Immunoglobulin-Related Amyloidosis

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 Vl 6 class are the most amyloidogenic. Clonal plasma cell proliferative diseases in which the Vl 6 gene is expressed are always associated with amyloid deposition. Among Vk genes, the Vk 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 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, in most patients, both. 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.[1]

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. Other suggested risk factors include genetic predisposition, environmental or occupational exposures, and chronic inflammation.

United States

Annually, one to five cases of immunoglobulin-related amyloidosis per 100,000 people occur. The best available direct data on the frequency of L chain–type amyloidosis in the United States come from Olmsted County, Minnesota, where the incidence rate of L chain–type amyloidosis was calculated to be 1.2 per 100,000 person-years.[2] The population in this location is primarily of northern European ancestry. Whether this finding applies to different populations is not known.

Based on indirect calculations, the frequency may be higher. The annual incidence of multiple myeloma is approximately five 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 one in five patients with L chain–type amyloidosis has frank myeloma; therefore, the total number of patients with L chain–type amyloidosis type is five times the number of patients with L chain–type amyloidosis and myeloma, or at least five cases per 100,000 people.

International

The international incidence of amyloidosis is not well documented, but has been estimated at 5 to 13 cases per million population per year. L chain–type amyloidosis is the most prevalent type, accounting for 65% of cases in the United Kingdom and 93% of cases in China.[3]   

Race-, Sex-, and Age-related Demographics

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

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

The median age at diagnosis of immunoglobulin-related amyloidosis in the largest published series (from the Mayo Clinic) was 64 years.[4]

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. 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, and is the most common cause of death in those patients.

Patients with clinical cardiac involvement have the worst prognosis, with a median survival rate of 6 months. In these patients, increased troponin is associated with worse left ventricular and left atrial functions. Increased troponin at baseline strongly predicts all-cause mortality.[5]

Median overall survival was 29 months in a retrospective study of 63 patients with L chain–type amyloidosis, of whom 32 (51%) presented with cardiac amyloid involvement. Overall survival did not differ between patients with or without cardiac involvement. During a median follow-up of 12.7 months, 38 (60%) patients died.[6]

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 kidney 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.

In a retrospective study of 146 patients with L chain–type amyloidosis that relapsed after treatment with chemotherapy and autologous stem cell transplant, median overall survival and 5-year overall survival from the time of post-transplant relapse were 51.7 months and 39%, respectively.[7]

In a single-institution review of 1551 patients with newly diagnosed AL amyloidosis seen from 2000 to 2014, Muchtar et al reported that overall, outcomes in these patients improved over that period, with earlier diagnosis, higher rates of very good partial response, lower early mortality, and improved overall survival. Four-year overall survival in the autologous stem cell transplant (ASCT) population showed the greatest gains after 2010, rising to 91% from 65%. In the non-ASCT group the greatest gains were after 2005, rising to 38% from 16%.[8]

The most common presenting signs and symptoms of immunoglobulin-related amyloidosis are nonspecific and include weakness and weight loss followed by purpura, particularly in loose facial tissue. 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.

In a case series of 24 patients with periocular and orbital amyloidosis,[9] clinical features included the following:

• 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%)
• Diplopia (8.3%) 

The kidneys are the most frequent site of deposition, with nephrotic syndrome being common; therefore, complaints of peripheral edema are common. Patients can present with kidney failure.

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 may also occur. 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 is typical, but may not be clinically evident. 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.[10]

Carpal tunnel syndrome may be part of the presentation. Approximately 20% of patients with L chain–type amyloidosis initially report weakness and paresthesia of one or both hands, suggesting carpal ligament involvement.

The most common initial physical findings in individuals with immunoglobulin-related amyloidosis include the following:

• Peripheral edema
• Orthostatic hypotension
• Purpura
• Peripheral neuropathy
• Carpal tunnel syndrome
• Hepatomegaly
• 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.

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.

Cardiac amyloidosis can also result in arrhythmias, including the following:

• Heart block
• Premature ventricular contractions
• Tachyarrhythmias

Purpura and ecchymosis

Bleeding may be a severe manifestation of L chain–type amyloidosis or of any of the systemic amyloidoses. Subendothelial deposition in these disorders 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 persons 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 erectile dysunction.

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 Transthyretin-Related Amyloidosis and Amyloidosis).

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. Macroglossia has apparently been described only in L chain–type and, occasionally, β2-microglobulin (B2M) amyloidosis.

Musculoskeletal manifestations

L chain–type amyloidosis deposits in the joints can produce a clinical picture resembling seronegative rheumatoid arthritis. 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. It may also 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. Localized pulmonary L chain–type amyloidosis often remains localized (ie, does not progress to systemic disease).

Once the diagnosis of L chain–type amyloidosis has been established (see Biopsy), the clinician should perform laboratory studies to observe for abnormalities that are commonly found in these patients (eg, impairment in kidney function or coagulation) and to evaluate for possible multiple myeloma.

Tests for monoclonal immunoglobulin

Monoclonal immunoglobulin L chain, the cardinal laboratory finding in L chain–type amyloidosis, is detected by electrophoresis or immunoelectrophoresis 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.

Overall survival is related to the free monoclonal light-chain concentration in the serum, independent of other risk factors, with higher concentrations associated with shorter survival.[11]

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 monoclonal immunoglobulin deposition disease (MIDD). In contrast, renal amyloid of the amyloid A type is usually associated with hypergammaglobulinemia related to persistent inflammation and interleukin-6 (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).[12] Risk of death was significantly higher 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.[13] An ALC-15 of 500 or greater is associated with significantly improved clinical outcomes.

Coagulation studies

Many clotting system abnormalities have been described in L chain–type amyloidosis. Occasionally, coagulopathy and prolongation of the prothrombin time (PT) and activated partial thromboplastin time (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. A decrease in protein excretion may be associated with improvement in response to treatment.

Liver and kidney 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.

On kidney function studies, severe azotemia is a late manifestation of renal L chain–type amyloidosis and is less common than proteinuria. However, 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.

Paiva et al reported that the use of multiparameter flow cytometry immunophenotyping to demonstrate plasma cell clonality in patients with amyloid-positive tissue staining could help in the differentiation of light chain amyloidosis from other forms of amyloidosis, and that the quantitative distribution of monoclonal and normal plasma cell populations may be useful in establishing the prognosis of individual patients with respect to overall survival.[14] However, the report did not specifically evaluate responses to therapy in general or any specific treatment. This kind of prognostic information requires a much larger patient cohort.

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 two-dimensional echocardiography (2-D echo) and electrocardiography (ECG), particularly when combined, can strongly suggest cardiac amyloidosis. Echocardiography in combination with cardiovascular magnetic resonance (CMR) imaging can also be used to diagnose and prognosticate cardiac amyloidosis.[15]

Other cardiac imaging studies, such as computed tomography (CT) scanning and nuclear scintigraphy, are of less value than ECG and echocardiography.

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 with 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.

Cardiac magnetic resonance imaging

CMR has high spatial resolution and provides tissue characterization. Late gadolinium enhancement (LGE) patterns on CMR are highly sensitive and specific for cardiac amyloidosis and may even precede morphologic increases in left ventricular wall thickness.[16] However, the area of involvement can also be patchy, diffuse, or transmural. Transmural enhancement has been associated with a poorer prognosis than other patterns of enhancement.[17]

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

In systemic L chain–type amyloidosis, amyloid may be deposited 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.

Nuclear medicine

Scintigraphy with radioiodine-labeled serum amyloid pentagonal component (SAP) is used in Europe for 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. The technique is not useful for diagnosing or monitoring cardiac amyloid, because the concentration of the radiolabeled agent in the intracardiac blood pool obscures the weaker signal from the labeled molecule bound to myocardial amyloid. However, SAP scintigraphy is not approved by the US Food and Drug Administration because the SAP is isolated from human sources.[18]

Amyloid imaging agents that do not involve human materials include a synthetic heparin-binding peptide, p5, radiolabeled with technetium 99m (99m Tc-p5). A study by Wall et al that compared radioiodine-labeled SAP with 99mTc-p5 concluded that 99mTc-p5 is an effective amyloid-imaging radiotracer in the murine model of amyloidosis, and may be rapidly translated for imaging patients with visceral amyloidosis.[19]

In an earlier phase I study, Wall and colleagues used a radiolabeled monoclonal amyloid antibody to visualize amyloid deposits in patients with AL amyloidosis. Nine of the 18 subjects showed striking uptake of reagent in liver, lymph nodes, bone marrow, intestine, and spleen (but not kidney or heart). These authors concluded that this method could be used to identify candidates for passive immunotherapy using the chimeric form of the antibody, which has been shown to produce marked regression of human light-chain–associated tumors in mice.[20]

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).

In monoclonal immunoglobulin deposition disease (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. In one study of 25 patients pathologically diagnosed as having tongue amyloidosis, although none had an enlarged tongue, 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.[21]

Immunohistochemical study demonstrated kappa light-chain deposition in 64% of cases, and lambda light-chain deposition in 36%.[21] 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 DDx).

The classic ECG finding in patients with cardiac amyloidosis 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.

Amyloidosis of all types is definitively diagnosed by a positive Congo red stain of 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, and further analysis with immunostaining and, in some cases, amino acid sequence analysis.

Currently, aspiration of subcutaneous abdominal fat is a simple and fast method for obtaining a specimen to detect systemic amyloidosis, with a routine sensitivity of 80%. If analysis of aspirated fat tissue yields negative results, 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.

The gold standard of cardiac amyloidosis diagnosis is myocardial biopsy. However, this procedure is invasive and may fail to detect cardiac amyloidosis if the biopsy sample is taken from a region of the myocardium unaffected by amyloidosis. The type of cardiac amyloidosis may be distinguished by taking a sample of the biopsy tissue and analyzing it by mass spectrometry. In clinical practice, most patients have tissue diagnosis from fat pad or kidney biopsies.[17]

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 kidney biopsy sample is rarely necessary, but findings in such cases include 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.

Immunostaining

After Congo red staining is used to establish a diagnosis of amyloidosis, the specific type of amyloidosis is determined 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.

Current choices for first-line treatment of systemic light-chain (AL) amyloidosis are autologous stem cell transplantation (ASCT) and combination chemotherapy.[22] Chemotherapy regimens include various combinations of the following:

• Dexamethasone
• Melphalan
• Cyclophosphamide
• Thalidomide
• Bortezomib
• Carfilzomib
• Lenalidomide
• Bendamustine 
• Daratumumab

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

Standard treatment of L chain–type amyloidosis aims to reduce production of the monoclonal immunoglobulin precursor via chemotherapy or, occasionally, via radiation therapy or surgical resection 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. Therefore, regimens most likely to benefit patients with this disease are the same as those that are useful for myeloma (eg, melphalan plus prednisone).

Many more studies have been published on the treatment of myeloma than 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.[23, 24] Taken together, these studies demonstrated a survival benefit of melphalan and prednisone compared with placebo in L chain–type amyloidosis.

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.[25] Nevertheless, 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.

Chemotherapy is most likely to produce objective improvement in end-organ damage in patients with kidney 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.

Duration of initial chemotherapy and potential adverse effects

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.

In patients whose disease responds to treatment but then progresses after treatment has been discontinued, chemotherapy (in 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 myeloid leukemia (AML) in one study of patients with myeloma treated with melphalan was 17% at 50 months. In two 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.

Therapeutic advances

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, providing better results than 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 (Velcade) 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 phase II studies confirmed the efficacy of bortezomib in patients with relapsed/refractory myeloma.[26, 27]

Subsequent studies demonstrated the benefit of bortezomib as part of combination therapy with melphalan and prednisone in the initial treatment of myeloma,[28, 29] and in combination with dexamethasone as induction treatment prior to autologous stem cell transplantation (ASCT) in patients with newly diagnosed myeloma.[30]

Drug resistance to bortezomib, probably related to high expression of heat-shock protein, led to the development of second-generation proteasome inhibitors (eg, carfilzomib, ixazomib).[31] These agents are approved for second-line therapy of myeloma.

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.

Thalidomide has a well-established role as first-line therapy, either as a single agent or in combination with steroids. The combination regimen of melphalan, prednisone, and thalidomide (MPT) has become one of the standard therapeutic combinations for elderly patients with myeloma.

Lenalidomide, an orally administered thalidomide analog, received US Food and Drug Administration (FDA) approval in 2006 for use with dexamethasone in patients with multiple myeloma who had received at least one prior therapy. In 2015, approval was expanded to include newly diagnosed multiple myeloma in patients who are not eligible for autologous stem cell transplantation. In 2017, the FDA approved lenalidomide as maintenance therapy for patients with multiple myeloma following ASCT.[32]

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. Carfilzomib is indicated for the treatment of patients who have received at least two prior therapies including bortezomib and an immunomodulatory agent, and have experienced disease progression during or within 60 days of completion of the last therapy.

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, depsipeptide, valproic acid
• Inhibitors of vascular-endothelial growth factor (VEGF): Bevacizumab and others
• Inhibitors of p38 mitogen-activated protein kinase

Pomalidomide is a distinct oral immunomodulatory agent with direct anti-myeloma, stromal cell-support inhibitory, and immune modulatory effects. It is approved for patients who have received two or more prior therapies, including lenalidomide and bortezomib, and have experienced progressive disease during or within 60 days of completion of the last treatment. Pomalidomide combined with low-dose dexamethasone has demonstrated significant progression-free and overall survival benefits with a tolerable safety profile in relapsed/refractory cases.[33, 34]

High-dose chemotherapy with rescue transplantation

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. As with 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 trials of high-dose chemotherapy in selected patients demonstrated favorable responses and survival rates compared with historical controls. 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.

The indication for high-dose chemotherapy in L chain–type amyloidosis 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 those 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 cyclosporine, mycophenolate mofetil, tacrolimus) have been 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.

Daratumumab

In 2021, the FDA granted accelerated approval to daratumumab plus hyaluronidase (Darzalex Faspro) in combination with bortezomib, cyclophosphamide, and dexamethasone (VCD) for newly diagnosed L chain amyloidosis.[35] Approval was based on the results of the ANDROMEDA (NCT03201965) study, an open-label, randomized, active-controlled trial in 388 patients, in which 42.1% of patients in the daratumumab/VCD arm achieved hematologic complete response, compared with 13.5% of those in the VCD arm (odds ratio4.8; 95% CI: 2.9, 8.1; P < 0.0001).[36] The most common adverse reactions (≥20%) in patients who received the daratumumab/VCD regimen are upper respiratory tract infection, diarrhea, peripheral edema, constipation, peripheral sensory neuropathy, fatigue, nausea, insomnia, dyspnea, and cough.[35]

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.

Five of eight patients in the first pilot trial of Idox responded with clinical improvement unrelated to any cytotoxic effect on the plasma cell clone.[37] In a subsequent European trial in 42 patients, 13 had disease responses and 15 had disease stabilization. However, the clinical responses were transient, and the disease typically progressed after a period of months. In a multicenter phase II trial in 40 US patients, six patients responded and 12 died; the investigators concluded that Idox was insufficiently active at the dose administered in the protocol.[38]

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 or 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

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 kidney 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 kidney injury.

Carpal tunnel release

Involvement of the carpal ligament is observed not only in L chain–type amyloidosis but also in dialysis-related beta-2m amyloidosis i and in transthyretin-related amyloidosis). 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 of organ transplantation in L chain–type amyloidosis are available to guide the decision-making process, but patients have received heart or kidney transplants. 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.

Kidney 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, kidney 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.

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

Complications of L chain–type amyloidosis reflect the organ systems involved. The most severe complication 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.

In 2015, Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) released consensus guidelines for the treatment of immunoglobulin light chain amyloidosis. Key recommendations include the following[39] :

• Initiate treatment immediately in virtually all patients with systemic AL amyloidosis.
• Consider high-dose chemotherapy with autologous stem cell transplant (ASCT) in selected patients based on troponin level, blood pressure, kidney function, and physiologic age.
• Dose-attenuated conditioning chemotherapy with ASCT is not recommended outside of a clinical trial.
• Induction therapy before ASCT is recommended for patients with 10% or greater bone marrow plasmacytosis.
• ASCT for patients undergoing hemodialysis is feasible, especially if kidney transplantation is being considered.
• For patients with underlying lymphoproliferative disease or IgM monoclonal protein, ASCT is a reasonable option.
• For patients ineligible for ASCT, standard-dose melphalan and dexamethasone is a valuable first-line option and the combination of thalidomide, cyclophosphamide, and dexamethasone is potentially beneficial as first-line therapy.
• Cyclophosphamide, bortezomib, and dexamethasone or bortezomib, melphalan, and dexamethasone can be used in patients with newly diagnosed or relapsed disease, but neither regimen has been systematically studied.

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

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.

Class Summary

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.

Class Summary

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.

Class Summary

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.

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.