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)

The treatment of multiple myeloma is multidisciplinary and requires attention not only to the primary disease itself but to its secondary manifestations. Melphalan remains the single most effective oral chemotherapeutic drug used to treat multiple myeloma. A major problem with the oral administration of the drug is its variable bioavailability. The presence of an L-phenylalanine moiety in the structure of melphalan makes it likely that gastrointestinal absorption occurs through the normal amino acid transport mechanisms and that the presence of food influences the drug's uptake. Another factor that complicates the bioavailability of this agent is the fact that melphalan undergoes spontaneous hydrolysis at physiologic pH. One of the controversies in myeloma therapy is the continuing debate over the possible superiority of complex, multiagent chemotherapy regimens compared with single melphalan and prednisone or cyclophosphamide and prednisone. It does appear that response frequencies are considerably greater with combination chemotherapy than with standard oral melphalan and prednisone treatment. It is probable that both approaches--single-agent chemotherapy with melphalan and prednisone versus combination chemotherapy--can play a role in remission induction therapy. It may be appropriate to treat the patient with a low tumor burden with melphalan and prednisone and treat more aggressive myeloma patients with triple alkylator therapy or other combinations of chemotherapy agents. The most promising activity of interferon alfa-2b (rIFN alpha 2b) in induction of myeloma remission appears to occur when rIFN alpha 2b is combined with multiple alkylating agents. Analysis of clinical trials suggests that sequential use of rIFN alpha 2b with cytotoxic therapy may be more active than when IFN alpha 2b is given concomitantly with cytotoxic therapy. It may be most plausible to use rIFN alpha 2b in maintenance of remission of myeloma. In the laboratory, interferons have the capacity to modulate oncogene expression and to decrease both in vitro colony formation and the labeling index of myeloma cells. Further, it has been shown that interferon can reduce the capacity for self-renewal in myeloma-forming cells. The following concepts will be discussed: 1. There is promising evidence that rIFN alpha 2b may improve the frequency and quality of remission in multiple myeloma when administered in an alternating schedule. There is some evidence that rIFN alpha 2b, when combined with cytotoxic therapy and given concomitantly, may be less active.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A review of the clinical studies of alpha-interferon in the management of multiple myeloma. 194 25

Five patients with high risk multiple myeloma not responsive to standard chemotherapy were treated by high-dose chemotherapy (Melphalan, Cyclophosphamide) (HDC) and total body irradiation (TBI) followed by autografting with blood stem cells. These cells were previously collected by leukaphereses from eight to twelve occasions during hematopoietic recovery following profound aplasia induced by each course of intensive chemotherapy (Vincristine, Adriamycin, Cyclosphosphamide, Prednisone) when the patient reached a neutrophil count of 1,000/microliters and a platelet count of 100,000/microliters. No patients had evidence of tumor plasmacells in leukaphereses products using cytology, immunocytochemistry and immunofluorescence. At this time the patient 5 is not evaluable because of the short follow-up. One died at day 30 from heart failure. All living patients achieved a complete remission which persisted at a follow-up of 300, 261 and 136 days. Autologous blood derived hematopoietic stem cells induced successful and sustained engraftment in all living patients. Our results indicate the feasibility of this therapeutic approach over allogenic or autologous bone marrow transplantation in selected patients with high tumour mass multiple myeloma.
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PMID:Blood stem cells autografts in patients with high risk multiple myeloma. 197 31

We present data describing a human myeloma cell line (8226/LR-5) selected for resistance to melphalan which exhibits a 7-fold level of resistance to melphalan and is partially cross-resistant to other bifunctional alkylators and X-irradiation. Melphalan resistance is relatively unstable with a decrease in resistance observed within 17 weeks in the absence of drug. The resistance observed in this cell line is not mediated by reduced intracellular melphalan accumulation. DNA interstrand cross-linking at equivalent intracellular drug accumulation is significantly reduced in the resistant subline. Whether this reduction is the result of a decrease in the formation of this lesion or to an increased rate of removal of the lesion remains to be determined. Growth characteristics and cell cycle kinetics, including S phase, were similar between sensitive and resistant cell lines. Intracellular nonprotein thiols were found to be significantly elevated in the resistant 8226/LR-5 cells; as cells revert or lose resistance, intracellular nonprotein sulfhydryl levels decline. Prior treatment of the cells with buthionine sulfoximine significantly reduced nonprotein sulfhydryl levels and enhanced melphalan cytotoxicity in both the sensitive and resistant cell lines. Thiols appear to play a role in mediating melphalan resistance.
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PMID:Development and characterization of a melphalan-resistant human multiple myeloma cell line. 198 43

It is exceptional to obtain a cure in multiple myeloma. We report a case of a 54-year old man with stage III, IgA K multiple myeloma in complete remission 12 years after the diagnosis. The patient was treated for 4 years with Melphalan-Prednisone. Eight years after the end of treatment the patient fulfilled the criteria of cure as defined by the "Chronic Leukemia Task Group" (no measurable myeloma protein and normal bone marrow) associated with the disappearance of some osteolytic lesions.
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PMID:Multiple myeloma: a case of a cure? 264 19

We have begun an autologous bone marrow transplantation (ABMT) treatment protocol for patients with myeloma who achieve a minimal disease (less than 10% marrow plasma cells) status. Sites of bony disease are irradiated before BMT. Melphalan 70 mg/m2 on days 1 and 2 is followed by 1200 rads total-body irradiation administered in fractionated doses over 3 d. Autologous marrow which has been previously treated with anti-CALLA, B1, and PCA-1 monoclonal antibodies is then thawed and reinfused. 4 males and 2 females with median age of 46 yr (41-56) have been treated. Granulocytes greater than 500/mm3 and platelets greater than 20,000/mm3 were noted at 21 (12-46) and 23 (12-53) d post-transplant (PT), respectively. Acute mucositis and dermatomal Herpes zoster developed in 3 patients each; all patients are clinically well at 233 (30-807) d PT. All patients achieved pathologically normal marrows, but monoclonal plasma cells and marrow myelofibrosis were each noted in a single patient at 486 and 272 d PT, respectively. A single patient has responded to alpha 2 interferon therapy PT; all others have received no therapy. AMBT offers an exciting new treatment for myeloma; however, relapses post-ABMT suggest that improved ablative regimens and/or marrow purging methods may be required.
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PMID:Autologous bone marrow transplantation therapy for multiple myeloma. 269 88

The pharmacokinetics of melphalan have been studied after oral doses of 5, 10 and 20 mg, and 10 mg i.v. Seven patients with multiple myeloma received the drug on 4 consecutive days and the concentration of melphalan was determined by liquid chromatography. Melphalan was rapidly absorbed after p.o. administration. Absorption lag-time was less than 1 h. The median time for attaining the peak concentration was 1.12 h (97% confidence interval: 0.68-1.55), 1.21 h (0.85-1.43) and 1.08 h (0.84-1.29) after doses of 5, 10 and 20 mg. The bioavailability showed large interindividual variations, and was not significantly affected by the dose given. There was a significant decrease in bioavailability during the treatment course (P less than 0.05). Absorption of melphalan obeys first-order kinetics in the dose interval studied. The results indicate that it might be of benefit to administrate oral melphalan for fewer days than the usually used 4 day regimen, in an attempt to achieve a higher bioavailability.
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PMID:Oral melphalan pharmacokinetics--relation to dose in patients with multiple myeloma. 274 8

A case of a 70 years old female who developed multiple myeloma during a course of neutrophilia, and later on terminated with acute monocytic leukemia (AML, M 5 b) following Melphalan therapy for five years is reported. This patient was first found to have neutrophilia in 1966, After six years, she developed monoclonal gammopathy, (IgG1 kappa type) which coexisted with the neutrophilia. She was put on Melphalan regimen for 5 years which was discontinued due to anemia, leukocytopenia and the reduction of serum IgG. By routine bone marrow examination, she was diagnosed as AMoL (AML, M 5 b) in July 1984. Thereafter, a combination chemotherapy of BH-AC, 6-MP and prednisolone was started and complete remission for the AMoL was achieved after 2 months. Sixteen months later, she relapsed and a similar combination chemotherapy for reinduction regimen was administered. However, the AMoL was resistant and after 7 months, she died of pneumonia and multiple organ failure. The association of neutrophilia with multiple myeloma, the occurrence of AMoL after prolonged Melphalan therapy for the multiple myeloma and the strategy of therapy for secondary leukemia is discussed.
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PMID:[Multiple myeloma following chronic neutrophilia terminated with acute monocytic leukemia (AML, M 5 b)]. 279 4

Experiments to determine the hydrolysis and protein binding of melphalan (L-phenylalanine mustard, L-PAM) were carried out in vitro for therapeutic concentration of the drug: the decrease in L-PAM concentration in plasma and whole blood during 24 h incubation at 37 degrees C was only 5% due to hydrolysis. Serum protein binding was about 90%, whereby 60% and 20% of this binding was due to interactions with albumin and acid alpha 1-glycoprotein, respectively. Immunoglobulins did not participate in the binding of L-PAM. The covalently bound part of L-PAM in serum was 30% in the concentration range of 1-30 micrograms/ml. The binding of dihydroxymelphalan (DOH) in serum did not exceed 20%. Glucocorticoids used in combination with L-PAM for treating multiple myeloma did not influence its protein binding. Our study with 35 sera from 15 patients with multiple myeloma shows that high levels of paraproteins do not increase but may decrease the binding of L-PAM, resulting in an elevated concentration of free drug.
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PMID:Relevance of the hydrolysis and protein binding of melphalan to the treatment of multiple myeloma. 291 May 15

Melphalan (L-phenylalanine mustard) is a bifunctional alkylating agent that is commonly administered orally to treat a wide variety of malignancies, including cancers of the breast and ovary, as well as multiple myeloma. Although commercially available in Europe and Canada, intravenous (IV) melphalan remains investigational in the United States. The role of IV melphalan in cancer chemotherapy is not well defined, despite its manageable toxicity and higher and more predictable blood levels following IV administration compared with oral administration. In addition, unlike oral melphalan, an extensive phase I evaluation of IV melphalan has not been undertaken. At lower doses (eg, 30 to 70 mg/m2), both as a single agent and in combination, the activity of IV melphalan has been evaluated in only a limited number of diseases. However, striking activity has been observed in previously untreated patients with rhabdomyosarcoma, a disease not generally considered responsive to alkylating agents. When administered at high doses (greater than 140 mg/m2) requiring bone marrow reinfusion, melphalan effects a high response rate (but no improvement in survival) in a variety of nonhematologic tumor types, including resistant tumors such as melanoma and colon carcinoma. In contrast, in poor-prognosis patients with non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, or neuroblastoma, high-dose melphalan-containing regimens have yielded both high response rates and improved survival, despite considerable toxicity. Additional clinical trials will be necessary to define the spectrum of activity of lower doses of IV melphalan and to define subgroups of patients most likely to benefit from high-dose melphalan.
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PMID:The systemic administration of intravenous melphalan. 305 5

A rare instance of IgG-kappa monoclonal gammopathy in a patient with beta-thalassaemia trait is reported. The patient had a smoldering multiple myeloma with no apparent clinical symptoms pertaining to the disease and was a non-responder to conventional Melphalan and prednisolone therapy. Beta-thalassaemia trait was detected while investigating him for anaemia. A state of altered immunological reactivity, chronic infections and associated biliary tract disease are some of the pathogenetic mechanisms suggested. However in this patient none of these were operative.
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PMID:Monoclonal gammopathy in beta thalassaemia. 308 4


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