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PubMed1981

Melphalan estimation by quantitative thin-layer chromatography. Observations on melphalan hydrolysis in vitro and pharmacokinetics in rabbits.

A simple and specific quantitative high-performance thin-layer chromatographic (HPTLC) assay for melphalan in plasma is described. This assay was linear over the investigated range of 50--3,000 ng/ml, with a minimum level of detection of 20 ng/ml. Comparison with a high-pressure liquid chromatographic (HPLC) technique yielded similar estimates for melphalan concentrations in human plasma samples. The HPTLC method, unlike the HPLC technique, does not resolve monohydroxymelphalan satisfactorily. The HPTLC method was used to determine the activation energy for in vitro melphalan hydrolysis: this was 14.5 kcal/mole. The pharmacokinetics of melphalan in rabbits were also investigated. The mean t1/2 in four animals was 32.6 +/- 10.3 (S.D.) min and following IV administration to two animals the apparent volumes of distribution were 2.20 and 1.73 l/kg.

Animals↗
PubMed2001

Cost-utility analysis of high-dose melphalan with autologous blood stem cell support vs. melphalan plus prednisone in patients younger than 60 years with multiple myeloma.

We evaluated the costs and the cost utility of high-dose melphalan and autologous stem cell support followed by interferon maintenance relative to conventional treatment with melphalan and prednisone, in patients less than 60 yr of age with multiple myeloma. From March 1994 to July 1997, 274 patients with newly diagnosed, symptomatic multiple myeloma were enrolled in a prospective, non-randomized, population-based, multicenter study to evaluate the treatment with high-dose melphalan and autologous blood stem cell support. Health-related quality-of-life was measured prior to treatment and during follow-up, using the EORTC QLQ-C30 questionnaire. Resource consumption was also recorded prospectively. The intensive treatment yielded a significant increase in median survival time from 44 to 62 months compared to conventionally treated patients. The corresponding gain in quality-adjusted life years (QALY) was found to be 1.2. Cost per QALY gained by the treatment with high-dose melphalan and autologous blood stem cell support was estimated at NOK 249,000 (USD 27,000).

Cost-Benefit Analysis↗
PubMed2000

Melphalan plus total body irradiation (MEL-TBI) or cyclophosphamide (MEL-CY) as a conditioning regimen with second autotransplant in responding patients with myeloma is inferior compared to historical controls receiving tandem transplants with melphalan alone.

The role of more intense conditioning for second transplant was evaluated in myeloma patients achieving at least partial remission (PR) after first transplant with melphalan at 200 mg/m2. Forty-three patients received more intensive conditioning for the second transplant. Nineteen patients received cyclophosphamide 120 mg/kg along with melphalan 200 g/m2 (MEL-CY; group 1) while 24 patients received total body irradiation (1125 cGy) in conjunction with melphalan 140 mg/m2 (MEL-TBI; group 2). Forty-three matched control patients were identified from 450 patients receiving melphalan alone for second transplant (MEL200; group 3). Engraftment and toxicities were comparable among the groups with the exception of increased treatment-related mortality of 8% in group 2 compared to none in groups 1 and 3 (P = 0.07). Despite identical CR rates of 74, 71 and 70%, respectively, in groups 1, 2 and 3 (P = 1.0), event-free survival (median: 27, 15 and 61; P < 0.0001) and overall survival (median: 39, 25 and 76 months; P = 0.003) were significantly decreased in patients receiving more intensive conditioning (groups 1 and 2). Lymphocyte recovery, evaluated as a surrogate for immune recovery, was inferior in more intensively treated patients (groups 1 and 2 compared to group 3). Our findings suggest that more intense conditioning appears to have no benefit in patients responding to their first cycle of high-dose therapy and may even be detrimental in this setting. Bone Marrow Transplantation (2000) 25, 483-487.

Antigens, CD34↗
PubMed2002

Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial.

High-dose therapy has become a common treatment for myeloma. The objective of this study (Intergroupe Francophone du Myélome [IFM] 9502 trial) was to compare in a prospective and randomized trial the 2 most widely used conditioning regimens before autologous stem cell transplantation in newly diagnosed symptomatic patients younger than 65 years old: 8 Gy total body irradiation plus 140 mg/m(2) melphalan (arm A) versus 200 mg/m(2) melphalan (arm B). A total of 282 evaluable patients were compared--140 in arm A and 142 in arm B. Baseline characteristics and disease response to 4 cycles of the VAD regimen performed before randomization and autologous stem cell transplantation were identical in the 2 treatment arms. In arm B, hematologic recovery was significantly faster for both the duration of neutropenia and thrombocytopenia, transfusion requirements were also significantly lower, and the median duration of hospitalization was significantly shorter. In arm A, the incidence of severe mucositis was significantly increased. The median duration of event-free survival was similar in both arms (21 vs 20.5 months, P =.6), but the 45-month survival was 65.8% in arm B versus 45.5% in arm A (P =.05). This difference might be attributed in part to better salvage regimens after relapse in arm B compared with arm A. We conclude that 200 mg/m(2) melphalan is a less toxic and at least as effective conditioning regimen when compared with 8 Gy total body irradiation with 140 mg/m(2) melphalan. This regimen should be considered as the standard of care before autologous stem cell transplantation in multiple myeloma.

Adult↗
PubMed1979

Amino acid conferred protection against melphalan interference with melphalan therapy by L-leucine, a competitive substrate for transport.

Melphalan uptake by L1210 leukemia cells obtained from tumor bearing mice is reduced to one-third of control by physiological concentrations of L-leucine. Kinetic analysis revealed that melphalan and leucine compete for transport carrier sites. Administration of leucine with optimal therapeutic doses of melphalan to tumor bearing mice negated the efficacy of the drug.

Animals↗
PubMed2001

Comparison of vincristine, carmustine, melphalan, cyclophosphamide, prednisone (VBMCP) and interferon-alpha with melphalan and prednisone (MP) and interferon-alpha (IFN-alpha) in patients with good-prognosis multiple myeloma: a prospective randomized study. Greek Myeloma Study Group.

OBJECTIVES: The purpose of the study was to evaluate, in a selected group of myeloma patients with favorable prognosis, the effect, on response and survival, of polychymotherapy compared with melphalan prednisone, plus interferon in both arms. METHODS: Eighty-nine previously untreated patients with multiple myeloma and prognostic factors indicating a good prognosis were randomized to either oral melphalan plus prednisone (MP) in combination with recombinant interferon-alpha (rIFN-alpha) or combination chemotherapy with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (VBMCP) alternating with rIFN-alpha. The two treatment groups were comparable in terms of pretreatment characteristics. RESULTS: The overall response rate was 67.4% (2.3% complete remission, 65.1% partial response) in the MP/IFN-alpha group and 69.1% (14.3% complete remission, 54.8% partial response) in the VBMCP/IFN-alpha group (p=0.59). There were no differences also in response duration and overall survival between the two treatment groups. The median response duration was 39.1 months in the MP/IFN-alpha group and was not reached in the VBMCP/IFN-alpha group (p = 0.6). Overall survival was long in both treatment groups. The estimated 5-yr survival was 66% and 62% in the MP/IFN-alpha and VBMCP/IFN-alpha group, respectively (p=0.8). Toxicity was modest and treatments were well tolerated. Neutropenia (WHO grade 3 or 4) was higher, but not statistically significant, in the VBMCP/IFN-alpha group. CONCLUSIONS: The results of the study show that in myeloma patients with good prognosis, combination chemotherapy alternating with interferon-alpha has no advantage over conventional MP plus interferon-alpha, in regard to response rate, response duration, and overall survival of patients.

Aged↗
PubMed1984

A randomized trial of melphalan and prednisone versus melphalan, prednisone, cyclophosphamide, MeCCNU, and vincristine in untreated multiple myeloma.

In a randomized study with 234 previously untreated patients with multiple myeloma, 129 were treated with melphalan (8 mg/m2 perorally for four days) and prednisone (40 mg/m2 perorally for seven days, both every four weeks) and 105 with melphalan and prednisone at the same doses plus cyclophosphamide (600 mg/m2 intravenously every four weeks), MeCCNU (100 mg/m2 PO every eight weeks), and vincristine (MPCCV, 0.6 mg/m2 IV every four weeks). A total of 49 (38%) of the 129 patients treated with melphalan and prednisone (MP) and 48 (46%) of the 105 patients treated with MPCCV showed good response (GR) (P not significant); the overall response rates were 58% and 70%, respectively. Thirty-seven percent of the MP group and 39% of the MPCCV group remain alive at 48 months from first treatment (P not significant). The estimated 48-month survival from first treatment, according to different prognostic factors at diagnosis, in both groups was as follows: stage 1,56%; stage II, 46%, and stage III, 23% (I and II v III P less than .001). Survival at 48 months according to response was GR, 68%; partial response (PR), 33%; and null, 16% (GR v null, P less than .0005; GR v PR, P less than .0005). Survival according to renal function was 43% for a creatinine level less than 2 mg/100 mL and 27% for a creatine level greater than or equal to 2 mg/100 mL (P less than .0005). No significant difference has been found between the two treatment schedules in terms of response rate and survival time, in any stage of disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1979

Amino acid conferred protection against melphalan: comparison of amino acids which reduce melphalan toxicity to murine bone marrow precursor cells (CFU-C) and murine L1210 leukemia cells.

The effect of the naturally occuring amino acids upon melphalan (L-phenylalanine mustard, L-PAM) toxicity to a host sensitive tissue, the granulocyte and macrophage precursor cells of murine bone marrow (CFU-C), was investigated. At physiological concentrations the L isomers of leucine and glutamine were found to be the most effective of the naturally occurring amino acids in reducing drug toxicity. Tyrosine, phenylalanine and methionine also protected murine CFU-C from melphalan toxicity although the amount of protection provided by these amino acids at physiological concentrations was less than that provided by leucine and glutamine. Little difference was observed in the pattern of amino acid protection of murine CFU-C and murine L1210 leukemia cells. Murine CFU-C however were more sensitive to melphalan both in the absence and presence of amino acids.

Amino Acids↗
PubMed1982

Hyperthermic regional perfusion with melphalan and a combination of melphalan and actinomycin D in the treatment of locally metastasized malignant melanomas of the extremities.

From September 1969 through 1979, 68 patients with already locally metastasized malignant melanomas of the extremities were treated by hyperthermic regional perfusion and local excision(s). Of these, 53 patients could be evaluated after a follow-up of at least 2 years: 31 had been perfused with melphalan and 22 with melphalan in combination with actinomycin D. Local recurrence rates were about the same in both groups: 32 versus 33%. The same applied to the symptom-free interval between perfusion and local recurrence: about 12 versus about 13 months. Virtually all recurrences in both groups (90 versus 85%) were seen within 2 years. The interval between perfusion and systemic metastization was also roughly the same: about 25 versus about 23 months. These results indicate the need for better chemotherapeutics in order to achieve further improvement. The results of these perfusions were otherwise by no means disappointing, and hyperthermic regional perfusion is indicated in the treatment of patients with locally metastasized malignant melanomas.

Adult↗
PubMed1996

Effect of interferon on the health-related quality of life of multiple myeloma patients: results of a Nordic randomized trial comparing melphalan-prednisone to melphalan-prednisone + alpha-interferon. The Nordic Myeloma Study Group.

In a Nordic multi-centre trial, 583 previously untreated multiple myeloma patients were randomized to receive melphalan-prednisone or melphalan-prednisone+ interferon alpha-2b at a dose of 5 million units subcutaneously, 3 d/week. A quality-of-life study was integrated into the trial, using the EORTC QLQ C-30 questionnaire supplemented with 11 questions concerning interferon toxicity. The questionnaire was completed prior to treatment and after 1, 6, 12, 24, 36 and 48 months. 90% of the patients participated in the quality-of-life study, and 83% completed all questionnaires submitted to them. During the first year of treatment the patients on interferon reported significantly more fever, chills, dry skin, fatigue, pain, nausea/vomiting and appetite loss than the control patients. There was a moderate reduction of the global quality-of-life score and slight, non-significant, reductions of physical, emotional, cognitive, social and role functioning scores. After the first year there were no statistically significant differences in any toxicity, symptom or quality-of-life score, except for an increased frequency of dizziness in the interferon group. As only 60% of the patients remained on interferon after 24 months, our data probably underestimate the potential toxicity of the drug. Although there was no significant survival benefit for the interferon patients, a 5-6 months prolongation of the response and plateau phase duration was observed. However, by intention-to-treat analysis, there was no late quality-of-life benefit for the interferon patients to compensate for the early impairment. Thus, the clinical significance of the plateau-phase prolongation is uncertain.

Activities of Daily Living↗
PubMed2004

Randomized comparison of dexamethasone combined with melphalan versus melphalan with prednisone in the treatment of elderly patients with multiple myeloma.

Melphalan-prednisone (MP) has been the gold standard treatment for more than 30 years in elderly multiple myeloma (MM) patients. In order to assess whether the combination of dexamethasone with melphalan (MD) could improve on the efficacy of MP, we have carried out a randomized trial comparing both treatment approaches. A total of 201 patients >/=70 years old were included in the study. The overall response rate was similar after six cycles (MP: 67.9%versus MD: 64.5%) and after 12 cycles (MP: 49.4%versus MD: 46.1%). However, the proportion of complete responses (CR) was higher in the MD arm, particularly after 12 cycles (MD: 22.4%versus MP: 9.1%; P < 0.05). There was no significant difference in event-free survival (MP: 15.9 months versus MD: 23.3 months). The median overall survival in both arms was almost identical (MP: 29.4 months versus MD: 27.2 months; P = 0.63). No significant differences in haematological toxicity were observed, but non-haematological toxicity was significantly higher in the MD arm. According to these results MP remains as the gold standard for treatment of MM and should be the reference for comparison of new therapeutic approaches involving novel agents.

Aged↗
PubMed1990

Melphalan and prednisone (MP) versus vincristine, BCNU, adriamycin, melphalan and dexamethasone (VBAMDex) therapy for multiple myeloma. Early results of a multicenter trial. The German Myeloma Treatment Group.

136 untreated multiple myeloma patients of stage II and III were collected in the study. 37/51 stage II patients had progressive disease and were treated with melphalan and prednisone (MP). 85 patients were of stage III and randomized into MP and vincristine, BCNU, adriamycin, melphalan and dexamethasone (VBAMDex) treatment groups. 55% of MP treated patients responded versus 75% of the VBAMDex group. Since the study has been activated only 16 months ago, no difference in survival could be observed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Second-line chemotherapy of stage III-IV ovarian carcinoma: a randomized comparison of melphalan to melphalan and hexamethylmelamine in patients with persistent disease after doxorubicin and cisplatin.

A total of 205 women with stage III or IV ovarian cancer who had persistent disease after initial treatment with doxorubicin and cisplatin were randomized to receive melphalan (8 mg/m2 orally for 4 days) or the combination of melphalan (6 mg/m2 for 4 days) and hexamethylmelamine (120 mg/m2 for 14 days) every 4 weeks. Only one of 64 patients with measurable disease had an objective response. The major determinants of survival after randomization were the amount of residual disease after initial chemotherapy and the type of response to initial chemotherapy. There was no overall difference in survival between the two chemotherapy regimens, but the small group of patients whose disease progressed on initial chemotherapy survived significantly longer when treated with the two-drug combination. Neither of these regimens provided effective therapy for women whose disease was not eliminated by first-line treatment. However, the superior results obtained in one subgroup with the addition of hexamethylmelamine suggest that the place of this agent in treating ovarian cancer should be carefully evaluated.

Adult↗
PubMed1994

Purification of an alpha class glutathione S-transferase from melphalan-resistant Chinese hamster ovary cells and demonstration of its ability to catalyze melphalan-glutathione adduct formation.

We have shown previously that a Chinese hamster ovary cell line (designated CHO-Chlr), generated by exposure to chlorambucil and demonstrating a greater than 20-fold collateral resistance to melphalan, showed increased expression of an alpha form of glutathione S-transferase (GST) associated with amplification of GST genes. Here, we demonstrate that GST purified from CHO-Chlr cells contains a form with a pI of 9, not present in CHO-K1 cells or Chinese hamster liver, which has the ability to accelerate the formation of glutathione-melphalan adducts. This result provides evidence that overexpression of the alpha class GST may be directly responsible for the development of resistance to bifunctional alkylating agents.

Amino Acid Sequence↗
PubMed1997

Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of multiple myeloma: results of Eastern Cooperative Oncology Group Study E2479.

BACKGROUND: The Eastern Cooperative Oncology Group (ECOG) performed a Phase III comparison of melphalan and prednisone (MP) with vincristine, carmustine (BCNU), melphalan, cyclophosphamide, and prednisone (VBMCP) in an attempt to determine which of these regimens should be the standard treatment for multiple myeloma. METHODS: Four hundred seventy-nine previously untreated patients with multiple myeloma from 23 ECOG institutions were enrolled. Treatment, assigned by randomization, consisted of either 4-week cycles of MP or 5-week cycles of VBCMP. After 1 year of induction therapy, patients received MP or VBMCP maintenance therapy at 6- and 8- week intervals, respectively, until relapse. Patients who experienced treatment failure with MP were eligible for crossover therapy with VBMCP. RESULTS: Objective responses were obtained for 51% of patients receiving MP, as compared with 72% of patients receiving VBMCP (P < 0.001). Response duration was also longer with VBMCP (median, 18 months with MP vs. 24 months with VBMCP; P = 0.007). Overall survival was not significantly different between MP and VBMCP (P = 0.30). The 5-year survival for VBMCP was 26%, as compared with 19% for MP. VBMCP was associated with more nausea, peripheral nerve toxicity, alopecia, and neutropenia, but the infection rate was equal to that observed with MP. Both regimens were generally well tolerated. The main exception was that elderly patients who were confined to bed had a higher risk of death with VBMCP. The two regimens produced a similar incidence of late secondary myelodysplastic syndrome and acute leukemia. Crossover VBMCP for patients failing with MP was only minimally effective, with an objective response rate of 20% and median survival of 11 months after crossover. CONCLUSIONS: VBMCP is more effective than MP in producing and sustaining remission of multiple myeloma. It is associated with a marginal survival advantage and an apparently greater chance of surviving 5 years for patients who can tolerate moderately intensive combination chemotherapy. Cancer 1997;79:1561-7. 1997 American Cancer Society.

Adult↗
PubMed2006

Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial.

BACKGROUND: Since 1960, oral melphalan and prednisone (MP) has been regarded as the standard of care in elderly multiple myeloma patients. This multicentre randomised trial compared oral MP plus thalidomide (MPT) with MP alone in patients aged 60-85 years. METHODS: Patients with newly diagnosed multiple myeloma were randomly assigned to receive oral MP for six 4-week cycles plus thalidomide (n=129; 100 mg per day continuously until any sign of relapse or progressive disease) or MP alone (n=126). Analysis was intention-to-treat. This study is registered at , number NCT00232934. RESULTS: Patients treated with thalidomide had higher response rates and longer event-free survival (primary endpoints) than patients who were not. Combined complete or partial response rates were 76.0% for MPT and 47.6% for MP alone (absolute difference 28.3%, 95% CI 16.5-39.1), and the near-complete or complete response rates were 27.9% and 7.2%, respectively. 2-year event-free survival rates were 54% for MPT and 27% for MP (hazard ratio [HR] for MPT 0.51, 95% CI 0.35-0.75, p=0.0006). 3-year survival rates were 80% for MPT and 64% for MP (HR for MPT 0.68, 95% CI 0.38-1.22, p=0.19). Rates of grade 3 or 4 adverse events were 48% in MPT patients and 25% in MP patients (p=0.0002). Introduction of enoxaparin prophylaxis reduced rate of thromboembolism from 20% to 3% (p=0.005). CONCLUSION: Oral MPT is an effective first-line treatment for elderly patients with multiple myeloma. Anticoagulant prophylaxis reduces frequency of thrombosis. Longer follow-up is needed to assess effect on overall survival.

Aged↗
PubMed2001

Buthionine sulfoximine and myeloablative concentrations of melphalan overcome resistance in a melphalan-resistant neuroblastoma cell line.

BACKGROUND: Alkylator resistance contributes to treatment failure in high-risk neuroblastoma. Buthionine sulfoximine (BSO) can deplete glutathione and synergistically enhance in vitro sensitivity to the alkylating agent melphalan (L-PAM) for many neuroblastoma cell lines, but optimal use of this combination needs to be defined because clinical responses have been less frequent and not durable. PATIENTS AND METHODS: The authors established and characterized a neuroblastoma cell line (CHLA-171) from a patient who died of progressive disease after treatment with BSO and low-dose L-PAM. RESULTS: CHLA-171 lacks MYCN amplification, expresses PGP (P-glycoprotein) 9.5 RNA, and shows cell surface antigen expression (human leukocyte antigen class I weakly positive, but HSAN 1.2 (hybridoma, SAN 1.2) and anti-GD2 (anti-ganglioside GD2 antibody) strongly positive) characteristic of neuroblastoma cell lines. Twenty-four hours of BSO treatment (0-1,000 micromol/L) maximally depleted CHLA-171 glutathione to 36% of baseline. The cytotoxic response of CHLA-171 to BSO and L-PAM, alone and in combination, was measured by digital image microscopy (DIMSCAN) over a range of drug concentrations and compared with drug levels obtained in the patient during BSO/L-PAM therapy. As single agents, CHLA-171 was highly resistant to L-PAM (LD90 = 42 micromol/L; peak plasma concentration in the patient equals 3.9 micromol/L) and moderately resistant to BSO (LD90 = 509 micromol/L; steady-state concentration in the patient equals 397 micromol/L). Treatment with a 10:1 (BSO:L-PAM) fixed ratio combination synergistically overcame resistance (3-4 logs of cell kill, combination index <1) at clinically achievable levels of BSO (100-400 micromol/L) and levels of L-PAM (10-40 micromol/L) clinically achievable only with hematopoietic stem cell support. CONCLUSIONS: The in vitro results obtained for CHLA-171 suggest that BSO/L-PAM therapy may be optimally effective for drug-resistant neuroblastoma using myeloablative doses of L-PAM.

Antimetabolites, Antineoplastic↗
PubMed1985

Thermochemotherapy with cis-platinum, CCNU, BCNU, chlorambucil and melphalan on murine marrow and two tumours: therapeutic gain for melphalan only.

The magnitude of potentiation by whole body hyperthermia (45 min at 41 degrees C) of cis-platinum (DDP), CCNU, BCNU, chlorambucil and melphalan (Mel) on two tumours was compared with that on marrow in C3H mice. Drug damage was assayed in the KHT tumour by growth delay and in the RIF-1 tumour by clonogenic cell survival 24 h after treatment and/or by growth delay. Toxicity to marrow stem cells was assayed 24 h after treatment, by the spleen colony technique. When drug was given at the start of heating, all drugs were potentiated both in tumour and marrow to varying degrees. However, there was no therapeutic gain for the combined treatment with DDP on RIF-1, with CCNU or BCNU on KHT, or with CHL on either RIF-1 or KHT. Therapeutic ratios for Mel of 1.9 to 2.0 for KHT and of 1.1 to 1.8 in RIF-1 were measured over the dose range 7.5 to 15.0 mg/kg in unheated animals, indicating net therapeutic gain under these conditions. An absolute therapeutic gain was found for Mel in KHT when Mel was given 30 min before the start of heat.

Animals↗