Dietrich Peest

Multiparameter analyses of normal and malignant human plasma cells: CD38++, CD56+, CD54+, cIg+ is the common phenotype of myeloma cells

Plasma cells obtained from bone marrow samples of 45 patients with MM, eight patients with MGUS, eight patients with Waldenströms 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 (FcγRIII) 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.

Autoimmunity Resulting From Cytokine Treatment Predicts Long-Term Survival in Patients With Metastatic Renal Cell Cancer

PURPOSEnIn patients undergoing cytokine therapy, systemically applied interleukin-2 (IL-2) and/or interferon-alpha (IFN-alpha) 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.nnnPATIENTS AND METHODSnFor 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-alpha2 therapy. For statistical analysis, we used both univariate and multivariate Cox proportional hazards models and the two-tailed Fishers exact test.nnnRESULTSnAntithyroglobulin 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< or =.05), and the Cw7 expression was associated with prolonged overall survival (P = .009).nnnCONCLUSIONnThe 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-alpha2-induced tumor control and prolonged survival may require breaking of immunologic tolerance against self-antigens.

Induction and maintenance therapy in multiple myeloma: a multicenter trial of MP versus VCMP

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.

High incidence of monoclonal immunoglobulins in patients after liver or heart transplantation.

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.

CYTOKINE THERAPY IN MULTIPLE MYELOMA

In vitro and in vivo studies performed during recent years have provided evidence that cytokines exert a major biological role in multiple myeloma (MM). Cytokines control myeloma cell proliferation, differentiation and apoptosis, and are involved in the tumour-induced bone destruction mediated by activated osteoclasts. Interferon(Inf) was introduced for therapeutic purposes in MM more than 15 years ago, and other cytokines have been evaluated more recently. Although controversies still exist, it seems appropriate in 1996 to discuss the indications for cytokine therapy in MM, and to correlate results obtained in vitro with the effects observed in vivo.

Effect of interleukin-2 on the ex vivo growth of human myeloma cells

SummaryShort-term cultures containing bone marrow mononuclear cells from multiple myeloma patients secrete monoclonal immunoglobulin and β2-microglobulin into the supernatant, which can be measured quantitatively in an enzyme-linked immunosorbant assay. In this system, the addition of interleukin-2 was shown to induce tumor cell regression in the cultures from 10 out of 14 multiple myeloma patients in a dose-dependent manner. Marker analyses of culture cell populations indicate that OKT3 antibody or interleukin-2 did not directly act on the malignant clone but augmented autologous T lymphocytes, which were responsible for the regression of tumor cells in the cultures.

Cytostatic drug sensitivity test for human multiple myeloma, measuring monoclonal immunoglobulin produced by bone marrow cells in vitro

SummaryAn in vitro cytostatic drug sensitivity test for human multiple myeloma has been developed, predicting differences in sensitivity of the individual tumor to various anticancer drugs. Bone marrow preparations containing the tumor cells were incubated with cytostatic drugs and cultured for 10 days. Using an enzyme-linked immunosorbent assay we measured tumor products—monoclonal immunoglobulin and β2-microglobulin — in the culture supernatants. The reduction of these products in vitro due to the drugs administered was compared with the patients further clinical course during treatment with different standard cytostatic drug regimens. We found a predictive value of more than 80% for this easily performed test.

Therapie des multiplen Myeloms

ZusammenfassungDas 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 Endorganschäden abgegrenzt werden. Eine hoch dosierte Chemotherapie mit Unterstützung durch autologe Blutstammzellen sollte bei den meisten Patienten angestrebt werden, um eine möglichst komplette und lang andauernde Remission zu erreichen. Ziele sind die weitgehende Symptomfreiheit, die Verhinderung von Organkomplikationen und die Lebensverlängerung. Patienten, bei denen dieses Konzept aufgrund des Alters und der Komorbiditäten nicht angewendet werden kann, können mit einer niedrig dosierten Chemotherapie behandelt werden, in der Regel mit Alkylanzien. Ziele sind hier die Verbesserung der Lebensqualität, aber auch die Lebensverlängerung. Durch Einbeziehung von Thalidomid, Lenalidomid, Pomalidomid, Bortezomib oder Carfilzomib in beide Konzepte konnten die Remissionsraten und Überlebenszeiten signifikant verbessert werden. Die allogene Stammzelltransplantation ist besonders im Verlauf des ersten Jahrs nach Transplantation mit einer relativ hohen Mortalität assoziiert und wird in Studien mit dem Ziel der Heilung weiterentwickelt. Sie ist für ausgewählte Patienten eine Alternative. Das Behandlungskonzept für MM-Patienten ist je nach individueller Konstellation durch lokale Strahlentherapie, Bisphosphonatgaben und supportive Immunglobulininfusionen zu ergänzen.AbstractMultiple 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.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.

Das multiple Myelom

ZusammenfassungDas multiple Myelom ist ein reifzelliges B-Zelllymphom mit einem Erkrankungsgipfel im höheren Lebensalter. Maligne Plasmazellen infiltrieren das Knochenmark und bestimmen über Interaktionen mit anderen Körperzellen und Organsystemen die individuell unterschiedliche klinische Symptomatik. Vorstadien sind die monoklonale Gammopathie unbestimmter Signifikanz und das Smoldering multiple Myelom, die üblicherweise keiner Behandlung bedürfen. Zur Diagnosesicherung eines therapiebedürftigen multiplen Myeloms sind verschiedene Laboruntersuchungen und bildgebende Verfahren nötig. Das Myelomprotein und die freien Leichtketten im Serum sind zur Verlaufsbeurteilung wichtige Surrogatmarker für die Tumormasse. Therapeutisch stehen konventionelle Chemotherapie, Proteasomeninhibitoren, Immunmodulatoren, monoklonale Antikörper, Hochdosischemotherapie, allogene Blutstammzelltransplantation, Strahlentherapie und verschiedene supportive Maßnahmen zur Verfügung. Die Therapie ist heute noch palliativ, Langzeitremissionen werden bei einzelnen Patienten beobachtet.