Light-chain amyloidosis, which is seen in 8 persons per million per year, is a disease of small amounts of monoclonal protein. Although the majority of small monoclonal gammopathies are innocuous, they may be associated with a syndrome characterized by “dangerous small clones.” Larger plasma cell clones are most often associated with multiple myeloma, which is about five times as prevalent as light-chain amyloidosis.
Much has been written on the physical findings of tongue enlargement and periorbital purpura. These are found in no more than 15% of patients and are overlooked half of the time because the purpura may only be visible when the eyes are closed, and most of the tongue enlargement is at the base and is limited to dental indentations on the underside of the tongue. It would be wrong not to consider light-chain amyloidosis in a patient who has a completely normal physical examination. If the patient has any of the syndromes listed in Table 1, immunofixation and electrophoresis of the serum and urine, and free light chain analysis should be done. If the results of any of these studies are positive, biopsies of the subcutaneous fat and bone marrow are warranted. At some centers, endoscopic, skin, or salivary gland biopsies are preferred, and these can be acceptable alternatives depending on the local expertise. A liver biopsy can lead to bleeding, and rarely to liver rupture, but if the diagnosis is suspected, a noninvasive sampling of fat, bone marrow, or skin will lead to the correct diagnosis with minimal risk. For the majority of patients, if light-chain studies are completely negative, the likelihood of light-chain systemic amyloidosis is very small and is probably not worth pursuing further. When amyloidosis is strongly suspected, biopsies are only required if the light-chain studies are abnormal. Localized forms of amyloidosis, secondary systemic amyloidosis, and familial forms of systemic amyloidosis are not associated with monoclonal light chains. The routine screening for amyloid deposits in the bone marrow of patients with multiple myeloma and smoldering myeloma is low yield and is not indicated unless the patient has symptoms consistent with amyloidosis. Recommended testing for patients who have received a histologic diagnosis of light-chain amyloidosis is given in Table 2.
The extent of cardiac involvement determines the outcomes seen in patients with amyloidosis. Defining the extent of cardiac involvement has changed as technologies have improved. In the early 1970s, cardiac amyloid was defined using the criteria of classic congestive heart failure: the chest radiograph showed cardiomegaly, pleural effusions, and Kerley B lines. In the 1980s, clinical assessment of cardiac failure was enhanced by the use of echocardiography. Thickening of the myocardial walls, a granular sparkling appearance, relaxation abnormalities seen during diastole, valvular thickening, right ventricular dysfunction, and echocardiographic strain abnormalities have all been shown to correlate with survival. Cardiac amyloidosis is a classic cause of a presentation of heart failure with normal systolic function. The low cardiac output state is a consequence of poor relaxation, poor diastolic filling, and low end-diastolic volumes.
In the past 10 years, cardiac biomarker levels have developed into sensitive measures of cardiac dysfunction, are now part of the response criteria for cardiac amyloidosis, and are highly correlated with outcomes. These blood tests require no specific technical expertise and are widely available in laboratories throughout the world. The troponins T and NT-proBNP are the most thoroughly researched of the biomarkers. Using cutoffs of 0.035 µg/L for troponin T and 322 pg/mL for NT-proBNP, patients can be classified into three stages based on whether the two biomarkers are both low (stage 1), both high (stage 3), or one normal and one abnormal (stage 2). The median survivals in these patients are 26.4, 10.5, and 3.5 months, respectively, for stage 1, stage 2, and stage 3. The value of cardiac biomarkers has also been validated in patients treated with stem-cell transplantation.[23,24] The troponin T is used as an exclusion criterion for stem-cell transplantation. High-sensitivity cardiac troponin T assays are also an excellent predictor of long-term outcome.[25,26]
Other biologic factors that have predicted poor outcome include the level of the immunoglobulin free light chain at diagnosis, with the free light chain level predicting early death, with a hazard ratio of 2.6. The number of organs involved also predicts survival, as does the serum uric acid level, but these features have not been incorporated into a staging system.[28,29]
Recently, new response criteria have been developed to define response. A complete response is defined as negative results on serum and urine immunofixation, a normal free light chain ratio, and normal bone marrow. A partial response is a 50% decline in the difference between involved and uninvolved serum free light chain levels (dFLC). A very good partial response has been defined as a dFLC < 40 mg/L. The new criteria for a cardiac response and cardiac progression are defined using the troponin NT-proBNP. An increase (or decrease) of 30% with a minimum absolute increase (or decrease) of 300 pg/mL are used to establish cardiac progression or response following treatment. To be considered evaluable for response, the level of pretreatment NT-proBNP must be > 600 pg/mL.
Therapy of Amyloidosis in 2012
Survival in AL amyloidosis has improved over time, with the greatest improvement occurring in the past decade (Figure 3). However, death within the first year following diagnosis remains high at 30%. In theory, agents that interfere with the misfolding of the soluble light chain into the insoluble fibril protein should be highly desirable. Research into antibodies specific to the amyloid fibril protein or to serum amyloid P, an integral component of the fibril structure, has been undertaken. Exploration of interfering messenger RNAs that might block the expression of the amyloid precursor protein is also being conducted. However, none of these techniques are ready for the bedside, and the mainstay of treatment since 1972 has been cytotoxic chemotherapy designed to destroy the plasma cells, the source of the immunoglobulin light chain that results in amyloidosis. Many of the advances in the treatment of amyloidosis are derived from our experience in the management of multiple myeloma, since both disorders share a clonal population of bone marrow plasma cells. In the pretransplant era, the melphalan(Drug information on melphalan) and prednisone(Drug information on prednisone)–based regimens and high-dose dexamethasone(Drug information on dexamethasone) therapy that were developed for multiple myeloma were explored in the treatment of light-chain amyloidosis. Melphalan and prednisone are active, but only in a minority of patients with light-chain amyloidosis.[36,37] Melphalan metabolism is minimally dependent on hepatic function and requires only minor dose modification for renal insufficiency. Dexamethasone as a single agent can produce significant organ responses in patients with amyloidosis who do not present with advanced cardiac failure. There are very few patients who would not be eligible for a trial of melphalan-based treatment or single-agent corticosteroids.
After stem-cell transplantation was validated as a method for improving the survival of patients with multiple myeloma, it was rapidly adapted to the management of patients with light-chain amyloidosis. Unique differences in the application of this technique to these two diseases were quickly detected. Patients with multiple myeloma have a relatively high tumor mass in their marrow and preserved organ function. Thus, the consequences and the complications of high-dose therapy in myeloma were primarily associated with myelosuppression and mucositis. The mortality rates for multiple myeloma transplant are approximately 0.5% when patients receive a transplant in the first plateau and 2% when patients have relapsing disease at the time of transplantation. Amyloidosis, on the other hand, is characterized by a relatively small tumor mass, so small that induction chemotherapy is often not necessary before proceeding directly to high-dose therapy. However, patients with amyloidosis are characterized by organ dysfunction, whether this be heart failure with preserved systolic function, massive proteinuria with resultant hypoalbuminemia, or reduced performance status related to peripheral or autonomic neuropathy. Transplantation in that setting not only carries the consequences of mucositis and myelosuppression but also hypotension, renal failure due to acute tubular necrosis, arrhythmia, intestinal bleeding from amyloid-laden blood vessels in the gastrointestinal tract, and sharp rises in serum alkaline phosphatase levels.[43-45] Thus, early trials of high-dose therapy for amyloidosis often resulted in mortality rates in the 15% range, and in the earliest studies rates approached more than 40%. As centers gained experience and patient selection was improved (through the use of functional status, cardiac biomarkers [Figure 4], and free light chain levels), this mortality has been greatly reduced. Since 2006, the day-100 all-cause mortality in patients with amyloidosis at the Mayo Clinic has been 7%, and our program has not experienced any treatment-related deaths since December 2009 (n = 74). For appropriately selected patients in whom it is believed stem-cell transplantation can be accomplished safely, 10-year survival is not uncommon (Figure 5). Complete hematologic responses are seen in 39%, organ responses in 47%. The achievement of a very good partial response or better is the strongest predictor of outcome. For selected patients, stem-cell transplantation is an important consideration.