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Das multiple Myelom ist ein reifzelliges B-Zelllymphom mit einem Erkrankungsgipfel im hoheren Lebensalter. Maligne Plasmazellen infiltrieren das Knochenmark und bestimmen uber Interaktionen mit anderen Korperzellen und Organsystemen die individuell unterschiedliche klinische Symptomatik. Vorstadien sind die monoklonale Gammopathie unbestimmter Signifikanz und das Smoldering multiple Myelom, die ublicherweise keiner Behandlung bedurfen. Zur Diagnosesicherung eines therapiebedurftigen multiplen Myeloms sind verschiedene Laboruntersuchungen und bildgebende Verfahren notig. Das Myelomprotein und die freien Leichtketten im Serum sind zur Verlaufsbeurteilung wichtige Surrogatmarker fur die Tumormasse. Therapeutisch stehen konventionelle Chemotherapie, Proteasomeninhibitoren, Immunmodulatoren, monoklonale Antikorper, Hochdosischemotherapie, allogene Blutstammzelltransplantation, Strahlentherapie und verschiedene supportive Masnahmen zur Verfugung. Die Therapie ist heute noch palliativ, Langzeitremissionen werden bei einzelnen Patienten beobachtet.

Das multiple Myelom (MM) ist eine maligne Plasmazellerkrankung mit klonaler Entwicklung. Die monoklonale Gammopathie unbestimmter Signifikanz (MGUS) gilt als Vorstadium zum MM und muss differenzialtherapeutisch ebenso wie das „smoldering multiple myeloma“ (SMM) vom MM mit seinen Endorganschaden abgegrenzt werden. Eine hoch dosierte Chemotherapie mit Unterstutzung durch autologe Blutstammzellen sollte bei den meisten Patienten angestrebt werden, um eine moglichst komplette und lang andauernde Remission zu erreichen. Ziele sind die weitgehende Symptomfreiheit, die Verhinderung von Organkomplikationen und die Lebensverlangerung. Patienten, bei denen dieses Konzept aufgrund des Alters und der Komorbiditaten nicht angewendet werden kann, konnen mit einer niedrig dosierten Chemotherapie behandelt werden, in der Regel mit Alkylanzien. Ziele sind hier die Verbesserung der Lebensqualitat, aber auch die Lebensverlangerung. Durch Einbeziehung von Thalidomid, Lenalidomid, Pomalidomid, Bortezomib oder Carfilzomib in beide Konzepte konnten die Remissionsraten und Uberlebenszeiten signifikant verbessert werden. Die allogene Stammzelltransplantation ist besonders im Verlauf des ersten Jahrs nach Transplantation mit einer relativ hohen Mortalitat assoziiert und wird in Studien mit dem Ziel der Heilung weiterentwickelt. Sie ist fur ausgewahlte Patienten eine Alternative. Das Behandlungskonzept fur MM-Patienten ist je nach individueller Konstellation durch lokale Strahlentherapie, Bisphosphonatgaben und supportive Immunglobulininfusionen zu erganzen.

A total of 153 diagnostic bone marrow biopsies from patients with advanced stages of multiple myeloma corresponding to stages II and III according to the Durie/Salmon classification were evaluated prior to any treatment in a prospective therapy trial of the German Myeloma Treatment Group. Histologic sections were analyzed according to a pre-defined system of criteria microscopically by 2 observers, determining three criteria: 1) grading by histopathology, regarding the cytologic differentiation of neoplastic cells and quantifying the percentage of plasmacytic, pleomorphic, and plasmablastic myeloma cells distributed within the sections; 2) the volume of infiltration; and 3) the pattern of neoplastic growth. Furthermore, four other criteria, namely hematopoiesis, fiber increase, osteomalacia, and micro-osteo-lesions, were evaluated. A cluster analysis using the three histological criteria revealed three groups of patients with significantly different survival times based on histological criteria only; the three criteria were mentioned above. It is concluded from these results that bone marrow biopsies, when evaluated histologically by grading and staging according to the three criteria, provide most valuable prognostic parameters in myeloma patients.

Die AL-Amyloidose ist eine monoklonale Plasmazellerkrankung, bei der Immunglobulinleichtketten oder Fragmente extrazellular im Gewebe zu Amyloidfibrillen vernetzt abgelagert werden. Mit Ausnahme des Zentralnervensystems konnen alle Organe betroffen und somit funktionsgestort sein. Am haufigsten befallen sind die Nieren, initial oft mit nephrotischem Syndrom, spater auch mit renaler Funktionseinschrankung. Viele Patienten sind aufgrund der Ablagerungen in den Gefasen und im Herz hypotensiv. Die Behandlung zielt auf eine weitgehende Elimination der monoklonalen Plasmazellen, um ein Fortschreiten der Amyloidablagerungen zu verhindern oder wenigstens zu verlangsamen. Alter, Organfunktionen und andere Kriterien werden zur Patientenselektion fur aggressive oder weniger belastende Behandlungsformen genutzt, um die therapieassoziierte Mortalitat moglichst niedrig zu halten. Trotzdem ist die Prognose unbefriedigend. Deshalb ist es notwendig, neue Medikamente und experimentelle Therapieformen in klinischen Studien weiter zu entwickeln, und nach Ansatzen zu suchen, die eine Ruckbildung der Ablagerungen ermoglichen konnten.

The multiple myeloma (MM) has an incidence of 3-4/100,000 in the Caucasian population. MM has to be distinguished from smouldering MM and monoclonal gammopathy of uncertain significance (MGUS). In younger patients (

Multiple myeloma (MM) is a malignant plasma cell disorder with clonal development. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are precursor stages of MM and both have to be differentiated from MM which is characterized by organ complications. High-dose chemotherapy combined with autologous stem cell support is the therapy of choice for most patients in order to achieve long-lasting complete remission with few symptoms, prevention of new organ complications and survival prolongation. Patients who cannot be intensively treated due to advanced age and comorbidities should be treated with low-dose chemotherapy, normally alkylating agents, for improved quality of life and also survival prolongation. Including thalidomide, lenalidomide, pomalidomide, bortezomib or carfilzomib in both high-dose and low-dose chemotherapy concepts results in a significantly higher remission rate and longer survival. Allogeneic stem cell transplantation is associated with a relatively high mortality during the first year after transplantation which will be refined with the aim of healing in various trials and is an alternative treatment approach for selected patients. A treatment concept for MM patients has to be individually complemented by local irradiation, administration of bisphosphonates and supportive infusions of immunoglobulins.

One hundred twenty-one anemic, transfusion-dependent patients with multiple myeloma (MM) or low-grade non-Hodgkin's lymphoma (NHL) were randomly allocated to receive (a) recombinant human erythropoietin (rhEPO) 10,000 U/d subcutaneously 7 days a week (fixed dose group) (n = 38), or (b) rhEPO 2,000 U/d subcutaneously for 8 weeks followed by step- wise escalation of the rhEPO dose (titration group) (n = 44), or (c) no rhEPO therapy (control group) (n = 39). The total treatment period was 24 weeks. There were no differences between the three groups with regard to baseline clinical, demographic, or health status measures. The cumulative response frequency, defined as elimination of the transfusion need in combination with an increase in the hemoglobin concentration by >20 g/L, was 60% in both rhEPO treatment groups and 24% in the control group (P = .01 and .02, respectively, log rank test). For patients in the titration group the response rate on the first dose level (2,000 U/d) was only 14%. Cox's univariate regression analysis revealed that an inadequately low endogenous erythropoietin concentration in relation to the degree of anemia and a baseline platelet concentration > or = 100 x 10(9)/L were significant predictors for response to rhEPO therapy (P < .01). Multivariate regression analysis showed that relative erythropoietin concentration was the most important factor and the platelet count had no additional influence on response. Treatment with rhEPO was well tolerated. We conclude that treatment with rhEPO may be indicated in anemic MM and NHL patients with a relative erythropoietin deficiency. An initial dose of 5,000 U/d subcutaneously may be recommended.

Follow-up data of 320 multiple myeloma (MM) patients entering the German Myeloma Treatment Group (GMTG) trial MM01 were analysed for factors predicting overall (OAS) and tumour related survival (TRS). Response to primary induction chemotherapy was relevant for prognosis if a limit of 25% tumour cell mass (TCM) reduction was used to separate responders from non-responders. Furthermore, TCM, histological grading of myeloma cells, degree of bone marrow infiltration, haemoglobin, platelet counts, calcium, creatinine, albumin, beta 2M, and Bence Jones proteinuria correlated to both OAS and TRS. Age was relevant for OAS only. The multivariate analysis revealed histological grading, TCM and platelets as the most reliable prognostic factors. Based on these data the Durie/Salmon classification could be improved by defining poor prognosis patients (50% TRS: 16 months) characterised by pretreatment platelets of < or = 150,000 and/or poorly differentiated myeloma cell morphology. Patients lacking both risk factors displayed 50% survival times of 46 months in stage III and 88 months in stage II.

The multiple myeloma (MM) has an incidence of 3-4/100,000 in the Caucasian population. MM has to be distinguished from smouldering MM and monoclonal gammopathy of uncertain significance (MGUS). In younger patients (65 years) a good long-term remission is the aim of therapy, while in the elderly patients with comorbidities the aim is a good partial remission with good quality of life. In the elderly this can be achieved with a combination of melphalan and prednisone. High-dose chemotherapy, often as a tandem transplantation, is part of standard therapy of MM patients65 years. However, allogeneic stem cell transplantation is the only curative approach. New substances approved for treatment of relapsed MM include bortezomib, thalidomide, and lenalidomide.

A 36 years old nurse had been suffering from prolonged weakness, weight-loss of 6 kg, night-sweat and painful swelling of neck lymph nodes for one year. On admission she was in a reduced physical condition. Nuchal, cervical and inguinal lymphnodes were enlarged bilaterally.Computed tomography showed enlarged lymph nodes in the neck and inguinally. Histology of the biopsies revealed the diagnosis of the mixed variant of Castleman's Disease.A steroid treatment was initiated, administering 100 mg prednisone for 2 weeks, 75 mg for another 2 weeks and 50 mg for a month. The dose was then gradually reduced by steps of 10 mg. After 3 months the patient's physical state and lymph nodes were normalized. So treatment was terminated and the nurse was able to take up work again.If confronted with general lymphadenopathy associated with B-symptoms even without fever a Castleman's Disease should be taken into consideration. The prognosis of the multivariant form is uncertain. Transformation to malignant lymphoma is frequent.

Alpha-interferon (Ifn-alpha) has anti-tumor activity in vivo when used as a single agent in multiple myeloma (MM). However, the mechanisms responsible for this activity have not been clarified so far. Ifn-alpha has been therapeutically tested in a number of clinical trials for remission induction, maintenance therapy, and in different combinations with chemotherapy or steroids. The results of these trials are partially controversial and do not undoubtedly support Ifn-alpha treatment in any of these indications. However, meta-analyses using individual patient data or published results of the trials revealed small but significant advantages for MM patients treated with Ifn-alpha monotherapy for maintenance or in combination with conventional chemotherapy for remission induction. These advantages weigh against reduction of quality of life due to adverse effects commonly seen in Ifn-alpha treated MM patients and in addition relatively high treatment costs. Future efforts should be made to find prognostic factors determining effectiveness of Ifn-alpha therapy. Furthermore, the outcome of Ifn-alpha treatment should be improved by new therapy strategies based on a better understanding of the pathophysiological mechanisms influenced by Ifn-alpha in MM.

PURPOSE: In patients undergoing cytokine therapy, systemically applied interleukin-2 (IL-2) and/or interferon-alpha (IFN-α) have been reported to induce thyroid dysfunction as well as thyroid autoantibodies. We analyzed the correlation of thyroid autoimmunity with HLA phenotype, various other autoimmune parameters, and patient survival. PATIENTS AND METHODS: For this purpose, antithyroglobulin autoantibodies, antimicrosomal thyroid autoantibodies, thyroglobulin receptor autoantibodies, thyroid dysfunction, and multiple clinical parameters were determined in 329 unselected patients with metastatic renal cell cancer before and after systemic IL-2 and IFN-α2 therapy. For statistical analysis, we used both univariate and multivariate Cox proportional hazards models and the two-tailed Fisher's exact test. RESULTS: Antithyroglobulin autoantibodies and antimicrosomal thyroid autoantibodies were detected in 60 patients (18%); positive autoantibody titers of various other autoimmune parameters were statistically unrelated. The presence of thyroid autoantibodies was correlated with prolonged survival (P < .0001). There was a statistically significant difference in frequencies of HLA-Cw7 expression between thyroid autoantibody-positive and -negative patients (P ≤ .05), and the Cw7 expression was associated with prolonged overall survival (P = .009). CONCLUSION: The evaluation of thyroid autoantibodies during cytokine therapy could be a useful prognostic marker for patients with renal cell carcinoma who benefit from cytokine treatment. IL-2– and IFN-α2-induced tumor control and prolonged survival may require breaking of immunologic tolerance against self-antigens.

277 untreated multiple myeloma patients of stage I (n = 33), II (n = 106) and III (n = 138) entered the study. Patients of stage II presenting a progressive tumor (n = 64) initially or during observat

Multiple myeloma (MM) is a B-cell non-Hodgkins lymphoma with a neoplastic proliferation of plasma cells in the bone marrow. In different studies median survival time has been measured between 19 and 50 months. Several prognostic factors help to subdivide the patient population in risk groups. The treatment is palliative until now and the individual concept of therapy includes chemotherapy, radiotherapy and other treatment modalities. Evidence of progressive or symptomatic disease is usually required for initiation of chemotherapy.

The relevance of quantitative determinations of urinary deoxypyridinolines (DPY) and pyridinolines (PY), and of serum type I collagen carboxyterminal cross-linked telopeptides (ICTP), has been evaluated for patient monitoring in multiple myeloma (MM). In 178 untreated MM patients, a clear correlation was found between ICTP concentrations, bone destructions and serum calcium levels. Furthermore, serum ICTP, urinary DPY and PY concentrations were estimated before and during treatment in a further 33 MM patients randomly allocated to four groups receiving intravenous melphalan/prednisone (MivP) chemotherapy alone, or MivP in combination with three different doses of i.v. clodronate. 1800 mg of i.v. clodronate combined monthly with MivP induced a rapid and sustained reduction in bone resorption parameters to the normal range, a result not obtained with either MivP alone, or with a lower clodronate dose. While confirming the relevance of determining pyridinium cross-links for estimating bone resorption in MM, our data indicate that measurements of these parameters could be useful for dose finding and monitoring of bisphosphonate therapy.

One hundred twenty-one anemic, transfusion-dependent patients with multiple myeloma (MM) or low-grade non-Hodgkin's lymphoma (NHL) were randomly allocated to receive (a) recombinant human erythropoietin (rhEPO) 10,000 U/d subcutaneously 7 days a week (fixed dose group) (n = 38), or (b) rhEPO 2,000 U/d subcutaneously for 8 weeks followed by step-wise escalation of the rhEPO dose (titration group) (n = 44), or (c) no rhEPO therapy (control group) (n = 39). The total treatment period was 24 weeks. There were no differences between the three groups with regard to baseline clinical, demographic, or health status measures. The cumulative response frequency, defined as elimination of the transfusion need in combination with an increase in the hemoglobin concentration by20 g/L, was 60% in both rhEPO treatment groups and 24% in the control group (P = .01 and .02, respectively, log rank test). For patients in the titration group the response rate on the first dose level (2,000 U/d) was only 14%. Cox's univariate regression analysis revealed that an inadequately low endogenous erythropoietin concentration in relation to the degree of anemia and a baseline platelet concentrationor = 100 x 10(9)/L were significant predictors for response to rhEPO therapy (P.01). Multivariate regression analysis showed that relative erythropoietin concentration was the most important factor and the platelet count had no additional influence on response. Treatment with rhEPO was well tolerated. We conclude that treatment with rhEPO may be indicated in anemic MM and NHL patients with a relative erythropoietin deficiency. An initial dose of 5,000 U/d subcutaneously may be recommended.

Multiple myeloma is a low-grade non-Hodgkin lymphoma. Treatment is palliative, and an individually adapted strategy for therapy is needed for each patient. A review about diagnostic methods for staging, prognostic factors and different aspects of therapy is presented.

Several mechanisms are discussed as inducers for polyclonal hypogammaglobulinemia in multiple myeloma. A soluble noncytotoxic activity which inhibits in vitro the proliferation of normal polyclonal spleen B lymphocytes was measured in the supernatant of cultured bone marrow mononuclear cells from multiple myeloma patients. In addition, human B lymphoblastic cell lines (CESS, Daudi) and human T lymphocytes were sensitive to the antiproliferative effect of the suppressor activity, while other cell lines (RPMI 8226, IM9, CTL6, L1210, HL-60, and K562) were not. The activity was detected in a 5-kDa fraction and was stable to heating (30 min, 56 degrees C) and proteolytic enzymes. Extraction experiments using chloroform:methanol (2:1) suggest a lipid character of the suppressor activity.

In vitro data have demonstrated autologous T-lymphocytes with anti-tumour activity in multiple myeloma (MM). Therefore a phase I/II trial was conducted to study the feasibility, the effect on several immunological parameters, and the tumour response induction of low-dose recombinant interleukin-2 (rIL-2) in MM patients. 18 MM patients of advanced stages in progress, who had failed on standard chemotherapy received 9 x 10(6) IU/m2 rIL-2 twice daily on days 1 and 2 and 0.9 x 10(6) IU/m2 twice daily for 5 subsequent days per week subcutaneously from days 3 to 56 (repeated every 12 weeks until progression). Patients were treated for between 8 and 1086 + d (mean 241 d) without serious side-effects. 6/17 patients experienced tumour response (2/17 objective tumour mass reduction, 4/17 long-lasting stable disease following tumour progression before initiation of rIL-2 treatment). During therapy the number of eosinophils increased 15-fold, CD4+ T lymphocytes were activated as demonstrated by enhanced CD25 antigen expression, and CD56+ NK cells expanded in the peripheral blood. Furthermore, a diminished pre-treatment ratio of CD4+/CD8+ lymphocytes was normalized during rIL-2 treatment. NK cell activity and lymphokine activated killer (LAK) cell activity was significantly enhanced. Endogenous IL-2 production and elevated soluble IL-2 receptor serum concentrations were induced. Low-dose rIL-2 can stimulate immune enhancement in MM despite the characteristic tumour-induced immunodeficiency. The treatment has proven though limited efficacy in advanced MM. Because most of the responders experienced termination of tumour progression rather than tumour regression, rIL-2 maintenance of chemotherapy-induced remissions should be investigated.

406 untreated multiple myeloma patients of stage I (n = 54), II (n = 148) and III (n = 204) were enrolled in the trial. 51/54 stage I and 60/148 stage II patients were asymptomatic and followed without treatment until disease progression (progression free survival: 60% after 4 years for stage I versus 50% after 1 year for stage II). Symptomatic patients of stage I (n = 3/54) and II (n = 88/148) presenting with tumour progression, received melphalan 15 mg/m2 intravenously (i.v.) and prednisone 60 mg/m2 oral days 1-4 (MP). Stage II disease remission rate was 59%, and 50% tumour related survival (TRS) was 59 months. Stage III patients were randomised to receive MP or VBAMDex (vincristine/BCNU/doxorubicin/melphalan/dexamethasone) treatment. 43% of MP treated patients responded compared with 64% of the VBAMDex group. 50% TRS was 36 months in both groups without a detectable difference. 117 responders of stage II and III with stable disease were randomised to receive either IFN-alpha (5 x 10(6) IU, subcutaneous (S.C.) 3 times per week) or no maintenance treatment. The relapse rate in both groups was 50% after 13 months. No survival benefit for IFN alpha treated patients was observed (50% TRS: 45 months).

Plasma cells obtained from bone marrow samples of 45 patients with MM, eight patients with MGUS, eight patients with Waldenström's macroglobulinaemia (WM), one patient with immunocytoma, and 12 controls were characterized by immunophenotyping, estimation of DNA content, and labeling index, as well as by morphological analysis. Plasma cells from 37/45 myeloma and 5/8 MGUS patients expressed CD38 and CD56 (N-CAM) on their surface but were negative for other NK cell-associated antigens such as CD16 (Fc gamma RIII) or CD2. All tumor cells of less-differentiated cell type (WM, immunocytoma) and normal polyclonal plasma cells were negative for CD56. CD56-specific mRNA was demonstrated in myeloma cells by northern blot analysis. Another adhesion molecule, ICAM-1 (CD54), was found on plasma cells from all patients and controls examined. Coexpression of CD19 (1/45), CD20 (9/45), or CD33 (3/45) was rare and CD10 with CD14 was expressed by a small tumor cell subpopulation of only one myeloma patient. The individual pattern of surface marker expression was not associated with a special-type myeloma protein isotype, stage or status of disease, LI or histological classification; however, a correlation between CD56 expression or histological classification and DNA content of the tumor cells was found.

The median survival of patients with stage II or III multiple myeloma (MM) treated with chemotherapy is 3 years. Since the introduction of melphalan/prednisone treatment no significant improvement in this prognosis has been attained even by applying other chemotherapy combinations [1]. Therefore, alternative therapy modalities should be developed and tested. Monoclonal immunoglobulin (mIg) produced by the malignant plasma cells is a marker for MM and in vivo an indicator for tumor cell mass changes during therapy [2, 3]. Measuring mIg in supernatants of short-term cultures from myeloma bone marrow cells is a system which can be used for in vitro studies on the regulation of individual myeloma clones [4]. Previous experiments provided strong evidence for growth control of myeloma tumor cells by autologous CD3 + lymphocytes. The suppressive effect of these autologous T lymphocytes can be enhanced by stimulation with anti-CD3 antibodies or interleukin 2 (IL-2) [5]. Trials in patients with other malignant diseases such as renal cell carcinoma, colorectal carcinoma, melanoma or non-Hodgkin’s lymphoma using recombinant IL-2 (rIL-2) for in vivo activation of cytotoxic T lymphocytes and natural killer (NK) cells or for ex vivo generation of lymphokine-activated killer cells clearly showed enhancement of immunological effector cells and significant though limited antitumor effects [6–8].

Pain symptoms caused by bone lesions of multiple myeloma can be relieved by a local irradiation treatment. To estimate the influence of systemic treatment on the palliative effect of local radiotherapy the records of 70 myeloma patients treated with chemotherapy combined with or followed by local irradiation were reviewed. The local response rate, defined as complete pain relief at the irradiated site, was 80 % in patients receiving irradiation during chemotherapy (melphalan and prednisone) and this palliative effect endured 31.8 ± 3.6 months. If irradiation was started in the period without systemic treatment the local response rate was 39.6% and lasted 24.8 ± 17.9 months. In sites treated with more than one radiotherapy course 94% response rate after the first treatment, 56 % after the second treatment and no response after the third course was achieved. The duration of local pain control was positively related to the applied radiation dose. It is concluded that irradiation during concomitant chemotherapy is superior to radiotherapy performed in a period without systemic treatment. Local long-term palliation can only be achieved by a sufficient hieh radiation dose.

277 untreated multiple myeloma patients of stage 1 (n = 33), II (n = 106) and III (n = 138) entered the study. Patients of stage II presenting a progressive tumor (n = 64) initially or during observation (n = 14) were treated with MivP (remissions: 61%). 138 patients of stage III were randomized to receive MivP or VBAMDex treatment. 51% of MivP treated patients responded versus 70% of the VBAMDex group. 71 responders of stage II and III with stable disease were randomized on Ifn-alpha maintenance versus no maintenance treatment. The relapse rate in both groups was 50% after 7 months. 75% survival was greater than 36 months in stage II and 11 months in stage III patients.

Ten cases of acquired antibody deficiency syndrome with chronic granulomatous infection were diagnosed in our hospital during the past 10 years. We were able to perform a retrospective analysis of the initial and follow-up chest radiographs in 8 of these patients. The following pathological findings could be demonstrated: 1. increased bronchovascular markings in the basal lung fields, 2. reticular densities in the middle and basal lung fields, 3. confluent nodular densities of varying size in the periphery of the basal and middle fields, 4. pulmonary infiltrates in the middle and lower lobes, 5. hilar node enlargement of moderate extent. Findings 2, 3 and 5 completely disappeared under steroid therapy whereas 1 showed only partial recovery. If both the radiologic and serological findings are considered, it is possible to differentiate this disease from sarcoidosis.

Pulmonary infection with mycobacterium tuberculosis and clonal B-cell expansion is described in a 26-year-old woman with granulomatous disease of lung, liver, and bone marrow as well as a late onset common variable immunodeficiency syndrome (CVID).

136 untreated multiple myeloma patients of stage II and III were collected in the study. 37/51 stage II patients had progressive disease and were treated with melphalan and prednisone (MP). 85 patients were of stage III and randomized into MP and vincristine, BCNU, adriamycin, melphalan and dexamethasone (VBAMDex) treatment groups. 55% of MP treated patients responded versus 75% of the VBAMDex group. Since the study has been activated only 16 months ago, no difference in survival could be observed.

S 243 Equivocal cases and cases with discordant differentiations of BM versus lymph node infiltrates may need confirmation by molecular studies of receptor rearrangements. Potential of bone marrow biopsy/aspirate for classification, staging and monitoring of multiple myeloma. A prospective study of the German Myeloma Treatment Group R. Bartll, H. Deicheti, D. Pee&, B. Frischg R. Leo’ and W. Wilmanr&, Medizinische Klinik IIt, Klinikum GroJhadem, University of Munich, Germany. ‘Abteilung Immunologic, Medizinische Hochscule Hannover, Germany. jThe Chaim Sheba Medical Center, TelHashomer, University of Tel-Aviv, Israel Our bone marrow studies of MM have demonstrated that the cytologic spectrum of myeloma cells could be divided into six cell types, whose clinical and prognostic relevance was confirmed by statistical evaluation of more than 1000 cases of MM. Moreover, the 6 cell types were combined into three prognostic grades: low, intermediate and high grade malignancy. These six cell types comprise Marschalko and small cell types (low grade), cleaved, polymorphous and asynchronus types (intermediate grade) and the blastic type (high grade). We also combined the 3 grades with the independent prognostic parameter of tumour growth: ‘diffuse’ or ‘nodular’, analogous to Rappaport’s classification of the malignant lymphomas. However, while nodularity in the bone marrow is the best single prognostic parameter in CLL, the presence of nodules in MM signals a progressive, unfavourable course. Three histologic stages were defined. when grouped according to the tumour cell mass in the biopsy. In a prospective study of the German Myeloma Treatment Group (MM01 and MM02) we have tested our morphologic system of classification and staging of MM. A multivariate regression analysis (Cox) has demonstrated that ‘cell grading’ is the most significant prognostic parameter. Our recently proposed prognostic strategy combining plasma cell grading, pattern of tumour growth and levels of SB2M, together with the PCL indicate that this clinicopathological monitoring combines information both on aggressivity and stage of MM and thus facilitates therapeutic decision in the various clinical phases of MM. Bone marrow involvement in plasma cell dycrasias. A clinician’s view Dr H. M. Lokhorst, Department of Immunology and Hematology. University of Utrecht, The Netherlands Long Term Bone Marrow Cultures (LTBMC) from patients with Multiple Myeloma (MM) and normal donors were analyzed for immunophenotype and cytokine production. Both LTBMC adherent cells from myeloma and normal donor origin expressed CDlO, CD13, the adhesion molecules CD44, CD54, VCAM-1, VLA-2 and VLA-5 and were positive for extracellular matrix components fibronectin, laminin and collagen types III and IV. LTBMC from myeloma patients and normal donors spontaneously secreted IL-6. The highest levels of IL-6 were found in LTBMC from patients with active myeloma. To identify the origin of IL-6 production, LTBMC from MM patients and normal donors were co-cultured with bone marrow derived myeloma cells and cells from myeloma cell lines. IL-6 was induced by plasma cell lines like ARH-77 and RPMI-8226, that adhered to LTBMC but not by non-adhering cell lines U266 and FRAVEL. Myeloma cells strongly stimulated IL-6 secretion in co-cultures with LTBMC adherent cells from normal donors and myeloma patients. When direct cellular contact between LTBMC and plasma cells was prevented by tissue culture inserts. no IL-6 production was induced. Binding of purified myeloma cells to LTBMC adherent cells was partly inhibited by monoclonal antibodies against adhesion molecules VLA-4, CD44 and LFA-1 present on the plasma cell. Antibodies against VLA-4, CD29 and LFA-1 also inhibited the induced IL-6 secretion in plasma cell LTBMC co-cultures. In situ hybridization studies performed before and after co-culture with plasma cells indicated that LTBMC adherent cells produce the IL-6. These results suggest that the high levels of IL-6 found in LTBMC of MM patients with active diseases are a reflection of their previous contact with tumour cells in vivo. These results provide a new perspective on tumour growth in MM and emphasize the importance of plasma cell LTBMC interaction on the pathophysiology of MM. Adhesion molecules in the pathophysiology of multiple myeloma Adries Bloem, Tanja Lamme*, Marjolein van Driel, Saskiu Boom, Martin de Smet* and Henk L.okhost*, *Department of Immunology and Hematology, University of Utrecht, Utrecht, The Netherlands Multiple myeloma (MM) is charecterized by the presence of proliferating malignant monoclonal plasma cells (PC). Since in human myeloma the tumour cells preferentially localize and grow in the bone marrow (BM) an important role for BM stroma in the pathogenesis of myeloma can be anticipated. Therefore studies on molecules which allow primary tumour cells to interact with their environment and their involvement in signalling processes may prove valuable in understanding myeloma tumour growth and spread. Adhesion molecules expressed on normal and myeloma plasma cells include VLA4, VLA-5, ICAM-1, CD22 and CD44. In addition, malignant plasma cells in MM can be distinguished from their normal counterparts by the expression of neural cell adhesion molecule (NCAM, CD56). Recently we reported the expression of LFA-1 on myeloma plasma cells correlated with the tumour growth in vivo. Myeloma plasma cells bind effectively to adherent 244 CURRENT DIAGNOSTIC PATHOLOGY growing cells isolated from longterm BM culture (LTBMC). This interaction is of consequence since IL-6 production is induced in the LTBMC after plasma cell binding. IL-6 is generally considered to be the most important myeloma growth factor. Monoclonal antibodies directed against different adhesion molecules expressed on the tumour cells (VLA-4, CD44 and LFA-1) were able to inhibit plasma cell LTBMC binding. Interference in binding resulted in inhibition of IL-6 secretion by the LTBMC. Our results imply that contact between tumour cells and BM stroma mediated by adhesion molecules, is necessary for stromal IL-6 production and is therefore of importance for pathophysiology of myeloma.

Sera from 56 recipients of liver or heart transplants were investigated for monoclonal immunoglobulins (mIg) by immunofixation electrophoresis (IFE) at different times during 4 years after transplantation. Transient, changing, or stable mIgs were found in 18 patients. A significantly increased mIg incidence was observed in heart Tx patients, patients over 40 years of age, and those receiving azathioprine or antithymocyte globulin in addition to prednisolone and cyclosporine as immunosuppressive treatment. No correlations could be found between the presence of mIg and the number of rejection episodes or intercurrent infections. Such serum mIg represent monoclones of at least 1 x 10(9) cells of B lymphocyte lineage that apparently proliferate without adequate suppressive control. Since immunosuppressed allograft recipients are at risk of developing B cell lymphomas, such monoclones may be regarded as prelymphomas necessitating a careful follow-up in these patients.

In a prospective multicenter trial, 320 untreated myeloma patients of stage II and III were randomized for remission induction into two groups receiving six monthly courses of either MP or VCMP treatment. Response rates were equal in both groups: 72% remission, 21% no change, 7% progress for patients evaluable by TCM changes and 56% remission, 11% no change, 33% progress for BJ- and non-secretory myelomas. The overall survival rate was 60% after 4 years. An unexpected finding was the significantly longer survival of MP treated patients compared to the VCMP group. After successful remission induction, patients were randomized into one group receiving maintenance treatment using the induction scheme q 8 weeks, and another group without further chemotherapy. Although patients in the latter group relapsed significantly earlier, differences between both groups concerning acquired resistance to first line therapy or survival have not been noticed to date.

In einer prospektiven multizentrischen Studie der Deutschen Myelom-Gruppe wurden 320 nicht vorbehandelte Myelompatienten der Stadien II und III randomisiert und mit omonatlichen Chemotherapieinduktionskursen MP oder VCMP behandelt. 72% der nach TZM-Veranderung beurteilbaren Patienten kamen in Remission, bei 21% war der Tumor unverandert und bei 7% progredient. 56% der Patienten mit BJ- oder nicht sezernierendem Myelom remittierten, 11% zeigten keine Anderung, 33% einen Tumorprogres. Wahrend die Remissionsraten in beiden Therapiearmen gleich waren, lebten MP-Patienten signifikant langer als VCMP-behandelte. Die Uberlebensrate aller Patienten betrug 60% nach 4 Jahren. Patienten nach erfolgreicher Remissionsinduktion wurden in eine Gruppe ohne und eine mit Erhaltungstherapie – dem Schema der Induktionsphase in 8wochigen Abstanden – randomisiert. Obwohl die Rezidivrate der Patienten ohne Erhaltungstherapie signifikant hoher war, lies sich kein Unterschied in der Uberlebensrate zwischen beiden Gruppen nachweisen.

Reports of allergic complications related to Alloferin are very infrequent. We report a case of anaphylactoid reaction to this drug. The diagnosis was confirmed by intradermal testing.

In vitro monoclonal immunoglobulin (mIg) production of cultured tumour cells--prepared from the bone marrow (BM) or from the peripheral blood (PB) of 40 multiple myeloma (MM) patients, 16 patients with monoclonal gammopathy of undetermined significance and two patients with M. Waldenström--was measured with an enzyme-linked immunosorbent assay (ELISA) using anti-idiotype and anti-class specific antisera. After in vitro stimulation with pokeweed mitogen (PWM) or OKT3 antibody, mIg production was regularly suppressed in BM cell cultures, whereas enhanced, unaltered or suppressed production was observed in PB cell cultures. These observations show that the expanded clone in MM can still be regulated in vitro. Separation experiments demonstrated the involvement of T cells in this in vitro system. The results could be explained by the hypothesis that activated T cells can suppress mature cells of B cell differentiation, as found in BM of the patients, but stimulate earlier B cells from the peripheral blood towards differentiation into Ig secreting cells.

Subpopulations of human T lymphocytes were analysed by monoclonal antibodies (OKT3, OKT4, OKT8) in healthy controls and in patients with multiple myeloma (MM), Waldenstrom's macroglobulinemia (WM) and benign monoclonal gammopathy (BMG). Lymphocytes forming rosettes with SRBC correlated well with T cells staining in indirect immunofluorescence by OKT3 monoclonal antibodies. The relative and absolute numbers of OKT4+ T cells were significantly lower in patients than in controls. Though, the percentage of OKT8+ T cells was increased in patients, the total OKT8+ cell counts were normal in all patient groups. The ratio between OKT4+ and OKT8+ lymphocytes was low in the groups of treated MM and of WM patients compared to controls (P less than 0.001). Moreover, the ratio was lower than the normal range in 27% of BMG and 38% of untreated MM patients. The imbalance between OKT4+ and OKT8+ T cells in untreated MM was more pronounced in clinical stage III patients than in stage I and II patients. The most pronounced changes were noted in treated MM patients. The significance of the altered T cell subsets in monoclonal gammopathies with regard to polyclonal and tumor B cell regulation remains to be established.

Antisera raised against idiotypic determinants of myeloma proteins and macroglobulins have been used to differentiate peripheral blood lymphocytes populations from individual patients. I.D.-positive lymphocytes not resembling plasma cells have been regularly found in peripheral blood in these diseases. This lymphocyte population is heterogeneous with respect to non-tumor-specific surface markers, such as SRBC-, Fc- and C-receptors. Tumor specific idiotypic determinants will thus allow a more correct recognition of the total tumor cell compartment in these diseases.

The in vitro monoclonal and polyclonal immunoglobulin (Ig) production of peripheral blood mononuclcar cells was studied in human multiple myeloma (four IgG myelomas, one IgA myeloma) and in one patient with benign monoclonal gammopathy. Using an enzyme-linked immunosorbent assay with anti-class-specific antisera and antisera against idiotypic structures on the myeloma protein, it was possible to quantilate separately monoclonal and polyctonal Ig of the same class in cell culture supernatants. After stimulation with pokcweed mitogen (PWM) patients' cells produced lower amounts of polyclonal Ig than cells from healthy adults. In contrast, production of monoclonal Ig could not be enhanced by PWM. Moreover, the kinetics of monoclonal Ig production was different from that of polyclonal Ig. Myeloma cells contained large amounts of monoclonal Ig while their content of polyclonal Ig was low. A rapid release of preformed monoclonal Ig during the first day of culture was not inhibited by puromycin. A later phase of release was partly suppressed by puromycin and was probably caused by active protein synthesis.

The specific quantification of human urinary free secretory component (FSC), secretory IgA (SIgA) and total IgA using ELISA has been hampered by mutual interferences of these three molecules. Using affinity chromatographically purified antisera an attempt was therefore made to reduce these interferences without necessitating further assay steps. FSC and total IgA were measured in unprocessed urine by means of anti-FSC and anti-IgA as well as alkaline phosphatase-coupled anti-FSC or anti-IgA antisera. SIgA was determined using anti-IgA as well as alkaline phosphatase-coupled anti-FSC. Nonsecretory urinary IgA was calculated from the measured SIgA and total IgA. The mutual interferences of FSC, SIgA or nonsecretory IgA in the three assay systems were low and not relevant for normal samples. Normal urinary concentrations were: FSC 344 +/- (SD) 208 ng/ml (n = 120), SIgA 1,874 +/- 1,133 ng/ml (n = 123) and nonsecretory IgA, depending on the way of standardization, 712 +/- 699 (n = 56) or 878 +/- 732 ng/ml (n = 51). SIgA excretion increased with age. Lower urinary SIgA as well as total and nonsecretory IgA levels were observed in males as compared to females. No correlation evolved between the hormonal status of women and the excretion of FSC, SIgA or IgA. In IgA-deficient patients virtually no nonsecretory IgA or SIgA was detected in the urine while the FSC concentration was in the normal range.