Monoclonal immunoglobulins with antibody activity in myeloma, macroglobulinemia and related plasma cell dyscrasias.
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Biomedical subjects
Publications and source records attributed to G Merlini.
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Twenty-nine patients with multiple myeloma, 16 untreated and 13 relapsing after treatment with melphalan and/or cyclophosphamide, were treated with Peptichemio (PTC), vincristine (VCR) and prednisone (PRD). The treatment was well tolerated and produced rapid resolution of bone pain and improved performance status in symptomatic patients. Rapid and marked monoclonal component reduction (greater than 50 per cent) was noted in 50% of previously untreated and 31% of previously treated patients. The median survival of previously untreated patients was 27 months, 19 months for stage III patients. Four patients resistant to common alkylating agents responded to PTC-VCR-PRD treatment and achieved long remissions (from 18 to 38 months). The therapeutic results suggest that the present combination regimen may be indicated for induction treatment of multiple myeloma patients in an advanced stage of the disease, and for treatment of myeloma patients refractory or resistant to melphalan and/or cyclophosphamide.
Twenty-five consecutive patients with previously untreated multiple myeloma were studied for bone marrow plasma cell labeling index, response to peptichemio induction therapy, and rate of M-component (MC) changes during the course of the disease. They received intermittent melphalan or cyclophosphamide as maintenance therapy and peptichemio associated with vincristine at first relapse. The response rate (76%) was independent of clinical stage, evaluated according to Merlini et al and to Durie and Salmon. Among responsive patients, rapid responders (half-life of MC decrease less than 47 days for IgA and IgG and less than 29 days for light chain myelomas) had a bone marrow plasma cell labeling index significantly higher (P less than 0.01) than that of slow responders. Rapid responders had a median survival of 15 months, while slow responders had a median survival of 42 months (P less than 0.05). The difference in survival between the two groups was accounted for mainly by the difference in duration of first response and the different rates of MC increase following it. Both of these parameters were directly related to the half-life of MC decrease at response in IgA and IgG myelomas. The duration of second response and the half-life of MC increase following it were shorter than the duration of first response and than the half-life of MC increase at first relapse.
The protein composition of three commercial extracts of Micropolyspora faeni, produced in U.S.A., England and Italy has been evaluated by agarose gel electrophoresis. By crossed immunoelectrophoresis, 'tandem'-crossed immunoelectrophoresis and by a modification of this last technique, the antigenic composition and the common antigens of the extracts have been investigated. Hyperimmune rabbit serum and a pool of five human sera with precipitins to Micropolyspora faeni have been used as source of antibody. Different quantity and quality of protein content was observed in the available batches. Different antigenic composition was also observed, not directly related to the different proteins contained therein; three antigens were definitely common to all extracts and two of them represented the major antigens of each extract. Despite the total protein content, the major and common antigens were found in similar concentrations in all three products examined. Therefore, the discrepancies observed in the precipitin reactions using the three commercial Micropolyspora faeni extracts are due to differences in the minor antigen composition of the extracts.
A calcium-binding immunoglobulin G (IgG1 lambda RUP) was identified in the serum of a patient with multiple myeloma, asymptomatic hypercalcemia, and a normal ionized serum calcium. Calcium binding by IgGRUP was confirmed by two-dimensional electrophoresis with calcium-45 and equilibrium dialysis. Amino acid analyses indicated an unusually high number of glutamic (or glutamine) residues in the L chain and Fab fragment but no detectable gamma-carboxyglutamic acid. As determined by equilibrium dialysis with 45Ca, the intact IgGRUP and its Fab fragments bound calcium at an optimum pH of 7.4. There was minimal binding of calcium to H chains and no binding by L chains or the Fc fragment. Recombination of H and L chains partially restored the binding activity. By Scatchard analysis, the binding affinity (Kd) of IgGRUP was 1.7 X 10(-3) M and the binding capacity was 4 mol of calcium/mol of IgG. The binding of 4 mol of calcium/mol of IgG is twice that reported previously for two other calcium-binding myeloma proteins and suggests unique properties of IgGRUP.
In 62 patients with multiple myeloma (MM) and related disorders, the nuclear DNA content distribution of bone marrow plasma cells was assessed by flow and conventional cytofluorometry. Abnormal distributions, suggesting the presence of aneuploid populations, were observed in 53% of MM at diagnosis, in 50% of benign monoclonal gammopathies and in 12% of Waldenström's macroglobulinemias. Eighty-six percent of aneuploid cases had DNA stem-lines falling between the diploid and triploid value. In advanced and relapsing MM, abnormal distributions were found in 75% of cases. In 4 out of 14 patients with MM serially studied during the course of disease, emergence of new abnormal clones was documented. The abnormal DNA content of bone marrow plasma cells was not correlated with any clinical and laboratory characteristic and it affected neither response to therapy nor survival in patients studied at diagnosis. In advanced phases of MM, the presence of abnormal clones was correlated with high plasma cell proliferation rates (studied by tritiated thymidine incorporation) and poor response to chemotherapy. Seven out of 8 patients in acute terminal phase of MM had abnormal clones. Among these, five had DNA stem-lines over triploid value.
Material from a selected group of dead myeloma patients has been analyzed for the application of the staging systems proposed by Durie and Salmon and by Merlini, Waldenstrom and Jayakar. Neither of the systems showed prognostic significance in this myeloma population. No significant correlation was found between bone marrow plasmocytosis, renal function and survival. The selection of the myeloma population may be the major determinant in these discrepancies with data in current literature.
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The immunosubtraction technique was used to identify the proteins in electrophoretically separated plasma. The technique consists of forcing the plasma through a layer of monospecific antibody purified by electrophoresis; the specific protein is thereby precipitated and is consequently absent from the subsequent electrophoretogram. This technique was successfully applied to the following proteins (in order of distance from the anode): prealbumin, albumin, alpha-lipoproteins, alpha 1-antitrypsin, Gc-globulins, alpha 2-macroglobulin, haptoglobin, fibronectin, transferrin, beta-lipoproteins, C3, fibrinogen. The method may be applied to the study of protein polymorphism.
Fifteen patients with multiple myeloma, two of whom had plasma cell leukemia, were treated between May 1974 and December 1978. Peptichemio was administered intravenously at doses of 40-80 mg/48 h, courses including 4-17 administrations in association with moderate doses of prednisone (15-50 mg/day) and androstanes at high dosages (250 mg weekly). In two patients PTC was associated with vincristine (VCR) administered on the first day of the course. Eight patients were previously untreated, four had been resistant to melphalan (MPH) and/or cyclophosphamide (CTX), and three had been treated irregularly with one or both of these alkylating agents. The criteria of response to therapy are reported. Out of a total of 15 PTC courses administered we obtained 13 responses, eight complete and five partial; no response was achieved in the other two patients. In the four patients who were resistant to MPH and/or CTX we obtained three responses, which were maintained with the same alkylating agent to which they had been resistant previously. The time needed to obtain a response in 90% of the patients was 6 weeks. Peptichemio was shown to be effective in patients in an advanced stage of the disease, in patients with light-chain myeloma and in those with plasma cell leukemia. The association of VCR potentiated the antitumor effect, but also increased the myelotoxicity. The PTC treatment was well tolerated. It is suggested that PTC be used in induction treatment of myelomatosis and in patients resistant to traditional alkylating agents.
Twenty-seven female patients with prolactin-secreting pituitary microadenoma, were studied at different intervals following selective transsphenoidal removal of the tumor. Postoperatively, all patients had normal prolactin (PRL) levels and regular menstrual cycles were restored. Sixteen of 27 patients showed positive responses to TRH and metoclopramide (MCP) within 1 mo after surgery. On the contrary, 9 patients showed evaluation of these patients demonstrated that normal neuroendocrine relationships were restored after several months since positive PRL responses to TRH and MCP could be elicited in such patients. The remaining 2 patients who showed basal PRL levels in the upper range of normal, exhibited negative responses to TRH and MCP. These patients had progressively to TRH and MCP exhibited 10-20 mo after surgery a normal decrease in PRL levels following administration of carbidopa plus L-Dopa. Negative responses to carbidopa plus L-Dopa were instead obtained in 6 postoperative patients with elevated PRL levels and negative responses to TRH and MCP. These results suggest that: 1) Hyperprolactinemia induced by "autonomous" pituitary adenomas increases hypothaLamic dopamine (DA) secretion, which in turn inhibits PRL secretion by nonadenomatous lactotropes. 2) Total selective removal of the microadenoma acutely decreases PRL concentration, but a functional inhibition of the normal lactotrope can persist for a period of few months following surgery in a certain number of patients. 3) Prolonged reduction of PRL concentration is accompanied to a normal DA tone with reestablishment of normal neuroendocrine relationships.
107 determinations of alpha 1-acid-glycoprotein (alpha 1S), haptoglobin (Hp) and complement fraction 3 (C3) were made in 85 consecutive patients with Hodgkin's disease, both in acute phase (77 measurements) and in complete remission (30 measurements). Only alpha 1S and Hp showed much higher levels in untreated disease than in remission, and elevation of alpha 1S in activity of the disease is correlated to advanced stages and - less significantly - to severe histology. The ability of alpha 1S, Hp and C3 to discriminate between activity and remission was compared with that of erythrocyte sedimentation rate (ESR), alpha 2-globinaemia (alpha 2), fibrinogenaemia (Fb), plasma copper (Cu) and iron (Fe), all data being collected at the same point in time in each patient. The well-known discrimination ability of combined Cu and Fe (75%) can be further improved by alpha 1S (81%) much more than by Hp, C3, ESR, alpha 2 and Fb singly computed and nearly up to the maximum allowed by the eight indexes together (82%).
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Immunofixation on cellulose acetate has been compared with immunoelectrophoresis on agarose gel. We studied 90 sera containing monoclonal components and 10 containing polyclonal immunoglobulins according to agarose gel screening electrophoresis. Results by the two methods agreed about 80% of the time for monoclonal components in concentrations exceeding 1-2 g/L. Immunofixation appeared more sensitive, but it is more susceptible to technical artifacts. Immunofixation may be adopted as a first-step method for easier cases, but it should be supported by immunoelectrophoresis for difficult cases, such as when there is an uncertain presence of monoclonal components at screening electrophoresis or presence of more and (or) small bands of monoclonal components.
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