Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Seventy-five patients with previously untreated multiple myeloma were randomly treated with the association of Peptichemio, Vincristine and prednisone (PTC-VCR-P) or of melphalan and P (MPH-P) for first induction therapy. After induction, all responsive patients received MPH and P until relapse, while unresponsive patients received it until unequivocal evidence of disease progression was observed. A second induction therapy with PTC-VCR-P was then administered, except to patients resistant to this association at first induction (who received combination chemotherapy which included cyclophosphamide and adriamycin). The response rate was 58% in the PTC-VCR-P and 41% in the MPH-P group (P greater than 0.05). The PTC-VCR-P responsive patients experienced a median duration of response shorter than MPH-P responsive patients (20.3 vs 39.7, P = 0.041). Median survival from the start of treatment was 26.2 months in the PTC-VCR-P and 54.1 months in the MPH-P group of patients (P = 0.039). Stage I and II myelomas had the same response rate to PTC-VCR-P and to MPH-P, but their survival was shorter on PTC-VCR-P than on MPH-P (P = 0.014). Stage III myelomas responded more frequently to PTC-VCR-P than to MPH-P (P less than 0.02) and there was a trend to survive longer on PTC-VCR-P than on MPH-P (22.0 vs 12.5 months, P greater than 0.05).
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PMID:Peptichemio, vincristine and prednisone versus melphalan and prednisone as induction therapy in multiple myeloma. 377 37

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.
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PMID:Peptichemio induction therapy in myelomatosis. 709 2

The purpose of the study was to ascertain whether the prognostic significance of staging in multiple myeloma (MM) is influenced by the aggressiveness of effective induction treatment and/or by continuing or discontinuing maintenance chemotherapy. Patients with untreated stage I MM (defined according to Durie and Salmon) were randomised between being followed without cytostatics until the disease progressed and receiving six courses of melphalan and prednisone (MP-P) just after diagnosis; stage II patients were uniformly treated with MPH-P and stage III patients were randomised between MPH-P and four courses of combination chemotherapy with Peptichemio, vincristine and prednisone (PTC-VCR-P). Within each stage, responsive patients were randomised between receiving additional therapy only until maximal tumour reduction was reached (plateau phase) and continuing induction therapy indefinitely until relapse. With resistant, progressive or relapsing disease, patients originally treated with MPH-P for induction received combination chemotherapy and vice versa. The overall first response rate was 43.8% (42.2% in 206 stage I, II and III patients treated with MPH-P and 48.0% in 75 stage III patients treated with combination chemotherapy, P = NS). Combination chemotherapy was more myelotoxic than MPH-P and, in particular, caused more non-haematological side-effects. Both the less and the more aggressive induction policies gave the same disease control. Progression of disease was statistically similar in stage I patients who were initially left untreated and in t hose who received MPH-P just after diagnosis; median duration of first response was similar in stage III patients receiving MPH-P and in those on combination chemotherapy. In all stages, discontinuing or continuing maintenance did not alter the median duration of first response. The overall second response rate was 28.5% (34.0% to MPH-P and 25.3% to combination chemotherapy, P = NS). Median survival was greater than 78 months in stage I, was 46.3 months in stage II and was 24.3 months in stage III patients, still independent of both induction and post-induction policies. In MM, the significance of staging for survival is independent of both the aggressiveness of induction and of continuing or discontinuing maintenance chemotherapy after the maximal tumor reduction has been achieved. Both MPH-P and and the association of PTC, VCR and P are effective in inducing first response and also second response in patients failing on the alternative regimen, but PTC-VCR-P causes more side effects. Thus, the overwhelming majority of patients with MM can safely be given MPH-P as first therapy, and this treatment may be delayed in early diseases.
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PMID:Treatment of multiple myeloma according to the extension of the disease: a prospective, randomised study comparing a less with a more aggressive cystostatic policy. Cooperative Group of Study and Treatment of Multiple Myeloma. 798 Oct 78

Multiple myeloma (MM) is a tumor of plasmablasts/plasma cells (PCs) characterized by the expansion of malignant PCs with complex genetic aberrations in the bone marrow (BM). Recent reports, by us and others, have highlighted the polycomb group (PcG) proteins as potential targets for therapy in MM. The PcG protein BMI-1 of the polycomb repressive complex 1 (PRC1) has been reported to be overexpressed and to possess oncogenic functions in MM. Herein, we report on the anti-myeloma effects of the BMI-1 inhibitor PTC-209 and demonstrate that PTC-209 is a potent anti-myeloma agent in vitro using MM cell lines and primary MM cells. We show that PTC-209 reduces the viability of MM cells via induction of apoptosis and reveal that the anti-MM actions of PTC-209 are mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, leaving other PRC1 subunits such as CBX-7 and the catalytic subunit RING1B unaffected. Importantly, we demonstrate that PTC-209 exhibits synergistic and additive anti-myeloma activity when combined with other epigenetic inhibitors targeting EZH2 and BET bromodomains. Collectively, these data qualify BMI-1 as a candidate for targeted therapy in MM alone or in combinations with epigenetic inhibitors directed to PRC2/EZH2 or BET bromodomains.
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PMID:The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomains. 2926 96

Future progress in the treatment of multiple myeloma (MM) requires both the characterisation of key drivers of the disease and novel, innovative approaches to tackle these vulnerabilities. The present study focussed on the pre-clinical evaluation of a novel drug class, BMI-1 modulators, in MM. We demonstrate potent activity of PTC-028 and PTC596 in a comprehensive set of in vitro and in vivo models, including models of drug resistance and stromal support. Treatment of MM cells with PTC-028 and PTC596 downregulated BMI-1 protein levels, which was found to correlate with drug activity. Surprisingly, BMI-1 was dispensable for the activity of BMI-1 modulators and MM cell growth. Our data rather point to mitotic arrest accompanied by myeloid cell leukaemia-1 (MCL-1) loss as key anti-MM mechanisms and reveal impaired MYC and AKT signalling activity due to BMI-1 modulator treatment. Moreover, we observed a complete eradication of MM after PTC596 treatment in the 5TGM.1 in vivo model and define epigenetic compounds and B cell leukaemia/lymphoma 2 homology domain 3 (BH3) mimetics as promising combination partners. These results bring into question the postulated role of BMI-1 as an essential MM gene and confirm BMI-1 modulators as potent anti-mitotic agents with encouraging pre-clinical activity that supports their rapid translation into clinical trials.
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PMID:The anti-mitotic agents PTC-028 and PTC596 display potent activity in pre-clinical models of multiple myeloma but challenge the role of BMI-1 as an essential tumour gene. 3223 50