Leukemia (1997) 11, 1318–1323  1997 Stockton Press All rights reserved 0887-6924/97 $12.00

POEMS syndrome: report on six patients with unusual clinical signs, elevated levels of , macrophage involvement and chromosomal aberrations of plasma cells C Rose1, M Zandecki2, MC Copin3, P Gosset4, M Labalette5, PY Hatron6, MO Jauberteau7, B Devulder6, F Bauters1 and T Facon1

1Service des Maladies du Sang; 2Laboratoire d’He´matologie A; 3Service d’Anatomie Pathologique C, CHU, Lille; 4Institut Pasteur Lille, 5 6 7 INSERM U416, Lille; Laboratoire d’Immunologie; Service de Me´decine Interne A, CHU, Lille; and Laboratoire d’Immunologie, CHU, Limoges, France

POEMS syndrome is a multisystemic disorder characterized by observed after surgery or local irradiation in patients with the association of polyneuropathy, organomegaly, endocrin- POEMS syndrome and a solitary plasmocytoma.9,10 Neverthe- opathy, M protein, skin changes and various other systemic clinical signs. The pathophysiology of this syndrome remains less, the biological characteristics of bone marrow plasma largely unknown. In order to gain insight into its pathophysiol- cells (BMPC) have not so far been studied and compared to ogy, we studied the clinical characteristics and performed those of BMPC from other gammopathies. In this study, we serum analysis (auto-, levels) and pheno- reviewed clinical aspects in six patients with POEMS syn- typic and cytogenetic studies of bone marrow plasma cells drome. We also evaluated the levels and producing sites of (BMPC) in six patients with unequivocal POEMS syndrome. three cytokines, IL-1-beta, IL-6 and TNF-alpha and the pres- Two unusual clinical signs were present in these patients: pul- monary hypertension (two patients) and diffuse cutaneous ence of auto-antibodies directed against peripheral nerve necrosis (one patient). No auto-antibodies against peripheral components. In addition, we studied phenotypic, kinetic and nerve (PN) antigens (SGPG and SGLPG glycolipids, GM1, genetic features of BMPC. GD1a, GD1b and GT1b gangliosides) were found. Sequential evaluations of serum cytokines (IL-1-beta, IL-6 and TNF-alpha) showed a moderate to marked elevations of IL-6 and TNF-alpha Patients and methods in all patients (up to six-fold for TNF-alpha and 16-fold for IL- 6). Using in situ hybridization of these cytokines mRNAs on lymph node specimens of two patients who had an angiofollic- Description of the population ular lymph node hyperplasia, a strong positivity was found with the IL-1-beta antisense probe in lymph node macrophages. On Between 1988 and 1995, six patients with unequivocal skin biopsy a high number of cells expressing TNF-alpha POEMS syndrome were referred to our department. Their mRNA was observed in the dermis. The biological features of main clinical and biological characteristics are summarized in BMPC: phenotype (expression of CD19 and CD56 antigens), kinetics (Ki-67 index), karyotype, DNA content and chromo- Table 1. All patients had severe chronic demyelinating neuro- somal in situ hybridization remained those of BMPC found in pathy and organomegaly. Endocrinopathy was also present in of undetermined significance. We all patients and included (6/6), high serum conclude that POEMS syndrome is a hypercytokinemic syn- FSH (4/5), high serum LH (1/4), hyperprolactinemia (3/4), glu- drome in which BMPC are not of malignant type. Macrophages cose intolerance (3/6), and hypotestosteronemia (4/5). Gynec- are involved in this syndrome and their role has to be further omasty was found in 2/4 patients. Serum monoclonal protein investigated as well as treatments which act through an anti- cytokine mechanism. was detected in 4/6 patients (IgA lambda 3/6; IgG lambda 1/6). Keywords: POEMS syndrome; interleukin-6; TNF-alpha; macro- Other classes of immunoglobulins had a normal level in these phage; patients. Serial and various electrophoresis (immuno- electrophoresis and immunofixation) were negative in patients 1 and 4 throughout the course of the disease. Median CRP Introduction level was 12 mg/l (range 3–89). Skin changes were observed in all patients and consisted of (5/6), skin POEMS syndrome is a variant of plasma cell dyscrasia with thickening (3/6), (3/6), telangiectasis (4/6), and polyneuropathy characterized by the association of poly- finger clubbing (2/6). One patient had diffuse disease-related neuropathy, organomegaly, endocrinopathy, M protein, and cutaneous necrosis (patient 4). Bone lesions were solitary skin changes.1 In addition to these five clinical features, a con- sclerotic in one patient and multiple sclerotic in three patients. stellation of other clinical manifestations may be associated Another patient had normal conventional bone X rays, but a with POEMS syndrome such as , peripheral , diffuse vertebral hypermagnetic resource imaging signal. Two , pleural effusions, or thrombocytosis.2–5 patients had angiofollicular lymph node hyperplasia resem- The pathophysiology of this syndrome remains largely bling Castelman’s disease. Other clinical manifestations unknown. Recently, an overproduction of proinflammatory reported in POEMS syndrome were present: edema (5/6), cytokines has been reported in POEMS syndrome.6–8 Further- (5/6), (4/6), proteinorachy greater than more, the question remains of the cellular origin of these cyto- 500 mg/l (6/6), acrosyndrom (4/6), chronic (3/6), and kine overproductions. The role of plasma cell-derived pro- cachexia (2/6), thrombocytosis (4/6), polycythemia (1/6). × 9 ducts might be supported by the improvement occasionally Median count was 395 10 /l (range 215–689). The white blood count was normal in all patients. Two patients had (PH) which was thought to be Correspondence: C Rose, Service des Maladies du Sang, CHU Lille related with POEMS syndrome. The diagnosis of PH was sug- 59037 Lille, France gested by progressive dyspnea appearing during the course of Received 29 April 1996; accepted 3 March 1997 the disease and confirmed by high mean pulmonary artery Unusual clinical signs in POEMS syndrome C Rose et al 1319 Table 1 Main clinical and biological findings in the six patients with POEMS syndrome

Patient No. 123456

Age (years)/Sex 62/M 32/M 33/F 44/M 74/M 65/F Polyneuropathy ++++++ −+++−+ −+++−+ ++−+++ Endocrinopathy ++++++ Skin change ++++++ Bone lesion solitary sclerotic no multiple sclerotic multiple sclerotic only MRI multiple hypersignal sclerotic Pulmonary hypertension −−−+−+ Angiofollicular hyperplasia + not tested −+not tested not tested Thrombocytosis ++−++− Polycythemia −−−−−+ M component never detected IgG lambda IgA lambda never detected IgA lambda IgA lambda 4g/l 4g/l 3g/l 3g/l Bone marrow plasmacytosis (%) 4 1 15 3 3 4 CD19 + PC (%) ND 16 37 ND 72 ND CD56 + PC (%) ND 0 10 ND 8 ND DNA index ND 0.92 0.90 ND 1.33 0.94 % of aneuploid PC ND 34 26 ND 42 61 Aneuploidy after FISH ND not demonstrated trisomy 9 ND trisomy 11 Not demonstrated

MRI, magnetic resonance imaging; ND, not done; PC, plasma cell; FISH fluorescence in situ hybridization. pressure (mPAP): mPAP = 28 mmHg at rest in case 4 and Detection of auto-antibodies directed against peripheral nerve 40 mmHg in case 6. Pulmonary hypertension was not associa- components: Screening of sera for an antiglycolipid reac- ted with other secondary causes in these two patients. A com- tivity was performed with glycolipids purified from normal plete description of these two patients and their hemodynamic human peripheral nervous system as previously described by parameters is reported elsewhere.11 Jauberteau et al.12 This glycolipidic fraction contained gang- liosides and the two antigens SGPG and SGLPG. Auto-anti- bodies to these sulfoglucuronyl glycolipids were characterized Serum study by immunodetection on thin layer chromatography plates.13

Antibodies specific to gangliosides GM1,GD1a,GD1b,GT1b Serum sampling: Peripheral blood was taken in dry tubes (according to the nomenclature of Svennerholm14) and to the between 9 am and 12 am. The storage of the whole blood sulfatide (cerebroside sulfate) were searched also by an was performed at room temperature. The serum was separated enzyme-linked immunosorbent assay as previously described within 30 min and was kept frozen at −80°C until analyzed. by Jauberteau et al15 and Brindel et al16 with purified glycolip- Blood samples were obtained in the absence of fever, shock ids from Sigma (St Louis, MO, USA). and infection.

Plasma cell study Serum cytokine levels: Serum cytokine levels were evalu- ated prospectively in all six patients. Patients had one to 11 The karyotype of BMPC was determined as previously serial cytokine measurements, leading to 24 evaluations for described.17 For interphase fluorescence in situ hybridization the six POEMS patients (19 samples only for TNF-alpha (FISH) analysis, biotinylated centromeric probes directed measure). In comparison, serum cytokine levels were also against chromosomes 3, 7, 8, 9 and 11 (D3Z1, D7Z1, D8Z2, determined in other monoclonal gammopathies. Multiple D9Z1, D11Z1; Oncor, Illkirch, France) were used.18 DNA myeloma and Waldenstro¨ m’s (MM + WM content of BMPC was measured using computerized imaged group: five samples), polyneuropathy and plasma cell dys- analysis19 and the respective numbers of diploid and aneu- crasia without criteria of POEMS syndrome (PPCD group: ploid BMPC were evaluated. Determination of the plasma cell three samples), and monoclonal gammopathies of undeter- growth fraction used Ki-67 ,20 and expression of mined significance (MGUS: four samples). CD19 and CD56 on BMPC were studied using immunocyto- chemistry.21

IL-1 beta, IL-6, and TNF-alpha assays: Interleukin-1-beta and interleukin-6 were measured using two sandwich type Immunohistochemistry and in situ hybridization for enzyme immunoassays (Medgenix, Fleurus, Belgium and cytokines Immunotech, Marseille, France). Interleukin-6 levels were confirmed by a radio immunologic assay (IL-6 IRMA; Two lymph nodes (patients 1 and 4), and one skin biopsy Medgenix). -alpha was measured using (patient 4) were studied. Normal lymph node and skin were the Medgenix kit. Cytokine levels were measured according used as negative controls. A benign follicular hyperplasia was to the kit procedures. used as control for in situ hybridization. Six bone marrow Unusual clinical signs in POEMS syndrome C Rose et al 1320 Table 2 Serum cytokine levels in patients with POEMS syndrome and other monoclonal gammopathies

Cases No. of IL-1-beta IL-6 TNF alpha samples (n Ͻ 15 pg/ml) (n Ͻ 8.5 pg/ml) (n Ͻ 20 pg/ml) median (range) median (range) median (range)

POEMS 1 2 4 (1–7) 91.5 (41–142) 38 (28–48) 2 11 2 (0–13) 10 (4–25) 33 (24–57) 3 5 2.5 (0–10) 17 (8–95) 55 (32–124) 4 2 3 (1–5) 25.5 (16–35) 45.5 (42–49) 5 3 1 (0–2) 16 (5–28) 52.5 (27–78) 6 1 0.8 18.5 ND PPCD 3 2 (1–4) 4 (3–5) 21 (20–27) MM + WM 5 1 (0–1) 12.5 (8–29) 20.5 (16–36) MGUS 4 4 (0–13) 9.5 (6–15) 22.5 (14–31)

PPCD, polyneuropathy and plasma cell dyscrasia; MM + WM, + Waldenstro¨m’s macroglobulinemia; MGUS, monoclonal gammopathy of undetermined significance. Data presented in this Table are those of the Medgenix kit. Only 19 samples were available for TNF-alpha measure.

biopsies were immediately fixed in formalin and studied with 6 was found in all patients and in 13/24 serum samples. Serum immunohistochemical methods only. Biopsy tissue was levels of TNF-alpha were elevated in all patients and all serum immediately cut into two parts. Tissue was processed no more samples (19 samples, elevation up to six-fold). All patients had than 30 min after surgical biopsy. One part was fixed in par- normal serum IL-1-beta levels using the Medgenix kit. One aformaldehyde or formalin and paraffin-embedded for diag- patient (patient 4) had a very slight increase of IL-1-beta using nostic evaluation. The other part was embedded in cryopre- the Immunotech kit (15.5 pg/ml; normal value р5 pg/ml). servative solution OCT (compound, Miles, Elkart, IN, USA), snap-frozen in isopentane and stored at −80°C until use.

Immunohistochemistry: We used the avidin-biotin tech- nique as previously described.22 Monoclonal antibodies employed included DBB42 (pan-B; Immunotech, Marseille, France), L26 (anti-CD20; Dakopatts, Dako, Denmark), CD43 (Leu 22; Dakopatts), UCHL-1 (anti-CR45RO; Dakopatts), CD68 (PG-M1; Dakopatts) and polyclonal IL-6 (Genzyme, Cambridge, UK). On bone marrow specimens, antibodies directed against kappa and lambda chains (Dakopatts) were only performed. The following mouse monoclonal antibodies were used to recognize B cells antigens: CD19 (Dakopatts), CD20 (Dakopatts), CD22 (Leu 14; Dakopatts), antigens: CD3 (Dakopatts), CD4 (T4; Dakopatts), CD8 (T8; Dakopatts).

In situ hybridization for cytokines: The cDNA for TNF and for IL-1-beta (a generous gift of Dr P Vassali, Geneva, Switzerland) were inserted into a p Bluescript vector, lin- earized with Pst1orEcoR1 to produce antisense or sense pro- bes before transcription. The IL-6 probe was generously pur- chased by Dr D Emilie (INSERM U131, Clamart, France).23 In situ hybridization was performed as previously described.24 Non-specific mRNA signals never exceeded five grains/cell, this observation leading to the definition of positivity threshold for hybridization with the antisense probes. Positive mRNA hybridization signals were only observed when slides were hybridized with antisense probes.

Results Figure 1 (a) Lymph node biopsy (patient No. 4): in situ hybridiz- Serum studies ation with anti-IL-1 probe. Dark signals indicate the presence of IL-1 mRNAs in interfollicular macrophages. Inset: positivity of an interfol- licular macrophage (clear cell with pale nuclei, original magnification No patient had auto-antibodies directed against peripheral × 400). (b) Lymph node biopsy (patient No. 4): anti-CD68 monoclonal nerve components. Serum cytokine levels are summarized in antibody stains some interfollicular macrophages (original magnifi- Table 2. A moderate to marked (up to 16-fold) elevation of IL- cation × 100). Unusual clinical signs in POEMS syndrome C Rose et al 1321 Plasma cell study beta using the Immunotech kit), had cutaneous necrosis and pulmonary hypertension. Patient 6, the second patient with All patients had a bone marrow aspirate and a bone marrow pulmonary hypertension, also had an elevated level of IL-6 in biopsy. Most results are reported in Table 1. Bone marrow serum. In the cutaneous biopsy of patient 4, the role of TNF- plasmacytosis was equal or less than 15% in all patients. alpha in the necrosis was confirmed by the presence of a high DNA index (DI) of BMPC was determined in four patients. number of cells expressing TNF-alpha mRNA in the dermis. The DI ranged from 0.98 to 1.00 in normal controls and was Pathologically, PPH is associated with the proliferation of abnormal in the four tested POEMS patients (Table 1). All smooth-muscle cells, fibroblasts, and endothelial cells in the patients had in fact two populations of BMPC, one diploid walls of small pulmonary arteries. The proliferative lesions are and another one aneuploid, the latter ranging from 26 to 61% associated with in situ microthrombosis.26,27 Interestingly, a of all BMPC. The karyotype (using conventional cytogenetics) recent study demonstrated increased serum levels of IL-1-beta failed to show any anomaly in the three tested patients. Using and IL-6 in severe PPH and strongly suggested a role for these interphase FISH, patient 3 had 10% BMPC with trisomy 9 and cytokines in the pathogenesis of PPH.28 This progressive clini- patient 5 had 17% BMPC with trisomy 11. The two other cal course is in accordance with the slow progression of the patients tested were disomic with all tested probes. growth of smooth muscle cells, fibroblasts and endothelial The number of Ki-67-positive BMPC was less than 1% in cells of the pulmonary arteries followed by microthrombotic all patients. The CD19 and CD56 antigens, studied in three lesions. Overall, two out of six patients had in this series patients, were expressed on 16–72% and 0–10% BMPC, proven PH and this incidence was possibly underevaluated. respectively (Table 1). We suggest that POEMS syndrome is an occasional cause of secondary PH and that patients with POEMS syndrome should be tested for PH, especially if they present with dys- Immunohistochemistry and in situ hybridization for pnea. cytokines No patient had auto-antibodies against peripheral nerve components. Although the search for these auto-antibody Lymph node biopsy of patients 1 and 4 demonstrated angio- activities remains limited, this result does not support the role follicular hyperplasia of the hyaline vacular type in patient 1 of the M protein in the pathogenesis of polyneuropathy. and of the mixed variety in patient 4. In patient 1, the interfol- Another argument against the role of the M protein is that licular zones contained a polymorphic lymphoid infiltrate some patients (patients 1 and 4 in this series) had neuropathy with scattered plasma cells whereas numerous plasma cells without detectable M protein all over the course of the were present in patient 4 in the same zones. The germinal disease. centers were often atrophic. They contained a thickened ves- Up to now, no study has been devoted to the BMPC in sel surrounded by concentric sheets of small lymphocytes. POEMS syndrome, probably because of their low number and Skin biopsy of patient 4 showed mild changes. The dermis the difficulty to biopsy osteosclerotic bone lesions. Over the was infiltrated by a few inflammatory cells with scattered past few years, we have studied biological features of BMPC small lymphocytes and mast cells around small vessels and in multiple myeloma and in MGUS, especially the Ki-67 adnexia. Immunohistochemical studies showed a predomi- kinetic index,17,19 immunophenotype,20 DNA content and nant population of B cells in the follicles and numerous T cells interphase FISH analysis.19 Our patients had a low BM plas- and CD68-positive macrophages in the interfollicular spaces. macytosis, a low proliferation rate and failed to exhibit kary- In both cases, a majority of interfollicular plasma cells were otype anomaly using conventional cytogenetics. In the three lambda light-chain positive on paraffin-embedded sections. In patients tested, CD19 was expressed by Ͼ10% BMPC in each situ hybridization with sections of lymph nodes showed a instance. In a previous study, we found that 77% of MGUS strong positive signal with IL-1-beta antisense probe in inter- patients had more than 10% CD19 positive plasma cells as follicular spaces. These cells were medium-sized and mono- compared to only 12% of myeloma patients.20 All four nuclear with an abundant clear cytoplasm. Localization in the patients tested had an abnormal plasma cell DNA content, lymph node and morphologic characteristics of these cells restricted to a part of BMPC (26 to 61%), and this was con- corresponded to those of macrophages. Immunohistochemis- firmed by the exhibition of interphase FISH anomaly in some try with antibody anti-CD68 showed a strong positivity in the BMPC. These findings were recently demonstrated as a quite same area (Figure 1a and b). In contrast, hybridization with common anomaly in MGUS, exhibited by BMPC from more TNF-alpha and IL-6 antisense probes was negative on these than 50% of patients.19 Taking togther all these data, biologi- sections as well as in those from controls. In the cutaneous cal characteristics of BMPC from our patients with POEMS biopsy from patient 4, who had diffuse cutaneous necrosis, a syndrome are not far from what we observed in MGUS high number of cells expressing TNF-alpha mRNA was patients. These data are in agreement with those from Miralles observed in the dermis whereas hybridization with IL-1-beta et al,4 in which the outcome of 38 patients with plasma cell and IL-6 antisense probes was negative. dyscrasia and polyneuropathy (of whom 28 had у3 features of POEMS syndrome) was multiple myeloma in only one case, an incidence not far from that observed in MGUS. Discussion Our study confirms the reports of Gherardi et al6–8 concern- ing the increase of IL-6 and TNF-alpha in the serum of patients To our knowledge, diffuse cutaneous necrosis has never been with POEMS syndrome. In contrast, we failed to demonstrate reported in patients with POEMS syndrome and pulmonary elevated levels of IL-1-beta comparable to those achieved by hypertension (PH) has been reported in only one Japanese Gherardi et al. Normal levels of IL-1-beta in serum were also case.25 There is some evidence that these two clinical signs found in a recent study from Japan.29 In our study, IL-1-beta were related to cytokine overproduction, especially high lev- levels were measured by two different kits. We have no expla- els of IL-6 and TNF-alpha. Patient 4, who had permanent high nation for this discrepancy and a larger number of patients levels of IL-6 and TNF-alpha (and a slight increase of IL-1- should be studied to solve this problem. The most consistent Unusual clinical signs in POEMS syndrome C Rose et al 1322 finding was an elevated level of TNF-alpha found in all 7 Gherardi RK, Belec L, Fromont G, Divine M, Malapaert D, Gaul- patients and all samples. In our opinion, the role of TNF-alpha ard P, Degos JD. Elevated levels of interleukin-1b (IL-1-beta) and in the pathophysiology of polyneuropathy has to be strongly IL-6 in serum and increased production of IL-1-beta mRNA in lymph nodes of patients with polyneuropathy, organomegaly, considered. A high level of TNF-alpha in serum is in fact one endocrinopathy, M protein, and skin changes (POEMS) syndrome. of the most frequent biological findings in these patients who Blood 1994; 83: 2587–2593. all suffer, by definition, from polyneuropathy. In addition, 8 Gherardi RK, Chouaı¨b S, Malapert D, Be´lec L, Intrator L, Degos high serum levels of TNF-alpha have been reported in patients JD. Early weight loss and high serum tumor necrosis factor-alpha with Guillain–Barre´ syndrome and polyneuropathy associated levels in polyneuropathy, organomegaly, M protein, skin changes with monoclonal gammopathy.30 It has also been implicated syndrome. Ann Neurol 1994; 35: 501–505. 31 9 Pruzanski W. Takatsuki syndrome: a reversible multisystem in auto-immune demyelination and may alter the blood– plasma cell dyscrasia. Arthr Rheum 1986; 29; 1534–1535. nerve barrier, leading to increased endoneural pressure and 10 Driedger H, Pruzanski W. Plasma cell neoplasia with peripheral damaging of nerve fibers.32 Finally, intraneural injections of polyneuropathy: a study of five cases and a review of the litera- TNF-alpha can cause nerve destruction.32 ture. Medicine 1980; 59: 301–310. The macrophage is the main producer of TNF-alpha and IL- 11 Ribadeau Dumas S, Tillie-Leblond I, Rose C, Saulnier F, Wemeau 1-beta.33 Taking into account the high and prolonged pro- JL, Hatron PY, Wallaert B. Pulmonary hypertension associated duction of TNF-alpha in POEMS syndrome, as well as the pre- with POEMS syndrome. Eur Respir J 1996; 9: 1460–1462. 12 Jauberteau MO, Cook JM, Drouet M, Preud’homme JL. Affinity liminary results we achieved with in situ hybridization using immunoblotting detection of serum monoclonal immunoglobulins the IL-1-beta probe, we can hypothesize that the macrophage reactive with glycosphingolipids. J Immunol Meth 1990; 134: is involved in POEMS syndrome, at least for the abnormal pro- 107–112. duction of these cytokines. The normal levels of interleukin- 13 IIyas AA, Quarles RH, McIntosh TD, Dobersen MJ, Trapp BD, 2 and IFN-gamma also suggest that activation of macrophages Dalakas MC, Brady RO. IgM in a human neuropathy related to rather than T cells is concerned in POEMS syndrome.6 paraproteinemia binds to a carbohydrate determinant in the mye- lin-associated glycoprotein and to ganglioside. Proc Natl Acad Sci In conclusion, this study demonstrates that POEMS syn- USA 1984; 81: 1225–1229. drome is an hypercytokinemic syndrome with elevated levels 14 Swennerholm L. Chromatographic separation of human brain gan- of IL-6 and TNF-alpha in serum. It describes diffuse cutaneous gliosides. J Neurochem 1963; 10: 613–628. necrosis as a new and probably TNF-alpha-related clinical 15 Jauberteau MO, Ben Younis Chenouffi A, Rigaud M, Baumann N. sign. It also establishes pulmonary hypertension as a frequent IgM gammopathies and polyneuropathies react with an antigenic sign which was probably underevaluated in previous series glycolipid present in human central nervous system. Neuroscience and is possibly IL-6-related. The biological characteristics of 1989: 97: 181–184. 16 Brindel I, Preud’homme JL, Vallat JM, Vincent D, Vasquez JL, Jau- bone marrow plasma cells were of non-malignant type. The berteau MO. Monoclonal IgM reactive with several gangliosides macrophage is involved in this syndrome. Further investi- in a chronic relapsing polyneuropathy. Neurosci Lett 1994; 181: gations will be necessary to fully appreciate its role, as well 103–106. as the impact of treatments which target the macrophage or 17 Laı¨ JL, Zandecki M, Mary JY, Bernardi F, Izydorczyk V, Flactif M, act through an anti-cytokine mechanism. Morel P, Jouet JP, Bauters F, Facon T. Improved cytogenetics in multiple myeloma. A study of 151 patients including 117 at diag- nosis. Blood 1995; 85: 2490–2497. 18 Zandecki M, Obein V, Bernardi F, Soenen V, Flactif M, Laı¨ JL, Acknowledgements Francois M, Facon T. Monoclonal gammopathy of undetermined significance: chromosome changes are a common finding within This work was supported by the Comite´s du Pas-de-Calais et bone marrow plasma cells. Br J Haematol 1995; 90: 693–696. du Nord de la Ligue Nationale de Lutte contre le Cancer and 19 Zandecki M, Bernardi F, Laı¨ JL, Facon T, Izydorczyk V, Bauters F, the CHRU, Lille. We thank Pierre Fenaux for critical review Cosson A. 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