Robert A. Kyle

The Spectrum of IgM Monoclonal Gammopathy in 430 Cases

IgM monoclonal gammopathy consists of a broad spectrum of diseases, ranging from apparently benign to malignant conditions. In a long-term follow-up study of 430 patients in whom a monoclonal IgM serum protein had been identified, 242 (56%) had monoclonal gammopathy of undetermined significance, 71 (17%) had Waldenströms macroglobulinemia, 28 (7%) had lymphoma, 21 (5%) had chronic lymphocytic leukemia, 6 (1%) had primary amyloidosis, and 62 (14%) had other malignant lymphoproliferative diseases. More than two-thirds of the patients died, and the most common cause of death was a lymphoid malignant process. Almost a fifth of the patients with an apparently benign monoclonal gammopathy subsequently had a lymphoid malignant lesion (in one patient, more than 20 years after the detection of the serum M protein). The median duration of time from the recognition of the M protein until the development of a malignant lymphoid disease ranged from 4 to 9 years. An increased number of lymphocytes or plasma cells on bone marrow examination was not a reliable indicator of the likelihood of such an outcome. Thus, follow-up of these patients should be conducted indefinitely.

Primary Systemic Amyloidosis—a Diagnostic Primer

Primary systemic amyloidosis (immunoglobulin light chain-derived) (AL) is an uncommon dysproteinemia with highly varied initial clinical manifestations. Among 153 patients with this disorder, the median survival was 20.4 months (5-year survival, 19.6%). The worst outcome was associated with overt congestive heart failure (median survival, 7.7 months; 5-year survival, 2.4%). The patients with the best outcome were those who had amyloid neuropathy without associated cardiac or renal involvement (median survival, 39.7 months; 5-year survival, 31.6%). Serum protein electrophoresis and immunoelectrophoresis are the most important tests because a monoclonal protein can be detected in almost two-thirds of the patients. When screening of both serum and urine is performed, a monoclonal protein is found in 86% of patients. Such screening is helpful if primary systemic amyloidosis is to be detected and treated early.

Immunofluorescence labeling indices in myeloma and related monoclonal gammopathies.

We measured plasma cell labeling indices (LI) in 52 patients with monoclonal gammopathies. Cytoplasmic reactivity with polyspecific or kappa- and lambda-specific light chain anti-Ig reagents identified monoclonal plasma cells, plasmablasts, and lymphocytoid plasma cells. Among newly diagnosed untreated patients, a high immunofluorescence LI distinguished those with multiple myeloma (MM) from those with stable monoclonal gammopathies (P less than 0.002). Among treated patients with MM, those in the plateau phase of the disease had low LI, whereas patients in the relapse phase or early in treatment had high LI. The immunofluorescence LI correctly classified three more patients with newly diagnosed MM than did the tritiated thymidine LI technique. LI specific for the neoplastic plasma cells resulted in excellent discrimination of patients with active disease. Because results are easily and rapidly obtained, this technique is useful clinically.

Serial Echocardiographic Observations in Patients With Primary Systemic Amyloidosis: An Introduction to the Concept of Early (Asymptomatic) Amyloid Infiltration of the Heart

Echocardiography was used for the serial assessment of 27 patients with primary systemic amyloidosis. Thirteen patients had no clinical cardiac deterioration between the two echocardiographic studies (group 1), whereas in 14 patients (group 2), congestive heart failure or arrhythmias (or both) appeared or worsened during a mean observation period of 19 months. The only echocardiographic changes in group 1 were a mild increase in left ventricular mass and a mild decrease in left ventricular wall systolic thickening. Patients in group 2 had significant changes in left ventricular wall thickness (mean increase, 34%), in left ventricular mass (mean increase, 42%), in right ventricular wall thickness (mean increase, 78%), in left atrial size (mean increase, 19%), in left ventricular mass/voltage ratio (mean increase, 68%), in left ventricular radius/thickness ratio (mean decrease, 29%), and in left ventricular fractional shortening (mean decrease, 13%). Significant correlations were found in group 2 between changes in systolic and diastolic blood pressure and changes in ventricular wall thickness and mass. Changes in left ventricular systolic function did not correlate significantly with changes in other clinical, electrocardiographic, or echocardiographic measurements. In six cases (two in group 1), in which amyloid infiltration of the heart was proved by myocardial biopsy or autopsy, the only echocardiographic abnormality when the patients were asymptomatic was a moderate increase in left or right ventricular wall thickness. We found that M-mode and two-dimensional echocardiographic examinations can substantiate progressive amyloid infiltration of the heart and are useful tools for the noninvasive serial assessment of patients with primary systemic amyloidosis.

Familial amyloidosis: a study of 52 North American-born patients examined during a 30-year period.

Between 1961 and 1990, 52 patients with biopsy-proven familial amyloidosis born in North America were examined at the Mayo Clinic. At the time of diagnosis of familial amyloidosis, 83% of these patients had peripheral neuropathy, 33% had autonomic neuropathy, and 27% had cardiomyopathy. Renal disease was noted in fewer than 10%, and liver involvement was rare. The median age at diagnosis was 64 years. The sensitivity of various diagnostic biopsies was similar to that for primary amyloidosis: deposits of amyloid were found in 77 and 78% of the subcutaneous fat aspirates or rectal biopsy specimens, respectively, and in 41% of specimens of bone marrow. The median duration of survival of 5.8 years for patients with inherited amyloidosis was superior to that for patients with primary amyloidosis. When patients were stratified by organ involvement, the survival of patients with familial amyloidosis remained superior. The presence of cardiomyopathy and an interactive variable of age and the presence of autonomic neuropathy were powerful predictors of survival. Of the 52 patients, 22 died, 12 (55%) of cardiac failure or cardiac arrhythmia. Nine patients (41%) died of inanition in conjunction with progressive peripheral or autonomic neuropathy. Transthyretin was identified by immunohistochemical studies in 31 of the 34 tissue specimens tested. A transthyretin mutation was identified in 24 of the 31. A transthyretin mutation was found in five additional patients for whom tissue was unavailable for immunostaining.

Autosomal Dominant Familial Mediterranean Fever-Like Syndrome With Amyloidosis

We report a pedigree in which a syndrome that resembled familial Mediterranean fever occurred in four family members over three successive generations. All four patients had systemic amyloidosis. Typically, patients with familial Mediterranean fever show an autosomal recessive inheritance pattern. The disorder commonly afflicts Sephardic Jews, Arabs, and persons of Turkish descent. Colchicine therapy dramatically reduces the attack rate of serositis. The family described herein is unique because of their European ethnicity and the autosomal dominant inheritance pattern. Unlike typical familial Mediterranean fever, colchicine had no influence on the attacks and did not prevent amyloidosis in the three patients who received this treatment.

Response of Primary Hepatic Amyloidosis to Melphalan and Prednisone: A Case Report and Review of the Literature

We report the first case of biopsy-proven primary hepatic amyloidosis in which histologic regression was demonstrated after therapy with melphalan and prednisone. On the basis of the cumulative reported experience regarding the treatment of this rare plasma cell dyscrasia, we recommend a trial of cytotoxic therapy for patients with primary hepatic amyloidosis.

78 – Monoclonal gammopathies

Each monoclonal protein (M-protein, or myeloma protein) consists of two heavy polypeptide chains of the same class and subclass and two light polypeptide chains of the same type. Electrophoresis on cellulose acetate membranes is satisfactory for screening, although agarose electrophoresis is more sensitive for detecting small M-proteins. Immunoelectrophoresis should be performed when myeloma, macroglobulinemia, amyloidosis, or a related disorder is suspected. Immunofixation is useful when results of immunoelectrophoresis are equivocal. The recognition of a Bence Jones protein depends on the demonstration of a monoclonal light chain by immunoelectrophoresis or immunofixation of an adequately concentrated urine specimen. The differential diagnosis of an M-protein includes monoclonal gammopathy of undetermined significance (benign monoclonal gammopathy), multiple myeloma, solitary plasmacytoma of bone or extramedullary plasmacytoma, macroglobulinemia, lymphoma, chronic lymphocytic leukemia, and primary systemic amyloidosis.