The Monoclonal Gammopathies (Paraproteins)

THE MONOCLONAL GAMMOPATHI ES (PARAPROTEINS) Robert A. Kyle and John A. Lust Division of Hematology and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Pathogenesis of Monoclonal Gammopathies .................

for Protein . . . . . . . . . . . . . . .

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5 . Differentiation 5.2. Bence Jones Proteinuria 5.4. 5.5. 5.6. 5.7.

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Bone Marrow Plasma Cell Labeling Index Peripheral Blood Labeling Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Follow-up . . . . . . . . . . . . . .

6.1. Lymphoproliferative Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Leukemia . . . . . . . . . .................. 6.4. Connective Tissue Disorders . . . . . . . . . . . . . . . . . . . . . . . . 6.5. Neurologic Disorders 6.6. Osteosclerotic Myeloma (POEMS Syndrome). . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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145 Copyrighl Q 1990 by Academic Press, Inc. All rights of reproductionin any form reserved.

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6.7. Other Neurologic Disorders . . .. 6.8. Dermatologic Diseases . . . . . . ................................. 6.9. Miscellaneous .......................... ..... ..... 7. Monoclonal Gammopathies with Antibody Activity 8. Multiple Gammopathies . . . . . . 8.1. Biclonal Gammopathies . 8.2. Triclonal Gammopathy . . 9. Benign Monoclonal Light-Chain Proteinuria (Idiopathic Bence Jones Proteinuria) . . . . References ...

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1. Introduction The monoclonal gammopathies are a family of proteins in which each monoclonal protein (M-protein, myeloma protein, or paraprotein) consists of two heavy polypeptide chains of the same class and subclass and two light polypeptide chains of the same type. The different monoclonal proteins are designated by capital letters that correspond to the class of their heavy chains, which are designated by Greek letters: y in immunoglobulin G (IgG), a in immunoglobulin A (IgA), p in immunoglobulin M (IgM), S in immunoglobulin D (IgD), and E in immunoglobulin E (IgE). The subclasses of IgG are IgG1, IgG2, IgG3, and IgG4. There are two subclasses of IgA-IgA1 and IgA2. No subclasses of IgM, IgD, or IgE have been recognized. The light-chain types are kappa (K) and lambda (0 This review covers the pathogenesis of monoclonal gammopathies, including their cause, animal models, role of T and B lymphocytes, cytogenetic aspects, and molecular biology. It then emphasizes the recognition of monoclonal proteins in the clinical chemistry laboratory, and a practical classification of the monoclonal gammopathies is given. We present our long-term follow-up data on a group of patients with monoclonal gammopathy of undetermined significance (MGUS). The differentiation of benign from malignant monoclonal gammopathies is examined, and the association of monoclonal gammopathies with other diseases is reviewed. The antibody activity of monoclonal gammopathies is presented, and biclonal (double) gammopathies and idiopathic Bence Jones proteinuria are discussed. In 1937, Tiselius (T3, using electrophoretic techniques, separated serum globulins into three components, which he designated alpha, beta, and gamma. Electrophoresis was applied to the study of multiple myeloma by Longsworth et al. (L1 l), who demonstrated the tall, narrow-based “church-spire” peak. This method was cumbersome and difficult, so electrophoresis was not readily available until the 1950s, when filter paper was introduced as a supporting medium (zone electrophoresis). Cellulose acetate or agarose gel is now commonly used. Before 1960, the term “y-globulin” (gamma globulin) was used to designate

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those proteins that migrated in the gamma mobility region (toward the cathode) of the electrophoretic pattern. The gamma component was increased by immunization and decreased when exposed to the specific antigen (absorbed). These proteins are referred to as immunoglobulins and are designated as IgG K , IgG A , IgA K , IgA A, IgM K , IgM A , IgD K, IgD A , IgE K, and IgE A.

2. Pathogenesis of Monoclonal Gammopathies Recent data suggest that characteristic changes occur at the cellular and molecular levels in patients with multiple myeloma or monoclonal gammopathy. We shall review these data, emphasizing the alterations that may be involved in the pathogenesis of monoclonal gammopathy or overt multiple myeloma. 2.1. ETIOLOGY Radiation may play a causal role. A modestly increased incidence of multiple myeloma in atomic bomb survivors 20 years after exposure among patients 2059 years of age who had received more than 50 rads (5.0 cases observed; 1.8 expected) was reported by Ichimaru et al. (11). In a long-term follow-up of 14,106 patients with ankylosing spondylitis who were given a single course of radiation therapy, the incidence of multiple myeloma was increased-8 .O cases when only 4.7 would be expected (D3). Radiation workers at the Sellafield plant in England had an excessive death rate from multiple myeloma (7.0 observed; 4.2 expected) (S22). However, another report demonstrated that residents who lived within 10 miles of a nuclear installation, compared with other districts, by age at death, did not show an increase in the relative risk of death from myeloma (Cl I). There is very little evidence that chemicals cause myeloma in humans, even though reports have linked multiple myeloma with benzene (A2) and asbestos (K1 , S9). An increased risk of multiple myeloma has been recognized in farmers, grain workers, rubber workers, cosmetologists, furniture workers, and persons exposed to pesticides or carbon monoxide (C 13). However, the number of cases is small and more data are necessary. The apparent increased incidence of myeloma in industrialized regions may be related to an occupational risk factor (C14). Repeated antigenic stimulation of the reticuloendothelial system may play a part in the development of a monoclonal gammopathy or multiple myeloma. In BALB/c mice, a plasmacytoma can be induced by repeated intraperitoneal injections of mineral oil or pristane to stimulate the immune system (P22). There have been several case reports of the development of multiple myeloma in patients with repeated antigenic exposure (such as allergy injections), rheumatoid arthri-

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tis, osteomyelitis, and recurrent streptococcal cutaneous infections (19, K2, M21, P12, R17). The findings of these reports are probably coincidental because the association between chronic antigenic stimulation and a monoclonal gammopathy could not be substantiated in three large case-control studies (C8, K23, L9). The largest study, comparing 698 myeloma cases with 1683 demographically similar controls, showed no statistically significant association between multiple myeloma and conditions believed to cause chronic stimulation of the immune system, such as chronic bacterial infection, autoimmune disorders, and allergy-related diseases (K23). Cohen et al. (C8) reported that patients with multiple myeloma, compared with a control population, actually had fewer immune-stimulating conditions such as chronic infections, connective tissue diseases, allergies, cholecystitis, and diverticulitis. There is evidence to suggest that a genetic factor may be important in the pathogenesis of monoclonal gammopathies. There are several well-documented reports of familial clusters of two or more first-degree relatives (siblings, parents, or children) with multiple myeloma (M3). In one study, a monoclonal gammopathy was found in five siblings (two brothers and three sisters) whose ages ranged from 60 to 72 years, four of whom were living with MGUS and one who had died of multiple myeloma. The M-protein was IgG A in three cases and IgG K in the other two (B 19). Multiple myeloma was found in two brothers who had an IgG K M-protein and the same human leukocyte antigen (HLA) genotype. No other case of monoclonal gammopathy was identified in 34 relatives, and none of them had the same HLA genotype (G17). Two additional reports have described the occurrence of multiple myeloma in a pair of monozygotic twins (C10, J5). However, in a control study of 439 patients with multiple myeloma and 1317 controls, only 3 patients and 4 controls had multiple myeloma in their families (B22). Genetic susceptibility may play a role in the development of a plasma cell dyscrasia in patients with a positive family history. Epstein-Barr virus (EBV) may be the etiologic agent in a subset of myeloma patients. Using a fluorescent EBV nuclear antigen (EBNA) technique, Rodriguez et al. (R16) showed that 13 (38%) of 34 bone marrow smears from individuals with multiple myeloma were positive. In addition, three of six EBNA-positive cases had unequivocal biotin EBV labeling in plasma cells when probed in situ with biotin-labeled EBV DNA. Voelkerding et al. (V9) described the occurrence of an IgM A nonsecretory plasma cell malignancy in a 31-year-old man who was HIV antibody positive and who presented with hypercalcemia and a reversal of the normal ratio of T-cell subsets. Southern blot analysis showed clonal rearrangements of the immunoglobulin heavy- and light-chain gene loci and the presence of EBV genomes in tumor tissue from the oropharynx and lung but not in nontumor tissues. Further studies are needed to determine whether the presence of EBV is coincidental or pathogenetically related.

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2.2. ANIMALMODELS Analogs of human monoclonal gammopathies have been seen in aging C57BL/KaLwRij mice (R5). Surgical removal of the thymus or congenital absence (nude mice) in C57BL mice resulted in a greater frequency and earlier onset of monoclonal gammopathy during aging (R4, V4). Van den Akker et al. (V4) showed that infusion of corticosteroid-resistant T cells into 9-month-old BALB/c nude mice resulted in a decrease in the frequency of monoclonal immunoglobulin from 43% at 9 months of age to 20% at 15 months. Bone marrow or spleen cells from aged C57BL mice with monoclonal gammopathy have been transplanted to young, lethally irradiated mice through three or four generations without the development of a lethal plasmacytoma or myeloma (R3). Long-term antigenic stimulation by multiple antigens ( pneumococcal polysaccharide, dinitrophenol conjugated to human serum albumin, and ovalbumin) in young C57BL mice resulted in the development of benign monoclonal gammopathies during aging in frequencies higher than those in the control group (V3). The investigators postulated that the M-protein developed in three stages: (1) impairment of T-cell function, (2) lack of suppression of B cells by T cells, and (3) a spontaneous or virus-induced mutation resulting in a monoclonal proliferation of B cells. 2.3. T LYMPHOCYTES IN PATIENTS WITH MONOCLONAL GAMMOPATHIES T cells play an important role in normal B-cell differentiation. Although characteristic changes in various T-cell subpopulations can be demonstrated in patients with multiple myeloma, it is unclear whether these alterations are reactive to the monoclonal gammopathy or are causally related. Several studies have demonstrated that, when compared with normal controls, patients with multiple myeloma in general had reduced percentages of CD4 cells, increased percentages of CD8 cells, and reduced T-helper/T-suppressor ratios utilizing monoclonal antibodies for the pan-T antigen CD3 and T-cell subset antigens CD4 (T helpedinducer) and CD8 (T cytotoxic/suppressor) (D7, H1 1, L5, P19, S2). Variable results were found in patients with MGUS. De Rossi et al. (D7) noted an increase in CD8 cells, whereas Gonzalez et al. (G10) found no statistically significant difference from control patients. The generation of cytotoxic T lymphocytes was decreased in individuals who had MGUS and was especially low in patients with myeloma who had a poor prognosis (M10). Alterations in natural killer cell activity or antibody-dependent cellular cytotoxicity were not found (D7). Massaia et al. (M1 1) have further determined that CD1 lb+ granular cells are significantly increased in CD8 subpopulations from individuals with a monoclonal gammopathy. Normal CD8+ lymphocytes can be divided into two main subsets with different morphologic and functional characteristics: (1) CD11b+

+

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lymphocytes with granular morphology that contain suppressor cells and (2) CD1 lb- lymphocytes with nongranular morphology that contain precursors of cytotoxic T lymphocytes. Many of these T-suppressor cells were also found to be activated (HLA-DR+). The number of HLA-DR+ cells in CD8+ subpopulations was closely related to diagnosis and clinical status. The number of these cells was significantly higher in multiple myeloma patients at diagnosis than in MGUS patients; the number decreased to MGUS levels in myeloma in stable remission, but not in myeloma with tumor progression (D1 1). These data may provide a phenotypic explanation for the enhanced suppressor activity reported in patients with monoclonal gammopathies. One study of myeloma patients showed an absolute increase of T y cells that suppressed pokeweed mitogen-induced B-cell differentiation (P16). The investigators postulated that the increase in T-suppressor cells may be responsible for the suppression of normal polyclonal immunoglobulin synthesis, whereas the Mprotein is resistant to the suppressive activity of the T y cells. This hypothesis remains to be proved, but such a T-cell response is likely to be reactive to the monoclonal B-cell process. In contrast, a potential etiologic role between T-cell alterations and the development of multiple myeloma is supported by the animal data described above. In addition, Beyer et al. (B18) described a patient with aplastic anemia who subsequently developed IgA multiple myeloma 10 months after treatment with antithymocyte globulin. This may be coincidental, but it is interesting to note that the incidence of monoclonal gammopathy in patients who were undergoing immunosuppressive treatment after renal transplantation was 10 times higher than that in a control group of patients with chronic renal failure who were on a dialysis regimen (R6). Other factors, such as age, heredity, and viral infection, may also play a role in the genesis of an M-protein in immunosuppressed patients.

2.4. B LYMPHOCYTES IN PATIENTS WITH MONOCLONAL GAMMOPATHIES Multiple myeloma has been considered a malignancy of the plasma cell, the most terminally differentiated cell in the B-cell series. However, recent evidence suggests that other plasma cell precursors are important in the genesis of myeloma cells. Epstein et al. (E2) found expression of the pre-B common acute lymphoblastic leukemia antigen (CALLA) on bone marrow aneuploid myeloma cells in 55% of patients studied. The coexpression of CALLA and monoclonal cytoplasmic immunoglobulin by the same aneuploid myeloma cells suggested a new tumor cell phenotype without a known counterpart in normal B-cell differentiation. Furthermore, in all cases of DNA-aneuploid myeloma, CALLA-positive cells with diploid DNA content but without cytoplasmic immunoglobulin expression were present. These findings raise the hypothesis that subpopulations of

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cells that are CALLA-positive/cytoplasmic immunoglobulin-negative, CALLApositive/cytoplasmic immunoglobulin-positive, and CALLA-negative/cytoplasmic immunoglobulin-positive may represent different maturation stages of myeloma and that the diploid cells may be the precursors of the aneuploid plasma cells (B6). A myeloma-pre-B-like malignant hybrid with coexpression of cytoplasmic p, CALLA, terminal deoxynucleotidyl transferase ( pre-B phenotype), and plasma cell antigens (PCA-1 and PC-1) has been found in direct and cultured bone marrow by Grogan et al. (G16). In culture, these aberrant clones produced a homogeneous .cytoplasmic p that had a molecular weight of 75,000 and an isoelectric point of pH 6.3. Heavy- and light-chain immunoglobulin gene rearrangements demonstrated monoclonality of these cells, and double-labeling experiments (immunophenotype and labeling index) demonstrated that the cultured pre-B-like myeloma hybrid had a proliferative component greatly exceeding that of myeloma. These pre-B myeloma cells were postulated to be the stem cell population of myeloma. Several lines of evidence suggest that the plasma cell precursors of myeloma circulate in the peripheral blood as well. Many investigators have demonstrated that a subpopulationof peripheral blood lymphocytesexpressed the same idiotype found in the myeloma cells (A1, B9, C2, S31). In addition, Southern blot analyses, using probes specific for immunoglobulin genes, have demonstrated clonal gene rearrangements in the peripheral blood of patients with myeloma that were identical to rearrangements seen in marrow cells (B12, K21). Circulating plasma cells were not detected, nor did any patient show T-cell receptor gene rearrangement. Other investigators have been unable to duplicate these results, which may have been secondary to differences in the sensitivity of the assays used (C7). Several lymphoid growth factors are involved in the differentiation of normal B cells. Resting B cells enter into DNA synthesis by interleukin-4 (IL4), proliferate with IL5, and differentiate into plasma cells via I L 6 (H14, K16, Rl). Bergui et al. (B14) demonstrated that peripheral blood mononuclear cells from 11 patients with myeloma when cultured in v i m in the presence of IL3 and I L 6 generated a population of morphologically evident plasma cells after 6 days that expressed in each individual case the same light and heavy chain produced by the bone-marrow malignant plasma cells. The authors concluded that circulating malignant plasma cell precursors exist and that their growth and terminal differentiation are under the synergistic control of I L 3 and IL6. Multiple myeloma has been associated with the overproductionof one or more cytokines. These cytokines may be responsible for the osteolytic bone disease and polyclonal hypogammaglobulinemiaassociated with myeloma. Lichtenstein et al. (L6) have shown that bone marrow cells from patients with myeloma secrete increased levels of IL1 and tumor necrosis factor (TNF) when compared with control individuals. I L 1 and TNF have bone-resorbing activity and can

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inhibit B-lymphocyte differentiation (B17, D15, G13, K5, P8). Commes et al. (C9) have shown that the defect in peripheral blood B-cell activation in patients with myeloma is not due to a deficiency of B-cell differentiation factors or IL6. RPMI 8226, an EBV-negative human myeloma cell line, produces a B-cell growth factor (IL5) (K19). Recombinant I L 6 (rIL6) did not enhance M-protein secretion in myeloma cells in virro (T3), but its in vitro effect on proliferation was directly correlated with the labeling index of the myeloma cells in vivo (23). In addition, granulocyte-macrophage colony-stimulating factor (GM-CSF) synergizes with I L 6 in supporting the proliferation of human myeloma cells in vitro (K18). Kawano et af. (K6) have proposed that I L 6 is an autocrine growth factor for myeloma cells. They have shown that myeloma cells freshly isolated from patients produce B-cell-stimulating factor-2 (IL6) and express its receptors. I L 6 augments the in vitro growth of myeloma cells, and anti-116 antibody inhibits their growth (K6, K17). In contrast, Klein et al. (K18, K20) have shown that the high production of I L 6 found in the bone marrow of patients with progressive multiple myeloma was confined to the adherent cells of the bone marrow environment but not to the myeloma cells. Their data suggest a paracrine rather than autocrine regulation of myeloma cell growth by IL6. Transgenic mice carrying the human I L 6 gene in association with an immunoglobulin enhancer developed polyclonal plasmacytoma cells. The authors postulated that constitutive expression of I L 6 induces a polyclonal proliferation of plasma cells. A second event, such as altered oncogene expression, may transform cells into a monoclonal process (K17). I L 6 is a potent growth factor for myeloma, and its altered expression may be involved in the oncogenesis of monoclonal gammopathies. 2.5. CYTOGENETIC AND MOLECULAR ALTERATIONS IN MONOCLONAL GAMMOPATHIES Cytogeneticstudies in multiple myeloma have been hindered because of the low proliferative activity of myeloma cells. However, in patients for whom results are available, no specific chromosome abnormality has been demonstrated. Flow cytometry has shown an aneuploid myeloma cell population in approximately 80%, hyperdiploidy being the most common (L2). Structural changes of chromosomes 1, 11, and 14 have been reported, as have monosomies and trisomies (D8, G12, P17). Approximately half of the patients with myeloma are thought to have an abnormal karyotype, with trisomy 3, 5 , 9 , and 15 and monosomy 13 and 16 being the most common abnormalities. Translocations have also been observed in myeloma and include t(8;14)(q24;q32)and t(l1;14)(13;q32); because the t(8;14) abnormality occurs predominantly in patients with IgA monoclonal gammopa-

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thies, a pathogenetic relationship is suggested (G 12). Interestingly, 8q24 and 11q 13 are the sites of the c-myc and bcl- 1 protooncogenes, respectively, and 14q32 is the locus of the immunoglobulin heavy-chain gene. In lymphoma, chromosomal translocation involving the juxtaposition of protooncogenes such as c-myc and bcl- 1 to the immunoglobulin heavy-chain gene locus results in the transcriptional deregulation of these genes and the subsequent neoplastic transformation of B lymphocytes (S16). A similar mechanism may be expected in patients with myeloma who have t(8;14) or t(l1;14) abnormalities, but molecular changes suggestive of c-myc translocation are infrequent (S 11). Meltzer et al. (M17) found loss of restriction sites in a region 44 base pairs upstream from the 3‘ border of the first c-myc exon in 8 of 13 cases. Barlogie et al. (B6) found rearrangement of bcl-1 in only 5 of 120 myeloma patients and of bcl-2 in none of 60 patients. Alterations in the expression of c-myc and H-rus have been reported as well (G5, S 11, T8). Elevated c-myc messenger ribonucleic acid (mRNA) levels were found in 9 of 37 myeloma patients (S11). Virtually all of the 37 patients had distinct rearrangements of the immunoglobulin heavy- and light-chain genes, and 2 of the 9 patients with increased c-myc MRNA also had evidence of c-myc rearrangement. Neither of these two patients had evidence of a chromosomal translocation, and somatic cell hybrid studies on one showed that the rearranged c-myc protooncogene was derived entirely from chromosome 8; this finding suggests that the mechanism of c-myc activation was different from that in Burkitt’s lymphoma. Molecular analysis of the human myeloma cell line LP- 1 showed an increased expression of the c-myc protooncogene and the presence of abnormally sized transcripts. Cytogenetic study and pulsed-field gel electrophoresis showed no structural rearrangements of the c-myc gene, a suggestion that the abnormal c-myc expression may be due to point mutations or small deletions within the gene (P9). Characterization of the human myeloma cell line NCI-H929, established from a malignant effusion occurring in a patient with IgA K myeloma, demonstrated a complex c-myc rearrangement involving the 3’ untranslated region and an association with the stabilization of chimeric c-myc transcripts (G5, H16, H17). Recent work has shown that this myeloma cell line has an activated rus allele in addition to a rearranged c-myc allele (E3). In another study, 74% of 23 patients with active myeloma had higher H-rus p21 protein fluorescence in aneuploid tumor cells than did patients with marrows in remission (T8). H-rus is located on chromosome 11, a chromosome frequently involved in myeloma, and there was an inverse relationship between the presence of trisomy 11 and p21 levels. Retroviral vectors used to introduce H- or N-ras oncogenes into human B lymphoblasts immortalized by EBV led to malignant transformation of these cells, shown by clonogenicity in semisolid media and

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tumorigenicity in immunodeficient mice. Terminal differentiation into plasma cells was observed by specific changes in morphology, immunoglobulin secretion, and cell surface antigen expression (S12). Palumbo et al. (P2) reported that the expression of three growth-related oncogenes (c-myc, c-myb, and p53) was similar in normal and myeloma bone marrow cells. However, protooncogene levels of expression were also compared to those of the H3 gene to distinguish between an increase in the fraction of cycling cells and true deregulation of a growth-regulated gene. The ratios of expression of these protooncogenes to histone H3 were markedly increased in multiple myeloma cells. Siimegi et al. (S32) found no rearrangement or detectable amplification of the c-myc gene in 21 cases of multiple myeloma. However, two of three cases of plasma cell leukemia showed amplification of the oncogene. In summary, alterations of protooncogenes such as c-myc and H-ras may be the second event that transforms a polyclonal proliferation of IL6-dependent plasma cells into a monoclonal gammopathy.

3. Recognition of Monoclonal Proteins Analysis of the serum and urine for M-proteins requires a sensitive, rapid, dependable screening method to detect the presence of a monoclonal protein and a specific assay to identify it according to its heavy-chain class and light-chain type (K30). Electrophoresis with cellulose acetate membrane is satisfactory for screening. High-resolution agarose gel electrophoresis is more sensitive for the detection of small monoclonal proteins (W4). Immunoelectrophoresis or immunofixation or both should be used to confirm the presence of a monoclonal protein and to distinguish the immunoglobulin class and its light-chain type. 3. I . ANALYSIS OF SERUM FOR PROTEIN 3.1.1. Electrophoresis for Detection Serum protein electrophoresis should be done when multiple myeloma, macroglobulinemia, or amyloidosis is suspected. In addition, this test is indicated in any patient with unexplained weakness or fatigue, anemia, elevation of the erythrocyte sedimentation rate, back pain, osteoporosis, osteolytic lesions or fracture, immunoglobulin deficiency, hypercalcemia, Bence Jones proteinuria, renal insufficiency, or recurrent infections. Serum protein electrophoresis should also be performed in adults with sensorimotorperipheral neuropathy, carpal tunnel syndrome, refractory congestive heart failure, nephrotic syndrome, orthostatic hypotension, or malabsorption because a localized spike or band is strongly suggestive of primary amyloidosis (AL).

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TABLE I CONSTITUENTS OF MAJORCOMFQNENTS OF THE SERUM ELECTROPHORETIC PATTERNa +(Anode) Albumin Albumin

al-Globulin

a+3lobulin

a,-Antitrypsin az-Macroglobulin a ,-Lipoprotein az-Lipoprotein al-Acid gly- Haptoglobin coprotein Ceruloplasmin (orosomu- Erythropoietin coid)

P-Globulin P-Lipoprotein Transfenin Plasminogen Complement Hemopexin

P-y-Globulin

, -(Cathode)

y-Globulin

Fibrinogen

IgG

-

IgA IgM I@ IgE

-

+nmunoglobulins may migrate from the slow y- to the a*-globulin area. [Modified from Kyle, R. A , , and Greipp, P. R . , Series on clinical testing. 3. The laboratory investigation of monoclonal gammopathies. Mayo Clin. Proc. 53, 719-739 (1978).]

The constituents of the major components of the serum protein electrophoretic pattern are listed in Table 1. Although the immunoglobulins (IgG, IgA, IgM, IgD, and IgE) make up the y component, it must be emphasized that they are also found in the p-y and p regions and that IgG actually extends to the a,-globulin area. Therefore, an IgG monoclonal protein may range from the slow y (cathode) to the a,-globulin region. A decrease in albumin and increases in a,-and a,-globulins as well as yglobulin are nonspecific features of inflammatory processes such as infection or metastatic malignancy. Rarely, two albumin bands (bisalbuminemia) may be found. This is a familial abnormality and produces no symptoms (A5, P20). Hypogammaglobulinemia is characterized by a decrease in the y component (y-globulin = 0.6 g/dl or less). The diagnosis should be confirmed by quantitation of immunoglobulinlevels. Hypogammaglobulinemia occurs in about 10%of patients with multiple myeloma. Most of these patients have a large monoclonal protein (Bence Jones protein) in the urine. Approximately one-fourth of patients with primary systemic amyloidosis (AL) have hypogammaglobulinemia.Reduction in the a,-globulin component is usually due to a congenital deficiency of a,antitrypsin and may be associated with recurrent pulmonary infections and chronic obstructive pulmonary disease. In the electrophoretic pattern, a monoclonal protein is usually seen as a narrow peak (like a church spire) in the y, P-y, P, or a2 regions of the densitometer tracing or as a dense, discrete band on the cellulose acetate membrane (Fig. 1). In contrast, an excess of polyclonal immunoglobulins (having one or more heavychain types and both K and X light chains) produces a broad-based peak or broad band. It is usually limited to the y region (Fig. 2). In 2-3% of sera there is an

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FIG. 1. Top: Monoclonal pattern of serum protein from densitometer tracing after electrophoresis on cellulose acetate (anode on left): tall, narrow-based peak of y mobility. Bottom: Monoclonal pattern from electrophoresis of serum on cellulose acetate (anode on left): dense, localized band representing M-protein in y area. [From Kyle and Garton (K30).By permission of Grune & Stratton.]

additional monoclonal protein of different immunoglobulin class, and this is designated as biclonal (double) gammopathy (K36). A discrete band or a tall, narrow, homogeneous peak (M-protein) is most suggestive of monoclonal gammopathy of undetermined significance, multiple myeloma, primary amyloidosis, Waldenstrom’s macroglobulinemia, or other lymphoproliferative disease. Other entities may suggest the presence of an M-protein in the serum. For example, a discrete band or peak in the a,-globulin region may represent free

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FIG. 2. Top: Polyclonal pattern of serum protein from densitometertracing after electrophoresis on cellulose acetate (anode on left): broad-based peak of y mobility. Bottom: Polyclonal pattern from electrophoresisof Serum on cellulose acetate (anode on left): y band is broad. [FromKyle and Garton (K30). By permission of GNne & Stratton.]

hemoglobin-haptoglobin complexes resulting from hemolysis. The serum is often pink. Large amounts of transferrin in patients with iron-deficiency anemia may produce a prominent band in the p region. Fibrinogen (in plasma) is seen as a discrete band between the p and the y regions. When this band is seen, the specimen should be examined for the presence of a clot. If no clot is found, thrombin should be added to the sample; this produces a clot if fibrinogen is present. If the discrete band disappears when electrophoresis is repeated, the presence of fibrinogen is almost certain. Fibrinogen may also be detected with immunoelectrophoresis or immunodiffusion. The point of application of the

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specimen in the cathodal region may suggest a monoclonal protein. Usually, this can be recognized when the two faint lines of the applicator are visible. A small M-protein, often of the IgM class, may also be seen in this area (G4). Other conditions may have recognizable electrophoretic patterns. A nephrotic syndrome typically produces a serum electrophoretic pattern with decreased albumin and y-globulin and an increase in the a,-globulin and P-globulin components. The increased a,- or P-globulin components may be mistaken for an Mprotein. The urinary pattern of a patient with nephrotic syndrome consists mainly of albumin and resembles a normal serum pattern. Chronic liver diseases, connective tissue disorders, and chronic infections may be characterized by a large, broad-based polyclonal pattern. This is particularly evident in chronic active hepatitis, in which the y component may be 4 or 5 g/dl or greater. This large gamma band may be confused with that seen in multiple myeloma or macroglobulinemia. We have also seen patients with lymphoproliferative processes with a large polyclonal increase in immunoglobulins. It must be kept in mind that a monoclonal protein may appear as a rather broad band on the cellulose acetate membrane or a broad peak in the densitometer tracing and may be mistaken for a polyclonal increase in immunoglobulins. Presumably, this broad band or peak is due to a complex of monoclonal protein with other plasma components, aggregates of IgG, polymers of IgA, or dimers of IgM. Immunoelectrophoresis or immunofixation is necessary for identification

(W5).

It must be emphasized that a patient can have a monoclonal protein when the total protein concentration, P- and y-globulin levels, and quantitative immunoglobulin values are all within normal limits. A small monoclonal protein may be concealed among the normal P or y components and be missed. The cellulose acetate pattern and densitometer tracing may appear normal even in the presence of a monoclonal protein (Fig. 3). A monoclonal light chain (Bence Jones proteinemia) is rarely seen in the cellulose acetate tracing. In some cases of IgD myeloma, the M-protein is very small or not evident at all. In the heavy-chain diseases, the monoclonal component is usually not apparent. In fact, the serum protein electrophoretic pattern is normal in half the cases of a heavy-chain disease, and an unimpressive broad band in the a2or P region is the only electrophoretic abnormality among the rest. A discrete band or tall peak characteristic of a monoclonal protein is never seen. In p heavy-chain disease, the electrophoretic pattern is normal except for hypogammaglobulinemia, and a localized band is rarely seen. In y heavy-chain disease, there is often a localized band in the Py region, but it is broad, appears heterogeneous, and is more suggestive of a polyclonal than a monoclonal protein. Thus, a normal value for the components of the electrophoretic pattern or a normal-appearing or nonspecific pattern may still contain an M-protein; immunoelectrophoresis or immunofixation is critical.

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FIG. 3. Results from analysis of serum samples containing monoclonal protein (same patient). Electrophoresis produced normal patterns in densitometer tracing (A) and on cellulose acetate (B). (C) Immunoelectrophoresis produced localized bowing of immunoglobulin G (y) and A arcs, indicating an IgG A protein. [From Kyle, R. A., and Greipp, R. P., series on clinical testing. 3. The laboratory investigation of monoclonal gammopathies. Muyo Clin. Proc. 53, 719-739 (1978). By permission of Mayo Foundation.]

3.1.2. Immunoelectrophoresis Immunoelectrophoresis is a useful technique for the identification of a monoclonal protein. It should be performed when a sharp peak or band is seen in the cellulose acetate tracing or when multiple myeloma or its variants, macroglobulinemia, amyloidosis, or a related disorder are suspected. It is helpful in the differentiation of a monoclonal from a polyclonal increase in immunoglobulins. A strong antiserum to whole human serum will produce more than 30 precipitin arcs and is difficult to interpret, Therefore, one should use monospecific antisera to the Fc fragment of IgG, IgA, IgM, IgD, and IgE as well as to K and h light chains. Because the antigenic determinants of some M-proteins are

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restricted, they may not be recognized by all antisera, so it is necessary to have antisera from various sources available when M-proteins are typed. In multiple myeloma, monospecific antisera to IgG, IgA, IgD, or IgE or to K or A produce a localized thickening and bowing of a heavy-chain arc and a similar change in a light-chain arc. The changes in the heavy-chain and light-chain arcs should be the same distance from the application well. Occasionally, a thickened arc appears to be cut off abruptly near the trough. This is due to an antigen excess or to formation of a soluble antigen-antibody complex. When this occurs, immunoelectrophoresis should be repeated with serum diluted 1 : 5 or 1 : 10. The presence of an additional light-chain arc (double bowing) without a similar bowing of a heavy-chain arc indicates a free monoclonal light chain (Bence Jones proteinemia). This apparently free monoclonal light chain may also be a component of a biclonal gammopathy in which the heavy-chain arc is not detected. Immunofixation is useful in this setting. The immunoelectrophoretic pattern of an IgG K monoclonal protein is shown in Fig. 4. An increase in polyclonal immunoglobulins often produces a rather localized thickening of the heavy chain, but both K and A light-chain arcs are increased. Interpretation of the arcs requires experience because the IgG and K components comprise the majority of a polyclonal increase, and this change must not be confused with a monoclonal IgG K protein. In Waldenstrom’s macroglobulinemia, the IgM antiserum produces a bowed and thickened arc and a similar arc with monospecific K or A antiserum (Fig. 5). Often, no diagnostic changes in the light-chain arcs are seen, and the mistaken diagnosis of heavy-chain disease may be made. Immunofixation is usually

FIG.4. Serum immunoelectrophoreticpattern. Top: antiserum to IgG (y) shows a thickened arc. Middle: Antiserum to K chains shows a thickened arc similar to the IgG arc. Bottom: Antiserum to A chains shows a faint normal arc. The patient’s serum contains a monoclonal IgG K protein. [From Kyle and Carton (K30). By permission of Grune & Stratton.]

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FIG. 5. Serum irnmunoelectrophoretic pattern. Top: Antiserum to IgM (p) shows a thickened arc. Middle: Antiserum to K chains shows a normal-appearing arc. Bottom: Antiserum to A light chains shows bowing corresponding to the IgM arc. The patient’s serum contains an IgM A protein. [From Kyle and Carton (K30). By permission of Grune & Stratton.]

diagnostic in this situation (Fig. 6). If the IgM monoclonal protein is large, the addition of a reducing agent such as dithiothreitol often makes an IgM K or IgM A monoclonal protein identifiable with immunoelectrophoresis. The monoclonal protein may precipitate in the gel and not migrate satisfactorily. In this situation, one must look very carefully for a small arc near the precipitate indicating the type of M-protein. Immunofixation is very useful in this setting. Repeating the immunoelectrophoresis with the addition of dithiothreitol or with a buffer of higher ionic strength may resolve the problem. If the cellulose acetate membrane contains a localized band in the p or y regions and immunoelectrophoresis is not diagnostic, one must proceed to immunofixation. The use of other monospecific antisera may also be helpful in this situation. Searching for IgD and IgE monoclonal proteins is absolutely essential when bowing of the K or A arcs is seen without an accompanying abnormality of the IgG, IgA, or IgM arc. Although Bence Jones proteinemia is the usual diagnosis, the possibility of an IgD or IgE monoclonal protein must be excluded. We screen all sera of patients with immunodiffusion using antisera to IgD and IgE. All sera forming a precipitin band are then subjected to immunoelectrophoresis with monospecific antisera to IgD or IgE plus K and A. Most sera do not produce a reaction with immunodiffusion, and immunoelectrophoresis is unnecessary. 3.1.3. Immunofixation

Immunofixation is often useful when results of immunoelectrophoresis are equivocal (R14). A monoclonal protein produces a sharp, well-defined band with a single heavy-chain class and light-chain type. A polyclonal increase in immu-

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FIG. 6 . Serum immunofixation. Top: Dense localized band with IgM ( p ) antiserum. Middle: No band with K antiserum. Bottom: Dense band with A antiserum corresponding to the IgM band. This patient has an IgM A monoclonal protein. [From Kyle and Garton (K30).By permission of Grune & Stratton.]

noglobulins is characterized by broad, diffuse, heavily stained bands with heavychain antisera and both K and A antisera. Interpretation may be difficult because overdilution of a serum sample will result in the loss of a monoclonal band. Alternatively, inadequate dilution of a serum specimen may obscure the recognition of a small monoclonal heavy or light chain in a serum with a normal background of immunoglobulins, producing a dense polyclonal band. A prominent polyclonal band may be misinterpreted as a monoclonal protein. Consequently, technical and interpretive expertise are necessary. Immunofixation is useful when the immunoelectrophoretic pattern shows bowing of a single heavy chain or a single light chain and the patient has a discrete band on the serum protein electrophoretic pattern. It is often helpful in cases of a monoclonal IgM protein because the bowing of the light chain is often not apparent on immunoelectrophoresis. Immunofixation may detect a small monoclonal protein in the presence of normal background immunoglobulins or a

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FIG.7 . lmmunofixation of serum. Top: Dense band with IgG (y) antiserum. Middle: Dense band with IgA (a)antiserum. Bottom: Two dense bands with K antiserum. This patient has biclonal gammopathy (IgG K and IgA K). [From Kyle and Carton (K30). By permission of Grune & Stratton.]

polyclonal increase in immunoglobulins. It is more sensitive than immunoelectrophoresis when one is looking for a small M-protein in treated patients with myeloma or macroglobulinemia or in apparently solitary plasmacytoma or extramedullary plasmacytoma after treatment with radiation. As previously mentioned, it is often helpful in the recognition of a biclonal gammopathy (Fig. 7). In suspected amyloidosis, immunofixation is very helpful for the detection of a small monoclonal immunoglobulin or light chain in the serum. Despite the obvious advantages of immunofixation, immunoelectrophoresisis useful as the initial procedure because it is technically easier and the results are generally satisfactory. In addition, interpretation of immunofixation may be misleading, and one can overdiagnose or underdiagnose monoclonal proteins because the dilution of the specimen is crucial. Despite its shortcomings, immunofixation is helpful, and in one report monoclonal proteins were detected in 15 cases when immunoelectrophoresis failed to recognize them (D 19).

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Monoclonal proteins may be identified without immunoelectrophoresis or immunofixation. A rate nephelometer using monospecific anti-lc and anti-A antisera as well as the appropriate heavy-chain antisera has been used to detect the lightchain type of large monoclonal gammopathies. However, small monoclonal proteins will have a normal K : A ratio and will not be recognized (D4). In another series of 336 serum samples, a monoclonal gammopathy was diagnosed in 88% with high-resolution electrophoresis, quantitation of immunoglobulins, and determination of the K : A ratio with a rate nephelometer (K12), Whicher et al. (W4) reported that 93% of monoclonal proteins had an abnormal K : A ratio. One must realize that small monoclonal proteins-IgG K in particular-may be missed with determination of K : A ratios with a rate nephelometer. 3.1.4. lmmunoblotting Immunoblotting in combination with high-resolution electrophoresis on agarose may detect monoclonal proteins in concentrations as low as 0.5 mglliter. In one report, immunoblotting detected a monoclonal protein in 76% of persons older than 95 years and in 79% of those with a kidney transplant. Agar electrophoresis and immunofixation had failed to find a definite M-protein in all sera (R2). In addition, immunoblotting with horseradish peroxidase-conjugated antisera to both heavy and light chains requires fewer repeated analyses than does immunofixation (N8).

3.1.5. Quantitation of Immunoglobulins Quantitation of immunoglobulins is much more useful than immunoelectrophoresis or immunofixation for the detection of hypogammaglobulinemia. Quantitation may be performed by radial immunodiffusion (F2), but the technique is tedious and is subject to spurious abnormalities and so is not recommended. For example, low-molecular-weight (7 S) IgM will produce a spuriously elevated value because its rate of diffusion is greater than that of the 19 S IgM used as a standard. Polymeric IgA will produce spuriously low values because diffusion is inhibited and the standards consist of 7 S IgA. A rate nephelometer is the preferred method for quantitation of immunoglobulins. The degree of turbidity produced by antigen-antibody interaction is measured by nephelometry in the near-ultraviolet region. It is not affected by molecular size of the antigen, and 7 S IgM, polymers of IgA, and aggregates of IgG are accurately measured (M6). 3.1.6. Serum Viscometry Serum viscometry should be done when the IgM monoclonal level is more than 3 g/dl, when the IgA or IgG value is more than 4 g/dl, and when the patient has oronasal bleeding, blurred vision, or other symptoms suggestive of a hyperviscosity syndrome. The Ostwald- 100 viscometer is a satisfactory instrument,

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165

but a Wells-Brookfield viscometer (Brookfield Engineering Laboratory, Stoughton, Massachusetts) is preferred because it can determine the viscosity at different shear rates and at variable temperatures. It also requires only 1 .O ml of serum. In addition, the determinations can be made much more rapidly than with an Ostwald-100 viscometer when the viscosity of the serum is high. Symptoms of hyperviscosity are rare unless the value is more than 4 centipoises (cP). 3.1.7. Cryoglobulins Cryoglobulins are proteins that precipitate when cooled and dissolve when heated (Fig. 8). Five milliliters of fresh, centrifuged serum kept at 37°C is placed in a tube and then incubated in an ice bath in a cold room for 24 hr. If a precipitate or gel is seen, the tube is centrifuged and the cryocrit level is read. The precipitate is washed in cold saline and is then placed in a 37°C water bath. Immunoelectrophoresis is performed on the resuspended cryoprecipitate with monospecific antisera to IgG, IgA, IgM, K , and h. If no precipitate occurs at 24 hr, the specimen is kept at 0°C for 7 days. Cryoglobulins may be classified as follows: type I (monoclonal-IgG, IgM, IgA, or, rarely, monoclonal light chains); type I1 (mixed-two or more immunoglobulins, of which one is monoclonal); and type 111 (polyclonal-in which no monoclonal immunoglobulin is found). In most cases, monoclonal cryoglobulins are IgM or IgG but rarely IgA, and Bence Jones cryoglobulins have been recognized. Unexpectedly, many patients with large amounts of cryoglobulin are completely asymptomatic, whereas others with modest amounts of monoclonal cryoglobulins, in the range of 1-2 g/dl,

FIG.8 . Cryoglobulinemia. Left: Precipitate formed on exposure to 0°C. Right: Disappearance of precipitate when heated to 37°C. [From Kyle, R. A . , and Greipp, P. R., series on clinical testing. 3. The laboratory investigation of monoclonal gammopathies. Muyo Clin. Proc. 53, 719-739 (1978). By permission of Mayo Foundation.]

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have pain, purpura, Raynaud's phenomenon, cyanosis, and even ulceration and sloughing of the skin and subcutaneous tissues on exposure to the cold. The temperature at which the cryoglobulin precipitates is much more important than the amount of M-protein. We have seen patients in whom the protein produced serious problems by precipitating at 26°C (L4).In contrast, we have been impressed with several patients who had 4-5 g/dl of a monoclonal IgG or IgM cryoglobulin that precipitated at 4°C but who had no symptoms whatever on exposure to cold. Cryoglobulinemia may produce a spurious elevation of the leukocyte count on the model S Coulter counter. This is believed to be due to particles formed by combination of the cryoglobulin and fibrinogen. Most commonly, mixed cryoglobulins (type 11) consist of monoclonal IgM and polyclonal IgG, but monoclonal IgG or monoclonal IgA may be seen with polyclonal IgM (B25). Usually the quantity of the cryoglobulin is less than 0.2 g/dl. It may not reach the maximal amount for 7 days. The serum protein electrophoretic pattern rarely shows a localized band and usually is normal or shows a diffuse hypergammaglobulinemia. Q p e I1 (mixed) cryoglobulinemia is characterized by purpura and polyarthralgias. Involvement of the joints is symmetrical and not migratory. Chronic deformities rarely develop. Vasculitis involving the skin is common. Raynaud's phenomenon, necrosis of the skin, and neurologic involvement may occur (M28). Renal involvement manifested as glomerulonephritis is often seen. In nearly 80% of renal biopsies, glomerular damage can be classified as diffuse proliferative glomerulonephritis with thickening of the glomerular basement membrane (D 1). Proteinuria with microscopic hematuria is frequent. Renal insufficiency is not common, and the development of end-stage renal failure is infrequent. Occasionally, a nephrotic syndrome may be seen. It has been thought that renal involvement in patients with mixed cryoglobulinemia is due to the deposition of cryoglobulins in the glomeruli; however, the evidence is mainly indirect. Sinico et al. (S20) demonstrated that the IgM found in glomerular deposits shared the same cross-reactive idiotype of the circulating cry0 IgM rheumatoid factor in 11 of 13 patients with essential mixed cryoglobulinemia. Presumably, the deposition of IgM is responsible for the glomerular damage that occurs in these patients. The exact mechanism for the temperature-dependent precipitation of cryoglobulins is not completely understood. Most mixed cryoglobulins have rheumatoid factor activity and this probably involves two steps. First, prolonged exposure to an antigen results in the production of IgG antibodies and soluble IgG-antigen complexes. Second, mixed cry0 IgM autoantibodies develop that have an affinity to IgG at low temperatures. Large insoluble aggregates form in the cold.

MONOCLONAL GAMMOPATHIES

167

Low-molecular-weight IgM (7 S) is the monomeric subunit of pentomeric IgM (19 S). Increased amounts of 7 S IgM were found in six patients with mixed cryoglobulinemia but not in a group of healthy subjects. In three of four patients studied, the 7 S IgM was monoclonal and of the same light-chain type as the pentomer. In addition to monomers, there were oligomers of IgM, suggesting a disorder of IgM assembly in mixed cryoglobulinemia (R15). Mixed cryoglobulinemia may be associated with lymphoproliferative disorders. In one report, infiltration of liver portal tracts with lymphocytes that stained with the same immunoglobulin type as in the serum was noted in 9 of 12 patients with essential mixed cryoglobulinemia. The bone marrow biopsy specimens of most of these patients had multiple foci of plasmacytoid cells in a paratrabecular location. All patients were negative for hepatitis B surface antibody. The authors postulated that most cases of cryoglobulinemia represent a low-grade lymphomatous process (M29). It will be interesting to see whether any of these patients develop a symptomatic malignant lymphoproliferative process. It is difficult to ascertain the activity of disease in patients with mixed cryoglobulinemia. Gabrielli et al. (GI) found higher serum concentrations of the basement antigen-laminin fragment P1 (LPl )-in patients with mixed cryoglobulinemia than in normal controls. The patients with visceral involvement had higher levels than those with only vasculitis. Patients with inactive disease had lower levels. We must keep in mind that not all patients with mixed cryoglobulinemia have elevated levels of LP1 and that the level may be increased in patients with malignancy or liver disease. Hepatic dysfunction and serologic evidence of previous infection with hepatitis B virus are common (G1 1). Few prospective studies have evaluated therapy for mixed cryoglobulinemia. Oral corticosteroids are the most common therapeutic agents. If there is no response, cyclophosphamide, chlorambucil, or azathioprine may be helpful. Plasmapheresis ( plasma exchange) or a,-interferon has been effective in some instances. The physician must be aware that renal manifestations wax and wane and that spontaneous remissions may occur. 3 . 1 . 8 . Pyroglobulins

Pyroglobulins precipitate when heated to 56°C and do not dissolve when cooled. They resemble Bence Jones protein in that both precipitate when heated to 60°C, but the two can be distinguished easily by immunoelectrophoresis with appropriate antisera. In most cases, pyroglobulinemia is associated with multiple myeloma (M9), but it may also occur in macroglobulinemia, lymphoproliferative disorders, and other neoplastic diseases. Pyroglobulins are usually of the IgG class, but IgM (C4, P7) and IgA pyroglobulins have been reported (17, S29). IgD pyroglobulinemia was found in one patient with plasma cell leukemia who also had a h monoclonal urinary protein with pyroglobulin properties (T9).

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3.2. ANALYSIS OF

URINE

3.2.1. Detection of Protein Analysis of urine is essential for patients with monoclonal gammopathies. Sulfosalicylic acid or Exton’s reagent is best for the detection of protein. Sulfosalicylic acid detects albumin and globulins as well as Bence Jones protein, polypeptides, and proteases. Penicillin or its derivatives, tolbutamide metabolites, sulfisoxazole metabolites, and organic roentgenographic contrast media may produce false-positive reactions (L8). Dipstick tests are used in many laboratories to screen for protein. The dipstick produces a color change proportional to the amount of protein bound to it because it is impregnated with a buffered indicator dye that binds to protein. The dipsticks, unfortunately, are often insensitive to Bence Jones protein (H12, S3) and should not be used for the detection of these proteins. 3.2.2. Bence Jones Protein Screening tests for the detection of Bence Jones protein that utilize the protein’s unique thermal properties have been in use for many years. All have serious shortcomings, but the heat test of Putnam et al. (P26) is the simplest. Characteristically, monoclonal light chains in the urine (Bence Jones protein) precipitate at 40-60°C, dissolve at 100°C, and reprecipitate with cooling. Both false-positive and false-negative results occur. For example, the heat test may be positive even though the patient’s urine shows no evidence of a monoclonal light chain with electrophoresis, immunoelectrophoresis, or immunofixation. In this situation, the urine usually contains a broad-based y band and normal-appearing K and A arcs or bands. The positive heat test is due to an excess of polyclonal light chains. This result occurs in patients with renal insufficiency, connective tissue disorders, or nonplasma cell malignant disease (P13). However, the Bence Jones heat test may be negative when the electrophoretic pattern shows a narrow-based spike and immunoelectrophoresis or immunofixation has demonstrated a monoclonal light chain. Furthermore, the heat test is relatively insensitive and will not detect small monoclonal urinary light chains. It is obvious that the heat test for Bence Jones proteins has many shortcomings and is not recommended. The recognition of Bence Jones proteinuria depends on the demonstration of a monoclonal light chain by immunoelectrophoresis or immunofixation of an adequately concentrated urine specimen. 3.2.3. Electrophoresis Electrophoresis and immunoelectrophoresisor immunofixation of urine should be performed on all patients with a serum monoclonal protein. These tests should be done in all instances of multiple myeloma, macroglobulinemia of Waldenstrom, primary amyloidosis, large monoclonal gammopathies of undeter-

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169

mined significance, or heavy-chain diseases, or whenever these entities are suspected. lmmunoelectrophoresis or immunofixation of urine should also be done in all patients older than 40 years who have a nephrotic syndrome of unknown cause. A urinary monoclonal protein is seen as a dense, localized band on the cellulose acetate strip or as a tall, narrow, homogeneous peak on the densitometer tracing (Fig. 9). A monoclonal protein in the urine often produces a wider band than a monoclonal protein in the serum. Two discrete globulin bands may be seen in the cellulose acetate strip. These bands may represent a monoclonal light chain

FIG.9. Monoclonal urine protein. Top: Densitometer tracing showing a tall, narrow-based peak of f3 mobility. Bottom: Cellulose acetate electrophoretic pattern showing a dense band of f3 mobility. This is consistent with a monoclonal urine protein (Bence Jones protein). [From Kyle and Garton (K30). By permission of Grune & Stratton.]

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ROBERT A . KYLE AND JOHN A. LUST

plus a monoclonal immunoglobulin fragment from the serum or monomers and dimers of the monoclonal light chains (Fig. 10). A polyclonal increase of light chains is seen as a very broad band extending throughout most of the y region. It has fuzzy, indistinct cathodal and anodal borders. The densitometer tracing is broad based, and immunoelectrophoresis shows both K and A arcs. 3.2.4. Immunoelectrophoresis Immunoelectrophoresis establishes the presence or absence of light chains and determines whether they are monoclonal or polyclonal. It is not unusual to have a negative reaction for protein and to have immunoelectrophoresis of concentrated urine reveal a monoclonal light chain. In some cases in which electrophoresis of urine shows a large amount of albumin and insignificant amounts of globulin (nephrotic pattern), the urine will contain a monoclonal light chain. In most of these cases, the patient has primary systemic amyloidosis, although some patients may have light-chain deposition disease (F3). A monoclonal light chain in the urine is sometimes the first clue that the nephrotic syndrome is due to amyloidosis. Immunoelectrophoresis should also be done when there is a narrowbased peak or band in the globulin region of the cellulose acetate pattern. Immunoelectrophoresis of concentrated urine is performed with antisera to K and A and the appropriate heavy chain. Theoretically, antisera that recognize only free K and A light chains would be preferable. However, such antisera are often either nonspecific or not potent enough. In addition, a patient may have heavychain and light-chain fragments that free K and A antisera would not recognize. Therefore, it is advisable to use K and A antisera that are monospecific and potent and recognize both free and combined light chains. A monoclonal protein produces an arc with K or A antiserum that is bowed locally or restricted (Fig. 1l), whereas a polyclonal increase in light chain causes elongation and fuzziness of both kappa and lambda arcs. In renal insufficiency, faint, fuzzy, elongated K and A arcs are often seen, but if there is an underlying multiple myeloma or amyloidosis, an additional bowed or restricted arc with either K or A antisera may be seen. If electrophoresis of the urine reveals a localized globulin band and immunoelectrophoresis does not demonstrate a monoclonal light chain, one must suspect the presence of y heavy-chain disease. Immunoelectrophoresis should then be done with antisera to the Fc fragment of IgG (y heavy chains). Immunoelectrophoresis should be performed on the urine of any patient with suspected monoclonal gammopathy even if the sulfosalicylic acid test is negative for protein. Immunoelectrophoresis of a concentrated urine specimen may reveal a monoclonal light chain when the sulfosalicylic acid test is negative for protein and the electrophoretic pattern shows no globulin spike. Immunoelectrophoresis with monospecific antisera should be performed on the urine of every adult older

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FIG. 10. (A) Densitometer tracing of urine showing albumin, p, and y peaks. This pattern may represent monoclonal immunoglobulin plus free monoclonal light chains or monomers and dimers of monoclonal light chain. (B) Immunoelectrophoresis of concentrated urine shows dense IgG (y) arc (top), double bowing of K arc corresponding to IgG (y) and another K arc representing free monoclonal K chains (middle), and small amount of polyclonal A (bottom). This pattern is indicative of IgG K monoclonal protein plus free monoclonal K in urine. (C) Immunoelectrophoresis of urine of another patient with p and y peaks in electrophoretic pattern. IgG (y) (top) shows no arcs; antiserum to K (middle) shows normal-appearing K arc; antiserum to A (bottom) shows dense, doubly bowed A arc overwhelming the antisera. This pattern is consistent with monomers and dimers of monoclonal A light chain. [From Kyle, R. A,, and Greipp, P. R., series on clinical testing. 3. The laboratory investigation of monoclonal gammopathies. Mayo Cfin.Proc. 53,719-739 (1978). By permission of Mayo Foundation.]

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FIG. 1 I . Immunoelectrophoresis of urine. Bowed arc with K antiserum. This is indicative of a monoclonal K protein (Bence Jones protein). [From Kyle and Garton (K30).By permission of Grune & Stratton.]

than 40 years who develops a nephrotic syndrome of unknown cause. A monoclonal light chain in the urine is often the first clue that the nephrotic syndrome may be due to amyloidosis. 3.2.5. Immunojixation Immunofixation is more sensitive than immunoelectrophoresis for the detection of monoclonal light chains (W3) (Fig. 12). Immunofixation is most helpful when a monoclonal light chain occurs in the presence of a polyclonal increase in light chains (Fig. 13). It is also useful in detecting monoclonal heavy-chain fragments in the urine (Fig. 14). 3.2.6. Measurement of Bence Jones Protein The need for collection of a 24-hr urine specimen cannot be overemphasized. This allows measurement of the amount of Bence Jones protein (monoclonal light chain) excreted in the urine, which is an excellent indication of the effect of chemotherapy (M16) or evidence of progression of the disease. The amount of Bence Jones protein directly reflects the size of the plasma cell burden. It is also very useful in following the course of a patient with amyloidosis and nephrotic syndrome. The demonstration of a monoclonal protein in the urine (Bence Jones protein) requires electrophoresis and either immunoelectrophoresis or immunofixation of an adequately concentrated aliquot from a 24-hr urine specimen.

FIG. 12. Left: Immunoelectrophoresis (IEP) with A antiserum shows no diagnostic arc. Right: Immunofixation (IF) with A antisera shows a localized band.

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173

FIG. 13. Immunofixation of urine. Top: Normal-appearing band with IgG (y) antiserum. Middle: Normal-appearing band with K antiserum. Bottom: Dense, narrow band with A antiserum. Patient has monoclonal A protein (Bence Jones protein). [From Kyle and Carton (K30).By permission of Grune & Stratton.]

4. Monoclonal Gammopathy of Undetermined Significance

The term “monoclonal gammopathy of undetermined significance” denotes the presence of a monoclonal protein (M-protein) in persons without evidence of multiple myeloma, macroglobulinemia, amyloidosis, or other related diseases. The term “benign monoclonal gammopathy” is misleading because one does not know at the time of diagnosis whether a monoclonal protein will remain stable and benign or will develop into symptomatic multiple myeloma, macroglobulinemia, or amyloidosis. Since Waldenstrom’s introduction of the term “essential hyperglobulinemia” in 1952, many similar terms have been used, including idiopathic, asymptomatic, benign, nonmyelomatous, discrete, cryptogenic, and rudimentary monoclonal gammopathy; dysimmunoglobulinemia; lanthanic monoclonal gammopathy; idiopathic paraproteinemia; and asymptomatic paraimmunoglobulinemia. Waldenstrom (W 1) stressed the constancy of the size of the protein spike obtained by electrophoresis of serum, contrasting it with the increasing quantity of the monoclonal protein in myeloma.

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FIG. 14. Immunofixation of urine. Top: Narrow, localized band with IgA (a)antiserum. Middle: No reaction with K antiserum. Bottom: TWOdiscrete bands with A antiserum. Patient has monoclonal A protein plus IgA A fragment. [From Kyle and Garton (K30).By permission of Grune & Stratton.]

4.1. CHARACTERIZATION OF MGUS 4.1.1. Incidence During 1988, 808 patients were found with a serum M-protein at the Mayo Clinic (Table 2). The most frequent clinical diagnosis was MGUS (benign monoclonal gammopathy), occurring in two-thirds of patients (Table 3). MGUS is characterized by a serum M-protein concentration less than 3 g/dl, less than 5% plasma cells in the bone marrow, no or only a small amount of Mprotein in the urine, absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency, and, most importantly, stability of the M-protein and failure of development of other abnormalities. The incidence of monoclonal gammopathies without evidence of multiple

175

MONOCLONAL GAMMOPATHIES TABLE 2

SERUMM-PROTEINSAT MAYOCLINIC,1 9 8 8 ~ Protein

Percentage

60 10 20 0.1

7 3 Total

100

“n = 808.

myeloma, macroglobulinemia, amyloidosis, or related diseases is 3% of patients older than 70 years in Sweden (A8, H3), in the United States (K38), and in France (Sl). In Sweden, among 6995 normal persons more than 25 years old, the overall prevalence of M-protein was 1% (A8); among 1200 patients 50 years old or older who were residents of a small Minnesota community, 1.25% had an Mprotein (K38); and 303 (1.7%) of 17,968 adults 50 years old or older in Finistere, France, had an M-protein (Sl). An M-protein was detected in 1.2% of 73,630 patients hospitalized in the United States (V8). The incidence of monoclonal gammopathies increases with advancing age. In Finistere, France, 4% of 720 patients older than 80 years had an M-protein (S 1).

TABLE 3 OF MONOCLONAL GAMMOPATHIES: MAYOCLINIC,1988 DIAGNOSIS Diagnosis Monoclonal gammopathy of undetermined significance Multiple myeloma Primary systemic amyloidosis Lymphoma or other lymphoproliferative disease Waldenstrom’s macroglobulinemia Chronic lymphocytic leukemia Smoldering multiple myeloma Solitary or extramedullary plasmacytoma Total

Number

Percentage

560

64

122 70 51

14

8 6

21 22 14 13 873

100

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ROBERT A. KYLE AND JOHN A. LUST

In another study utilizing agarose gel electrophoresis, M-proteins were found in 11 (10%) of 111 patients older than 80 years in a population of ambulatory residents of a retirement home. Although the incidence of multiple myeloma is greater in the American black population than in the white population, the incidence of M-proteins is essentially the same (S6). In our past experience and in that of others, approximately 15% of M-proteins are of the IgM type. In contrast, in a study of 4193 patients with monoclonal gammopathies from three regions in France, Hurez et al. (H21) reported that 33% had IgM. There is no explanation for this unexpectedly high frequency of IgM . More sensitive techniques will detect a greater number of M-proteins. For example, Papadopoulos et al. (P4) detected homogeneous bands in the sera of 30 (5%) of 600 healthy adults who were 22-65 years of age. Immunoisoelectric focusing, a more sensitive technique, detected an M-protein in the sera of 11% of patients older than 45 years who were hospitalized for operation for a nonmalignant condition. Agarose electrophoresis detected an M-protein in only 2% of that population (S19). It is important to both the patient and the physician to determine whether the M-protein will remain benign or will progress to multiple myeloma, amyloidosis, macroglobulinemia, or other lymphoproliferative disease, given that the prevalence of MGUS is considerable. 4.1.2. Mayo Clinic Study We reviewed the medical records of all patients with monoclonal gammopathy who were seen at the Mayo Clinic before January 1, 1971. Patients with multiple myeloma, macroglobulinemia, amyloidosis, lymphoma, or related diseases were excluded. Two hundred forty-one patients remained for long-term study. The median age of the patients was 64 years; 4% were younger than 40 years and 33% were 70 years or older when the M-protein was recognized. 4.1.2.1. Physical Examination. The liver was palpable in 15% of patients and the spleen was palpable in 4%. In those with hepatosplenomegaly 5 cm or more below the costal margin, the causes were congestive heart failure, myelofibrosis with myeloid metaplasia, cirrhosis, or other conditions not directly related to the monoclonal gammopathy. 4.1.2.2. Hematologic and Chemistry Values. Anemia was not a feature of the monoclonal gammopathy. The hemoglobin level at initial evaluation ranged from 7.2 to 16.6 g/dl. In the nine patients whose hemoglobin value was less than 10 g/dl, melena, myeloid metaplasia, myeloproliferative disease, Wegener’s granulomatosis, hypoplasia of bone marrow, chronic cold agglutinin disease, and hypernephroma were responsible. The leukocyte count was less than 20W/mm3 in only one patient (lupus erythematosus); it exceeded 20,WO/mm3 in two patients (one with an undifferentiated myeloproliferative process and the other with

MONOCLONAL GAMMOPATHIES

177

myeloid metaplasia). Thrombocytopenia was uncommon. In the five patients with a platelet count less than 100,000/mm3, the causes were myeloid metaplasia, acute leukemia, idiopathic thrombocytopenic purpura, lupus erythematosus, and hypoplasia of the bone marrow. Platelet counts more than 500,000/mm3 occurred in only two patients (one with pneumonitis and one with rectal bleeding). Five patients had a serum creatinine concentration of more than 2.0 mg/dl-this was related to nephrosclerosis in three, diabetes mellitus in one, and uric acid nephropathy in one. The serum albumin concentration was less than 2 g/dl in two patients-one with Wegener’s granulomatosis and the other with a hypernephroma. The median serum albumin value of the 241 patients was 3.2 g/dl. Only two patients had hypercalcemia, and both had hyperparathyroidism. 4.1.2.3. Serum Electrophoresis and Immunoelectrophoresis. The M-protein migrated in the y area in 77% of patients and in the p region in 20%. Electrophoresis revealed a broad-based polyclonal-appearing peak in three patients and no discrete spike was seen in two others, but immunoelectrophoresis revealed a monoclonal protein in all five. The size of the M-protein ranged from 0.3 to 3.2 g/dl (median, 1.7 g/dl). Immunoelectrophoresis revealed IgG (74%), IgA (lo%), and IgM (16%). The monoclonal light-chain type was K in 63% and A in 37%. A biclonal gammopathy was found in five patients (2.1%); they were classified according to their major M-protein component. The heavy-chain class and lightchain type and the electrophoretic mobility of the M-protein did not change throughout the period of observation. Of 184 patients, 52 (28%) had a decrease in uninvolved (background) immunoglobulins. The subclass was IgGl in 86%, IgG2 in 4%, IgG3 in 4%, and IgG4 in 6%. 4.1.2.4. Urinary Electrophoresis and Immunoelectrophoresis. These studies were performed in less than half the patients because they are frequently not done if the serum M-protein is small or if no proteinuria is found on routine urinalysis. Fifteen patients had a urinary monoclonal light chain at the time of recognition of the monoclonal gammopathy-the light chain was K in nine and A in six. In all but three patients, the M-protein was 1 g or less per 24 hr. A bone marrow aspirate was done in 109 patients at the time of recognition of the M-protein. The percentage of plasma cells ranged from 1 to 10% (median, 3%). 4.1.2.5. Associated Diseases. No diseases or abnormalities other than the Mprotein were found at diagnosis in 25.7% (Table 4). Inflammatory disorders were found in 26 patients, including 4 with fever of undetermined origin that had been present intermittently for 4 to 22 years, 3 with recurrent deep-vein phlebitis, 2 with chronic inflammatory bowel disease, and 1 with sprue. Sixteen patients had a malignancy (one had acute leukemia and another had Kaposi’s sarcoma). Of the 15 patients with neurologic disorders, 5 had carpal tunnel syndrome and still were alive without systemic amyloidosis. One had the Guillain-Barr6 syndrome.

178

ROBERT A. KYLE AND JOHN A. LUST TABLE 4 MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE: PRESENT AT DISCOVERY OF SERUM MONOCLONAL DISEASES PROTEIN Cases ~

Disease None Cardiovascular or cerebrovascular Inflammatory Malignant Neurologic Connective tissue Hematologic Endocrine Benign tumor Miscellaneous Total

Number

Percentage

62 31 26 16 I5 14 9 9 8 51

25.1 12.9 10.8 6.6 6.2 5.8 3.1 3.1 3.3

24 I

100.0

21.1

The connective tissue disorders occurring in 14 patients included rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, and scleroderma. Nine patients had a hematologic disease [two had myelofibrosis with myeloid metaplasia, two had idiopathic thrombocytopenic purpura, and one each had von Willebrand’s disease, hypoplastic anemia, aregenerative anemia (red cell aplasia), undifferentiated myeloproliferative disease, and idiopathic neutropenia]. Of the nine patients with endocrine disorders, three had hyperparathyroidism, three had idiopathic osteoporosis, and one each had Cushing’s disease, Graves’ disease, and Turner’s syndrome. Benign thyroid nodules and colonic polyps were also seen. Among the miscellaneous disorders were psychoneurosis, hyperventilation syndrome, duodenal ulcer, melena, pruritus, diabetes, Peyronie’s disease, and plane xanthoma. 4.1.2.6. Findings at Follow-up 4.1.2.6.1. Group 1 (Stable; 57 Patients, 24%). At current follow-up (median, 19 years; range, 11-32 years), the number of patients whose M-protein had remained stable and could be classified as “benign” monoclonal gammopathy had decreased to 57 (24%)(K34). Seventeen patients had been followed for 20 or more years without developing myeloma, macroglobulinemia, amyloidosis, or lymphoproliferativedisease. The M-protein disappeared from the serum in two patients-IgG K and IgA K; in the one with IgG K, it gradually decreased and disappeared at 17 years. In a third patient, the IgG A protein became undetectable for 2 years but then reappeared and has not changed significantly. The level of

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179

hemoglobin, size of the serum M-protein, and the number of plasma cells in the bone marrow did not differ substantially in the stable or benign group from those in the total group. In four patients, a monoclonal light chain was found in the urine (K in two and A in two). One of these patients had grade 3-4 proteinuria for 31 years. The urinary monoclonal K light chain excretion was 1.5 g/24 hr and has remained stable for the past 13 years. His serum M-protein level has been approximately 2.6 g/dl for 24 years. Renal failure has not developed. A second patient has had a persistent small monoclonal K protein in the urine for 12 years without change. A third patient had a small monoclonal A protein in the urine that disappeared after 2 years but reappeared 17 years later. A fourth patient had a small monoclonal A protein, but this disappeared and has not recurred. These patients have been left in group 1 because the urinary protein has not increased during the period of observation, the serum protein has remained stable, and there is no evidence of serious disease. Although these 57 patients have been followed for a median of 19 years, they must continue to be observed because serious disease is still developing. 4.1.2.6.2. Group 2 (Increase in M-Protein Only; Seven Patients, 3%). The M-protein increased to more than 3 g/dl in seven patients (3%)(4 g/dl or more in two patients). The range of increase was 1.1-2.3 g/dl (median, 1.5 g/dl). However, these patients did not develop symptomatic multiple myeloma, macroglobulinemia, or other disease and have not been treated. The median interval from the recognition of the M-protein to the maximal increase was 19.4 years (range, 11-28 years). The median interval from the recognition of the M-protein to the level of 3.0 g/dl ranged from 0.8 to 23 years (median, 1 1 years). Of the 13 patients in group 2 at the last major evaluation (K28), three had developed serious disease (multiple myeloma, macroglobulinemia, and amyloidosis, one each) and were transferred to group 4 and two had died of unrelated disease (one had a serum M-protein of 4 .6 gldl, but she was asymptomatic and there was no evidence of active multiple myeloma at autopsy). The M-protein decreased in four patients, and they were transferred to group 1 . Four patients remain in group 2. The usual pattern of increase of M-protein was gradual, but there was waxing and waning of the protein level, both before and after the maximal level was attained. No patient whose M-protein was stable for a longer period had a sudden increase. A monoclonal light chain was detected in the urine of four patients, but the level was less than 300 mg/24 hr in all four. The level did not increase during observation; in one patient the protein disappeared. Urinary M-protein was not found in the three remaining patients despite multiple determinations. 4.1.2.6.3. Group 3 (Died without Development of Myeloma, Macroglobulinemia, Amyloidosis, or Related Disease; 124 Patients, 51 %). The me-

180

ROBERT A. KYLE AND JOHN A. LUST TABLE 5 CAUSESOF DEATHOF PATIENTS WITHMONOCLONAL OF UNDETERMINED SIGNIFICANCE GAMMOPATHY Cause of death

Number

Percentage

Cardiac Cerebrovascular

43 18

35 14

Malignancy Infection Renal failure Miscellaneous Unknown

17 13

'4

6 20 7

10 5 16 6

Total

124

100

dian interval from diagnosis of the serum M-protein to death of the 124 patients (51%) was 7.9 years (range, 0-24.5 years). Forty-eight patients (39%)survived more than 10 years after the M-protein was found. Fifteen (12%)of the 124 patients developed a serum M-protein of 3.0 g/dl or more during observation, but none had multiple myeloma or macroglobulinemia that required therapy. Cardiac disease was the most frequent cause of death, followed by cerebrovascular disease and malignancy (Table 5). 4.1.2.6.4. Group 4 (Developed Multiple Myeloma, Macroglobulinemia, Amyloidosis, or Related Diseases; 53 Patients; 22%). Multiple myeloma, macroglobulinemia, amyloidosis, or a malignant lymphoproliferative process developed in 53 patients (actuarial rate was 17%at 10 years and 33% at 20 years) (Fig. 15). Of these 53 patients, 36 (68%)had multiple myeloma. All but two patients had a bone marrow aspirate or biopsy specimen that contained more than 15% abnormal plasma cells at the time of diagnosis of multiple myeloma. Of the two exceptions, one had a paravertebral mass with destruction and collapse of T-5, and the other had a large destructive plasmacytoma of the sacrum. Of the 36 patients with myeloma, 29 had serum M-protein levels of more than 3 g/dl. An M-protein was found in the urine of 18 patients. All but four patients had anemia. Lytic bone lesions were recognized in 16 patients, osteoporosis and compression fractures in 3, destructive bone lesions in 2, osteoporosis in 1, and a large extradural plasmacytoma (producing paralysis) in 1. These findings fulfill the criteria for the diagnosis of multiple myeloma. The interval from the time of recognition of the monoclonal gammopathy to the diagnosis of multiple myeloma ranged from 23 to 25 1 months [median, 115 months (9.6 years)]. The median survival after the diagnosis of multiple myeloma was 35 months. The myeloma developed either gradually or abruptly. In

181

MONOCLONAL GAMMOPATHIES

50

r -

(33%)

-

I

10

0

I

I

1

I

J

FIG. 15. Incidence of multiple myeloma, macroglobulinemia, arnyloidosis, or lyrnphoproliferative disease after recognition of monoclonal protein.

19 patients, the M-protein was stable for 5-20.8 years, after which multiple myeloma developed abruptly or gradually during periods up to 6 years. In seven other patients, the M-protein was stable for 11-41 months before multiple myeloma developed. Data on the development of myeloma in the remaining patients were inadequate. Macroglobulinemia of Waldenstrom developed in seven patients. The median interval from the recognition of the M-protein to the diagnosis of macroglobulinemia was 8.5 years. Six of the patients had serum levels of IgM K monoclonal protein that ranged from 3.1 to 8.5 g/dl during the course of the disease. One patient had a biclonal gammopathy (IgM K and IgA K). All patients had anemia, and their bone marrow aspirates or biopsies or autopsy specimens showed increased numbers of lymphocytes and plasma cells. In five patients, the number of serum protein determinations during the development of macroglobulinernia was not sufficient to determine whether the onset of the disease was gradual or abrupt. In the sixth patient, the serum M-protein level was stable for 5 years and then increased gradually for 3 years before symptomatic macroglobulinemia occurred. The M-protein slowly progressed from the time of recognition in the seventh patient. Primary systemic amyloidosis (AL) was found in seven patients 6 to 16.5 years after the recognition of the M-protein (median, 8 years). Histologic evidence of amyloidosis was present at autopsy in three cases and by renal biopsy in two, lymph node biopsy in one, and rectal biopsy in one. One patient with lupus erythernatosus had a biclonal garnmopathy (IgG A and IgM K). Seven years later, an aggressive, diffuse, undifferentiated malignant

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ROBERT A. KYLE AND JOHN A. LUST

lymphoma developed, and the patient died. Another patient experienced anorexia, lost weight, and had generalized bone pain 22 years after the recognition of an IgM A monoclonal gammopathy. A bone marrow examination revealed an immunoblastic lymphoma with plasmacytic differentiation. A computed tomography scan showed extensive retroperitoneal lymphadenopathy. The spinal fluid contained large malignant-appearing lymphocytes. The patient failed to respond to chemotherapy and died 1 month later. In another patient, chronic lymphocytic leukemia developed after 56 months of observation, but the monoclonal gammopathy did not increase. Four courses of chlorambucil were given for recurrent lymphocytosis. The IgM K gammopathy remained stable for 16 years and probably was not directly related to the chronic lymphocytic leukemia. The patient died 18.5 years after recognition of the monoclonal gammopathy. The serum M-protein did not increase in 10 of the 53 patients: 1 had multiple myeloma and a small monoclonal IgA K (1.8 g) but a large increase in urinary light chain (0.7 to 3.2 g/24 hr), 6 had amyloidosis, 1 had chronic lymphocytic leukemia, and 2 had lymphoma. Five of the 10 patients had an IgM monoclonal gammopathy. 4.1.2.7. Analysis by Immunoglobulin Group. Of the 241 patients in the study, 53 (22%)developed multiple myeloma, macroglobulinemia, amyloidosis, lymphoma, or chronic lymphocytic leukemia (group 4). The actuarial rate of development of serious disease in the patients with an IgG or an IgA monoclonal protein was 13% at 10 years and 29% at 20 years (Fig. 16). The actuarial rate of

8

40 50

L C l

8

.-rn

s B

F -

20

-

10

-

0 0

(29%)

I

I 1

I

I

5

10

15

20

Years FIG. 16.

Incidence of serious disease in patients with an IgG or IgA monoclonal protein.

183

MONOCLONAL GAMMOPATHIES

0

5

10

15

20

Years FIG. 17. Incidence of serious disease in patients with an IgM monoclonal protein.

development of a serious disease in patients with an IgM monoclonal protein was 21% at 10 years and 49% at 20 years (Fig. 17). In addition, seven (3%) had an M-protein value of 3.0 g/dl or more during follow-up but did not develop symptomatic multiple myeloma or other serious disease. The 60 patients who developed a serious plasma cell proliferative process or an M-protein of more than 3 g/dl accounted for 23% of those with IgG or IgA and 37% of those with IgM. 4.1.2.8. Results of Long-Term Follow-up in Other Series. During a 20-year follow-up of 64 Swedish patients with an M-protein in a survey of 6995 patients, Axelsson (A7) reported that 2 had died of multiple myeloma and 1 had died of malignant lymphoma. Three of the 19 surviving patients had shown an increase in the M-protein, and a fourth patient had shown a large monoclonal IgA K protein and then developed Bence Jones proteinuria (5 g/liter). A tentative diagnosis of multiple myeloma was made, but treatment was not necessary. Thus, 11% of the patients with long-term follow-up had evidence of some progression of their “benign” monoclonal gammopathy. In another series, 4 of 20 patients with asymptomatic monoclonal gammopathy for 3 to 14 years developed malignant disease during follow-up (F8). Manthorne et al. (M5) reported that 8 patients developed multiple myeloma and 2 had amyloidosis during a follow-up of 1-17 years (median, 3 years) in 113 patients with MGUS. In another group of 313 patients with idiopathic monoclonal gammopathy, 48 (15%) developed a malignant B-cell disorder during a follow-up of 5 years or more. The malignancy was detectable 63 months (range, 27-38 months) after the recognition of the

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ROBERT A. KYLE AND JOHN A. LUST

monoclonal protein. The authors stated that this outcome in none of the patients who developed a malignant transformation could be recognized in advance (Pl).

5. Differentiation of MGUS from Multiple Myeloma and Macroglobulinemia

Patients with MGUS have less than 3 g/dl of M-protein in the serum and no or small amounts of Bence Jones proteinuria, usually less than 5% plasma cells in the bone marrow aspirate or biopsy, a normal serum albumin level, and no anemia, hypercalcemia, renal insufficiency, or osteolytic lesions unless caused by other diseases. N o increase in the M-protein level or development of features of a plasma cell lymphoproliferative disease during long-term follow-up is proof that a patient has MGUS. In contrast to patients with MGUS, patients with smoldering multiple myeloma (SMM) have a serum M-protein level greater than 3 g/dl and more than 10% atypical plasma cells in the bone marrow. Frequently, they have a small amount of monoclonal light chain in the urine and a reduction of uninvolved immunoglobulins in the serum. These findings are consistent with those in multiple myeloma. However, anemia, renal insufficiency, and skeletal lesions do not develop, and the patient’s M-protein level in the serum and in urine and the bone marrow plasma cells remain stable. Furthermore, the plasma cell labeling index is very low. Therefore, these patients have a benign monoclonal gammopathy, but it is not possible to make this diagnosis when the patient is initially seen because most patients with this level of bone marrow plasma cells and M-protein in the serum and urine have symptomatic myeloma. Patients with SMM should not be treated unless laboratory abnormalities progress or symptoms of myeloma develop (K32). Differentiation of the patient with “benign” monoclonal gammopathy from one in whom myeloma or macroglobulinemia eventually develops is very difficult when the M-protein is first recognized. The size of the monoclonal protein is of some help-higher levels are associated with a greater likelihood of malignancy (M27). The presence of a serum M-protein of more than 3 g/dl usually indicates overt multiple myeloma or macroglobulinemia, but some exceptions such as SMM do exist. 5.1. NORMALPOLYCLONAL IMMUNOGLOBULINS Levels of immunoglobulin classes not associated with the M-protein (normal polyclonal or background immunoglobulins) may help in differentiating benign from malignant gammopathies. In most patients with multiple myeloma, the levels of polyclonal (normal or uninvolved) immunoglobulins are reduced, al-

MONOCLONAL GAMMOPATHIES

185

though a similar reduction of background immunoglobulins in patients with benign monoclonal gammopathy also may occur. Peltonen er al. (P11) emphasized that the background or uninvolved immunoglobulins were decreased in 88% of patients with a lymphocytic or plasmacytic cell neoplasm, but these immunoglobulins were also reduced in 38% of patients with benign monoclonal gammopathy. Consequently, levels of uninvolved immunoglobulins are not a reliable differentiating feature.

5.2. BENCEJONESPROTEINURIA The association of a monoclonal light chain (Bence Jones proteinuria) with a serum M-protein is suggestive of a neoplastic process. In a study of 42 patients with benign monoclonal gammopathy, Dammacco and Waldenstrom (D2) reported a weakly positive response to the Bence Jones heat test in one case and small amounts (less than 60 mg/liter) of light chains in 10 cases. Lindstrom and Dahlstrom (L7) found that 40% of their patients with “benign monoclonal gammopathy” had a monoclonal light chain in the urine. We have also seen many patients with a small monoclonal light chain in the urine and an M-protein in the serum whose conditions have remained stable for many years. 5.3. BONEMARROWPLASMA CELLS The presence of more than 10% plasma cells in the bone marrow is suggestive of multiple myeloma, but some patients with a greater degree of plasmacytosis have remained stable for long periods. Bone marrow plasma cells in multiple myeloma are often atypical, but these morphologic features also may be seen in MGUS and SMM. The assessment of nuclear cytoplasmic asynchrony (B16) has been proposed to help differentiate benign from malignant disease, but in our experience, plasma cell nucleolar size, grade, and asynchrony are of limited use in differentiating MGUS from multiple myeloma (G14). The light-chain ratio (number of positively reacting plasma cells for the predominant light chain divided by the number of positively reacting plasma cells for the majority light chain) may be helpful in the differentiation of multiple myeloma from MGUS (P14). Although the presence of osteolytic lesions is strongly suggestive of multiple myeloma, metastatic carcinoma may produce lytic lesions as well as plasmacytosis and be associated with an unrelated monoclonal gammopathy. 5.4. BONEMARROWPLASMA CELLLABELING INDEX The plasma cell labeling index measures the synthesis of DNA and is helpful in differentiating the patient with MGUS or SMM from the patient with multiple myeloma. An elevated plasma cell labeling index is good evidence that the

186

ROBERT A. KYLE AND JOHN A. LUST

patient has multiple myeloma or will soon have symptomatic myeloma. We have developed a monoclonal antibody (BU- 1) reactive with 5-bromo-2-deoxyuridine (BrdUrd) in mice (G9). Bone marrow plasma cells are exposed to BrdUrd for 1 hr. Cells synthesizing DNA will incorporate BrdUrd, which is recognized by the BU- 1 monoclonal antibody that is conjugated to goat antimouse immunoglobulin-rhodamine complex. Staining with propidium iodide identifies the cells incorporating BrdUrd in S phase. The BU-1 monoclonal antibody does not require denaturation for its activity. Consequently, use of fluorescein-conjugated immunoglobulin antisera (K and A) identifies monoclonal plasma cells and plasmacytoid lymphocytes. An immunofluorescent labeling index can be performed in 4 or 5 hr and is a practical aid for assisting with therapeutic decisions. We believe that the immunofluorescent plasma cell labeling technique is superior to the [3H]thymidine method (G15).

5 . 5 , PERIPHERAL BLOODLABELING INDEX

Currently, we also perform the plasma cell labeling index on peripheral blood. Mononuclear cells are isolated on Ficoll-Hypaque and incubated with BrdUrd. Cytocentrifuge slides are prepared. After staining with BU-1 and goat antimouse IgG labeled with rhodamine isothiocyanate, the cells are stained with K and A antisera, and a 500-cell count of peripheral blood B cells bearing the same cytoplasmic light-chain isotype as the M-protein is done. The median peripheral blood labeling index was 0.2% for 29 patients with MGUS or SMM, 0.8% for 35 patients with new, untreated multiple myeloma, and 1.7% for 41 patients with multiple myeloma in relapse. Four patients had an elevated index but clinically inactive disease at the time of study; all developed active multiple myeloma, requiring chemotherapy within 6 months. There was a good correlation of the peripheral blood labeling index with the bone marrow labeling index of 92 patients in whom the tests were performed simultaneously (W7).

5.6. MISCELLANEOUS Levels of P,-microglobulin are not helpful in differentiating benign monoclonal gammopathy from low-grade multiple myeloma because there is too much overlap between the two entities (G3). Neither the presence of J chains in malignant plasma cells (B8) nor the acid phosphatase levels in plasma cells are reliable for differentiation (T6). Reduced numbers of OKT4+ T cells (S25), increased numbers of monoclonal idiotype-bearing peripheral blood lymphocytes (C2), and increased numbers of immunoglobulin-secreting cells in peripheral blood are characteristic of multiple myeloma (S14), but there is overlap with MGUS.

MONOCLDNAL GAMMOPATHIES

187

5.7. FOLLOW-UP If the serum M-protein concentration is less than 2.0 g/dl, electrophoresis should be repeated 6 months later, and if the concentration is stable, electrophoresis should be repeated annually thereafter. If the M-protein value is 2.0 g/dl or more and there is no evidence of myeloma, macroglobulinemia, or amyloidosis, electrophoresis should be repeated in 3 months. If the M-protein level is stable, electrophoresis should be repeated in 6 months, and if there is no progression, electrophoresis should be performed annually thereafter. If the M-protein level increases by more than 0.5 g/dl, immunoelectrophoresis of a 24-hr urine specimen and hemoglobin, calcium, and creatinine determinations should be done. If abnormalities are found, bone marrow and roentgenographic examinations are indicated. If an M-protein is present in the urine, the patient should be followed more closely. In summary, there is no single reliable technique for differentiating a patient with a benign monoclonal gammopathy from one who subsequently will develop symptomatic multiple myeloma or other malignant disease. The most reliable means of differentiating a benign from a malignant course is the serial measurement of the M-protein level in the serum and urine and periodic reevaluation of clinical and laboratory features to determine whether multiple myeloma, systemic amyloidosis, macroglobulinemia, or other malignant lymphoplasma cell proliferative disease develops.

6. Association of Monoclonal Gammopathies with Other Diseases

Although monoclonal gammopathy frequently exists without other abnormalities, certain diseases are associated with it, as would be expected in an older population. The association of two diseases depends on the frequency with which each occurs independently. Furthermore, there may be an association because of differences in the referral practice or in other selected patient groups. The investigator must use valid epidemiologic and statistical methods in evaluating these associations. The need for appropriate control populations cannot be overemphasized. For example, the association of monoclonal gammopathy and hyperparathyroidism has been reported (D9, S8). In an effort to clarify the relationship of hyperparathyroidism to monoclonal gammopathies, we reviewed our cases of surgically proved parathyroid adenoma in which serum protein electrophoresis had been done within the 6 months preceding parathyroidectomy. Among 911 patients who met these criteria and were older than 50 years, immunoelectrophoresis revealed MGUS in 9 (1%) (M32). This prevalence of MGUS is

188

ROBERT A. KYLE AND JOHN A. LUST

similar to the 1.25-1.7% found in studies of three normal populations (A8, K38, Sl). Thus, the association of hyperparathyroidism and MGUS seems to be due to chance alone. An increased prevalence of monoclonal gammopathy in association with carcinoma of the colon has been reported on several occasions. However, in two large studies (M24, T2), the prevalence of monoclonal gammopathies was no greater than that expected in a population of similar age. These studies demonstrate the need for comparison with an adequate control population before it can be assumed that an association exists between monoclonal gammopathy and any disease. 6.1. LYMPHOPROLIFERATIVE DISORDERS In 1957, Azar er al. (A9) reported that malignant lymphoma and lymphocytic leukemia were associated with a myeloma-type serum protein. In 1960, Kyle et al. (K37) described six patients with lymphoma who had serum or urine electrophoretic patterns suggestive of multiple myeloma. The presence of M-proteins in patients with lymphoma was confirmed by Krauss and Sokal (K25), who emphasized the frequency of P2-M (IgM). In a report published that same year, Hallen (H4) described five patients with reticulum cell sarcoma and a serum Mcomponent. Kim et al. (K14) also noted IgM monoclonal proteins in patients with malignant lymphoproliferative diseases. Moore et al. (M30) found an IgM monoclonal gammopathy in the serum in 3.6% of 526 patients with diffuse lymphoma but in only 2 of 40 patients with nodular lymphoma. Among 1150 patients with lymphoma, Alexanian (A3) recognized M-proteins in 49. M-proteins were detected in 29 (4.5%) of the 640 patients with diffuse lymphoproliferative disease (chronic lymphocytic leukemia, lymphocytic lymphoma, and reticulum cell sarcoma) but in none of the 292 patients with a nodular lymphoma. Hobbs et al. (H15) reported that two-thirds of their patients with an IgM protein had a diffuse histologic pattern and only 13% had a follicular pattern. Pangalis et al. (P3) found an M-protein in 20 of 108 patients with a well-differentiated lymphocytic lymphoma. Bain and Belch (B2) concluded that the association of nodular lymphoma and a serum M-protein was rare. IgM monoclonal gammopathies are more common than IgG or IgA gammopathies in patients with lymphoproliferative disease. KO and Pruzanski (K22) detected an IgM protein in 33 of 62 patients with lymphoma who had an M-protein in their serum. Similarly, Magrath et al. (M2) found IgM proteins with agarose gel electrophoresis and immunofixation in the sera of 12 of 21 patients with undifferentiated lymphoma of Burkitt’s and non-Burkitt’s types. These proteins disappeared after therapy but reappeared at relapse. We reviewed the medical records of 430 patients in whom a serum IgM monoclonal gammopathy had been identified between 1956 and 1978 at the

189

MONOCLONAL CAMMOPATHIES TABLE 6 OF IcM MONOCLONAL CAMMOPATHIES CLASSIFICATION AMONG430 PATIENTS Patients Classification Monoclonal gamrnopathy of undetermined significance Waldenstrom’s macroglobulinernia Lymphoma Chronic lymphocytic leukemia Primary arnyloidosis Lymphoproliferative disease Total

Number 242 71 28 21 6 62 430

Percentage 56 17 7 5 I 14

I00

From Kyle and Carton (K31). [By permission of Mayo Foundation.]

Mayo Clinic (Table 6). Patients were classified as follows: (1) Waldenstrom’s macroglobulinemia-these patients had an IgM spike of 3.0 g/dl or more in the serum protein electrophoretic pattern and an increase in lymphocytes or plasmacytoid lymphocytes in the bone marrow; (2) lymphoma-on initial examination, these patients had lymphadenopathy or an extranodal lymphoid tumor, and biopsy findings were consistent with a lymphoma; (3) chronic lymphocytic leukemia-these patients had a lymphocyte count of more than 9000/mm3; (4) primary amyloidosis-these patients had histologic proof of amyloid on a biopsy specimen of appropriate tissue; ( 5 ) MGUS-these patients had an IgM protein value less than 3.0 g/dl, no constitutional symptoms, no hepatosplenomegaly or lymphadenopathy, and no anemia and required no chemotherapy; and (6) malignant lymphoproliferative disease-these patients could not be classified in the foregoing categories; they had an IgM protein value less than 3.0 g/dl and usually had bone marrow infiltration with lymphocytes or plasmacytoid lymphocytes and required therapy because of anemia or constitutional symptoms. More than half of the patients with an IgM monoclonal protein had MGUS. It was of interest to find that the development of a malignant disease was similar to that in our original group of 241 MGUS cases. During follow-up, 40 of the 242 patients (17%) with MGUS of the IgM class developed a malignant lymphoid disease (Table 7). Twenty-two patients developed Waldenstrom’s macroglobulinemia, nine others had a malignant lymphoproliferative process requiring chemotherapy, and six others developed lymphoma. The median duration from the recognition of the IgM protein until the diagnosis of lymphoid disease was more than 4 years (range, 0.4-22 years). The median duration of survival after

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ROBERT A. KYLE AND JOHN A. LUST

TABLE I DEVELOPMENT OF MALIGNANT LYMPHOID DISEASES I N 40 OF 242 PATIENTS WITHMONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE Subsequent diseasea

Number of cases Duration until progression (years) Median Range

WM

LY

CLL

AL

LP

22

6

1

2

9

8.0 1.8-16.3

6.8 4.8-21.9

9.2 9.2

4.3 2.4-6.1

4.2 0.4-12.0

UAbbreviations: AL, primary amyloidosis; CLL, chronic lymphocytic leukemia; LP, malignant lymphoproliferative disease; LY, lymphoma; WM, Waldenstrom’s macroglobulinemia. [From Kyle and Garton (K31). By permission of Mayo Foundation.]

the diagnosis of Waldenstrom’s macroglobulinemia in these 22 patients was 6.5 years. This duration is similar to that in patients with Waldenstrom’s macroglobulinemia at presentation. In addition, 10 patients with MGUS (4%)had an increase in serum M-protein of more than 1.0 g/dl, and nine others had an increase of 0.5-0.9 g/dl. None of these 19 patients developed symptomatic Waldenstrom’s macroglobulinemia, malignant lymphoproliferative disease, or lymphoma. Currently, 14 of the 19 patients are alive and under observation. More than two-thirds of the 430 patients with IgM monoclonal gammopathy have died. The median survivals of patients with Waldenstrom’s macroglobulinemia and of those with a malignant lymphoproliferative disease were similar (5 and 5.5 years, respectively) (Fig. 18). Although the size of the serum M-protein in patients with Waldenstrom’s macroglobulinemia differs from that in patients with lymphoproliferative disease, survival was virtually the same for both groups. It is evident that patients with Waldenstrom’s macroglobulinemia and lymphoproliferative disease who have lymphocytic proliferation of the marrow producing constitutional symptoms or anemia requiring chemotherapy are not different. Consequently, no rationale exists for differentiating patients with lymphoproliferative disease from those with Waldenstrom’s macroglobulinemia. They can be combined in future prospective studies of Waldenstrom’s macroglobulinemia (K3 1). Although an increase of polyclonal immunoglobulin is common in angioimmunoblastic lymphadenopathy (S5), an M-protein may be seen (01). Investigators at the National Institutes of Health estimated that 2% of patients with angioimmunoblastic lymphadenopathy had a monoclonal gammopathy (S28). Angiofollicular lymph node hyperplasia (Castleman’s disease) may be associated with an M-protein (G8, H13). Sugai et al. (S30) reported that 5 of 10 Japanese patients

191

MONOCLONAL GAMMOPATHIES 100 hronic lymphocytic leukemia (CLL)

80

$! 60 ci, C .-

Waldensirom s macroglobulinemla (WM)

>

.$

40

(I)

20

0

0

3

6

9

12

15

18

Years from diagnosis FIG. 18. Survival of patients with various IgM monoclonal gammopathies. [From Kyle and Garton (K31). By permission of Mayo Foundation.]

with Sjogren’s syndrome had an IgA monoclonal protein. Two patients with Sjogren’s disease and M-protein in the serum subsequently developed a malignant lymphoma (H20). Kaposi’s sarcoma has been associated with a serum M-protein (B10). 6.2. LEUKEMIA M-proteins have been found in the sera of patients with leukemia (K29). We described 100 patients with chronic lymphocytic leukemia and an M-protein in the serum or urine (N6). IgG accounted for 51% and IgM for 28%. The median concentration of M-protein was 1.0 g/dl. There were no major differences in patients with chronic lymphocytic leukemia on the basis of whether they had an IgG or an IgM M-protein. There is no evidence that IgG or even IgM monoclonal proteins are directly related to chronic lymphocytic leukemia. Sinclair et al. (S18), using immunoisoelectric focusing, found that 34 of 56 (61%) patients with chronic lymphocytic leukemia had an M-protein in the serum; 88% were IgM. Monoclonal gammopathies have been recognized in hairy-cell leukemia (52). Matsuzaki et al. (M14) described three patients with monoclonal gammopathy and adult T-cell leukemia. Buonanno et al. (B27) described a patient with Ph’positive chronic myelogenous leukemia who developed a monocytic blast cell transformation associated with an IgG A protein (R9). An IgG K M-protein was

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ROBERT A. KYLE AND JOHN A. LUST

recognized in the serum and on the surface of leukemic cells of a patient with acute promyelocytic leukemia. The blast cells did not appear to secrete the monoclonal protein (A6). Transient M-proteins have been reported with acute myelomonocytic leukemia (V2). We have also seen several patients who had chronic granulocytic leukemia and an M-protein in their sera. Data are inadequate to determine whether the incidence of an M-protein is greater in patients with leukemia than in a normal population. 6.3. OTHERHEMATOLOGIC DISEASES Paraproteins have been reported with many different hematologic diseases, including pernicious anemia (S 10) and acquired von Willebrand’s disease (M4). Desmopressin (DDAVP) presumably induces the release of factor VIII (von Willebrand factor) from endogenous stores and may prevent or stop bleeding in patients with acquired von Willebrand’s disease and monoclonal gammopathy (C3). Gaucher’s disease may be associated with a monoclonal gammopathy. In one series, 4 of 16 patients had an IgG K protein in their serum and 6 others had a diffuse increase of IgG (P25). Marti et al. (M7) found that 2 of 23 patients with Gaucher’s disease had a monoclonal gammopathy, 6 others had an oligoclonal gammopathy, and I0 had a polyclonal hypergammaglobulinemia. The presence of pure red cell aplasia and an M-protein has been reported in six patients (R11). The M-protein may block the maturation of the erythroid burstforming unit, thereby producing red cell aplasia (B4). M-proteins may be associated with polycythemia Vera, myelofibrosis, and chronic myelocytic leukemia (B15). In one series of 46 patients with idiopathic myelofibrosis, 3 had a monoclonal gammopathy and 1 had multiple myeloma (D20). The myelodysplastic syndrome was associated with a monoclonal gammopathy in 6 of 52 patients (El). 6.4. CONNECTIVE TISSUEDISORDERS Rheumatoid arthritis (22) is associated with monoclonal gammopathies. Mproteins have also been reported in patients with seronegative erosive arthritis (H22). Lupus erythematosus and other connective tissue disorders have been associated with M-proteins (M23). However, in a series of 279 consecutive patients with rheumatoid arthritis at our institution, no significant increase in the incidence of benign monoclonal proteins was found. Monoclonal gammopathies have been noted in polymyalgia rheumatica (12), but because both conditions are more common in an older population, the relationship is questionable. Four patients with polymyalgia rheumatica-like symptoms and an underlying lymphoreticular neoplastic process and a monoclonal gammopathy have been described (K3). Polymyositis was reported in three patients with an IgG K monoclonal protein (K15).Relapsing polymyositis has been reported with an IgG monoclonal protein (T4). Discoid lupus erythematosus

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and an M-protein were described in eight patients (P23). A transient IgM K protein was recognized in a patient with hydralazine-induced lupus erythematosus (F1 1 ). The association of an IgG K protein and scleroderma with the subsequent development of multiple myeloma has been reported (N2). Psoriatic arthritis has been noted with monoclonal gammopathy (S7), but this occurrence is probably fortuitous.

6.5. NEUROLOC~C DISORDERS In a series of 279 patients with a clinically recognized sensorimotor peripheral neuropathy of unknown cause, Kelly et al. (K11) detected 16 cases (5.7%) of MGUS. The incidence would have been greater if the diagnosis of neuropathy was based only on electrophysiologic evidence. In another series of 239 patients with peripheral neuropathy or myopathy, 5.4% had an M-protein (18). A monograph on neurologic disorders associated with plasma cell dyscrasias has been published (K9). In approximately half of the patients with an IgM monoclonal gamrnopathy and peripheral neuropathy, the M-protein binds to myelin-associated glycoprotein (MAG) (H2, Ll). In one series of 10 patients with peripheral neuropathy, an IgM protein with activity against the myelin sheath was reported (D6). IgM monoclonal proteins with anti-MAG activity may react with Po,the major protein of myelin in human peripheral nerves (B20). Brouet et af. (B26) have shown that 9 of 10 monoclonal IgM proteins with anti-MAG activity expressed a public cross-reactive idiotype. The shared idiotype is very likely involved in the combining site of those IgM monoclonal proteins. The MAG-reactive polyneuropathies are homogeneous and are characterized by a slowly progressive, mainly sensory neuropathy beginning in the distal extremities and extending proximally. Discriminative and proprioceptive modalities are more severely involved than touch, pain, and temperature. Sensory involvement is more prominent than motor involvement. Cranial nerves and autonomic function are intact (K8). The clinical and electrodiagnostic manifestations resernble those of chronic inflammatory demyelinating polyneuropathy. There is a reduction of large myelinated fibers and segmental demyelination with rernyelination (D14). Patients with sensorimotor peripheral neuropathy may have an IgM protein binding to chondroitin sulfate (F10, S 13, YI), specific gangliosides (14, 15, K27), or glycolipids (13, K26). The demonstration of IgM monoclonal protein with direct electron microscopic immunochemistry studies with colloidal gold reveals deposition of IgM within the myelin and extending throughout the compact myelin in both large and small myelinated fibers (M12). This finding suggests that the deposition of monoclonal IgM protein plays a role in the pathogenesis of the neuropathy. Approximately one-third of murine plasmacytomas induced by mineral oil or

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ROBERT A. KYLE AND JOHN A. LUST

pristane have morphologic evidence of neuropathy (N3). Intraneural injection of sera from three patients with an IgM protein reacting with MAG and an associated neuropathy produced demyelination in feline sciatic nerves (H6). Steck et al. (S27) reported that demyelination was greater than that induced by sera with an M-protein unreactive to MAG. The occurrence of a demyelinating peripheral neuropathy in a brother and sister with an IgM monoclonal protein raises the possibility of a genetic element (54). Treatment of patients with peripheral neuropathy and monoclonal gammopathy has been disappointing. Nine of 13 patients with peripheral neuropathy and an IgM or IgG monoclonal protein improved with plasmapheresis and chemotherapy (S23). Plasmapheresiswas beneficial in two other cases-one with an IgG K and another with an IgA K monoclonal protein (F9). Plasmapheresis benefited one patient with an anti-MAG monoclonal protein. The patient’s signs and symptoms correlated with the IgM level during the year of therapy (Hl). Intravenous yglobulin has produced benefit in some patients with chronic inflammatory demyelinating polyneuropathy (Fl). This should be tried for patients with sensorimotor peripheral neuropathy and monoclonal gammopathy. Although patients with IgG monoclonal gammopathy and peripheral neuropathy have been described, the relationship of the monoclonal protein to the peripheral neuropathy has not been well documented (K9). Patients with an IgA monoclonal gammopathy and peripheral neuropathy have been described as showing binding of the monoclonal protein to normal human endoneurium

(D10).

Because there is no known effective therapy for patients with monoclonal gammopathy and peripheral neuropathy, we are engaged in a prospective study in which patients are randomized to plasmapheresis (plasma exchange) or to sham plasmapheresis. Patients who fail this program are then entered into a prospective study in which patients with an IgM monoclonal gammopathy are randomized to chlorambucilor placebo and those with IgG or IgA monoclonal gammopathiesare randomized to melphalan and prednisone or to placebo. We have seen some responses with both plasmapheresis and chemotherapy but do not have enough data to provide specific advice for therapy. 6.6. OSTEOSCLEROTIC MYELOMA (POEMS SYNDROME) Bardwick et al. (B5) suggested the acronym POEMS for this syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes), but not all patients have all of the features. This syndrome is characterized by a chronic sensorimotor polyneuropathy with predominating motor disability. Single or multiple osteosclerotic bone lesions are important features in the recognition of this entity. The cranial nerves are not involved, except for papilledema. Hepatosplenomegaly and lymphadenopathy may be seen. Hyperpigmentation, hypertrichosis, gynecomastia, and testicular atrophy are features that suggest the

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possibility of osteosclerotic myeloma. In contrast to multiple myeloma, polycythemia and thrombocytosis are common findings. Almost all patients have an M-protein of the A light-chain class. The M-protein is almost always less than 3 g/dl. Osteosclerotic myeloma is rarely associated with Bence Jones proteinuria, renal insufficiency, hypercalcemia, or pathologic fractures. The bone marrow aspirate and biopsy usually contain less than 5 % plasma cells (K10, TI). Cherrylike and subcutaneous hemangiomas may be prominent (K4). Microangiopathic glomerular lesions and features of scleroderma have also been recognized (V7). The diagnosis is confirmed by biopsy of an osteosclerotic lesion and the demonstration of a plasmacytoma. 6.7. OTHERNEUROLOGIC DISORDERS Amyotrophic lateral sclerosis and spinal muscular atrophy may be associated with monoclonal gammopathies (P6, S17). Rudnicki et af. (R18) described one patient with an IgM protein and progressive muscular atrophy. The patient improved temporarily with prednisone therapy and subsequently stabilized with azathioprine and plasmapheresis . The relationship of monoclonal gammopathies and motor neuron diseases is not yet clear. Myasthenia gravis has been associated with an M-protein (B7, G2). Multiple sclerosis (T10) and ataxia-telangiectasia ((25) have been reported with monoclonal gammopathies, but the association may be only fortuitous. 6.8. DERMATOLOGIC DISEASES Lichen myxedematosus (papular mucinosis, scleromyxedema) is a rare dermatologic condition that is frequently associated with a cathodal IgG A protein (JI). Dermal papules, macules, and plaques infiltrate the skin. Biopsy reveals an increased deposition of acid mucopolysaccharides. Scleredema (Buschke’s disease) has been reported with a monoclonal gammopathy in several instances, but the role of the M-protein has not been elucidated (K24, 02). Cardiomyopathy and congestive heart failure from deposition of acid mucopolysaccharide have been reported in a patient with scleroderma (R13). Hyperpigmentation and hyperlipoproteinemia have also been reported with scleredema and a monoclonal gammopathy (M15). Pyoderma gangrenosum has been associated with monoclonal gammopathies. In a series of 67 patients, 7 had a benign monoclonal gammopathy and 1 patient had multiple myeloma. Of the 8 patients, 7 had an IgA monoclonal gammopathy (P24). Necrobiotic xanthogranuloma is frequently found with a monoclonal IgG protein (F7). More than a dozen patients have been reported with a monoclonal gammopathy and SCzary’s syndrome; only two had multiple myeloma (V5).Five patients with mycosis fungoides and monoclonal gammopathy have been described (V6).

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ROBERT A. KYLE AND JOHN A. LUST

It is obvious that cutaneous T-cell lymphomas may be associated with monoclonal gammopathies, but there may be no etiologic relationship. Erythema elevatum diutinum has been reported with monoclonal gammopathy (D18). Monoclonal proteins have been noted in patients with diffuse plane xanthomatosis (B 11, 53). Although monoclonal gammopathies have been found with psoriasis (H19, PlO), it is doubtful that an association exists because of the frequency of psoriasis in a normal population. 6.9. MISCELLANEOUS Angioneurotic edema and acquired deficiency of C1 esterase inhibitor were reported in 15 instances. Five had a 7 S IgM monoclonal protein (G6). Pascual et al. (P5) described two patients with acquired C1 esterase inhibitor deficiency, an IgG K protein, and recurrent episodes of febrile panniculitis and hepatitis. Eight of nine patients with periodic systemic capillary leak syndrome (increased capillary permeability) had a monoclonal protein in the serum (L10). Monoclonal gammopathies have been reported in children. Of 4000 pediatric patients evaluated with agar gel electrophoresis and immunoelectrophoresis, 155 (3.9%) had a monoclonal protein. This finding was most frequently seen in children with primary or secondary immunodeficiency diseases, hematologic malignancies, autoimmune diseases, and severe aplastic anemia. Most of the monoclonal gammopathies were transient. There was a predominance of monoclonal proteins with a A light chain whereas there was a paucity of IgA monoclonal gammopathies (G7). Although polyclonal increases in immunoglobulins are most common in liver disease, M-proteins have been noted. In one series, an M-protein was found in 11 of 272 patients with chronic active hepatitis (H8). Monoclonal proteins have also been recognized in patients with primary biliary cirrhosis (H9). In a group of 130 homosexual men, HIV antibody was found in 65. Four of these patients had a monoclonal protein-two IgG K and two IgM K (C12). Monoclonal proteins were found in more than half of a series of patients with acquired immunodeficiency syndrome or lymphadenopathy syndrome (H 10). The appearance or disappearance of an M-protein in patients with asymptomatic HIV infection does not seem to be of prognostic significance (L3). Monoclonal proteins have been found in the sera of patients after renal, bone marrow, or liver transplantation. Renoult e l al. (RlO) found a monoclonal protein in 12.7% of 141 patients who had renal transplantation; the gammopathy was transient in 7. In another series of 213 patients with renal transplantation, a monoclonal or multiclonal gammopathy was detected in 26 patients (12%). The authors described three additional patients with a persistent gammopathy who subsequently developed multiple myeloma (two patients) or solitary plasmacytoma (one patient) (S26). Pollock et al. (P21)found M-proteins in only 4 of 110 patients with a renal transplant.

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Transient monoclonal gammopathies after bone marrow transplantation were detected in 18 of 42 patients (43%). The gammopathy was most often of the IgG A class (H5). In a series of 60 patients with allogeneic or syngeneic bone marrow transplantation, 16 had a single monoclonal protein and 6 had a biclonal gammopathy. All were of the IgG (82%) or IgM (18%) class. No IgA monoclonal proteins were identified. There was a strong correlation between the development of graft-versus-host disease and the presence of a monoclonal protein. The incidence of monoclonal proteins was higher in patients receiving marrow ablative regimens, including total body irradiation or busulfan, than in those receiving nonablative regimens (M25). We have recognized several patients who had transient, persistent, or varying monoclonal gammopathies after liver transplantation. A wide variety of conditions have been associated with a monoclonal gammopathy, such as Henoch-Schonlein purpura (D 16), bacterial endocarditis (F5), Hashimoto’s thyroiditis (G18, M13), septic arthritis (N9), purpura fulminans (F12), idiopathic pulmonary fibrosis (B2 l), pulmonary alveolar proteinosis (M3 1), idiopathic pulmonary hemosiderosis (N7), thymoma (S24), hereditary spherocytosis (S4), Doyne’s macular heredodystrophy (M33), subcorneal pustular dermatosis (R19), eosinophilic fibrohistiocytic lesions of the bone marrow (Nl), corneal crystalline deposits (B23, 03), chronic urticaria (D17), and hyperlipoproteinemia (Zl). The relationship of monoclonal gammopathy to these diseases is unclear and in many instances may be fortuitous. Rapidly progressive glomerular nephritis with epithelial glomerular crescents has been reported with monoclonal gammopathy (M22). Although proliferative glomerulonephritis and monoclonal gammopathy have been recognized in 25 cases, the causal relationship is unclear (K7). One patient had recurrence of the crescentic glomerulonephritis and deposition of IgG A in a cadaveric renal transplant (Cl). We are not aware of any well-documented cases in which surgical removal of a nonhematologic tumor resulted in the disappearance of the monoclonal protein. In one instance, an IgG gammopathy in the serum and urine disappeared 2 years after surgical removal of a carcinoma of the colon (C6). However, the monoclonal gammopathy was first recognized 2 months after operation, indicating that the tumor did not produce the M-protein.

7. Monoclonal Gammopathies with Antibody Activity Of 612 patients with a monoclonal protein, 36 (5.9%) had antibody activity when tested with actin, tubulin, thyroglobulin, myosin, myoglobin, fetuin, albumin, transfemn, and double-stranded DNA. The antibody activity was directed mainly against actin in 32 of the 36 patients. Most of these patients had a malignant lymphoplasma cell disorder (D 12). In patients with MGUS, myeloma, or macroglobulinemia, the monoclonal

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protein has exhibited unusual specificities to dextran (S 15), antistreptolysin 0 (K2), antinuclear activity (I6), riboflavin (F4,M20), von Willebrand factor (B24, M26), thyroglobulin (a), insulin (S2 l), double-stranded DNA (F6), apolipoprotein (K13), thyroxine (T7), cephalin (W6), lactate dehydrogenase (B l), anti-HIV (N4), and antibiotics (D5). A patient with multiple myeloma developed a thrombasthenic-like state producing a bleeding diathesis. The patient’s monoclonal IgGl K protein reacted with platelet glycoprotein IIIa (D13). Pseudothrombocytopenia was noted in a patient whose IgM K monoclonal protein agglutinated platelets (H 18). The binding of calcium by M-protein may produce hypercalcemia without symptomatic or pathologic consequences (H7, M19). This phenomenon must be recognized in order that patients are not treated for hypercalcemia (A4). Copperbinding M-proteins have been found in two patients with multiple myeloma (B3). Hypercupremia was also noted in a patient with a monoclonal IgG A protein and carcinoma of the lung (M8). Spurious elevation of the serum phosphorus level has been reported in a patient with an IgG K protein binding phosphate (P15). Two other similar patients-one with multiple myeloma and one with MGUShave been described with hyperphosphatemia, presumably from binding of serum phosphorus by the M-protein (P18). Transient monoclonal gammopathies with antibody activity have been recognized after infection. In one instance, a newborn with congenital toxoplasmosis had an IgG A protein, but such a monoclonal gammopathy was not found in the mother (Vl). Waldenstrom (W2) emphasized the antibody activity of M-proteins. Monoclonal gammopathies with antibody activity in plasma cell dyscrasias were reviewed by Merlini et al. (M18). More monoclonal gammopathies with antibody activity will undoubtedly be discovered in the future.

8. Multiple Gamrnopathies 8.1. BICLONAL GAMMOPATHIES Biclonal gammopathies occur in 2-3% of patients with monoclonal gammopathies. Most are not associated with a specific underlying disease and are designated as biclonal gammopathy of undetermined significance (BGUS). Clinical findings of biclonal gammopathies are similar to those of monoclonal gammopathies. We found that 37 (65%) of 57 patients with biclonal gammopathy were classified as having BGUS. Their ages ranged from 39 to 93 years (median, 67 years). Twenty were women and 17 were men (K36). Biclonal gammopathies are often not recognized unless immunofixation is performed. In our experience, electrophoresis on cellulose acetate strips showed

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two localized bands in only one-third of cases. In the remainder, the second Mprotein was recognized with immunoelectrophoresis or immunofixation. A monoclonal light chain was found in the urine of 6 of 22 patients. The patients with BGUS had normal hemoglobin, leukocyte, and platelet values. The plasma cell level ranged from 1 to 7% and did not have the morphologic features of malignancy. Symptomatic multiple myeloma developed 2 years later in one of our patients with biclonal gammopathy. The IgG K component increased and the IgA and IgM levels remained unchanged. In another patient, the biclonal gammopathy (IgG K and IgM K) disappeared after 7 years without apparent cause. This group of 37 BGUS patients was followed for a median of 31.5 months. Seven died-one each of acute granulocytic leukemia, metastatic prostatic carcinoma, malignant melanoma, alcoholic hepatitis, subdural hematoma, congestive heart failure, and undetermined cause (age, 91 years). Of our 57 patients, 35% had multiple myeloma, macroglobulinemia, or other malignant lymphoproliferative processes. In another series of 20 patients with biclonal gammopathy, almost half had BGUS. Multiple myeloma subsequently developed in two of them (N5). Of 1135 patients with monoclonal gammopathy, 28 (2.5%) actually had biclonal gammopathy. In some patients the M-protein arose from two separate plasma cell clones, and in others the M-protein behaved in a concordant fashion consistent with incomplete class switching in a single plasma cell clone (R12). Lucivero er al. (L12) described a patient with IgA K and IgG K biclonal gammopathy in whom the plasma cell clone simultaneously synthesized a,y, and K chains. The authors postulated that the neoplastic plasma cell clone was “frozen” at the IgGto-IgA switch. Biclonal gammopathies have been associated with sensorimotor peripheral neuropathy (14). 8.2. TRICLONAL GAMMOPATHY Triclonal gammopathy has been reported in a patient with a plasma cell dyscrasia who subsequently developed AIDS (R7, R8). Non-Hodgkin’s lymphoma has also been associated with triclonal gammopathy (B13). We have seen several patients with triclonal gammopathies.

9. Benign Monoclonal light-Chain Proteinuria (Idiopathic Bence Jones Proteinuria)

Bence Jones proteinuria is a recognized feature of multiple myeloma, primary amyloidosis, Waldenstrom’s macroglobulinemia, and other malignant lymphoproliferative disorders. However, a benign monoclonal gammopathy of the lightchain type may occur.

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We described two patients with a stable serum M-protein who excreted 0.8 g or more of Bence Jones protein daily for more than 17 years. One of these patients had proteinuria 10 years before the recognition of Bence Jones proteinuria. The patient did not develop multiple myeloma and died of pneumonia 27 years after proteinuria had been recognized. The second patient died of a hypernephroma 19 years after Bence Jones proteinuria was detected. Neither patient developed symptomatic multiple myeloma or amyloidosis (K35). We have described seven other patients who presented with Bence Jones proteinuria (more than 1 g/24 hr) but who had no M-protein in the serum and no evidence of multiple myeloma, macroglobulinemia, amyloidosis, or related disorders (K33). Multiple myeloma developed in one patient after 20 years, but he died of a bleeding diathesis after a surgical procedure. He had no significant renal insufficiency despite having excreted more than 45 kg of A light-chain protein. His kidneys had “proved equal to the novel office assigned them” and had “discharged the task without sustaining, on their part, the slightest danger” (Ml). Symptomatic myeloma developed after 8.8 years in a second patient. He responded well to melphalan and prednisone therapy but subsequently died of his multiple myeloma. Severe chronic renal insufficiency developed in a third patient after two episodes of acute renal failure. His renal failure was believed to be due to nephrosclerosis rather than to myeloma kidney or amyloidosis, but tissue confirmation was not possible. A fourth patient had a slowly evolving multiple myeloma over 9 years but died of an unrelated cause before overt myeloma could be diagnosed. Another patient developed symptoms of carpal tunnel syndrome after excreting 2-3 g of K Bence Jones protein daily for 14 years. He had welldocumented systemic amyloidosis. The sixth patient produced 3 g of Bence Jones protein daily for 7.7 years and then developed an extensive squamous cell carcinoma involving the mediastinum and lungs. The seventh patient has excreted approximately 1 g of K light-chain protein daily for 20 years without developing evidence of multiple myeloma or related disease. Thus, although idiopathic Bence Jones proteinuria may remain stable for years, multiple myeloma or amyloidosis often develops. Consequently, these patients must be observed indefinitely. REFERENCES A l . Abdou, N. I . . and Abdou, N. L., The monoclonal nature of lymphocytes in multiple myeloma: Effects of therapy. Ann. Intern. Med. 83, 42-45 (1975). A2. Aksoy, M . , Erdem, S . , Dingol, G . , Kutlar, A., Bakioklu, I . , and Hepyiiksel, T., Clinical observations showing the role of some factors in the etiology of multiple myeloma: A study in 7 patients. Actu Huemarol. 71, 116-120 (1984). A3. Alexanian, R., Monoclonal gamrnopathy in lymphoma. Arch. Inrern. Med. 135, 62-66 (1975).

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A4. Annesley, T. M., Burritt, M. F., and Kyle, R. A., Artifactual hypercalcemia in multiple myeloma. Mayo Clin.Proc. 57, 572-575 (1982). AS. Arai, K., Ishioka, N., Huss, K., Madison, J., and Putnam, F. W., Identical structural changes in inherited albumin variants from different populations. Proc. Natl. Acad. Sci. U.S.A. 86, 434-438 (1 989). A6. Atkins, H., Drouin, J., Izaguirre, C. A., and Sengar, D. S., Acute promyelocytic leukemia associated with a paraprotein that reacts with leukemic cells. Cancer (Philadelphia) 63, 1750-1751 (1989). A7. Axelsson, U.,A 20-year follow-up study of 64 subjects with M-components. Acta Med. Scad. 219, 519-522 (1986). A8. Axelsson, U., Bachmann, R., and Hallen, J., Frequency of pathological proteins (M-components) in 6,995 sera from an adult population. Acra Med. S c a d . 179, 235-247 (1966). A9. Azar, H. A,, Hill, W. T.,and Osserman, E. F., Malignant lymphoma and lymphatic leukemia associated with myeloma-type serum proteins. Am. J. Med. 23, 239-249 (1957). B1. Backer, E. T., Harff, G. A,, and Beyer, C., A patient with an IgG paraprotein and complexes of lactate dehydrogenase and IgG in the serum. Clin. Chem. (Winston-Salem. N . C . ) 33, 1937-1938 (1987). B2. Bain, G . O., and Belch, A,, Nodular mixed cell lymphoma with monoclonal gammopathy. Am. J . Clin. Pathol. 76, 832-837 (1981). B3. Baker, B. L., and Hultquist, D. E., A copper-binding immunoglobulin from a myeloma patient: Purification, identification, and physical characteristics. J. Biol. Chem. 253, 11951200 (1978). B4. Balducci, L., Hardy, C., Dreiling, B., Tavassoli, M., and Steinberg, M. H., Pure red blood cell aplasia associated with paraproteinemia: In vitro studies of erythropoiesis. Haematologia 17, 353-357 (1984). B5. Bardwick, P. A., Zvaifler, N. J., Gill, G. N., Newman, D., Greenway, G. D., and Resnick, D. L., Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes: The POEMS syndromes. Report on two cases and a review of the literature. Medicine (Baltimore) 59, 31 1-322 (1980). B6. Barlogie, B., Epstein, I., Selvanayagam, P., and Alexanian, R., Plasma cell myeloma-New biological insights and advances in therapy. Blood 73, 865-879 (1989). 8 7 . Bartoloni, C., Scoppetta, C., Flamini, G., Guidi, L., Bartoccioni, E., Lambiase, M., Gambassi, G., and Terranova, T., Waldenstrom’s macroglobulinemia and myasthenia gravis. J. Clin. Lab. Immunol. 6, 275-278 (1981). B8. Bast, E. I. E. G., Van Camp, B., Boom, S. E., Jaspers, F. C. A,, and Ballieux, R. E., Differentiation between benign and malignant monoclonal gammopathy by the presence of the J chain. Clin.Exp. Immunol. 44, 375-382 (1981). B9. Bast, E. J. E. G., Van Camp, B., Reynaert, P., Wiringa, G., and Ballieux, R. E., Idiotypic peripheral blood lymphocytes in monoclonal gammopathy. Clin. Exp. Immunol. 47,677-682 (1982). B10. Ben-Chetrit, E., Ben-Amitai, D., and Levo, Y.,The association between Kaposi’s sarcoma and dysgammaglobulinemia. Cancer (Philadelphia) 49, 1649- 1651 (1982). B11. BCrard, M., Antonucci, M., and Beaumont, J.-L., Cytotoxic effect of serum on fibroblasts in one case of normolipidemic plane xanthoma and myeloma IgGX. Atherosclerosis 62, I1 1115 (1986). B12. Berenson, J., Wong, R., Kim, K., Brown, N., and Richtenstein, A,, Evidence for peripheral blood B lymphocyte but not T lymphocyte involvement in multiple myeloma. Blood 70, 1550-1553 (1987). B13. Berg, A. R., Weisenburger, D. D . , Linder, J., and Armitage, J. O., Lymphoplasmacytic

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M5. M6. M7. M8.

M9. M10. MII. M12. M13. M14. M15. M16. M17. M18. M19. M20. M21. M22.

21 1

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