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MONOCLONAL GAMMOPATHY IN HUMAN NEOPLASIA PHILIPJ. MIGLIOREM,D,* AND RAYMOND ALEXANIAMND, ** Monoclonal gammopathy unassociated with overt multiple myeloma was detected in 0.65% of 5066 individuals who were referred for the evaluation of known or suspected neoplasia. The incidence, age and sex distributions were similar to those found in a large population of normal adults, suggesting that the association of monoclonal gammopathy with nonreticuloendothelial neo- plasms has a fortuitous rather than a cause and effect relationship. T h e failure of effective treatment of the associated neoplasm to alter favorably the concentration of the serum gammopathy supported this view. This abnormality may represent an early phase in the slow evolution of multiple myeloma; this emphasizes the importance of early recognition and long term evaluation. THE DISCRETE, HOMOGENEOUS PROTEIN IDENtified on serum electrophoresis as a "para- protein," "M-protein" or more commonly now as a "monoclonal gammopathy" consists of biochemically distinct and immunochemically specific molecules presumably derived from a single clone of immunoglobulin-producing cells. Because of the common association of monoclonal gammopathy with multiple myeloma and macroglobulinemia of Waldenstrom, such clones in these conditions are presumed to result Erom malignant transformations. I n recent years monoclonal gammopathy has been recognized in apparently normal individuals as well as in subjects with a variety of diseases, including those with different malignant neoplasms. In the absence of overt multiple myeloma or macroglobulinemia this condition has been variously termed "benign monoclonal gammopathy,'' "monoclonal gammopathy of unknown etiology," "essential hyperglobulinemia" and "dysimmunoglobuline- From the Department of Pathology and the Department of Medicine, The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, Tex. Assistant Pathologist, Department of Pathology and Assistant Professor of Pathology, The University of Te*xasAMsso. cDia.teAnIdnetresronnisHt, osSpeitcatlioanndoTf umEoxrpeIrnismtietunttea.l Hematology, Department of Medicine and Associate Professor of Medicine, The University of Texas M. D. Anderson Hospital and Tumor Institute. This study was supported in part by grants CA 06939 and CA 03195 from the National Cancer Insti- tut*esBeocfkHmeaanlthIn. struments, Inc., Fullerton, Calif. ** Hyland Laboratories, Los Angeles, Calif. Received for publication October 13, 1967. mia."l7,19,20.23 Numerous case reports have attested to the association of this form of monoclonal gammopathy with neoplasms other than those derived from the reticuloendothelial system, some implying a cause and effectrelationship.6. 7.109 11+16,17,21,22 This relationship was examined in this study which determined the incidence of monoclonal gammopathy in a large number of cancer patients. MATERIALASND METHODS The population studied consisted of 5066 randomly selected patients examined at The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston between June 1964 and April 1966. Of the patients surveyed 81% had malignant neoplasms, 50/, had benign tumors, 91% were older than 30 years and 56% were women, All serum specimens submitted for a serologic test for syphilis, representing approximately 57% of all new clinic admissions during this period, were studied. Initial screening for monoclonal gammopathy was performed by an agar gel electrophoresis technique (Fig. 1). When present, the concentration of monoclonal components was determined by microcellulose acetate electrophoresis (Model R100 Microzone System"). All monoclonal garnmopathies were typed by immunoelectrophoresis.13 Antisera specific for immunoglobulins IgG, IgA and IgM were obtained commercially.** Anti-K and anti-L antisera were prepared in rabbits by serial intramuscular injections of Kappa and Lambda Bence Jones proteins, emuIsified in complete Freund's ad- 1127 1128 CANCERJune 1968 Vol. 21 FIG. 1. The albumin fractions (positive pole) are to the ex- treme right. Each specimen demonstrates a gammopathy which is monoclonal in nature and which can easily be seen in the left half of each pattern as a discrete oval fraction. juvant. The proteins had been isolated from the urine of patients with multiple myeloma and purified by column chromatography prior to injection.2 When possible, patients with monoclonal gammopathy were evaluated further for the presence of multiple myeloma. Additional studies included examination of sternal marrow aspirates, radiographs of the axial skeleton and immunochemical analysis of urine for Bence Jones protein. Periodic follow-up evaluations on 21 patients continued for 1 to 43 months after initial detection of the protein abnormality. RESULTS A monoclonal gammopathy was detected in the serum of 56 patients with a variety of neoplasms and suspected neoplasms, an overall incidence of 1.1%. Twenty-three of these patients were referred with known multiple myeloma and excluded from further analysis. Of the remaining 33 patients with unexplained monoclonal gammopathy (0.65%), 27 had malignant neoplasms, most commonly of epithelial origin (Table 1). Twenty-one of the 33 subjects were men. T h e median age was 65, ranging from 33 to 81. This figure compares with a median age of 60 for 82 patients with multiple myeloma treated at the Anderson Hospital between 1959 and 1966 (age range 33 to 83 years). Of the 33 monoclonal components detected, 31 were of IgG, 2 of IgM and none of IgA specificity. Among IgG components, 18 demonstrated Kappa specificity (IgGK) and 13 Lambda specificity (IgGL). Both IgM components were of Kappa specificity (IgMK). These components were detected in a median concentration of 1.0 Gm/100 ml, ranging from approximately 0.3 Gm/100 ml to 3.5 Gm/100 ml. I n 82 patients with multiple myeloma studied with the same techniques, the median concentration of monoclonal gammopathies was 4.7 Gm/100 ml and ranged from 1.4 to 11.4 Gm/100 ml. The incidence of unexplained monoclonal gammopathy increased with age, rising from 0.4% in the fourth decade to 2.8% in the ninth (Fig. 2). Between the fourth and ninth decades the incidence among women increased from 0.6 to 1.4% and among men from none to 4.2%. Additional studies are summarized in Table 1. The percentage of plasma cells in those bone marrows studied exceeded the normal (3%) in only 4 of 20 cases: in no case did plasma cells constitute more than 10% of the cellularity. One marrow was replaced by cells typical of chronic lymphocytic leukemia. In one patient (JM) a single lytic lesion of the ilium was caused by a local plasmacytoma. A second patient with lytic lesions (HB) had bone marrow metastases from his associated carcinoma. In 20 of 21 patients with available follow-up information, treatment of the primary neoplasm by surgery, radiotherapy or chemotherapy did not favorably alter the concen- No. G MONOCLONGALAMMOPATHi~YNEOPLASIA Migliore and Alexanian 1129 TABLE1. Summary of Patients with Monoclonal Gammopathy Patient Age Race Sex Primary cancer Initial Marrow Gammo- conc. Plasma pathy Gm/100 ml cells (%) Bone x-rays IW 53 C F Breast IgGK 0 . 5 normal normal SH 63 C F Breast IgGK 1 . 0 normal normal BM 80 C F Breast so 35 C F Breast IgGL IgGL 1.7 normal osteoporosis 2.5 7% normal BD 64 C F Breast IgGK 0 . 6 normal 0steoporosis HH 63 C M Nasopharynx CM 58 C M Larynx ww 6 0 C M Larynx CG 66 N M Lung ws 6 4 C M Lung GP 63 C M Lung CL 62 N M Esophagus IgGK IgGL IgGK IgGL IgGK IgGK IgGK 1.4 * 0 . 5 normal * * 1.0 * * 1 . 8 normal lytic lesions skull ? 1 . 2 normal normal ** 3 . 5 normal * * DB 70 N F Rectum IgGK 0.8 normal normal HH 79 C M Rectum WR 69 C M Bladder IgGK IgGK 0.8 5% osteoporosis * * osteoporosis HB 80 N M Prostate IgGK 0.8 normal lytic lesions vertebrae TS 80 C M Prostate IgGL 2 . 0 9% osteoporosis J M 33 C F Cervix IgGL KS 66 C F Uterus A 0 73 N F Uterus FN 81 C M Lip CM 63 C M Skin MS 69 C F Melanoma IgMK IgGL IgGK IgGK IgGL ED 55 JR 76 JC 53 LW 67 C F Origin unknown C M Chronic lymphocytic leukemia C F Hodgkin's Disease C M Lymphoma WF 74 C M None ? GJ 51 C M None JO 73 C M None EJ 58 C M JP 52 C M ES 73 C F * No data available. None None None IgGK IgGK IgGL IgGL IgMK IgGK IgGL IgGK IgGL IgGK 0.6 normal lytic lesions ilium & rib 0.9 0.9 * * * * 1 . 0 normal normal ** * 1.7 normal normal 0.7 * normal 0.8 normal normal 2 . 3 normal * 1.1 * * ** * 1 . 1 normal normal 0.8 6% normal 1.3 1*. 4 * * * * * * Status of gammopathy Unchanged in 38 months Unchanged in 29 months Unchanged in 43 months Unchanged in 12 months Unchanged in 26 months * Unchanged in 23 mon*ths Unchanged in 32 months Unchanged in 26 mon*ths Dead within 2 months Dead. Unchanged in 12 months Unchanged in 4 months Dead. Unchanged in 6 months Dead. Increase to 1.5 Gm/100 ml in 8 months Trace Bence Jones proteinuria. Increase to 2.5 Gm/ 100 ml in 15 months Dead. Increase t o 1.5 Gm/100 ml in 22 mon*ths * Unchanged in 17 mon*ths Increase to 2.3 Gm/ 100 ml in 17 months* Unchanged in 8 months Dead within 1 month Unchanged in 21 mon*ths * Unchanged in 20 mon*ths * * 1130 CANCEJRune 1968 VOl. 21 7t I I -I I 4I 345 678 9 DECADE F a . 2. The overall incidence of unsuspected monoclonal garnmopathy in the Anderson Hospital adult cancer population (solid line) compared with that in a general adult population (broken line)? tration of the monoclonal serum peak. In the only exception (JM) a serum IgGL abnormality (0.6 Gm/100 ml) disappeared temporarily after curettement and irradiation of a localized plasmacytoma. Of four patients who demonstrated progressive increase of at least 0.5 Gm/100 ml in the serum concentration of the monoclonal globulin, two have died. One (JM) probably died of progressive multiple myeloma and the other (HB) of advanced carcinoma. However, postmortem examinations were not performed in either case. A total of nine patients are now dead. Autopsies have been performed on two (CL and JC) and no explanation for the gammopathy was found in either case. DISCUSSION The significance of monoclonal gammopathy in the absence of overt multiple myeloma is poorly understood. Although its occurrence in patients without multiple myeloma or other reticuloendothelial malignancies is now recognized, the prevalence in normal individuals, the relationship to various diseases and the significance with respect to the evolution of multiple myeloma are unknown. In a recent analysis of serum electrophoreses from 6995 adults over 25 years of age the incidence of monoclonal gammopathy was found to be 0.9%, increasing with age from 0.2 to 5.7% between the fourth and ninth decades (Fig. 2). I n the same decades the incidence in women ranged from 0.5 to 1.6% and in men from none to 9.2y0.3 The similarity of these figures to those found in this analysis of patients with malignant diseases suggests that the association of monoclonal gammopathy with cancer is probably fortuitous and contrasts with the cause and effect relationship implied by some previous reports. This conclusion is further supported by the failure of effective treatment of associated primary neoplasms to alter favorably the level of the serum immunoglobulin abnormality in the patients observed during this study. The incidence of unexplained monoclonal gammopathy is apparently many times greater than that of overt multiple myeloma, which is estimated to be approximately 0.010.02%.l9 3 Conceivably, many, if not most, people with this condition represent cases of multiple myeloma in an early, latent or "insitu" phase, the serum protein abnormality preceding the development of more apparent disease by a period of many months to many years. That such a long evolution of multiple myeloma may occur is demonstrated by reports of individuals living as long as 18 years between the initial detection of an immunoglobulin abnormality and the diagnosis of overt multiple myeloma.s.12,15,1* Additional support for the concept of early myelomatous disease is suggested from studies of mouse myeloma which have shown a direct correlation between tumor weight and the amount of serum myeloma protein.99 14 Most of the individuals evaluated during this study, in comparison with patients with overt myeloma, had serum monoclonal gammopathies in relatively low concentrations, suggesting a low volume of total body "tumor", Unfortunately, few parameters are available to predict the likelihood that a specific individual with unexplained monoclonal gammopathy will develop overt and progressive plasma cell myeloma. Overt myeloma is more likely to be present in individuals with rapidly increasing levels of monoclonal components or in individuals presenting with IgG components of more than 2.0 Gm/100 ml or IgA components of more than 1.0 Gm/lOO ml.4~20 However, in individuals with low constant levels of unexplained monoclonal gammopathy, these particular aids are not No. 6 -MONOCLONGAALMMOPATHINYNEOPLASIA Migliore and Alexanian 1131 helpful. Careful long-term evaluation of all individuals with this abnormality is essential to detect as early as possible the development of progressive myelomatous disease. Recognition of the early phases of multiple myeloma may provide an opportunity to further improve response rates and survival following earlier and more sustained application of effective therapeutic regimens.5 Consequently, in individuaIs oIder than 40, serum electrophoresis should be considered an important screening procedure to aid in the detection of those likely to have or to develop multiple myeloma. REFERENCES 1. A report of the El Pam County Medical Sodety follow-up program. Unpublished observations. 2. Adams-Mayne, M. E., and Jirgensons, B.: Purification and characterization of four Bence Jones proteins. Arch. Biochem. 113:575-583, 1966. 3. Axelsson, V., Bachmann, R., and HalIen, J.: Frequency of pathological proteins (M-components) in 6995 sera from an adult population. Acta Med. Scand. 179:235-247, 1966. 4. Bachmann, R.: T h e diagnostic significance of the serum concentration of pathological proteins (M-components). Ibid. 178:801-808, 1965. 5. Bergsagel, D. E., Griffith, K. M., Haut, A., and Stuckey, J. W.. Jr.: The treatment of plasma cell myeloma. In Advances in Cancer Research vol. 10. New York, Academic Press, 1967; pp. 311-359. 6. Case records of the Massachusetts General Hospital. New Eng. J . Med. 276:1144-1152, 1967. 7. Causey, J. Q.: IgG paraproteinemia associated with bronchogenic carcinoma. Arch. Intern. Med. 119407410, 1967. 8. Drivsholm, A.: Myelomatosis-A clinical and biochemical study of 105 cases. Acta Med. Scand. 176509524, 19G4. 9. Fahey, J. L., Potter, M., Gutter, F. J., and Dunn, T. B.: Distinctive myeloma globulins associated with a new plasma cell neoplasm of strain C,H mice. Blood 15:103-113, 1960. 10. Hallen, J.: Frequency of "abnormal" serum globulins (M-components) in the aged. Acta Med. Scand. 173;737-744, 19G3. 11. Hosley, H. F.: M-proteins, plasmacytomas and cancer. Cancer 20:295-307, 1967. 12. Kyle, R. A., and Bayrd, E. D.: "Benign" monoclonal gammopathy-A potentially malignant condition? Am. J. Med. 40:426-450, 1966. 13. Migliore, P. J.: Immunoelectrophoresis and immunodiffusion techniques in diagnosis of neoplastic diseases. In Recent Advances in the Diagnosis of Cancer. Chicago, Year Book Medical Publishers, Inc., 1966; pp. 158-169. 14. Nathans, D., Fahey, J. L., and Potter, M.: The formation of myeloma protein by a mouse plasma cell tumor. J. Exp. Med. 108:121-130, 1958. 15. Norgaard, 0.: Recherches sur l'6volution prkclinique du multiple myeloma. Acta Med. Scand. 176: 137-146, 1964. 16. Osserman, E. F.: Natural history of multiple myeloma before radiological evidence of disease. Radiology 712157-174, 1958. 17. Osserman, E. F., and Takatsuki, K.: Plasma cell myeloma-Gamma globulin synthesis and structure. Medicine 42:357-384, 1963. 18. Stevens, A. R.: Evolution of multiple myeloma. Arch. Intern. Med. 115:90-93, 1965. 19. Waldenstrom, J.: Studies on conditions associated with disturbed gamma globulin formation (gammopathies). Humey Lect. 56211-231, 1961. 20. -. . The occurrence of benign, essential monoclonal (M-type), non-macromolecular hyperglobuiinemia and its differential diagnosis. Acta Med. Scand. 176:345-365, 1964. -21. . Clinical diagnosis and biochemicaI find- ings in material of 296 sera with M-type narrow y globulins. Ibid. Suppl. 367:llO-119, 1961. 22. Weitzel. R.A.: Carcinoma coexistent with malig- nant disorders of plasma cells. Cancer 11:546-549, 1958. 23. Zawadski, 2. A., and Edwards, G. A.: Dysimmunoglobulinemia in the absence of clinical features of multiple myeloma and macroglobulinemia. Am. J. Med. 42~67-88,1967.