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Journal of Chromatography. B,... May 2023As a hydrolysis mediated drug in vivo, the pharmacokinetics of melphalan are highly variable in patients. Few methodologies could simultaneously measure the...
As a hydrolysis mediated drug in vivo, the pharmacokinetics of melphalan are highly variable in patients. Few methodologies could simultaneously measure the concentrations of melphalan and its hydrolyzed metabolites in plasma. The aim of this study was to develop a simple, rapid and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of melphalan and its hydrolyzed metabolites, monohydroxy melphalan (MOH melphalan) and dihydroxy melphalan (DOH melphalan). A simple protein precipitation was employed for sample preparation and melphalan-d8 was used as internal standard. Baseline separation of target analytes was achieved using an XSelect HSS T3 column (2.1 × 50 mm, 5 µm) with a gradient elution at a flow rate of 0.5 mL/min in 5 min. The monitored transitions were m/z 305.1 → 287.7 for melphalan, m/z 287.1 → 228.0 for MOH melphalan, m/z 269.3 → 251.8 for DOH melphalan, and m/z 313.1 → 295.7 for melphalan-d8. The method was fully validated in accordance with the FDA guideline. The calibration curves were established over the range of 5.22-5220 ng/mL for melphalan, 7.94-1588 ng/mL for MOH-melphalan, and 15.0-3000 ng/mL for DOH-melphalan with the regression coefficients greater than 0.99. The intra- and inter-day coefficients of variation for the analytes were ≤11.0% and all the biases were less than 8.3%. The method has been successfully applied to the quantification of melphalan and its metabolites in clinical plasma samples obtained from hematopoietic stem cell transplantation patients who received a dose of melphalan for pre-transplant conditioning.
Topics: Humans; Chromatography, Liquid; Tandem Mass Spectrometry; Melphalan; Hydrolysis; Reproducibility of Results; Chromatography, High Pressure Liquid
PubMed: 37060813
DOI: 10.1016/j.jchromb.2023.123698 -
The Annals of Pharmacotherapy Aug 2022The objective of this article was to review existing data of melflufen (Pepaxto) as an additional treatment option for heavily pretreated relapsed and refractory... (Review)
Review
OBJECTIVE
The objective of this article was to review existing data of melflufen (Pepaxto) as an additional treatment option for heavily pretreated relapsed and refractory multiple myeloma.
DATA SOURCES
A PubMed search was completed using the search terms melphalan flufenamide; melflufen; melflufen AND relapsed refractory multiple myeloma; melphalan flufenamide and relapsed refractory multiple myeloma between January 1, 2013, and October 18, 2021. Additional information was obtained from the National Institutes of Health Clinical Trial Registry, Federal Drug Administration (FDA) web updates, and Pepaxto prescribing information.
STUDY SELECTION/DATA EXTRACTION
Clinical trials including melflufen in relapsed refractory multiple myeloma and trials related to safety and clinical pharmacology were included.
DATA SYNTHESIS
The findings of this review show melflufen in combination with dexamethasone can be used as a treatment option for patients with relapsed and refractory multiple myeloma who have previously received greater than 4 previous lines of therapy, and documented resistance to a proteosome inhibitor, an anti-CD38 monoclonal antibody, and an immunomodulator.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
Melflufen in combination with dexamethasone is a reasonable option for patients with relapsed and refractory multiple myeloma who have received at least 4 previous lines of therapy and considered ineligible for autologous stem cell transplant. Further clinical utilization in earlier lines of therapy is under review, pending the in-depth safety analysis by the FDA.
CONCLUSIONS
The FDA approval of melflufen in combination with dexamethasone provides an additional therapy option for patients with heavily pretreated relapsed and refractory multiple myeloma.
Topics: Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Melphalan; Multiple Myeloma; Peptides; Phenylalanine
PubMed: 34963319
DOI: 10.1177/10600280211058388 -
Annals of Hematology Dec 2022We evaluated 413 adult patients with lymphoma who underwent unrelated cord blood transplantation (UCBT) with fludarabine and melphalan (FM)-based reduced-intensity...
Improved survival after single-unit cord blood transplantation using fludarabine and melphalan-based reduced-intensity conditioning for malignant lymphoma: impact of melphalan dose and graft-versus-host disease prophylaxis with mycophenolate mofetil.
We evaluated 413 adult patients with lymphoma who underwent unrelated cord blood transplantation (UCBT) with fludarabine and melphalan (FM)-based reduced-intensity conditioning between 2002 and 2017 to investigate longitudinal changes in outcomes and the optimal melphalan dose and graft-versus-host disease (GVHD) prophylaxis regimen. Outcomes were compared between FM80/100 (melphalan dose: 80 or 100 mg/m) and FM140 (melphalan dose: 140 mg/m), as well as between calcineurin inhibitor (CNI) plus methotrexate (MTX), CNI plus mycophenolate mofetil (MMF), and CNI alone. The 3-year overall survival (OS) and non-relapse mortality (NRM) rates improved over time (OS: 27% in 2000s vs. 42% in 2010s, p < 0.001; NRM: 43% in 2000s vs. 26% in 2010s, p < 0.001). Multivariable analysis showed that in the 2000s, melphalan dose and GVHD prophylaxis regimen did not affect any outcomes. In the 2010s, FM80/100 (vs. FM140) related to better OS (hazard ratio [HR] 0.62, p = 0.01) and NRM (HR 0.52, p = 0.016). MTX + CNI and CNI alone (vs. CNI + MMF) related to worse OS (CNI + MTX, HR 2.01, p < 0.001; CNI alone, HR 2.65, p < 0.001) and relapse/progression (CNI + MTX, HR 2.40, p < 0.001; CNI alone, HR 2.13, p = 0.023). In recent years, the use of FM80/100 and CNI + MMF significantly reduced the risk of NRM and relapse/progression, respectively, and resulted in better OS after UCBT for lymphoma.
Topics: Adult; Humans; Mycophenolic Acid; Melphalan; Graft vs Host Disease; Cord Blood Stem Cell Transplantation; Neoplasm Recurrence, Local; Transplantation Conditioning; Hematopoietic Stem Cell Transplantation; Calcineurin Inhibitors; Lymphoma; Methotrexate
PubMed: 36195679
DOI: 10.1007/s00277-022-04990-w -
International Journal of Molecular... Feb 2022Despite the continuous developments in pharmacology and the high therapeutic effect of new treatment options for patients with hematological malignancies, these diseases...
Despite the continuous developments in pharmacology and the high therapeutic effect of new treatment options for patients with hematological malignancies, these diseases remain a major health issue. Our study aimed to synthesize, analyze in silico, and determine the biological properties of new melphalan derivatives. We obtained three methyl esters of melphalan having in their structures amidine moieties substituted with thiomorpholine (EM-T-MEL), indoline (EM-I-MEL), or 4-(4-morpholinyl) piperidine (EM-MORPIP-MEL). These have not yet been described in the literature. The in vitro anticancer properties of the analogs were determined against THP1, HL60, and RPMI8226 cells. Melphalan derivatives were evaluated for cytotoxicity (resazurin viability assay), genotoxicity (alkaline comet assay), and their ability to induce apoptosis (Hoechst33342/propidium iodide double staining method; phosphatidylserine translocation; and caspase 3/7, 8, and 9 activity measurements). Changes in mitochondrial membrane potential were examined using the specific fluorescence probe JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazol carbocyanine). The EM-T-MEL derivative had the highest biological activity, showing higher cytotoxic and genotoxic properties than the parent drug. Moreover, it showed a high ability to induce apoptosis in the tested cancer cells. This compound also had a beneficial effect in peripheral blood mononuclear cells (PBMC). In conclusion, we verified and confirmed the hypothesis that chemical modifications of the melphalan structure improved its anticancer properties. The conducted study allowed the selection of the compound with the highest biological activity and provided a basis for chemical structure-biological activity analyses.
Topics: Apoptosis; Caspases; Cell Line, Tumor; DNA Fragmentation; Hematologic Neoplasms; Humans; Leukemia; Melphalan; Membrane Potential, Mitochondrial; Models, Biological; Staining and Labeling
PubMed: 35163680
DOI: 10.3390/ijms23031760 -
Clinical Lymphoma, Myeloma & Leukemia Sep 2023Allogeneic hematopoietic stem cell transplantation (alloHCT) is potentially curative for relapsed/refractory (r/r) B-cell non-Hodgkin's lymphoma (B-cell NHL). However,...
Results of a Phase II Trial of Allogeneic Hematopoietic Stem Cell Transplantation Using Y-Ibritumomab Tiuxetan (Zevalin) in Combination With Fludarabine and Melphalan in Patients With High-Risk B-Cell Non-Hodgkin's Lymphoma.
BACKGROUND
Allogeneic hematopoietic stem cell transplantation (alloHCT) is potentially curative for relapsed/refractory (r/r) B-cell non-Hodgkin's lymphoma (B-cell NHL). However, relapse remains a major cause of treatment failure, especially in patients with either positron emission tomography (PET)-positive and/or chemoresistant disease prior to alloHCT. Y-ibritumomab tiuxetan (Zevalin) is a radiolabeled anti-CD20 antibody which is a safe and effective therapy in multiple histologic subtypes of B-cell NHL and has also been incorporated in both autologous HCT (autoHCT) and alloHCT conditioning regimens.
OBJECTIVES
The purpose of this study was to evaluate the efficacy and confirm the safety of the radiolabeled anti-CD20 antibody ibritumomab tiuxetan (Zevalin) combined with the reduced intensity conditioning (RIC) regimen of fludarabine and melphalan (Flu/Mel) in patients with high-risk B-cell NHL.
STUDY DESIGN
We conducted a phase II trial (NCT00577278) of Zevalin with Flu/Mel in patients with high-risk B-cell NHL. We enrolled 41 patients from October 2007 to April 2014, all of whom had either a fully matched sibling or 8/8 or 7/8 matched unrelated donor (MUD). Patients received In-Zevalin (5.0 mCi) on day -21 pre-HCT, followed by Y-Zevalin (0.4 mCi/kg) on day -14. Fludarabine (25 mg/m daily) was given from days -9 to -5 and melphalan (140 mg/m) was administered on day -4. All patients received rituximab 250 mg/m2 on day +8 and an additional dose on either day +1 or -21 depending on the baseline rituximab level. Patients with a low rituximab level were given rituximab on days -21 and -15. All patients received tacrolimus/sirolimus (T/S) with or without methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis starting on day -3, and stem cells were infused on day 0.
RESULTS
The 2-year overall survival (OS) and progression-free survival (PFS) for all patients were 63% and 61%, respectively. The incidence of relapse at 2 years was 20%. Nonrelapse mortality (NRM) at day +100 and 1 year were 5% and 12%, respectively. The overall cumulative incidence of grade II-IV and III-IV acute GVHD (aGVHD) were 44% and 15%, respectively. Extensive chronic GVHD (cGVHD) occurred in 44% of patients. On univariate analysis, histology (diffuse large B cell lymphoma (DLBCL) vs. others) was negatively predictive for OS (P = .0013) and PFS (P = .0004), while histology (DLBCL vs. others, P = .0128) predicted for relapse. PET positivity pre-HCT did not correlate with any of the efficacy endpoints.
CONCLUSION
Addition of Zevalin to Flu/Mel is safe and effective in high-risk NHL and met the prespecific endpoint. Results were suboptimal in patients with DLBCL.
Topics: Humans; Melphalan; Rituximab; Neoplasm Recurrence, Local; Lymphoma, B-Cell; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Transplantation Conditioning
PubMed: 37301631
DOI: 10.1016/j.clml.2023.05.011 -
Expert Review of Clinical Pharmacology Jan 2022For patients with multiple myeloma who are eligible for high-dose melphalan therapy and autologous stem cell transplant (ASCT), the strategy of maintenance with low-dose... (Review)
Review
INTRODUCTION
For patients with multiple myeloma who are eligible for high-dose melphalan therapy and autologous stem cell transplant (ASCT), the strategy of maintenance with low-dose lenalidomide therapy has become the current standard of care. However, this strategy is not curative, and many unanswered questions remain regarding the optimization of lenalidomide-based maintenance therapy.
AREAS COVERED
In this review, we evaluate the current data supporting the use of lenalidomide maintenance, either alone or in combination, following ASCT. We provide an overview of the management of lenalidomide-associated toxicities as well as address the unresolved topics of optimal treatment duration and use of minimal residual disease assessment.
EXPERT OPINION
While single-agent lenalidomide maintenance is a current standard of care, a one-size-fits-all approach to maintenance therapy is not optimal. The rapidly evolving landscape of multiple myeloma therapy in conjunction with ongoing clinical trials should enable a future where an individualized approach based on disease characteristics, response to induction and ASCT (or even non-ASCT consolidation approaches such as CAR T-cell therapy or bispecific antibodies), as well as patient preferences will influence the use of lenalidomide maintenance.
Topics: Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Transplantation, Autologous
PubMed: 35061547
DOI: 10.1080/17512433.2022.2032656 -
Cancer Research Dec 2015
Topics: Animals; Antigens, Surface; Antineoplastic Agents, Alkylating; Calreticulin; Humans; Melanoma; Melphalan; Skin Neoplasms
PubMed: 26627012
DOI: 10.1158/0008-5472.CAN-15-1184 -
Cancer Research Dec 2015
Topics: Animals; Antigens, Surface; Antineoplastic Agents, Alkylating; Calreticulin; Humans; Melanoma; Melphalan; Skin Neoplasms
PubMed: 26627014
DOI: 10.1158/0008-5472.CAN-15-2061 -
Blood Mar 2016The combination of melphalan, prednisone, and thalidomide (MPT) is considered standard therapy for newly diagnosed patients with multiple myeloma who are ineligible for... (Comparative Study)
Comparative Study Randomized Controlled Trial
The combination of melphalan, prednisone, and thalidomide (MPT) is considered standard therapy for newly diagnosed patients with multiple myeloma who are ineligible for stem cell transplantation. Long-term treatment with thalidomide is hampered by neurotoxicity. Melphalan, prednisone, and lenalidomide, followed by lenalidomide maintenance therapy, showed promising results without severe neuropathy emerging. We randomly assigned 668 patients between nine 4-week cycles of MPT followed by thalidomide maintenance until disease progression or unacceptable toxicity (MPT-T) and the same MP regimen with thalidomide being replaced by lenalidomide (MPR-R). This multicenter, open-label, randomized phase 3 trial was undertaken by Dutch-Belgium Cooperative Trial Group for Hematology Oncology and the Nordic Myeloma Study Group (the HOVON87/NMSG18 trial). The primary end point was progression-free survival (PFS). A total of 318 patients were randomly assigned to receive MPT-T, and 319 received MPR-R. After a median follow-up of 36 months, PFS with MPT-T was 20 months (95% confidence interval [CI], 18-23 months) vs 23 months (95% CI, 19-27 months) with MPR-R (hazard ratio, 0.87; 95% CI, 0.72-1.04; P = .12). Response rates were similar, with at least a very good partial response of 47% and 45%, respectively. Hematologic toxicity was more pronounced with MPR-R, especially grades 3 and 4 neutropenia: 64% vs 27%. Neuropathy of at least grade 3 was significantly higher in the MPT-T arm: 16% vs 2% in MPR-R, resulting in a significant shorter duration of maintenance therapy (5 vs 17 months in MPR-R), irrespective of age. MPR-R has no advantage over MPT-T concerning efficacy. The toxicity profile differed with clinically significant neuropathy during thalidomide maintenance vs myelosuppression with MPR.
Topics: Aged; Aged, 80 and over; Disease-Free Survival; Female; Humans; Lenalidomide; Maintenance Chemotherapy; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Thalidomide; Treatment Outcome; Withholding Treatment
PubMed: 26802176
DOI: 10.1182/blood-2015-11-679415 -
Journal of Pediatric Hematology/oncology Aug 2022The study by Whelan and colleagues showed that addition of busulfan and melphalan conditioning and autologous stem cell rescue to conventional EURO-E.W.I.N.G STUDY...
The study by Whelan and colleagues showed that addition of busulfan and melphalan conditioning and autologous stem cell rescue to conventional EURO-E.W.I.N.G STUDY chemotherapy in local nonmetastatic Ewing sarcoma improves prognosis. However, almost 30% of these study patients will have relapsed before this stage of therapy is reached, and 78% of his patients were at high risk because of inadequate response to the initial chemotherapy given. Further improvement could be achieved by the integration of other novel advances with this approach. Ash and colleagues have shown that the separation of such cases into high- and low-risk groups by using CD56 negativity of the tumor cells is an improvement over current methods with a 100% 10-year progression-free survival in CD56- nonpelvic local isolated Ewing sarcoma patients. Their patients were treated on the SCMCIE 94 protocol, associated with no relapses before 30 months in 24 consecutive patients independent of the CD status. Integration of these novel approaches in diagnosis and treatment would allow truly high-risk patients, who would benefit from the procedure, to reach the busulfan and melphalan stage of therapy and delineate those patients who can be cured without such therapy. Details of the SCMCIE 94 protocol are given and the possible reasons for the different relapse patterns are discussed.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Busulfan; Disease-Free Survival; Humans; Melphalan; Neoplasm Recurrence, Local; Sarcoma, Ewing
PubMed: 35537008
DOI: 10.1097/MPH.0000000000002481