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Amyloid : the International Journal of... Mar 2022AL amyloidosis is a systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. High dose intravenous melphalan and autologous stem cell...
AL amyloidosis is a systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. High dose intravenous melphalan and autologous stem cell transplantation was developed for the treatment of AL amyloidosis in the early 1990s and was prompted by its success in multiple myeloma. This application has evolved significantly over the past three decades. These guidelines provide a comprehensive assessment of eligibility criteria, stem cell collection and mobilisation strategies and regimens, risk-adapted melphalan dosing, role for induction and consolidation therapies, specific supportive care management, long-term outcome with respect to survival, haematologic response and relapse and organ responses following stem cell transplantation. These guidelines are developed by the experts in the field on behalf of the stem cell transplant working group of the International Society of Amyloidosis (ISA) and European Haematology Association (EHA).
Topics: Amyloidosis; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Neoplasm Recurrence, Local; Stem Cell Transplantation; Transplantation, Autologous; Treatment Outcome
PubMed: 34783272
DOI: 10.1080/13506129.2021.2002841 -
Journal of Clinical Oncology : Official... Mar 2021Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into...
PURPOSE
Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need.
PATIENTS AND METHODS
Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing.
RESULTS
Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class-refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class-refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4.
CONCLUSION
Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class-refractory and extramedullary disease.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disease Progression; Drug Resistance, Neoplasm; Europe; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Phenylalanine; Progression-Free Survival; Recurrence; Time Factors; United States
PubMed: 33296242
DOI: 10.1200/JCO.20.02259 -
Drugs Jun 2021Melphalan flufenamide (melflufen, Pepaxto) is a peptide conjugated alkylating drug developed by Oncopeptides for the treatment of multiple myeloma (MM) and amyloid... (Review)
Review
Melphalan flufenamide (melflufen, Pepaxto) is a peptide conjugated alkylating drug developed by Oncopeptides for the treatment of multiple myeloma (MM) and amyloid light-chain amyloidosis. It is an ethyl ester of a lipophilic dipeptide consisting of melphalan and para-fluoro-L-phenylalanine. Due to its lipophilicity, melphalan flufenamide is rapidly transported across the cell membrane and almost immediately hydrolyzed by aminopeptidases in the cytoplasm to yield more hydrophilic alkylating molecules, such as melphalan and desethyl-melflufen. Like other nitrogen mustard drugs, melphalan flufenamide exerts antitumor activity through DNA crosslinking. In February 2021, melphalan flufenamide, in combination with dexamethasone, received its first approval in the USA for the treatment of adults with relapsed or refractory (r/r) MM who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor (PI), one immunomodulatory agent, and one CD38-directed monoclonal antibody. A multinational clinical study of melphalan flufenamide in amyloid light-chain amyloidosis is underway across several countries, and preclinical studies for various haematological and solid cancers are underway. This article summarizes the milestones in the development of melphalan flufenamide leading to this first approval.
Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Humans; Melphalan; Multicenter Studies as Topic; Multiple Myeloma; Randomized Controlled Trials as Topic
PubMed: 33961277
DOI: 10.1007/s40265-021-01522-0 -
The Malaysian Journal of Pathology Dec 2017POEMS syndrome is the syndrome of Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein and typical Skin changes. A 65-year-old lady presented with the...
POEMS syndrome is the syndrome of Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein and typical Skin changes. A 65-year-old lady presented with the 2-day-history of inability to walk, 4-month-history of progressive worsening of muscle weakness of both lower limbs and 1-year-history of progressive worsening of bilateral numbness of lower limbs. Nerve conduction study revealed generalized sensorimotor demyelinating polyneuropathy. She was initially treated as chronic inflammatory demyelinating polyradiculoneuropathy with intravenous immunoglobulin (IVIG) and high-dose prednisolone. However, she had no significant neurological improvement despite getting standard therapy. In addition to peripheral neuropathy, the presence of hepatosplenomegaly, skin changes, polycythaemia and thrombocytosis prompted for further investigations. She was diagnosed as POEMS syndrome based on the presence of two mandatory major criteria [polyneuropathy, monoclonal plasma cell proliferative disorder (lambda)], one major criterion (sclerotic bone lesions) and three minor criteria (organomegaly, skin changes and thrombocytosis/polycythaemia). She received treatment with melphalan and prednisolone. She achieved clinical improvement and partial response (haematologic and radiological) after six cycles of therapy. We highlight the awareness of this rare syndrome, for patients presenting with peripheral neuropathy and not responding to its standard therapy, by recognizing other associated clinical manifestations and proceeding further diagnostic work-up.
Topics: Aged; Anti-Inflammatory Agents; Female; Humans; Melphalan; Myeloablative Agonists; POEMS Syndrome; Prednisolone
PubMed: 29279594
DOI: No ID Found -
Blood Jan 2016In this issue of Blood, Mateos et al report that bortezomib plus melphalan and prednisone (VMP) and lenalidomide plus low-dose dexamethasone (Rd) administered in a...
In this issue of Blood, Mateos et al report that bortezomib plus melphalan and prednisone (VMP) and lenalidomide plus low-dose dexamethasone (Rd) administered in a sequential or an alternating scheme were equally active and induced comparable toxicities in elderly myeloma patients.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Female; Humans; Male; Melphalan; Multiple Myeloma
PubMed: 26823507
DOI: 10.1182/blood-2015-11-678524 -
Retina (Philadelphia, Pa.) Jan 2017To review preclinical and clinical pharmacokinetic studies of the three most important chemotherapy drugs used for intraocular retinoblastoma and the contribution of the... (Review)
Review
PURPOSE
To review preclinical and clinical pharmacokinetic studies of the three most important chemotherapy drugs used for intraocular retinoblastoma and the contribution of the reported results to optimize treatment.
METHODS
Systemic review of pharmacokinetic studies identified by a literature search at Pubmed using the keywords carboplatin, melphalan, topotecan, intravitreal, ophthalmic artery chemosurgery, pharmacokinetics, and retinoblastoma.
RESULTS
A total of 21 studies were reviewed for assessing the preclinical and clinical pharmacokinetics of carboplatin, topotecan, and melphalan delivered by intravenous, periocular, ophthalmic artery, and intravitreal routes. Some preclinical studies were done before translation to the clinics. Others, despite encouraging preclinical data as reported for periocular topotecan did not correlate with clinical use. In addition, as was the case for melphalan after ophthalmic artery chemosurgery and despite nonfavorable preclinical information, some routes of drug delivery are clinically effective. Besides topotecan, complete knowledge of the pharmacokinetics of melphalan and carboplatin is still lacking.
CONCLUSION
Pharmacokinetic knowledge of chemotherapy may aid to guide retinoblastoma treatment in favor of safety and efficacy. Nonetheless, results obtained in preclinical models should be translated with care to the clinics.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Infusions, Intra-Arterial; Injections, Intraocular; Melphalan; Retinal Neoplasms; Retinoblastoma; Topotecan
PubMed: 27617542
DOI: 10.1097/IAE.0000000000001275 -
Hematology/oncology Clinics of North... Apr 2024No therapy in multiple myeloma has been as extensively investigated as stem cell transplantation following high-dose chemotherapy. A search of the national library of... (Review)
Review
No therapy in multiple myeloma has been as extensively investigated as stem cell transplantation following high-dose chemotherapy. A search of the national library of medicine in February 2023 revealed over 27,000 publications covering stem cell transplantation. No other treatment for multiple myeloma has been so vigorously investigated. However, given the rapid advances seen in the treatment of multiple myeloma, it is legitimate to ask whether the technique first introduced in 1983 by Thomas McIlwain still has relevance. In 1984,Barlogie introduced infusional vincristine, doxorubicin, and dexamethasone and in 1986 published a first series on high-dose therapy with autologous marrow-derived stem cells. At this point, the only available therapies were melphalan, prednisone, other intensive steroids such as methylprednisolone, and interferon. Cyclophosphamide was used both orally and parenterally. VBMCP was introduced as a combination therapy at Memorial Hospital subsequently shown not to be superior to melphalan and prednisone.
Topics: Humans; Multiple Myeloma; Melphalan; Prednisone; Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Antineoplastic Combined Chemotherapy Protocols; Vincristine; Transplantation, Autologous; Dexamethasone
PubMed: 38151401
DOI: 10.1016/j.hoc.2023.12.005 -
Drugs of Today (Barcelona, Spain : 1998) Aug 2022Despite therapeutic advances and improved patient outcomes in recent years, multiple myeloma (MM) remains a mostly incurable hematologic malignancy. Patients with... (Review)
Review
Despite therapeutic advances and improved patient outcomes in recent years, multiple myeloma (MM) remains a mostly incurable hematologic malignancy. Patients with relapsed/refractory MM (RRMM), especially those with triple-class-refractory disease or poor-prognostic features, have substantially unmet needs for new therapies with novel mechanisms of action. Melphalan flufenamide (melflufen) is the first alkylating peptide-drug conjugate that targets aminopeptidases to show efficacy and manageable safety, in combination with dexamethasone, in patients with RRMM who had received at least 4 prior lines of therapy, including at least 1 immunomodulatory drug, at least 1 proteasome inhibitor and at least 1 anti-CD38 monoclonal antibody, and received accelerated approval by the U.S. Food and Drug Administration (FDA) in early 2021 for use in this patient population. Initial analyses of the phase III OCEAN study data led to melflufen being voluntarily withdrawn from the U.S. market in late 2021, but subsequent analyses have prompted the manufacturer to rescind its voluntary withdrawal to allow further discussions with the U.S. FDA and the regulatory review with the European Medicines Agency (EMA) is also ongoing. Here, we provide a review of the novel mechanism of action and pharmacokinetics of melflufen, as well as key efficacy and safety from clinical studies that supported its initial approval, and discuss the nuances of the OCEAN study data. Melflufen demonstrates the potential of novel peptide-drug conjugates to positively impact the treatment landscape in RRMM.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Melphalan; Multiple Myeloma; Phenylalanine
PubMed: 35983927
DOI: 10.1358/dot.2022.58.8.3367680 -
Der Ophthalmologe : Zeitschrift Der... Feb 2015This article reports a case of primary localized conjunctival λ light-chain (AL) amyloidosis.
BACKGROUND
This article reports a case of primary localized conjunctival λ light-chain (AL) amyloidosis.
METHODS
Case report.
RESULTS
A 73-year-old woman presented with a 1-year history of a painless growth in the conjunctiva of the left eye. A yellow-salmon pink diffuse mass of tissue was identified in the inferomedial bulbar conjunctiva and inferior fornix. An incisional biopsy was performed. The histopathological and immunohistochemical examinations revealed interstitial and vascular amyloid deposits of λ light chains. The diagnosis was amyloidosis of the conjunctiva. The systemic evaluation revealed normal findings and systemic amyloidosis was excluded. Nevertheless, due to an unexplained cardiac insufficiency and after consultation with the treating hematologist a treatment with three cycles of systemic chemotherapy with melphalan and prednisolone was initiated but 6 months later the conjunctival mass in the inferior fornix showed persistence and complete excision was performed. At 16, 24 and 44 months of follow-up no evidence of recurrence was seen on clinical examination. The magnetic resonance imaging (MRI) at 16 and 24 months of follow-up showed no associated cranial or orbital infiltration.
CONCLUSION
Conjunctival AL amyloidosis is a rare clinical entity. Because of the heterogeneity of amyloidosis in clinical presentation, pattern of amyloid-related organ toxicity, association with lymphoproliferative diseases and rate of disease progression, identification of amyloid deposits is essential and systemic involvement has to be excluded.
Topics: Aged; Amyloidosis; Anti-Inflammatory Agents; Conjunctival Diseases; Female; Humans; Melphalan; Prednisolone; Treatment Outcome
PubMed: 25134460
DOI: 10.1007/s00347-014-3091-3 -
European Journal of Medicinal Chemistry Aug 2022Cancer is an uncontrolled expansion of atypical cells in the body. These unusual cells are labelled as cancerous or malignant cells. Melphalan, an anticancer drug which... (Review)
Review
Cancer is an uncontrolled expansion of atypical cells in the body. These unusual cells are labelled as cancerous or malignant cells. Melphalan, an anticancer drug which is imperatively recognized under the class of alkylating agents. It exhibits broad spectrum antitumor activity, as observed in ovarian cancer, breast cancer, etc. However, it is mainly utilized in the management of multiple myeloma. Several studies across the globe suggest that resistance to melphalan is the major concern that leads to relapsed myeloma. In the present paper, several pivotal approaches to compensate resistance associated with melphalan have been discussed. Numerous chemical and formulation developments concerning melphalan to enhance its salient characteristics and targeted profile have also been portrayed. The rationale of the current article also summarizes the recent analytical methods, structure-activity relationship, pharmacokinetics, interactions, potential adverse effects along with medicinal updates of melphalan. Special attention is also laid on their synthetic developments viz. melphalan derivatives, conjugates and prodrugs along with encouraging insights and research findings.
Topics: Antineoplastic Agents, Alkylating; Drug Resistance, Neoplasm; Humans; Melphalan; Multiple Myeloma; Prodrugs; Structure-Activity Relationship
PubMed: 35665692
DOI: 10.1016/j.ejmech.2022.114494