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)

Almost all patients with multiple myeloma still relapse or become refractory in 2 to 3 years. Interferon (IFN) therapy has clearly influenced the levels of abnormal serum proteins in some patients. A multi-institutional phase II clinical trial used alfa-2b recombinant interferon (Intron A, Schering, Kenilworth, NJ) in 38 evaluable patients with relapsing and refractory multiple myeloma; two thirds of the patient population had received extensive prior treatment. Seven responded, of whom three continued to do so beyond 1 year--one with an ongoing complete remission. An additional 13 had at least a 25% decrease in abnormal paraproteins. Of nine patients who were initially refractory to chemotherapy, two responded to IFN. Of nine relapsing patients returned to chemotherapy following IFN therapy, six then responded. Thirty previously untreated patients with multiple myeloma were treated with IFN followed by melphalan and prednisone; of 24 evaluable patients, 18 responded with a median duration of 10+ months. Alfa-2b IFN apparently does not antagonize melphalan or prednisone, nor does it appear to worsen the response of the two drugs alone. Effectiveness of recombinant alfa-2b IFN in pretreated relapsing patients suggests additional trials are needed to study its effects in previously untreated patients. A significant number of patients who relapsed on their original chemotherapy and subsequent interferon will apparently respond to the reinstitution of chemotherapy.
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PMID:The use of interferon in the treatment of multiple myeloma. 329 11

Both in vitro and in vivo studies have demonstrated antiproliferative effects of interferon alfa-2b (Intron A; Schering-Plough) when tested with human tumor cells. A clonogenic assay has been widely used to determine its direct antiproliferative effects on human tumor cells in vitro using colony reduction as a reproducible endpoint. As a single agent, interferon alfa-2b shows maximum tumor cell colony reduction when used in high concentrations with continuous cell exposure. Short-term exposure to interferon alfa-2b does not produce significant tumor cell colony reduction. Clonogenic assays have also been used to test combinations of interferon alfa-2b with cytotoxic drugs. Variations in drug scheduling, sequencing and concentrations have indicated the best combinations which maximize tumor cell colony reduction. Combinations of interferon alfa-2b with doxorubicin, cisplatin, vinblastine, melphalan and cyclophosphamide have been shown to have at least additive and occasionally synergistic antiproliferative effects. In clinical trials, optimal pairs of agents have been identified frequently combining either doxorubicin, cisplatin or vinblastine with interferon alfa-2b. Pretreatment with interferon alfa-2b has been adopted from in vitro studies and applied to most clinical trials. One study has enrolled 135 patients having a variety of advanced or recurrent solid tumor types, using a schema which combines interferon alfa-2b and doxorubicin administration, both given on a weekly basis for three weeks, followed by treatments every two weeks in responding patients. Clinical responses have been seen using this regimen in patients with ovarian, cervical, colorectal and pancreatic carcinomas and in one lymphoma patient. Another study has been designed combining melphalan, prednisone and interferon alfa-2b for the treatment of patients with relapsing multiple myeloma. This is also based upon preclinical data. New methods of administration are being studied giving interferon alfa-2b as a single agent or in combination with cisplatin by the intraperitoneal route to patients with relapsing ovarian carcinomas limited to the peritoneal cavity. This method can maximize both the levels of interferon alfa-2b as well as the tumor cell exposure time.
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PMID:Overview of preclinical and clinical studies of interferon alfa-2b in combination with cytotoxic drugs. 329 33

Studies of the effect of interferon on the growth of colonies of myeloid leukemic blasts, myeloma colony-forming cells and normal hemopoietic precursor cells have shown that interferon does not specifically inhibit the growth of the malignant cells in culture, i.e. the growth of the malignant and the normal precursor cells are inhibited equally. However, interferon markedly reduces the self-renewal capacity of acute myeloid leukemic blasts and myeloma cells. This observation suggested that interferon should be tested for its ability to prolong remissions rather than as a remission-inducing agent. We have tested the ability of interferon alfa-2b (Intron A; Schering-Plough) to prolong remissions induced by busulfan in patients with chronic granulocytic leukemia (CGL). The leukocyte doubling time (Td) and remission duration on no therapy was compared to the values observed during interferon alfa-2b maintenance therapy. Fourteen patients have been started on study and seven have received interferon alfa-2b for three months or more. All seven have shown slowing of the leukocyte Td and prolongation of the remission duration after interferon alfa-2b therapy. A larger study, with longer follow-up, will be required to determine whether interferon alfa-2b therapy will slow or prevent progression of CGL to the blast phase and prolong survival.
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PMID:Interferon alfa-2b in the treatment of chronic granulocytic leukemia. 329 36

Studies of the effect of interferon on the growth of colonies of myeloid leukemic blast cells, myeloma colony-forming cells, and normal hemopoietic precursor cells have demonstrated that interferon shows no specificity in inhibiting the growth of these cells in culture (ie, growth of the malignant and normal precursor cells is equally inhibited). However, interferon markedly reduces the self-renewal capacity of acute myeloid leukemic blast cells and myeloma cells. This observation suggested that interferon's ability to prolong rather than induce remissions should be tested. We have studied the ability of interferon alfa-2b (Intron A) to prolong remissions induced by busulfan (Myleran) in patients with chronic granulocytic leukemia (CGL). The leukocyte doubling time and remission duration among patients receiving no therapy was compared with the values observed during interferon alfa-2b maintenance therapy. Nine patients have begun the study; five have completed 3 months of interferon alfa-2b therapy. In four (80%) of the five patients, there has been a significant slowing of the leukocyte doubling time and prolongation of the remission duration. A larger study, with longer follow-up, will be required to determine whether interferon alfa-2b therapy will slow progression of CGL to the blast phase and prolong survival.
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PMID:Interferon alfa-2b in the treatment of chronic granulocytic leukemia. 346 99

Interferon alfa-2b (Intron A; Schering Plough) has been shown to be active in advanced previously treated multiple myeloma (MM). Recent in vitro evidence has suggested synergy between cytotoxic agents and interferon alfa-2b. This phase I-II protocol was initiated to study interferon alfa-2b in combination with melphalan and prednisone. Groups of five patients received interferon alfa-2b twice-weekly for two weeks at dose levels of 0.5, 1.0, 2.0, 5.0 and 10.0 X 10(6) IU/m2. During week 2, melphalan (9 mg/m2) and prednisone (40 mg/m2) were administered concurrently with interferon alfa-2b followed by a rest period during nadir myelosuppression, the cycles being repeated every 28 days. Thirty patients were entered of whom 21 were Stage III, 3 Stage II and 6 Stage I. Median nadir WBC/mm3 and platelets/mm3 at the various dose levels are given in the table. Serious adverse reactions while on study included myocardial infarction, renal failure and leukopenia-related sepsis. Early response information is available. Twenty-six patients are evaluable for response. Seven have had progressive disease and 19 (69%) a partial response, the median duration was 11+ months. Interferon alfa-2b does not appear to antagonize melphalan/prednisone effectiveness and may be additive or synergistic. Full evaluation of this combination will be undertaken in randomized controlled trials which are now underway.
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PMID:Interferon alfa-2b/melphalan/prednisone in previously untreated patients with multiple myeloma: a phase I-II trial. 359 2

Recombinant DNA technology has made adequate quantities of human interferons available for both in vitro and in vivo testing. In the clonogenic assay, RPMI-8226 myeloma cells were tested with recombinant interferon alfa-2b (Intron A), melphalan, cyclophosphamide, and prednisone. Prednisone used as a single agent had the least cytotoxic effect. Concentrations of alfa-2b as low as 1 unit/mL (international antiviral activity) showed a reduction in colony number of less than 30% of the untreated controlled cultures. Melphalan and cyclophosphamide showed measurable cytotoxic activity, expressed in terms of 50% inhibition of colony growth, at doses of 0.15 microgram/mL and 0.4 microgram/mL, respectively. Additive antiproliferative effects were noted with combinations of alfa-2b plus cyclophosphamide and alfa-2b plus prednisone. However, the alfa-2b-melphalan combination had a synergistic effect on tumor-cell colony reduction. Even greater cytotoxic activity was seen with the three-drug combination of alfa-2b, melphalan, and prednisone. Clinical trials have shown that alfa-2b may be effective in patients with relapsing and refractory multiple myeloma. Of 38 patients evaluated, seven responded to treatment. Three of the seven responders have continued to respond for over 33 months, with monoclonal proteins approaching undetectable levels. A pilot study of the feasibility of combining alfa-2b with melphalan and prednisone in previously untreated patients with multiple myeloma has been completed. Although response was not the primary objective of this study, an overall response rate of 78% was achieved using criteria established by the Chronic Leukemia Task Force. Phase II trials conducted thus far have established tumor responsiveness to interferons in human myeloma. To clearly define the role of these agents in the treatment of myeloma, well-planned multicenter studies are needed.
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PMID:Interferons in the treatment of multiple myeloma. 376 41

Since interferon alfa-2b (Intron A) is useful as a single agent, it is important to determine if interferon can be combined with standard chemotherapy to improve both response and survival in patients with cancer. Using clonogenic assays, interferon was tested alone and in combination with cyclophosphamide (Cytoxan) or melphalan (Alkeran) using several dose and exposure schedules to evaluate cytotoxicity. In vitro, continuous-exposure interferon produced optimal cell kill. Maximum enhancement of cytotoxicity occurred with cyclophosphamide or melphalan pretreatment (1 hour) and/or simultaneous interferon treatment. Based upon these data, a phase I-II study was designed to determine the tolerance of cancer patients to a fixed dose of cyclophosphamide (150 mg/m2 p.o. daily X 4 days [days 2 to 5]) combined with increasing doses of interferon. Interferon was administered subcutaneously on treatment cycle days 1 to 5, plus days 8, 10, 12, 15, 17, and 19 of the 21-day regimen. Three patients had partial responses: one breast cancer, one angiosarcoma, and one myeloma (mixed). All patients reported mild flu-like symptoms, fatigue, and anorexia. Leukopenia occurred in all patients; three required treatment interruption to allow recovery. Eight patients had a fall in hemoglobin (mean decrease 1.4 g/dL). The combination of cyclophosphamide and interferon was safe and deserves further trial in cancer treatment. However, using this combination schedule, interferon doses greater than or equal to 5 X 10(6) IU were poorly tolerated and compromised administration of full-dose cyclophosphamide.
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PMID:Interferon alfa-2b-cyclophosphamide combination studies: in vitro and phase I-II clinical results. 376 44

Recently, recombinant DNA methods have been successfully applied to interferon production, making adequate quantities available for both in vitro and in vivo testing. Although interferons are in the class of biologic response modifiers, they do have some direct cytotoxic effects on human tumor cells that can be quantitated in vitro with the colony-forming assay. In the clonogenic assay, RPMI-8226 myeloma cells were tested with interferon alfa-2b (Intron A, Schering Corp., Kenilworth, NJ), melphalan, cyclophosphamide, and prednisone. With concentrations of interferon alfa-2b as low as 1 U/ml (international antiviral activity), colony number was reduced to less than 30% of the untreated control cultures. Both melphalan and cyclophosphamide showed measurable cytotoxic activity, with the ID50 of melphalan at 0.15 microgram/ml and that of cyclophosphamide at 0.4 microgram/ml. Prednisone had the least cytotoxic effect when tested with these myeloma cells as a single agent. Additive antiproliferative effects were noted with combinations of interferon alfa-2b plus cyclophosphamide and interferon alfa-2b plus prednisone. However, the interferon-melphalan combination showed synergistic effects on tumor colony cell reduction. Even greater cytotoxic activity was seen with the three-drug combination of interferon alfa-2b, melphalan, and prednisone. Clinical trials have shown that interferon alfa-2b may be effective in relapsing and refractory patients with multiple myeloma. Of 38 evaluable patients, a total of seven responded to treatment; one patient had a complete response, and six had a partial response. Three of the seven responders have continued to respond for over 33 months, with monoclonal proteins approaching undetectable levels. A pilot study of the feasibility of combining interferon alfa-2b with melphalan and prednisone in previously untreated patients with multiple myeloma has been completed. It is concluded that interferon alfa-2b, in dosages not exceeding 2.0 X 10(6) IU/m2, can be safely given in combination with melphalan and prednisone, without compromising melphalan dosage. Although response was not the primary objective of the study, an overall response of 75% was achieved using the criteria established by the Chronic Leukemia-Myeloma Task Force.
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PMID:Interferons in the treatment of multiple myeloma. 380 25

Eighty-four patients with myeloma were randomized to receive maintenance Intron A (Schering-Plough, Suffolk, UK), 3 mega units/m2 s.c. three times weekly or no treatment following induction therapy with cyclophosphomide, vincristine, doxorubicin, methyl prednisolone (C-VAMP), consolidated with high-dose melphalan (HDM) 200 mg/m2 + autologous bone marrow transplantation (ABMT). The patients have been followed up for a median of 52 months. Overall, median progression-free survival (PFS) from HDM was 27 months in the control group and 46 months in the Intron A group (< 0.025). For the 65 patients who achieved complete remission (CR) with HDM, there was a significant prolongation of remission (p = 0.02) for those who received Intron A and 49% of these patients remained in remission four years after high-dose treatment. However, for partial responders (PR) and nonresponders to HDM there was no significant prolongation of PFS. Overall, survival was also significantly better for the Intron A group, with 5 deaths versus 14 deaths in the control group (p = 0.006). Subsequently, 54 consecutive patients received the same HDM followed by rescue with peripheral blood stem cells after induction chemotherapy which included C-VAMP. Intron A was started in 45 of these patients at a median of 62 days which was comparable to the ABMT arm. The overall response rate in these patients was 79.62% (43/54-CR+PR) and the probability of survival at 18 months was 74.2% by the Kaplan Meier method.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Maintenance therapy for remission in myeloma with Intron A following high-dose melphalan and either an autologous bone marrow transplantation or peripheral stem cell rescue. 852 Apr 98