Document 2q8aw29wyBpDxe69EZZYxKBz7

British Journal of Haematology, 1985, 59, 55-66 The association of chronic lymphocytic leukaemia and multiple myeloma: a study of eleven patients J. C. BROUET, J. P. FERMAND, G . LAURENT.*M. J . GRANGE,^ A . C HEVALIER, C. JACQUILLAT$ AND M. SELIGMANLNaborutoire d'lmmunologie et d'Immunopathologie INSERM U 108, Laboratoire du CNRS and Service d'lmmunopathologie, Hdpital Saint-Louis, 2 Place du Docteur Fournier, 75475 Paris Cedex 10, *Department d'Hkmatologie,Hdpital Purpan, Toulouse, TDepartment d'Himatologie, Hdpital LariboisiZre, Paris, and $Department d'oncologie, Hdpital de la Piti4 Salpetrikre, Paris, France I Received 1 February 1984; accepted for p u b l i c a t i o n E l T K 4 .j S-Y. We present haematological and immunological data obtained in 11 patients with the rare association of chronic lymphocytic leukaemia (CLL) and multiplemyeloma (MM). C U occurred beforeMM in six cases and both diseaseswere diagnosed simultaneously in five. With regard to C U . no peculiar clinical feature Was found; in six patients, MM was characterized by extra-osseous lesions. A SiWcant remission (3-7 years) was obtained in three patients. In six patients, CLL and plasma cells synthesized Ig molecules with different light chains, probably indicating the coexistence of two distinct clonal proliferations. In two cases where monoclonal Ig synthesized by both types of cells had the same type qf light chains, Studies with anti-idiotypic antibodies showed that the two proliferations were also & a c t . The pathophysiology of this rare associationis discussed in the light ofthese andings and of data from the literature. neOccurrence of both chronic lymphocytic leukaemia (CLL) and multiple myeloma (MM)in patient is a rare and noteworthy association of two B cell neoplasias. We report here the clinical course and immunologic features of 11 such cases which were studied in our department during the last 20 years, andreview the 24 similar cases previously reported in the literature. In seven of our patients, a study of both surface and cytoplasmic Ig expressed by CLL and m k including in two cases a search for shared idiotypes, was performed to elucidate this association represents the progression and maturation of a pre-existing CLL Of the occurrence of two distinct malignancies. Dr J. C. Brouet. H6pital Saint-Louis. 2 Place du Dr Fournier, 75475 Paris Cedex 10. 55 56 /. C. Brouet et a! PATIENTS A N D METHODS Case reports Case 1.In 1955 the diagnosis of CLL was made in this 45-year-I)Id male patient on the basis of moderate splenomegaly, lymph node enlargement an 1 blood and marrow lymphocytosis (Table I). A lymph node biopsy showed a diffuse infiltration by small mature lymphocytes without plasma cells. He received a course of radiatil In therapy to involved lymph nodes. Two years later, the haematological data were unchai iged and several serum electrophoreses were normal. Intermittent chlorambucil therapy was given during the next 4 years. At this time, a tumour of the right upper gum was noted A biopsy revealed an infiltration by abnormal plasma cells. SkeletalX-rays showed a sing11 lytic lesion of the right maxillary bone. Bone marrow examination disclosed a persisten lymphocytosis (70%) without any plasma cells: serum immunoelectrophoresis showed a c ecrease of IgG and IgA. Local irradiation therapy was given. Nine months later, several soft ti ;sue tumours appeared. Pertinent haematological data at this time are listed in Table I. E-rays showed a diffuse osteoporosisand multiple lytic lesions. Urinary analysis performed foi the first time, identified a K Bence Jones protein (1g/l). The patient died 4 months later with extensive bone lesions, Post-mortem examination showed a proliferation of abnormal plasm a cells in bone marrow, liver and spleen. Lymphocytic infiltrates were discrete and predomir ated in liver and lymph node. Case 2. In 1960 the diagnosis of CLL was made in this 59-year-01 1woman on the basis of slight lymphadenopathy, splenic enlargement and blood and mar *owlymphocytosis (see Table I). Intermittent chlorambucil was started. Four years later the patient had fever, weight loss and back pains. On examination, the liver and spleen I rere massively enlarged and a pelvic mass was felt. Pertinent laboratory values at this time arc listed in Table I. A bone marrow biopsy showed a nodular infiltration by both immature plasma cells and small lymphocytes in distinct foci. Lymph node aspirate contained only a )normal plasma cells as did liver biopsy. Serum immunoelectrophoresis revealed a monoclc nal IgAA and a marked decrease of IgG and IgM. Lambda Bence Jones proteinuria (24 g/l) was found. The disease rapidly progressed, the WBC reached 161x 109/1with 98% lympi,ocytes, and the patient died from sepsis. At autopsy, the bone marrow, lymph nodes, liver ar d spleen were infiltrated predominantly by plasma cells with small focal lymphoid infiltrati 8s. The pelvic mass was plasmacytic. Case 3. In 1963 this 71-year-old male experienced symptoms of spinal cord compression at the level of the fifth dorsal vertebral body. He was treated by surgc ry followed by radiation therapy. The vertebral body was heavily infiltrated by small matu -e lymphocytes without any plasma cells. There was a slight blood lymphocytosis (see Tabla I). Two years later, the clinical status was unchanged but a marked abnormal plasmacyt x i s was found on bone marrow examination (Table I). Bone marrow biopsy showed a hyl ercellular bone marrow with nodular lesions composed either of mature lymphocytes or o abnormal plasma cells. Serum electrophoresis was normal but the immuno-electrophc retic study disclosed a monoclonal IgA1. A 1Bence Jones protein was found (0.35g/l). Ske eta1X-rays were normal Chronic Lymphocytic Leukaemia and Multiple Myeloma 57 58 1. C. Brouet et a1 except for the vertebral lesions. Chlorambucil therapy was starte 1. During the next Years several bone marrow aspirates showed a varying percentage of ymphocytes and plasma cells: a small Ig spike appeared on serum electrophoresis. SkeletalX-rays showed a lytic lesion in the femoral neck. At this time, chlorambucil was stopped and melphalan therapy was given. During the next 6 years the patient remained in good healtl I in spite a progression of bone lesions. No modification of the haematologic or protein pr ,files was observed. The patient died suddenly of unknown cause. Case 4 . In 1968 this 55-year-old man was referred because of haemolytic anaemia. Clinical examination was normal. The Coombs test was positive for 1gG and complement.The haematologic data were compatible with associated CLI, (see Tablc I). Bone marrow biopsy showed a nodular infiltration by mature lymphocytes. There was a : light hypogammaglobulinaemia ( 5 g/l) with a monoclonal IgAI. High dose steroids were -equired to maintain the haemoglobin level above 10 g/l. One year later X-ray studie: showed marked bone demineralization with a lytic lesion of the right tibia. Lymphai igiograms were grossly abnormal. A splenectomy was performed as well as abdominz I lymph node biopsies, Pathologic examinations disclosed an extensive infiltration by sm all mature lymphocyte and some foci of plasma cells. During the next year the patient was ( loing well under steroids and chlorambucil treatment. Bone marrow biopsy and aspiratr showed still a purely lymphocytic infiltration. The level of the IgA spike steadily increase 1 to reach 10 g/l. At this time the clinical condition deteriorated with bone pains. X-rays s lowed several vertebral fractures and lytic lesions of the humerus pelvis and femoral neck. Bone marrow aspirates showed 10%abnormal plasma cells. Despite melphalan chernother tpy, the condition ofthe patient worsened and a plasma cell leukaemia developed. Post-mort1:m examination showed a plasma cell infiltration of lymph nodes, bone marrow, liver and spleen. Case 5 . In 1968 this 76-year-old patient was referred for lymph1)cytosisand back pains. On examination, moderate enlargement of liver and lymph nodes wa ;found.Laboratorydata were compatible with both CLL and MM. There was a strikiiig blood and marrow hyperlymphocytosis but abnormal plasma cells were also found ir marrow aspirates (see Table I).X-rays showed a diffuse osteoporosis with a collapse of the fif h dorsal vertebral body. Protein studies showed in the serum a small amount of monoclonal IgMK and a decrease of IgG and IgA. In the urine, there was a large quantity of K Bence Jones protein. Chlorambucil therapy was given. One year later, the vertebral lesion progressed an 1a bone marrow biopsy showed a proliferation of both lymphocytes and plasma cells in disti ict nodules; melphalan was added. During the next 1 8 months the clinical condition imprc ved and the laboratory values showed an objective improvement (WBC 7.5 x 109/mlwith 8(1% lymphocytes).There were less than 30% abnormal cells in bone marrow. Bence Jones protein excretion was 3 g/24 h. Thereafter, bone lytic lesions progressed in the pelvis, fen ur and ribs: the lymph nodes enlarged rapidly and the bone marrow was infiltrated main y by plasma cells. The patient died from sepsis. Post-mortem examination showed a lym phocytic infiltration of lymph nodes with some foci of plasma cells and a total invasion of b me marrow by plasma cells. Case 6 .The diagnosis ofCLL was made in 1962 in this 65-year-old woman. on the basis of blood and marrow lymphocytosis (see Table I). There was no abqormality on physical , ~ 1 Chronic Lymphocytic Leukaemia and Multiple Myeloma 59 examination. Without chemotherapy, her clinical and haematological status remained unchanged until 1 3 years later when thoracic pain developed. On examination, there was a slight splenomegaly and a fractured rib. Haematologic data were compatible with both CLL and MM (see Table I). X-rays showed a diffuseosteoporesis. Serum Ig levels were slightly depressed and K Bence Jones was found in the serum and urine ( 4 g/l). Intermittent steroids and melphalan therapy gave a good remission. Two years later, a relapse was observed with costal and cutaneous plasma cell tumours and a malignant pleural effusion. The bone marrow was heavily infiltrated by plasma cells. Case 7. This 62-year-old woman was referred for CLL of the prolymphocytic type. There was a marked splenomegaly. The main laboratory data are listed in Table I. There was no abnormal serum or urinary Ig. The patient was treated by chemotherapy (chlorambucil)and splenectomy. There was only a partial remission during the three following years. At that time, fever, weight loss and skin nodules developed. Laboratory data were compatible with both CLL and MM (Table I). Serum electrophoresis and immunoelectrophoresis disclosed a monoclonal IgM ( 5 g/l) and there was a massive excretion of K-type Bence Jones protein (10-20 g/24 h). The patient was treated by combined chemotherapy with cyclophosphamide, adriamycin, prednisone and vincristine. She died from infection 6 months after the beginning of this treatment. Case 8. This 77-year-old man was referred in 1981 for bone pains and hypercalcaemia. Physical examination revealed an acutely ill patient with weight loss and fever. There was no lymph node, liver or spleen enlargement. Haematological data are listed in Table I. Bone marrow biopsy confirmed the existence of an infiltration by both small lymphocytes and abnormal plasma cells. Serum electrophoresis and immunoelectrophoresis showed the Presence of two monoclonal Ig, one IgGE. (50g/l) and the other IgAK (17 g/l).Monoclonal free and 1chains were found in urine. There were multiple osteolytic lesions of skull, pelvis and vertebral bodies. The patient died from heart failure 1 month after the beginning of chemotherapy. Case 9. This 86-year-old man was referred in 1982 for weakness and hypercalcaemia. Physical examination was unremarkable except for long-standing psoriasis. Laboratory data were compatiblewith CLL and MM (seeTable I).Bone marrow biopsy confirmed the existence of an infiltration by both small lymphocytes and plasma cells. Serum electrophoresis and immunoelectrophoresisrevealed a monoclonal IgAK ( 33 g/l) with a decrease of polyclonal k M and IgG. Skeletal X-rays were normal. The patient died soon after starting chemo- therapy. Case 10.This 70-year-old patient wasreferred in 1981,for bone pains and lymphocytosis. examination was unremarkable except for an hepatomegaly. Laboratory data were consistent with both CLL and MM (see Table I). Bone marrow biopsy showed the coexistence Of both lymphoid and plasmacytic proliferations in distinct nodules. Serum immunoelectrophoresis revealed a monoclonal IgD I protein (10 g/l) with a decrease of IgM, IgG and IgA. showed multiple bone lesions and several rib fractures. The patient died despite chemotherapy with prednisone and melphalan. Case 11. This 74-year-old man without significant medical past story was referred because of recent discovery of a severe renal failure (plasma creatinine 800 pmol/l). There t 60 I. C. Brouet et a1 was slight splenomegaly on examination. Haematological data (Table I) showed blood lymphocytosis and bone marrow infiltration by abnormal plasm;I cells and small mature lymphocytes. Skeletal survey revealed multiple lytic lesions. Immu ioelectrophoretic Studies showed the presence of large amount of a ,IBence Jonesprotein in serum and urine. The renal failure did not improve and dialysis was necessary. A percutanec )us renal biopsy showed features of myelomatosis tubulopathy. Polychemotherapy with cyclophosphamide and melphalan was begun without significant remission. Surface and cytoplasmic l g Surface and cytoplasmic Ig expressed by lymphocytes and plasma CI:Ils were studied in Seven patients by direct immunofluorescence with monospecific antisera to the various light and heavy Ig chains on blood and marrow lymphoid cells as previmly reported in detail (Preud'homme& Labaume, 1975). Surface and cytoplasmic lg Results are summarized in Table 11. RESULTS ldiotypic studies In cases 6 and 8. the relationship between the surface Ig present on he lymphocytes and the serum monoclonal Ig was investigated further with an anti-idiotyp c antiserum. These sera were obtained in rabbits immunized with the K Bence Jonesprotein ( :ase 6)or purified serum IgGi. and IgAK (case8).The immune sera were absorbed on erythroc ytes, tonsil lymphocytes and normal serum, IgG, IgA, IgM, K and l chains coupled to Sepbirose 4B. The absorbed sera were used by indirect immunofluorescence with a second layer of rhodamine conjugated Fab'2 fragments from IgG antibodies of a sk eep antiserum to rabbit IgG. Absorbed sera still stained cytoplasmic Ig from plasma cells of the: corresponding patients whereas they were negative with unrelated myeloma plasma cells or normal plasma cells obtained after stimulation of normal peripheral blood by pokeweed mitogen, Likewise, they did not stain normal blood lymphocytes. Case 6. CIL lymphocytes bearing PK molecules were not stain:d by the anti-idiotypic antiserum raised against urinary K Bence Jones protein. Case 8. Two different anti-idiotypic antisera were raised against either the I g G l or IgAK serum monoclonal Ig. We could not detect shared idiotypes bctween the two serum monoclonal Ig (data not shown). The anti-idiotypic serum to thi: I g G l component was negative on blood lymphocytes either by surface or cytoplasmic staining. The anti-idiotypic serum to the IgAK monoclonal Ig stained intracellularly a few blood 1ymphoplasmacytic cells whereas it was negative by either surface or cytoplasmic staining on small lymphocytes. Positive cells corresponded most likely to the few blood cells (mainly plasma cells)which were similarly stained with anti t( and K reagents. Chronic Lymphocytic Leukaemia and Multiple Myeloma 61 O + W % EE Nri hW E 2 10 h Nro m 3 v W D D tz0 62 1. C. Brouet et al Table 111. Chronic lymphocytic leukaemia and multiple n iyeloma: membrane markers of malignant cells CLL cells Myelc ma cells surface Ig cytopl asmic Ig Present study Case 3 Case 6' Case 7 Case 8* Case 9 Case 10 Case 11 Literature Hoffman & Rudders (1977) r i. Kough & Makary ( 1978) None (Fcy+) Pedersen-Bjegaard et al (19 78) ,,K Zalcberg et nl (1982) Pati Jeha et al (1981) dK 'K (ti Ji. ,ii. pi * No shared idiotypes between SIg and cIg molecules. I I I 1 ! i I 1 I i I DISCUSSION CLL and MM represent the neoplastic expansion of a single B ce 1 clone. CLL is usually considered as a leukaemic process involving lymphocytes which are rozen at a given stage of the B cell differentiation pathway whereas MM is the expression of ihe proliferation of moa mature B cells (Seligmann et aJ. 1973). However, some data sugge: t that in myeloma both some circulating B cells (Seligmann et al, 1 973) as well as pre-B cells (Kubagawa et al, 1979) may belong to the neoplastic clone. The occurrence of the two diseasc s in the same individual is quite rare since only 35 cases, including our own 11cases, have bc en identified (Table In). The clinical picture in such patients is usually a composite of the typical features of both CLL and MM. However, several points deserve emphasis. In a single :ase, MM antedated the development of CLL (Zalcberg et al, 1982).In contrast, CLL was dial nosed before MM in six out of our 11cases and in 14 out of 24 cases in the literature; the ir terval between the two diagnoses ranges from 2 to 15 years. In the other cases the diagnosis ( 4both CLL and MM was either simultaneous or made within 1year. However, in those cases H here CLL preceded MM. detailed haematological and protein studies are available in only a ew patients at the time when CLL was diagnosed. In two patients of this series (patients 4 and 7, Table I) detailed studies were performed 2 and 5 years before the diagnosis of MM M as suspected. In case 7 neither infiltration by plasma cells nor Ig abnormalities were detect able. In patient 4 blood and marrow examination (including bone marrow biopsies) wert compatible with CLL, without any excess in bone marrow plasma cells. However. serum mmunoelectrophoresis disclosed a small amount of monoclonal IgAi. and a decrease of IgG ar d IgM and, 1year later, I Chronic Lymphocytic Leukaemia and Multiple Myeloma 63 a lymph node biopsy showed small fociof abnormal plasma cells.The level of the monoclonal protein steadily increased to reach 10 g/1 2 years later. At this time, the marrow was i d b a t e d by 10%plasma cells and lytic bone lesions developed. From these data, it is hardly W b l e to determine whether or not latent myeloma is present at the time CLL is diagnosed. severtheless it is of note that in five of the 3 3 cases we reviewed, the clinical phase of MM appeared more than 10 years after the diagnosis of CLL. The haematological diagnosis of CLL is not questionable in the group of 3 5 patients with associated myeloma. No peculiar features emerge from the clinical charts. The immunological identification of the leukaemic cells was performed in seven of our cases and in five cases reported in the literature (Table 11); it revealed. as in common CIL, a homogenous proliferationof B lymphocytes carrying monoclonal surface Ig. The circumstances leading to the diagnosis of MM were variable. Six of our patients experiencedback pains with vertebral bone lesions whereas in four other cases the diagnosis of M M was based on the finding of a malignant plasma cell infiltration located to the gum, lymph nodes or bone marrow. The onset of MM in five of our patients was also indicated by a sudden deterioration of the clinical status with high fever, sweats, weight loss and a rapidly downhill course. In all reported patients the bone marrow was infiltrated by abnormal plasma cells and, with three exceptions, lytic bone lesions were observed. However, it is of interest than in six of our patients extra-osseous plasma cell tumours were found, especially in skin, pleura and lymph nodes. Pathological studies showed in bone marrow and/or lymph nodes the coexistence of a nodular plasma cell proliferation with a diffuse lymphocytic Infiltrationwithout any mixing of the two cell populations. only scarce data are available on the evolution and treatment of both diseases. In our series, death occurred less than 1 year after the diagnosis of MM in six patients despite chemotherapy. In three other cases a remission was obtained with chlorambucil and mebhalan in two patients and melphalan and prednisone in one. The remission lasted 3 Years in two patients and 7 years in the third. In those cases where MM develops during the course of CLL, two explanations have been (`ked. First, the malignant B CLL clone may further mature giving rise to MM; second, the IWO malignancies represent distinct clonal proliferations. In the first hypothesis, one could to find several cases ofplasma cell tumours secreting IgM, if the process occurs without 'f! imtYpe switching. since most CLL are featured by membrane IgM. In two of our cases monoclonal IgM was indeed present. Nevertheless, in these two cases, a large urinary rxcR%onof Bence Jones protein was coincident with the onset of MM. Therefore, the mondonal IgM most likely corresponded to the product of the CLL clone. Immunologic performed in one of these cases showed, however, that the malignant plasma cells intra-cellular p and K chains, a n unreported finding in Bence Jones myeloma `Pre'Jd'hommeet al, 1976),which may suggest that the original CLL clone was also involved In MM. However, in another case where a monoclonal IgM was found in serum, IgM mo'ecth found at the surface of the CLL clone and secreted by the plasma cells possessed types of light chains (Zalcberg et a!, 1982). Therefore, the occurrence of IgM vcreting Plasma cells tumours, although distinctly unusual, does not allow firm conclusions. 'evenheless, it is of interest to note that the class distribution of monoclonal serum or 64 1. C. Brouet et al urinary Ig in MM supervening on CLL is rather unusual siiice IgA cases (10 patients) predominated over IgG ( 8 ) .light chains (8).IgM (2),IgD ( 1 ) or lion-secreting (1 myelomas. Obviously the comparison of the immunologic phenotype ol both CLL and myeloma in a given patient is needed to reach meaningful conclusions. As s iown in Table 11. such data have been collected in 12 cases only. In six patients, CLL cells and plasma cells synthesized Ig molecules with different light chain types indicating the OCCUI rence of two distinct clonal proliferations. In two cases where monoclonal Ig synthesized b v` both types of cells had the same type of light chains, we performed a study with anti-idiotypic reagents: in both cases idiotypic determinants expressed by serum (or urinary) and intracellular plasmacytic Ig were not detectable on the surface immunoglobulins synthesized bj the CLL B cells. A similar negative study had been reported in another case (Hoffman & Ritdders, 1977).In one of our cases there was in addition a second monoclonal spike which w 1s shown to be idiotypically unrelated to both CLL and plasma cells. Taken together these finc ings strongly argue against the possibility that CLL B cells `transformed' into plasma cells. rhese results contrast with those obtained in the Richter's syndrome and in acute crisis of C , L where it has been shown that the phenotype of supervening blast cells is usually identical t 3 that of CLL cells (Brouetet al, 1973, 1976). Having in mind that CLL and MM are most likely not the expr :ssion of a single malignant clone, it is of note that oligoclonal lymphoid malignancies m1y not be so rare. Indeed. examples of biclonal CLL have been observed (Preud'homine & Seligmann. 1972); furthermore, monoclonal serum immunoglobulins with an idiotypic specificitydifferent from that of the Ig molecule synthesized by the leukaemic B cells, are not infrequent in CLL (Seligmann et al, 1973). They may well have the same significence as the development of overt MM in CLL patients. In addition, some evidence has bee11obtained that malignant tumours may be polyclonal at onset (Woodruffet al, 1982).Burk tt's recurrence may be due to the emergence of a second malignant clone as assessed by i&PD phenotype (Fialkow, 1976). Finally. as postulated in chronic myelocytic leukaemia, the target cell for the oncogenic event may be a stem cell with distinct developmeiital capabilities. This last hypothesis could account for the occurrence of myeloid leukaeinias in untreated patients with CLL or MM (Turszet al, 1 974). Interestingly, it has been receiitly reported that MM may develop in patients affected with another B cell malignancy, namely hairy cell leukaemia (Catovskyet al, 1981). An intriguing possibility would be that, in such cases, the leukaemic B cell (or another cell type) may secrete some factor(s)which may tiigger either normal B cells or plasma cells. REFERENCES BONNAZI,L., AZZINIC, .F. & FOSTE, P.L. (1968) Gamrnapathie rnonoclonale et hypergammaglobulinemie au cours d'une leucemie lyrnphatique maligne. Frcastoro. 61, 950-959. BROUET. J.C.. PREUD'HOMME. J.L.. FLANDRIN. G., CHELLOUL. N. &! SELIGMANMN.. ( 1976) Membrane markers in so-called `hystiocytic' lym- phomas. Journaloj the National Cancer Institute. 56, 6 3 1-633. BROUET. J.C..PREUD'FOMMJ.LE.. SELIGMANMN.,& BERNARD, J. (19 7 3 I Blast cells with monoclonal surface immunogl ibulins in two cases of acute blast crisis superveling on chronic lymphocytic leukaemia. British Medical Journal. iv, 2 3-24. Chronic Lymphocytic Leukaemia and Multiple Myeloma 65 CATOVSKY,D.. COSTELLO. C., LOUKOPOULOS. D., FESSASP,.R.. FOXLEY. J.M., TRAUB, N.E., MILLS, M.J.& O'BRIENM, . (19 8 1) Hairy cell leukemia and myelomatosis: chance association or clini- cal manifestations of the same B cell diseases spectrum. Blood, 57, 758- 763. CROWLEY,J.P.. CHURCHILLW..H., SIMON. J. & ALBALA,M.M. (1976) Absence of lymphocyte immunoglobulin production in chronic lym- phatic leukemia and multiple myeloma. Annals of Internal Medicine, 86, 750. FIALKOW. P.J. (1976) Clonal origin of human tumors. Biochimica et Biophysica Acta. 4 5 8 , 283-421. FITZGERALPD.H. ., RASTRICK.J.M. & HAMER. J.W. (1973) Acute plasma cell leukemia following chronic lymphatic leukaemia: transformation or two separate diseases. British )ournal of Haematology. 25, 171- 177. GHOSH, M.L. & SAYEED, A. (1974) Unusual cases of myelomatosis. Scandinavian Journalof Haemato- logy, 12, 147-154. HOFFMAN. K.D. & RUDDERS, R.A. (1977) Multiple myeloma and chronic lymphocytic leukemia in a single individual. Immunologic studies and review of the literature. Archives of Internal Medicine, 137, 232- 235. JEHA. M.T., HAMBLIN, T.J. & SMITH, J.L. ( 1 9 8 1 ) Coincident chronic lymphocytic leukemia and osteosclerotic multiple myeloma. Blood, 57, 6 1 7-6 1 9 . KOUGH, R.H. & MAKARY, A.Z. (1978) Chronic h p h o c y t i c leukemia (CLL) terminating in multiple myeloma. Blood. 52, 532-535. KUBAGAWA, H.. VDGLER,L.B., CAPRA, J.D.. CONRAD. M.E., LAWTON, A.R. & COOPER. M.D. (1979) Studies on the clonal origin of multiple mye- loma. Journal of Experimental Medicine, 150, 792-807. hWA",M.P., SCHNEIDER. G.. MERTEN. K. & TENBAUMA., ( 1972) Koinzideng von FamiIias gehauf auftretenden Plasmozytom, c h n i s c h e r lymphatische Leukamie und rec- tum Kaninom. Hut. 24, 356-364. NArDU. R.T. & ROSNER, M.O. (1971) Combined multiple myeloma and chronic lymphatic leuk- emia. New England Journal of Medicine. 2 8 4 , 108. N A R A S I ~ P~..~KA~ N,DHASAMY. J.. ELIZALDE. A.M. ti ROSNERF, . (1975) Chronic lymphocytic leukemia and lymphosarcoma associated with multiple myelcma: report of three cases. Archives of Internal Medicine, 135, 729-732. PEDERSEN-BJERGAARD, J., DRAMINSKYPETERSEN, H., THOMSEN, M., WIIK, A. & WOLFF-JENSEN, J. ( 1 9 7 8 ) Chronic lymphocytic leukaemia with subsequent development of multiple myeloma. Scandinavian journal of Haematology. 21, 256-264. PETERS, J.H.. HELLER. P. & VALAITIS. J. ( 1 9 6 1 ) Malignant lymphoma, plasmocytosis dysproteinaemia. Archives of Internal Medicine, 107, 903-907. PREUD'HOMME. J.L.. HUREZ. D.. DANONF..,BROUET. J.C. & SELIGMANMN..(1976) Intracytoplasmic and surface bound immunoglobulins in `non secretory' and Bence Jones myeloma. Clinical and Experimental Immunology, 25, 4 2 8 4 3 6 . PREUD'HOMME. J.L. & LABAUME, S. ( 1 9 7 5 ) Im- munofluorescent staining of human lymphocytes for the detection of surface immunoglobulins. Annals of the New York Academy ofsciences 254, 254-261. PREUD'HOMME, J.L. & SELIGMANN, M. ( 1 9 7 2 ) Surface-bound immunoglobulins as a cell marker in human lymphoproliferative diseases. Blood. 40, 777-794. REIMER.E. (1974) Chronische lymphatische Leukaemie und Plasmozytom: kazuistische. langzeitbeobachtung. Blut, 28, 231. REINHARD. E.. SAGELS.., KORNFIELDS, .. SCHROER. K., NADLER. P. & LYNCH, R. ( 1 9 7 5 ) Multiple malignancies: chronic lymphocytic leukemia, malignant melanoma, multiple myeloma and acute myelo-monocytic leukemia. American )ournu/ of Medicine, 58, 4 0 8 4 1 6 . SANY, J.- MOALOCK,G., CLOT, J.* BALDET. P.. CARCASSONNE. Y. & SERRE. H. ( 1 9 7 6 ) LeucCmie lymphoide chronique et myelome multiple. Revue du Rhumatisme. 43, 1-9. SELIGMANNN.M, .. PREUD'HOMME, J.L. & BROtJET, J.C. (1973) B and T cell markers in human proliferative .blood diseases and primary irnmunodeficiencies. with special reference to membrane bound immunoglobulins. Transplantation Reviews. 16, 85-1 13. SHUSTERM. . & CAUSING, W.C. (1971) Chronic lymphatic leukemia and lymphosarcoma terminating a multiple myeloma. journal of Medical Society ofNew Jersey. 68. 365-368. 66 1. C. Brouet et a1 SPENGLER, G.A.. ROULET. D.L.A., RICCI,C., SCINDER. u.. SCHOOPU...KAPPELER. R. & RIVA, G. (1961) Paraproteinamie bei chronischen Lymphadenose. Schweizerische Medizinische Wochenschrift, 1025-1029. STOBBE, M. (1962) Syntropis von chronischen Lymphadenose und Plasmozytom. Acta Haematologica, 27, 180-188. TUBIANA. N.. ANDRAC. L., OLIVE,D. 81 CARCASSONNE, Y. (1978) Association IeucCmie lymphoide chronique plasmocytome. Nouvelle Presse Me'dicale, 13,967. TURSZT. ., FLANDRIN. G.. BROUET, J.C.. BRIERE. J. & SELIGMANN, M. (1974) Simultaneous occurrence of acute myeloblastic leukaemia and multiple myeloma without previous chemotherapy. British Medical Journal. ii, 642-643. VANDER. J.B. & JOHNSON, H.A. (1960) Chronic lymphatic leukemia and multiple myeloma in the same patient. Annals of Internal Medicine, 53,1052-1059. WALDENSTRJ.~(M19, 62) Hypergammaglobuline. mia as a clinical iematological problem: a study in the gamma1)athies. Progress in H e m a h logy, Vol. 3, pp. 265-293. Grune & Stratton, New York. WOODRUFF. M.F.A., AVSELL,J.D.. FORBES, G.M., GORDON, J.C., BURTON, D.I. & MICKLEM. H.S. (1982) Clonal interiiction in tumours. Nature, 299, 822-824. ZALCBERG. J.R., COR![ELL, F.N.. IRETON.J.c., MCGRATH,K.M.. M~:LACHLANR. ., WOODRUFF, R.K. & WILEY. J.S. 11982) Chronic lymphatic leukaemia developing in a patient with multiple myeloma. Cancer, 5 0 , 594-597. ZBIGNEW, A,, ZADAWA:)ZKIM, .D., KAPADIA. S. & BARNES, A.E. (1978) Leukemic myelomatosis (plasma cell leukeriia). American Journal O/ Clinical Pathology. 711, 605-611. I I I i I I I I I I