Case fteporfr Monoclonal Gammopathyin Beta Thalassaemia Sumitra Dash, John Punnose and R J Dash A rare instance of IgG-kappa monoclonal gammopathy in a patient with beta-thalassaemia trait is reported. Thepatient had a smoldering multiple myelomawith no apparent clinical symptomspertaining to the disease and was a non-responder to conventional Melphalan and prednisolone therapy. Beta- thalassaemia trait was detected while investigating him for anaemia. A state of altered immunological reactivity, chronic infections and associated biliary tract disease are some of the pathogenetic mechanisms suggested. Howeverin this patient none of these were operative. Key words: Beta-thalassaemia, Monoclonal gammopathy Development of monoclonal gammopathy in thalassaemia trait. Three of his 5 children also association with long standing haemolytic anae- had evidence of beta-thalassaemia trait. He had mia is rare. Till today only ll instances of such hypergammaglobulinaemia (4.5 g out of 7.3 g/dl associations have been reported ' . Of these only of total serum proteins) with prominent mono- 2 had beta-thalassaemia trait. We report here a clonal spike (Fig 1). Protein electrophoresis of case of monoclonal gammopathyin a beta-thalas- urine revealed trace of . He saemia trait and discuss the possible interrelation- was given another course of Melphalan and pred- ship. nisolone besides 3 packed red cell transfusions. CASE STUDY The transfusions produced significant subjective A 63-year-old known type II (non-obese) and physical improvement. His condition wors- diabetic was seen for vague aches and pains, ened abruptly and he developed unstable angina, anaemia and cervical spondylosis. During his followed by a complete right bundle branch block visit to USA he was investigated for anaemia and runs of ventricular ectopics. He developed at the Memorial Medical Center of Jacksonville, congestive heart failure and had pulmonary Florida. A routien serum electrophoresis revealed infarction involving the right lower lobe. He was IgG-kappa monoclonal gammopathy (Table 1). managed conservatively with heparin, digoxin, Bone marrow aspirate contained 30% immature lasix etc. and was discharged after a hospital stay and multinucleated plasma cells. The skeletal of about 6 weeks. He was readmitted in January survey revealed generalised osteoporosis but no 1985 in left heart failure and expired after a expansile or punched out lesions were noted. He brief hospital stay. was treated with Melphalan 0.25 mg/kg a day DISCUSSION and prednisolone 60 mg/day for 4 days in each In our patient monoclonal gammopathy was course, which was repeated 4 times at monthly discovered accidentally. He did not have the intervals. Chemotherapy produced subjective usual symptoms of multiple myeloma. Even improvement but no change in the gammaglobulin after courses of chemotherapy the level of mono- profile. clonal protein never came down. However, there Approximately 3 months after the therapy he was subjective improvement. Such behaviour of was admitted with us for re-evaluation. He had the disease has been described- as smoldering several episodes of effort angina. He had severe multiple myeloma. anaemia (Hb-6 g/dl, PCV-17%) at this time. De- In a series of 153 cases of multiple myeloma tailed haematological workup revealed a beta- with pre-existing disease, reported by Schafer From Department of Pathology () and Medicine (Endocrinology), Postgraduate Institute of Medical Education and Research, Chandigarh-1 6001 2, India. Received for publication April 30, 1985. Reprint request to: R. J. Dash, MD, Professor and Head, Dept. Endocrinology, PGIMER, Chandigarh-12, India.

JapJ MedVol 25, No 1 (February 1986) 57 Dash et al

Table 1. Relevant investigations of the patient IMMUNOLOGICAL Totalserumproteins -7.3g/dl IgA -35mg/dl Albumin -2.8g/dl IgM -26mg/dl Globulin -4.5g/dl IgG - 1687 mg/dl SerumProtein electrophoresis: Monoclonal band in gammaregion. Urine protein electrophoresis: Trace of BenceJones protein, HAEMATOLOGICAL Fig. 1. Serum protein electrophoresis showing RBC 5.23x lO12/l MCV -70.0(fl) monoclonal band in the gamma region. WBC 8.1 x 109/l MCH -21.3(pg/cell) Hb ll.1 g/dl MCHC -30.7 (g/dl RBC's) et al , haematological disease was present in & Hct 36.3% Serumiron 89vug/dl (5%). Of these 4 had HbS trait, 2 beta-thalas- Platelets 231,000/cmm TIBC - 357 Mg/dl saemia trait and the remaining 2 were cases of Peripheralblood smear: HbA2 - 5.0% hereditary and hereditary ellipto- Moderate microcytosis, slight hypochromia and basophilic stipping of red cells. cytosis. In the same study 3 of the 8 had IgG existence of these two conditions in our patient paraproteinemia. The same was not true of the 2 beta-thalassaemia trait. In Schafer et al's study1^ as mere association. The prevalence of B-thalas- both the beta-thalassaemia traits had secondary saemia in India ranges from 3-15%9^ and that of multiple myeloma is approximately 1 in 30,000 biliary tract disease, which is a common compli- (0.0003%)10\ These observations would suggest cation of chronic haemolytic anaemia. It has random coincidence of both conditions in this also been implicated in the pathogenesis of multi- patient. ple myeloma. In our case there was no evidence REFERENCES of cholecystitis or any biliary tract disease. Altered immunological status in beta-thalas- 1) Schafer AI and Miller JB: Association of IgA multi- ple myeloma with pre-existing disease. Brit J Haema- saemia trait has been suggested by Macrolongo tol41: 19,1979. et al . They found higher incidence of rheumatoid 2) Schafer AI, Miller JB, et al: Monoclonal gammo- arthritis in these patients. In a study of 15 patients pathy in patients with : with thalassaemia intermedia6' increased levels of a possible pathogenetic relation. Annals Int Med 88:45, 1978. IgA and IgG were observed with serum immuno- 3) Kyle RA and Greipp PR: Smoldering multiple globulins higher than 200 mg/dl. In one of our myeloma. New EnglJ Med 302: 1346, 1980. previous studies7' IgM levels were significantly in- 4) Isobe T and Osserman EF: Pathologic conditions creased in a series of 20 beta-thalassaemia traits. associated with dyscrasias: a study of 806 cases. Annals New York Acad Sciences 90: It has been suggested by Schafer et al.1'2' that 507, 1971. patients of beta-thalassaemia trait are particularly 5) Macrolongo R, Trotta F, et al: Beta thalassaemia prone to persistent stimulation of the reticulo- trait and rhematoid arthritis. Lancet 1: 1141, 1975. endothelial system because of chronic haemolysis. 6) Kapadia A, Sousa MD, et al: Lymphoid sets and An initial antigen exposure results in immunocyte serum immunoglobulins in patients with thalas- saemia intermedia. Relationship to serum iron and proliferation; Under certain circumstances an splenectomy. BritJ Haematol 45: 405, 1980. oncogenic stimulus and/or mutation might induce 7) Dash S and Dutta U: Immunological reactivity in a susceptible sub-population of this clone to beta thalassaemia. Ind J Med Res (submitted for proliferate, leading to the development of multi- publication) 1985. ple myeloma. Recently it has been shown that 8) Weitzman SA, Weitberg AB, et al: Phagocytes as toxic intermediates and by products of oxygen carcinogens: malignant transformation produced by human neutrophils. Science 227: 1231, 1985. metabolism generated by stimulated phagocytes 9) Weatherall DJ and Clegg JB: In "The Thalassaemia may play a role in the carcinogenic process by Syndromes", 1981, p 303. damaging DNA and chromosome and causing 10) Sehgal S, Dutta U, Gulati DR, et al: Spectrum of transformation of target cells . lymphoreticular malignancies in India with particular Despite these attractive arguments and circum- reference to myelomatosis. Proceedings of a Work- shop on "Role of environments in lymphoid malig- stantial evidence linking beta-thalassaemia to the nancies" held at NIH, May 1982. Raven Press, pathogenesis of multiple myeloma, we consider USA, 1982. 58 JapJ Med Vol 25, No 1 (February 1986)