thickness, increased septal thickness, and an appearance of granular "sparkling." This finding is neither sensitive nor specific enough to be diagnostic, but it is highly suggestive when present.
    • L chain–type amyloid deposits in the heart occur in the ventricular interstitium, leading to thickening of the ventricular walls and intraventricular septum without an increase in intracardiac volume. Evaluation of diastolic function by using Doppler echocardiography reveals impaired ventricular relaxation early in the course of disease, which progresses to short deceleration. The ejection fraction is preserved until late in the disease course.Other echocardiographic findings include valvular thickening and insufficiency and atrial enlargement. Atrial thrombosis has also been described. Combining ECG and echocardiography appears to provide the most diagnostic value.
  • Radiolabeled pentagonal (P) component scanning: This test, available only in Great Britain and France as of 2000, is a useful means of evaluating the total body burden of amyloid and is a sensitive, noninvasive means of diagnosing amyloid deposits in most organs. Serial studies are useful for monitoring response to therapy. P component scanning is not useful for diagnosing or monitoring cardiac amyloid, because the concentration of the label in the intracardiac blood pool obscures the weaker signal from the labeled molecule bound to myocardial amyloid.
  • Other cardiac imaging studies: Computed tomography (CT) scanning and nuclear scintigraphy are of less value than ECG and echocardiography.  
• Bone imaging: As in any patient with a plasma cell dyscrasia, patients with L chain–type amyloidosis should have a skeletal survey that includes the skull, the entire spine, and the pelvis. Any bony pain that develops can result from plasma cell infiltration; therefore, obtain radiographs of any area where pain develops.
• Chest radiography: Systemic L chain–type amyloidosis may deposit in any part of the respiratory tree, from the nasopharynx to the pulmonary alveoli. Involvement is often asymptomatic, although alveolar or diffuse interstitial involvement can cause dyspnea. Chest radiographs reveal a reticular nodular pattern or interstitial infiltration.

Other Tests

• ECG: The classic ECG finding is a low-voltage QRS complex in the limb leads, resulting from replacement of normal cardiac tissue by nonconducting amyloid material. In some cases, loss of anterior forces suggests anteroseptal infarction that is not confirmed at autopsy. A variety of arrhythmias are observed and can be life threatening.

Procedures

• Biopsy with Congo red staining and immunostaining
  • Amyloidosis of all types is definitively diagnosed by exhibiting Congo red binding material in a biopsy specimen. For many years, a biopsy of the rectum was the procedure of choice. However, it is known that capillaries in subcutaneous fat are frequently involved. These capillaries can provide sufficient tissue for the diagnosis of amyloidosis, immunostaining, and, in some cases, amino acid sequence analysis. Currently, aspiration of subcutaneous abdominal fat is a simple and fast method for detecting systemic amyloidosis with a sensitivity of 80% that is associated with the use of a routine approach. If the results of fat tissue aspiration are negative, the additional value of a subsequent biopsy of the rectum is negligible.Thus, obtaining a biopsy from the organ with the most severe clinical involvement is not always necessary. However, a biopsy from an organ with impaired function, such as a kidney or the heart, definitively establishes a cause-and-effect relationship between the organ dysfunction and the amyloid deposition.
  • L chain – type amyloid deposition in the peripheral nerves leads to axonal degeneration of the small nerve fibers, which leads to polyneuropathy. The diagnosis can often be made through findings from a biopsy of the sural nerve, although the deposits may be proximal to the sural nerve and, therefore, not found in the biopsy sample.
  • Obtaining a renal biopsy sample is rarely necessary, but findings exhibit deposits in the glomerular mesangium and, later, along the basement membrane.
  • Other potential biopsy sites include the salivary glands, the stomach, and the bone marrow.
  • Avoid obtaining a percutaneous liver biopsy. Such biopsies are contraindicated in the presence of coagulopathy. Severe and even fatal bleeding has occurred in this setting.
  • After Congo red staining is used to establish a diagnosis of amyloidosis, determine the specific type of amyloidosis by immunostaining a biopsy specimen using commercially available, specific antisera against k and l chains.
  • Do not assume that the amyloid is of the L-chain type based on indirect tests, such as serum or urine protein electrophoresis or immunofixation, because monoclonal proteins are common in the elderly population and may be present as incidental findings in patients with other types of amyloidosis.
  • Distinguishing between L chain–type amyloidosis and TTR cardiac amyloidosis on clinical grounds alone is particularly difficult. Without immunologic identification of the deposited protein, an incorrect presumptive diagnosis of L chain–type amyloidosis could lead to ineffective and perhaps harmful treatment.

Histologic Findings

Obtaining a biopsy sample of an affected organ followed by routine hematoxylin and eosin staining reveals homogeneous, interstitial, eosinophilic material. Amyloid material stained with Congo red and viewed under polarized light appears bright green. Specific staining with antibodies against kappa and lambda L chains proves the diagnosis of L chain – type amyloidosis (as opposed to other types of amyloidosis, which have a similar appearance after hematoxylin and eosin or Congo red staining) (see Amyloidosis, Overview).

In MIDD, the immunoglobulin deposits do not bind Congo red stain, they do not contain P component or other components of amyloid fibrils, and (unlike in amyloidosis) they are not fibrillar. MIDD occurs most frequently in the kidneys and the heart. Nodular glomerulosclerosis observed on routine histologic examination in the absence of diabetes mellitus suggests MIDD. The pathologic diagnosis of nonamyloid MIDD depends on the identification of immunoglobulin deposits in tissues via immunostaining. MIDD may be underdiagnosed because immunostaining is not routinely performed.

The clinical pathologic feature and diagnostic criteria of tongue amyloidosis is important. Twenty-five patients were pathologically diagnosed as tongue amyloidosis, although none had an enlarged tongue.⁷ Hematoxylin and eosin and immunohistochemical staining were employed to detect the amyloid deposition on the tongue, with amyloid depositions in the basement membrane, muscle cell, vessel wall, and nerve fiber.

Immunohistochemical study demonstrated kappa light-chain deposition in 64% of cases, and lambda light-chain deposition in 36% of them.⁷ Thus, biopsy is an important means for the diagnosis of early tongue L chain – type amyloidosis, and the wide variety of amyloid light chains is helpful in the differential diagnosis (see Differential Diagnoses).

Treatment

Medical Care

Standard treatment of L chain–type amyloidosis aims to reduce production of the monoclonal immunoglobulin precursor via chemotherapy or, occasionally, via radiation therapy or surgery of a localized amyloidogenic plasmacytoma. Experimental drugs that bind to amyloid fibrils, leading to their resorption, are also being studied. Supportive therapy to maintain organ function is equally important.

• Chemotherapy: Chemotherapy is based on the principle that, as in myeloma, proliferation of a plasma cell clone causes L chain–type amyloidosis. Regimens most likely to benefit patients with this disease are the same as those that are useful for myeloma (ie, melphalan, prednisone).
  • Many more studies have been published on the treatment of myeloma than that of L chain–type amyloidosis, because myeloma is more common, and the response to therapy can be more easily monitored. In myeloma, the level of serum or urine monoclonal protein usually serves as a quantitative marker of tumor burden. In L chain–type amyloidosis, determining the response to therapy is difficult and requires indirect measurements of end-organ damage, serial biopsies, or serial P component scans when available.
  • After melphalan and prednisone were demonstrated to be useful for myeloma, the regimen was tried for L chain–type amyloidosis. The first 2 randomized studies of melphalan and prednisone versus placebo or colchicine suggested a value to chemotherapy but did not reach statistical significance for improved survival.
  • In the mid 1990s, 2 randomized placebo-controlled trials demonstrated a statistically significant survival benefit of melphalan and prednisone compared with colchicine. The colchicine arm in these trials essentially served as a placebo group, because colchicine is now known to be ineffective for L chain–type amyloidosis and is no longer used.
    • Patients in 1 trial were randomized to 1 of 3 arms (melphalan and prednisone; melphalan, prednisone, and colchicine; or colchicine alone).⁸ The median survival rate was greater in patients in the melphalan, prednisone, and colchicine arm (18 mo) and those in the melphalan and prednisone (17 mo) arm than patients in the colchicine-alone arm (8.5 mo).⁸
    • In another trial, 100 patients were randomized to receive either oral melphalan, prednisone, and colchicine or colchicine alone.⁹ The overall survival rate for the melphalan, prednisone, and colchicine group was 12.2 months compared with 6.7 months for the colchicine-alone group. This difference did not quite reach statistical significance (P = 0.087), reflecting the small sample size and several early deaths of patients with severe disease in both treatment groups. In addition, several patients did not receive the intended chemotherapy or were crossed over to chemotherapy by their physicians (analysis was performed on an intent-to-treat basis).⁹
    • Taken together, these studies demonstrate a survival benefit of melphalan and prednisone compared with placebo in L chain–type amyloidosis.
  • Patients whose conditions are most likely to respond to chemotherapy with objective improvement in end-organ damage are those with renal involvement and nephrotic syndrome. Approximately 25% of this group has at least a 50% decrease in proteinuria, with most of these patients experiencing complete resolution of proteinuria. Improvement can occur in nearly any organ, but improvement in L chain–type amyloidosis neuropathy is rare.
  • Other chemotherapeutic regimens used for multiple myeloma are also expected to benefit patients with L chain–type amyloidosis and are reasonable therapeutic options for this disease. In one randomized study, melphalan and prednisone use was compared with a 5-drug myeloma regimen (vincristine, carmustine, melphalan, cyclophosphamide, prednisone).¹⁰ Response rates and survival did not differ between the 2 groups. In a phase II trial, high-dose dexamethasone also produced occasional objective organ responses, including responses in some patients who had received previous chemotherapy. Many experts consider melphalan plus prednisone to be standard therapy for L chain–type amyloidosis for patients not enrolled in a clinical trial, and it is the only regimen that has been shown to prolong survival compared with no chemotherapy. No regimen has been shown in a randomized trial to be superior to melphalan plus prednisone.
  • Duration of initial chemotherapy and potential adverse effects are as follows:
    • No data indicate the optimal treatment duration in patients whose conditions respond to chemotherapy. In patients in whom a response occurs with objective improvement in organ function and in whom toxicity does not develop, chemotherapy is usually continued for 1-2 years.
    • When the disease initially responds and then progresses off treatment, chemotherapy, whether the same or a different regimen, can be resumed. Little information exists regarding whether any maintenance therapy, such as alpha interferon, is useful, again mirroring the situation in myeloma.
    • When contemplating the duration of therapy, keep in mind the leukemogenic potential of melphalan. The actuarial risk of acute myelogenous leukemia (AML) in 1 study of patients with myeloma treated with melphalan was 17% at 50 months. In 2 studies of patients with L chain–type amyloidosis treated with melphalan-containing regimens, 5% of patients developed myelodysplasia within 3 years of treatment. Some patients' conditions progressed to AML.
  • During the past decade, understanding of the molecular and cellular pathophysiology of myeloma has improved significantly, allowing identification of novel molecular pathways and targeting development of several new therapeutic possibilities. Among these, thalidomide has been the first antiangiogenetic drug effectively adopted initially in refractory-relapsed patients and then as first-line treatment with better results respect to vincristine/doxorubicin/dexamethasone (VAD) or VAD-like regimens. Inhibitors of proteasome, such as bortezomib, and other immunomodulatory agents, such as lenalidomide, have been also studied more recently in myeloma patients.
• In 2003, bortezomib became the first proteasome inhibitor approved for the treatment of relapsed myeloma. Inhibition of proteasome activity appears to have greater cytotoxicity in malignant cells than in normal cells. Two phases II studies confirmed the efficacy of bortezomib in patients with relapsed/refractory myeloma.^11,12 In the first study, 10% of patients exhibited a complete/almost complete response; 18%, a partial response; and 7%, a minimal response. The median time to disease progression was 13 months for complete and partial responses. 72 patients who did not attain at least a minimal response were given dexamethasone in combination with bortezomib; 18 demonstrated some response. Phase III studies have confirmed the superiority of bortezomib compared with dexamethasone.
• Bortezomib has been investigated in a number of combination regimens (eg VMPT [bortezomib/melphalan/prednisone/thalidomide]; bortezomib and pegylated liposomal doxorubicin; bortezomib with corticosteroids, etc). In a phase II study, bortezomib with dexamethasone was compared with a standard-dose VAD regimen in patients with newly diagnosed myeloma.¹³ Complete response (20%) and objective response rate (82%) were higher in the bortezomib group than in the group that received standard-dose VAD (complete response, 9%; objective response rate, 67%).
• Several bortezomib-containing combinations are now being evaluated as induction therapy before high-dose therapy with autologous stem cell transplantation. The outcomes are sumarized in Table I, below. 

• Drug resistance to bortezomib, probably related to heat-shock high protein expression led to the development of second-generation proteasome inhibitors (eg, salinosporamide A).
• The immunomodulatory drugs   thalidomide, lenalidomide and carfilzomib affect myeloma through pleiotropic effects. Twenty-five to thirty percent of patients exhibit at least a partial response when these agents are given as monotherapy. In combination with other drugs (dexamethasone, cyclophosphamide, melphalan), the response rate is considerably higher.
• In a phase III study, thalidomide plus dexamethasone produced a significant improvement in the overall response rate (63%) compared with dexamethasone alone (41%; P = 0.0017).
• Combination melphalan/prednisone/thalidomide (MPT) therapy has been demonstrated to have superiority over melphalan/prednisone (MP) alone. The MPT regimen has become one of the standard therapeutic combinations for elderly patients with myeloma.
• Phase I and II studies in relapsed/refractory myeloma have confirmed a 29% partial response rate with lenalidomide. Similarly, a phase III trial confirmed the superiority of combination lenalidomide/dexamethasone therapy (complete response, 12,9%; objective response rate, 59%) versus dexamethasone alone (complete response, 0,6%; objective response rate 21%) (P <0.001). These results led to the approval of lenalidomide as a second-line therapy for multiple myeloma.
• Lenalidomide has also been investigated as first-line combination therapy for myeloma. In a phase II trial, 91% of patients exhibited at least a partial response, with 32% exhibiting a complete or almost complete response.
• Thalidomide and lenalidomide are also being evaluated as maintenance therapy after autologous transplantation.
• Carfilzomib is a structurally and mechanistically novel proteasome inhibitor that exhibits a high level of selectivity for the unique N-terminal threonine active sites within the proteasome. Carfilzomib is similar to bortezomib in that it is a potent inhibitor of the proteasome chymotrypsinlike activity; but, unlike bortezomib, carfilzomib has shown minimal cross-reactivity with the other catalytic sites within the proteasome or across other protease classes. Phase 1 clinical studies confirmed that patients whose condition has relapsed or progressed following multiple therapies can still achieve durable antitumor responses with carfilzomib. In addition to the two phase 2 single-agent trials in myeloma and ongoing studies in lymphoma, a clinical trial in solid tumors and a trial exploring carfilzomib in combination with a Federal Drug Administration (FDA)-approved agent is pending.
• In the past few years, a number of agents have been developed to target specific aspects of myeloma cell biology. Major strategies are disruption of molecular pathways of myeloma cell growth and impairment of the drug-resistance mechanism. These agents target myeloma cells and the microenvironment. Among these agents, many of which are in early phases of clinical trials in relapsed myeloma, the most important include the following:
  • Inhibitors of the PI3KI/Akt/mTOR pathway: Perifosine  
  • Inhibitors of the heat-shock protein 90: Tanespimycin
  • Mitogen-activated protein kinase (MAPK) and farnesyl transferase inhibitors: Tipifarnib, lonafarnib
  • Histone deacetylase inhibitors: Vorinostat, desipeptide, valproic acid
  • Inhibitors of vascular-endothelial growth factor (VEGF): Bevacizumab and others
  • Inhibitors of p38 mitogen-activated protein kinase
  • Targeting cell surface molecules
• High-dose chemotherapy followed by stem cell or autologous bone marrow rescue is as follows:
  • In both L chain–type amyloidosis and myeloma, standard dose regimens rarely, if ever, completely eradicate the plasma cell clone. Therefore, high-dose chemotherapy followed by autologous bone marrow or peripheral blood stem cell rescue has been studied in selected patients. Similar to standard dose regimens, studies of high-dose therapy for myeloma predate similar studies for L chain–type amyloidosis, and more data are available on myeloma.
  • In myeloma, several phase II trials of high-dose chemotherapy in selected patients have demonstrated favorable responses and survival rates compared with historical controls. One phase III trial randomized patients younger than 65 years to either a standard dose, 6-drug regimen or high-dose therapy (4-6 cycles of the same 6-drug regimen, followed by 140 mg/m² of melphalan and total body irradiation) with autologous bone marrow transplantation. This trial found a 5-year survival benefit for high-dose therapy. However, even in myeloma, indications for high-dose therapy remain controversial; no consensus exists about which patients should be offered high-dose therapy with rescue.
  • In L chain–type amyloidosis, the indication for high-dose chemotherapy is even less established. Several centers have reported phase II trials of high-dose chemotherapy, followed by rescue with autologous bone marrow or peripheral blood stem cells. In one highly selected group of patients (median age 48 y; patients with severely impaired cardiac, pulmonary, or renal function were excluded), 11 (65%) of 17 patients exhibited a response, as assessed by objective improvement in end-organ function. Based on these data, high-dose chemotherapy regimens have become the recommended therapy in some centers for patients who are deemed able to tolerate the conditioning regimen.
  • In early studies of high-dose therapy with peripheral blood stem cell rescue, patients with severe cardiac involvement experienced very high early mortality. This complication is attributed to intolerance of fluid shifts that occur with peripheral blood stem cell harvesting. Therefore, patients with severe cardiac involvement are now generally deemed ineligible for high-dose chemotherapy. Another concern with high-dose therapy followed by stem cell rescue is that the autologous stem cells collected for reinfusion generally contain the clonal cells that produce the amyloidogenic L chain.
  • Diseases in which high-dose chemotherapy has the most significant impact are those in which the malignant cell population is dividing rapidly. However, this criterion does not apply to L chain–type amyloidosis. Until standard-dose chemotherapy is compared with high-dose chemotherapy with rescue in a phase III randomized trial, deciding which therapy to use in individual patients will remain difficult and controversial.
  • The place of allogeneic stem cell transplantation in the management of myeloma remains controversial. Although it may induce long-term clinical and molecular remissions, high transplant-related toxicity after myeloablative preparative regimens has limited the role of allogeneic stem cell transplantation as first-line treatment. Moreover, the toxicity related to infections and to graft versus host disease (GVHD) is very high. As a consequence of this toxicity, allogeneic stem cell transplantation could not be proposed for those older than 50-55 years, whereas the median age at diagnosis was over 65 years. Some reduced-intensity conditioning regimens (including the addition of immunosuppressive agents as ciclosporine A, mycophenolate mofetil, tacrolimus) were developed.Allogeneic stem cell transplantation should be considered for patients with chemosensitive disease and a low tumor burden, which can be obtained after high-dose chemotherapy plus autologous stem cell transplantation. Results of ongoing trials will determine the place of these remedies related to the introduction of the novel therapeutic agents listed above.
• Pharmacologic therapy to solubilize amyloid fibrils
  • An anthracycline analogue of doxorubicin, 4'-iodo-4'-deoxydoxorubicin (Idox), is the first small molecule found with in vivo activity to solubilize L chain–type amyloid deposits. The antiamyloid activity of Idox was discovered fortuitously when the analogue was being studied as a chemotherapeutic agent in multiple myeloma. A patient with myeloma and L chain–type amyloidosis excreted L chains into the urine and improved symptomatically within days. Idox was then demonstrated to bind to amyloid fibrils, although the parent compound, doxorubicin, does not.
  • The ideal use of small molecule amyloid inhibitors, such as Idox, likely lies in combination with cytotoxic chemotherapy, both to decrease clonal L-chain production and to mobilize deposited L chains. Other small molecules that bind to amyloid fibrils of the L chain–type amyloidosis and other types of amyloidosis are under investigation.
• Treatment of localized amyloid L-chain type 
  • Treatment of localized L chain–type amyloidosis (most often found in the pulmonary tract or the genitourinary tract) has not been studied systematically. Because progression to systemic disease does not occur often, treatment with chemotherapy is not indicated.
  • Localized radiation therapy aimed at destroying the local collection of plasma cells producing the L chain–type amyloid can be administered when a plasma cell collection can be identified.
  • Local collections of L chain–type amyloid in the genitourinary tract, even in the absence of an identified clonal plasma cell collection, can cause hematuria. In these patients, surgical resection of amyloidomas may be required to control the bleeding.
• Supportive care
  • Treatment of cardiac involvement is as follows:
    • Diuretics are the mainstay of therapy for L chain–type amyloid–related congestive heart failure. The optimal degree of diuresis is often difficult to judge. When edema is troubling and symptomatic postural hypotension is not present, fluid can be removed with careful diuresis. Conversely, hypotension resulting from a low ejection fraction, autonomic neuropathy, or both may limit diuretic use.
    • Digoxin and calcium channel blockers are contraindicated in cardiac amyloidosis because these agents bind to amyloid fibrils, which may worsen heart failure and produce arrhythmias. Pacemakers are of use in some patients with symptomatic bradycardia.
  • Treatment of renal involvement is as follows:
    • Hemodialysis and peritoneal dialysis can stabilize the course of patients with extensive kidney involvement.
    • Hemodialysis should be offered to patients developing renal failure.

Surgical Care

• Carpal tunnel release
• Involvement of the carpal ligament is observed not only in L chain–type amyloidosis but also in B2M amyloidosis in patients undergoing dialysis and in patients with TTR amyloidosis (see Amyloidosis, Overview and Amyloidosis, Transthyretin-Related).
• Treatment is surgical. At the time of carpal tunnel release, perform a biopsy if a definitive diagnosis has not been established, so that both Congo red staining and immunostaining can be performed. Why the carpal ligament is a favored location for amyloid deposition remains unknown.
• Organ transplantation: No randomized trials about organ transplantation in L chain–type amyloidosis are available to guide the decision-making process, but patients have received heart or kidney transplants.
• Cardiac transplantatio
• A few patients with L chain–type amyloidosis have received heart transplants. This therapy may be life saving for patients with severe disease, but, in the absence of effective systemic therapy to eliminate production of the amyloidogenic L chain, amyloidosis can recur in the transplanted organ.
• For young patients with severe cardiac involvement, cardiac transplantation followed by high-dose chemotherapy and autologous stem cell or autologous bone marrow reinfusion has occasionally been considered.
• Renal transplantation
• Renal transplantation has been reported often in patients with amyloidosis, but most such cases have not been of the L chain–type amyloidosis.
• Because L chain–type amyloidosis is generally a systemic disease and hemodialysis is generally effective and available, renal transplantation is rarely indicated in L chain–type amyloidosis, except perhaps in the occasional patient whose condition has had particularly good responses to chemotherapy and in whom long-term survival may be expected.
• Percutaneous cementoplasty
• A study by Tran Thang et al confirmed the beneficial effect of percutaneous cementoplasty on bone pain and functional improvement.¹⁹

Consultations

A hematology and/or oncology, cardiology, nephrology, or other subspecialty consultation may be indicated, depending on the disease's organ involvement.

Diet

No known diet changes affect L chain–type amyloidosis directly. Patients with nephrotic syndrome, renal failure, or congestive heart failure arising from L chain–type amyloidosis should receive appropriate dietary treatment for those conditions.

Medication

Melphalan plus prednisone is considered standard therapy for L chain–type amyloidosis, with any myeloma regimen offering a reasonable therapeutic choice.

An anthracycline analogue of 4'-iodo-4'-deoxydoxorubicin is the first small molecule found with in vivo activity to solubilize L chain–type amyloid deposits. The antiamyloid activity of 4'-iodo-4'-deoxydoxorubicin was discovered fortuitously when it was being evaluated as a chemotherapy agent in multiple myeloma. A patient with myeloma and L chain–type amyloidosis excreted L chains into the urine and improved symptomatically within days. 4'-Iodo-4'-deoxydoxorubicin was then demonstrated to bind to amyloid fibrils, although the parent compound, doxorubicin, does not.

Five of 8 patients in the first pilot trial of 4'-iodo-4'-deoxydoxorubicin responded with clinical improvement unrelated to any cytotoxic effect on the plasma cell clone.²⁰ From 1995 to 1997, 4'-iodo-4'-deoxydoxorubicin was administered to another 42 patients in Europe. Of the 42 patients, 13 had disease responses and 15 demonstrated stabilized disease. However, the clinical responses were transient, and the disease typically progressed after a period of months. From 1999 to 2000, 4'-iodo-4'-deoxydoxorubicin was studied for treatment of  L chain–type amyloidosis in a phase II trial at 2 US centers. Results from this trial are not yet available.

The ideal use of small molecule amyloid inhibitors, such as 4'-iodo-4'-deoxydoxorubicin, likely lies in combination with cytotoxic chemotherapy, both to decrease clonal L-chain production and to mobilize deposited L chains. Various small molecules that bind to amyloid fibrils of the L chain – type amyloid and other types are under investigation.

Diuretics are the mainstay of therapy for L chain – type amyloidosis – related congestive heart failure. The optimal degree of diuresis is often difficult to judge. When edema is troubling and symptomatic postural hypotension is not present, fluid can be removed with careful diuresis. Conversely, hypotension resulting from a low ejection fraction and/or autonomic neuropathy may limit diuretic use.

Digoxin and calcium channel blockers are contraindicated in cardiac amyloidosis, because these agents bind to amyloid fibrils, which may worsen heart failure and produce arrhythmias.

Immunosuppressive Agents

Two slightly different regimens of melphalan and prednisone have been used in 2 large studies. Either regimen can be used to treat this condition.

Melphalan (Alkeran) and prednisone (Deltasone, Orasone, Meticorten)

Melphalan reduces clonal plasma cell population. Inhibits mitosis by cross-linking DNA strands. Individual tolerance to melphalan varies. Adjust dosage after the first cycle, based on the degree of cytopenia in the previous cycles. Nadir counts appear 2-3 wk following administration. Should be taken on an empty stomach. Prednisone reduces clonal plasma cell population.

Dosing

Adult

2 regimens have been studied:

Regimen 1 (Mayo Clinic): 0.15 mg/kg melphalan PO plus 0.8 mg/kg prednisone PO qd for 7 d; increase melphalan dose by 2 mg in each 6-wk cycle until midcycle leukopenia or thrombocytopenia develops; repeat cycle q6wk for 2 y or until serious toxicity develops

Regimen 2 (Boston University): 0.15 mg/kg melphalan PO plus 1.5 mg/kg prednisone PO qd for 4 d; repeat cycle q6wk for 1 y; increase melphalan dose by 2 mg in each 6-wk cycle until leukopenia or thrombocytopenia develops (not to exceed 0.25 mg/kg/dose); limit total melphalan dose over entire treatment regimen to 600 mg

Pediatric

Not established

Interactions

Concurrent administration of melphalan with cyclosporine increases nephrotoxicity; cimetidine and H2 antagonists increase gastric pH, decreasing effects of melphalan; coadministration of prednisone with estrogens may decrease prednisone clearance; concurrent use of prednisone with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase the metabolism of glucocorticoids (consider increasing the maintenance dose); monitor for hypokalemia with the coadministration of diuretics.

Contraindications

Documented hypersensitivity; severe bone marrow depression; viral, fungal, connective tissue, or tubercular skin infections; peptic ulcer disease; hepatic dysfunction; GI disease

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Amenorrhea may occur; caution in patients with previously diagnosed myelosuppression; perform CBC count before each treatment course and 2-3 wk after beginning treatment in the first cycle and selected cycles thereafter to monitor nadir counts; if severe thrombocytopenia or leukopenia develops, delay the next cycle or reduce the dose; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, and infections may occur with glucocorticoid use.

Antineoplastic Agent, Proteasome Inhibitor

Proteasome inhibitors are antineoplastic agents that inhibit cell growth and proliferation.

Bortezomib (Velcade)

First drug approved of anticancer agents known as proteasome inhibitors. The proteasome pathway is an enzyme complex existing in all cells. This complex degrades ubiquitinated proteins that control the cell cycle and cellular processes and maintains cellular homeostasis. Reversible proteasome inhibition disrupts pathways supporting cell growth, thus decreases cancer cell survival.

Dosing

Adult

1.3 mg/m² IV bolus 2 times/wk for 2 wk (ie, days 1, 4, 8, and 11); rest for 10 d (ie, days 12-21), then repeat cycle

Pediatric

Not established

Interactions

Substrate of CYP450 isoenzymes 1A2, 2C9, 2C19, 2D6, and 3A4; may inhibit CYP450 2C19, therefore caution with coadministration of isoenzyme 2C19 substrates (eg, barbiturates, phenytoin, valproic acid, imipramine, lansoprazole, warfarin)

Contraindications

Documented hypersensitivity to bortezomib, boron, or mannitol

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Common adverse effects include nausea, fatigue, diarrhea, constipation, headache, decreased appetite, thrombocytopenia, anemia, fever, vomiting, or peripheral neuropathy (modify the dose if neuropathy occurs); may cause hypotension; caution in patients with hepatic impairment; at least 72 h should elapse between each dose

Immunosuppressant Agents

Immunosuppressant agents may suppress the production of factors that mediate immune reactions.

Thalidomide (Thalomid)

Immunomodulatory agent that may suppress excessive production of tumor necrosis factor-alpha (ie, TNF-alpha) and may downregulate selected cell-surface adhesion molecules involved in leukocyte migration. Because of concerns regarding teratogenicity, thalidomide can only be prescribed by registered physicians and dispensed by registered pharmacists. Patients must participate in ongoing surveys to receive therapy, and only a 28-day supply can be prescribed at a time. Indicated in conjunction with dexamethasone to treat newly diagnosed multiple myeloma.

Dosing

Adult

200 mg PO qhs; administer at least 1 h pc

Pediatric

Not established

Interactions

May increase sedation of alcohol, barbiturates, chlorpromazine, and reserpine

Contraindications

Documented hypersensitivity; sexually active males not using latex condom (risk to the fetus from the semen of patients taking thalidomide is unknown), women of childbearing potential not using 2 forms of contraception

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Perform pregnancy test within 24-h period before initiating therapy (weekly during the first month, followed by monthly tests in women with regular menstrual cycles or q2wk in those with irregular menstrual cycles); bradycardia may occur; decrease the dose or temporarily discontinue if constipation, oversedation, or peripheral neuropathy occur; use protective measures (eg, sunscreens, protective clothing) against exposure to sunlight or UV light (eg, tanning beds); prescribing physician must register with the "System for Thalomid Education and Prescribing Safety" (STEPS) program established by the manufacturer.

Lenalidomide (Revlimid)

Indicated for transfusion-dependent MDS subtype of deletion 5q cytogenetic abnormality. Structurally similar to thalidomide. Elicits immunomodulatory and antiangiogenic properties. Inhibits proinflammatory cytokine secretion and increases anti-inflammatory cytokines from peripheral blood mononuclear cells.

Dosing

Adult

10 mg PO qd initially; dose adjustment required if renal impairment, thrombocytopenia, or neutropenia occurs

Pediatric

<18 years: Not established

>18 years: Administer as in adults.

Interactions

Data limited; none reported

Contraindications

Documented hypersensitivity; pregnancy

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Available only through RevAssist, a risk-management plan to prevent fetal exposure; only pharmacists and prescribers registered with the program may prescribe and dispense (program requires mandatory pregnancy testing and limits prescription to 1-mo supply via mail); male patients, including those with vasectomy, must use latex condom during sexual contact with a female of childbearing potential; women must not become pregnant 4 wk before starting lenalidomide and 4 wk after discontinuing lenalidomide; may cause anemia, DVT, pulmonary embolism, thrombocytopenia, neutropenia, diarrhea, pruritus, rash, and fatigue; renal excretion is substantial: caution in elderly patients or those with renal impairment (may need to decrease the dose); do not break, chew, or open capsules

Follow-up

Further Outpatient Care

• A hematologist with experience in administering chemotherapy should care for patients with L chain–type amyloidosis on an ongoing basis.

Complications

• Complications of L chain–type amyloidosis reflect the organ systems involved.
• The most severe complication of systemic L chain–type amyloidosis is extensive cardiac deposition, with consequent congestive heart failure, arrhythmias, or both.
• Cardiac involvement eventually occurs in most patients and appears to be the cause of death in more than 50% of patients with L chain–type amyloidosis.

Prognosis

• The prognosis for patients with L chain–type amyloidosis depends largely on the specificity of the tissue deposition. Any organ can be involved, with symptoms and physical findings reflecting the pattern of anatomic compromise.
• Patients with clinical cardiac involvement have the worst prognosis, with a median survival rate of 6 months. Patients with involvement limited to the peripheral nerves have the longest survival. Other favorable prognostic features include a small number of clonal plasma cells in the bone marrow and normal renal function.
• In the absence of chemotherapy, systemic L chain–type amyloidosis is always progressive. A subgroup of cases respond to chemotherapy with temporary resorption of amyloid fibrils and improvement of end-organ function.

Miscellaneous

Medicolegal Pitfalls

• The physician must be certain that the type of amyloidosis has been determined definitively. Patients with other types of amyloidosis can present with symptoms similar to L chain–type amyloidosis; they should not receive chemotherapy. (See Amyloidosis, Overview for a full discussion.)

Multimedia

Media file 1: The relationship among light chain–type amyloidosis (AL), the other monoclonal plasma cell disorders, and the other amyloidoses. Ig = immunoglobulin; MGUS = monoclonal gammopathy of undetermined significance.

References

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Keywords

immunoglobulin-related amyloidosis, amyloidosis, immunoglobulin, AL, light chain amyloidosis, primary amyloidosis, primary systemic amyloidosis, myeloma-associated amyloidosis, Ig-related amyloidosis, monoclonal plasma cell dyscrasias, monoclonal plasma cell disorder, amyloid deposits, amyloid L chain type, multiple myeloma, monoclonal gammopathy of undetermined significance, MGUS, nonamyloid monoclonal immunoglobulin deposition disease, MIDD, lymphoproliferative disorders

Contributor Information and Disclosures

Author

Slavomir Urbancek, MD, PhD, Head, Department of Dermatology, FD Roosevelt Hospital, Slovakia; Scientific Secretary, Slovak Dermatovenereological Society
Slavomir Urbancek, MD, PhD is a member of the following medical societies: American Academy of Dermatology, European Academy of Dermatology and Venereology, Slovak Dermatovenereological Society, and Slovak Society of Allergology and Clinical Immunology
Disclosure: Nothing to disclose.

Coauthor(s)

Pere Gascon, MD, PhD, Professor and Director, Division of Medical Oncology, Institute of Hematology and Medical Oncology, IDIBAPS, University of Barcelona Faculty of Medicine, Spain
Pere Gascon, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, New York Academy of Medicine, New York Academy of Sciences, and Sigma Xi
Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Daniel R Jacobson, MD, Professor of Medicine, Boston University School of Medicine; Chief of Oncology, Veterans Affairs Boston Healthcare System
Disclosure: Nothing to disclose.

Joel Buxbaum, MD, Professor, Department of Molecular and Experimental Medicine, The Scripps Research Institute
Joel Buxbaum, MD is a member of the following medical societies: American Society for Clinical Investigation, American Society of Human Genetics, and Association of American Physicians
Disclosure: Nothing to disclose.

Carol A Bogdan, MD, Consulting Staff, Coastal Cancer Center, Myrtle Beach, SC
Disclosure: Nothing to disclose.

Medical Editor

Robert E Wolf, MD, PhD, Professor Emeritus, Department of Medicine, Louisiana State University Health Sciences Center at Shreveport; Chief, Rheumatology Section, Medical Service, Overton Brooks Veterans Administration Medical Center of Shreveport
Robert E Wolf, MD, PhD is a member of the following medical societies: American College of Rheumatology, Arthritis Foundation, and Society for Leukocyte Biology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Lawrence H Brent, MD, Associate Professor of Medicine, Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center
Lawrence H Brent, MD is a member of the following medical societies: American Association of Immunologists, American College of Physicians, and American College of Rheumatology
Disclosure: Genentech Honoraria Speaking and teaching; Genentech Grant/research funds Other; Amgen Honoraria Speaking and teaching; Wyeth Honoraria Speaking and teaching; Abbott Immunology Honoraria Speaking and teaching

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

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