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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 -
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 -
Transplantation and Cellular Therapy May 2022Autologous hematopoietic cell transplantation (AHCT) remains a standard therapeutic option for patients with multiple myeloma (MM). Outcomes have improved for this... (Review)
Review
Autologous hematopoietic cell transplantation (AHCT) remains a standard therapeutic option for patients with multiple myeloma (MM). Outcomes have improved for this patient group after first AHCT, with the use of novel agents in induction, as well as post-transplantation maintenance. High-dose melphalan remains the gold standard as the conditioning regimen for MM. Traditional melphalan is a lyophilized formulation that after reconstitution has insufficient chemical stability and water solubility, thus requiring the addition of propylene glycol to act as a cosolvent to improve these characteristics. After the reconstitution of melphalan with propylene glycol-containing solution, impurities can develop within 30 minutes, and if further dilution occurs, the potency of melphalan diminishes. Propylene glycol is associated with a spectrum of toxicities that can be dose limiting. Evomela is a propylene glycol-free melphalan (PGF-Mel) that at a high dose of 200 mg/ (100 mg/m/d for 2 days) is approved for conditioning before AHCT in MM patients. Once reconstituted by directly dissolving in saline solution, PGF-Mel solution can be stored in the vial for up to 1 hour at room temperature or for up to 24 hours at refrigerated temperature (2° to 8°C) with no significant degradation. The demonstrated stability, up to 24 hours at room temperature, results in reduced handling requirements and increased convenience and flexibility of administration. Since its approval, Evomela has been the subject of several retrospective and investigator-initiated studies. This review summarizes the prospective and real-world evidence on practical aspects of PGF-Mel and critically appraises the available data and its clinical implications.
Topics: Humans; Amyloidosis; Hematopoietic Stem Cell Transplantation; Melphalan; Multiple Myeloma; Propylene Glycol; Prospective Studies; Retrospective Studies
PubMed: 35196581
DOI: 10.1016/j.jtct.2022.02.014 -
International Journal of Molecular... Dec 2022Histone deacetylase inhibitors show synergy with several genotoxic drugs. Herein, we investigated the biological impact of the combined treatment of panobinostat and...
Histone deacetylase inhibitors show synergy with several genotoxic drugs. Herein, we investigated the biological impact of the combined treatment of panobinostat and melphalan in multiple myeloma (MM). DNA damage response (DDR) parameters and the expression of DDR-associated genes were analyzed in bone marrow plasma cells (BMPCs) and peripheral blood mononuclear cells (PBMCs) from 26 newly diagnosed MM patients. PBMCs from 25 healthy controls (HC) were examined in parallel. Compared with the ex vivo melphalan-only treatment, combined treatment with panobinostat and melphalan significantly reduced the efficiency of nucleotide excision repair (NER) and double-strand-break repair (DSB/R), enhanced the accumulation of DNA lesions (monoadducts and DSBs), and increased the apoptosis rate only in patients’ BMPCs (all p < 0.001); marginal changes were observed in PBMCs from the same patients or HC. Accordingly, panobinostat pre-treatment decreased the expression levels of critical NER (DDB2, XPC) and DSB/R (MRE11A, PRKDC/DNAPKc, RAD50, XRCC6/Ku70) genes only in patients’ BMPCs; no significant changes were observed in PBMCs from patients or HC. Together, our findings demonstrate that panobinostat significantly increased the melphalan sensitivity of malignant BMPCs without increasing the melphalan sensitivity of PBMCs from the same patients, thus paving the way for combination therapies in MM with improved anti-myeloma efficacy and lower side effects.
Topics: Humans; Melphalan; Multiple Myeloma; Panobinostat; Leukocytes, Mononuclear; DNA Repair
PubMed: 36555311
DOI: 10.3390/ijms232415671 -
Scientific Reports Aug 2023Breast cancer is the second most common type of cancer worldwide and the leading cause of cancer death in women. Dietary bioactive compounds may act at different stages...
Breast cancer is the second most common type of cancer worldwide and the leading cause of cancer death in women. Dietary bioactive compounds may act at different stages of carcinogenesis, including tumor initiation, promotion, and progression. Spices have been used for thousands of years and have many bioactive compounds with chemopreventive and chemotherapeutic properties. Curcumin has a multitude of beneficial biological properties, including anti-inflammatory and anticancer effects. This study investigated the effects of cotreatment with curcumin and the chemotherapeutic drug melphalan in cultured MDA-MB-231 breast cancer cells. When used alone, both curcumin and melphalan had a cytotoxic effect on breast cancer cells. Combined treatment with 11.65 µM of curcumin and 93.95 µM of melphalan (CURC/MEL) reduced cell viability by 28.64% and 72.43% after 24 h and 48 h, respectively. CURC/MEL reduced the number of colony-forming units and increased ROS levels by 1.36-fold. CURC/MEL alter cell cycle progression, induce apoptosis, and upregulate caspases-3, -7, and -9, in MDA-MB-231 cells. Cotreatment with curcumin and melphalan have anti-breast cancer cells effects and represent a promising candidate for clinical testing.
Topics: Female; Humans; Melphalan; Curcumin; Breast Neoplasms; Cell Cycle Checkpoints; Apoptosis
PubMed: 37596331
DOI: 10.1038/s41598-023-40535-5 -
Experimental Eye Research Mar 2021The use of intravitreal chemotherapy has revolutionized the treatment of advanced intraocular retinoblastoma, as intravitreal melphalan has enabled difficult-to-treat... (Comparative Study)
Comparative Study
Intravitreal melphalan hydrochloride vs propylene glycol-free melphalan for retinoblastoma vitreous seeds: Efficacy, toxicity and stability in rabbits models and patients.
The use of intravitreal chemotherapy has revolutionized the treatment of advanced intraocular retinoblastoma, as intravitreal melphalan has enabled difficult-to-treat vitreous tumor seeds to be controlled, leading to many more eyes being saved. However, melphalan hydrochloride (MH) degrades rapidly in solution, increasing logistical complexity with respect to time between medication preparation and administration for intravitreal administration under anesthesia for retinoblastoma. A new propylene glycol-free melphalan (PGFM) formulation has greater stability and could therefore improve access and adoption of intravitreal chemotherapy, allowing more children to retain their eye(s). We compared the efficacy and toxicity of both formulations, using our rabbit xenograft model and clinical patient experience. Three weekly 12.5 μg intravitreal injections of MH or PGFM (right eye), and saline (left eye), were administered to immunosuppressed rabbits harboring human WERI-Rb1 vitreous seed xenografts. Residual live cells were quantified directly, and viability determined by TUNEL staining. Vitreous seeds were reduced 91% by PGFM (p = 0.009), and 88% by MH (p = 0.004; PGFM vs. MH: p = 0.68). All residual cells were TUNEL-positive (non-viable). In separate experiments to assess toxicity, three weekly 12.5 μg injections of MH, PGFM, or saline were administered to non-tumor-bearing rabbits. Serial electroretinography, optical coherence tomography (OCT) and OCT-angiography were performed. PGFM and MH both caused equivalent reductions in electroretinography amplitudes, and loss of retinal microvasculature on OCT-angiography. The pattern of retinal degeneration observed on histopathology suggested that segmental retinal toxicity associated with all melphalan formulations was due to a vitreous concentration gradient-effect. Efficacy and toxicity were assessed for PGFM given immediately (within 1 h of reconstitution) vs. 4 h after reconstitution. Immediate- and delayed-administration of PGFM showed equivalent efficacy and toxicity. In addition, we evaluated efficacy and toxicity in patients (205 eyes) with retinoblastoma vitreous seeds, who were treated with a total of 833 intravitreal injections of either MH or PGFM as standard of care. Of these, we analyzed 118 MH and 131 PGFM monotherapy injections in whom serial ERG measurements were available to model retinal toxicity. Both MH and PGFM caused reductions in electroretinography amplitudes, but with no statistical difference between formulations. Comparing those patient eyes treated exclusively with PGFM versus those treated exclusively with MH, efficacy for tumor control and globe salvage was equivalent (PGFM vs. MH: 96.2% vs. 93.8%, p = 0.56), but PGFM-treated eyes received fewer injections than MH-treated eyes (average 3.2 ± 1.9 vs. 6.4 ± 2.1 injections, p < 0.0001). Taken together, these rabbit experiments and our clinical experience in retinoblastoma patients demonstrate that MH and PGFM have equivalent efficacy and toxicity. PGFM was more stable, with no decreased efficacy or increased toxicity even 4 h after reconstitution. We therefore now use PGFM over traditional MH for our patients for intravitreal treatment of retinoblastoma.
Topics: Animals; Antineoplastic Agents, Alkylating; Electroretinography; Female; Fluorescein Angiography; Humans; In Situ Nick-End Labeling; Infant; Intravitreal Injections; Male; Melphalan; Neoplasm Seeding; Pharmaceutical Preparations; Rabbits; Retina; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Tomography, Optical Coherence; Treatment Outcome; Tumor Cells, Cultured; Vitreous Body; Xenograft Model Antitumor Assays
PubMed: 33444583
DOI: 10.1016/j.exer.2021.108439 -
Clinical Lymphoma, Myeloma & Leukemia Nov 2021In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved...
Daratumumab Plus Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma: Frailty Subgroup Analysis of ALCYONE.
BACKGROUND
In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status.
PATIENTS AND METHODS
Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (≥2); a nonfrail category combined fit and intermediate patients.
RESULTS
Among randomized patients (D-VMP, n = 350; VMP, n = 356), 391 (55.4%) were nonfrail (D-VMP, 187 [53.4%]; VMP, 204 [57.3%]) and 315 (44.6%) were frail (163 [46.6%]; 152 [42.7%]). After 40.1-months median follow-up, nonfrail patients had longer PFS and OS than frail patients, but benefits of D-VMP versus VMP were maintained across subgroups: PFS nonfrail (median, 45.7 vs. 19.1 months; hazard ratio [HR], 0.36; P < .0001), frail (32.9 vs. 19.5 months; HR, 0.51; P < .0001); OS nonfrail (36-month rate, 83.6% vs. 74.5%), frail (71.4% vs. 59.0%). Improved greater than or equal to complete response and minimal residual disease (10)-negativity rates were observed for D-VMP versus VMP across subgroups. The 2 most common grade 3/4 treatment-emergent adverse events were neutropenia (nonfrail: 39.2% [D-VMP] and 42.4% [VMP]; frail: 41.3% and 34.4%) and thrombocytopenia (nonfrail: 32.8% and 36.9%; frail: 36.9% and 39.1%).
CONCLUSION
Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status.
Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Female; Humans; Male; Melphalan; Multiple Myeloma; Prednisone
PubMed: 34344638
DOI: 10.1016/j.clml.2021.06.005 -
Transplantation and Cellular Therapy Aug 2022High-dose melphalan is one of the main cytotoxic DNA alkylating agents and is used in many transplantation conditioning regimens. Studies have shown a wide range of drug...
High-dose melphalan is one of the main cytotoxic DNA alkylating agents and is used in many transplantation conditioning regimens. Studies have shown a wide range of drug exposure when a traditional weight-based dose of melphalan is used. The optimal melphalan dose in BEAM (carmustine, etoposide, cytarabine, and melphalan), which results in maximum efficacy with acceptable toxicity, is unknown. In this pharmacokinetic (PK) analysis of 105 patients with lymphoma undergoing treatment with BEAM and autologous hematopoietic cell transplantation, we initially estimated melphalan exposure as area under the curve (AUC) by a noncompartmental analysis and subsequently compared it with a newly developed 2-compartment population-PK model. The 2 models correlated closely with each other. We found that the traditional fixed weight-based dosing of propylene glycol-free (captisol-enabled) melphalan in BEAM results in a wide variation in exposure as estimated by both models. Higher melphalan exposure was significantly associated with increased metabolic toxicities but did not seem to impact progression-free survival. Although our study suggests a melphalan AUC of 8 mg·h/L as a potential target in BEAM, larger prospective studies using personalized PK-directed melphalan dosing are needed to determine the optimal melphalan exposure in lymphomas.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Melphalan; Prospective Studies; Transplantation, Autologous
PubMed: 35545213
DOI: 10.1016/j.jtct.2022.05.003 -
Drug Design, Development and Therapy 2021Despite recent therapeutic advances, multiple myeloma (MM) patients experience relapses as they become resistant to various classes and combinations of treatment.... (Review)
Review
Despite recent therapeutic advances, multiple myeloma (MM) patients experience relapses as they become resistant to various classes and combinations of treatment. Melphalan (L-PAM) is an ageless drug. However, its use in the autologous stem cell transplantation (ASCT) setting and the innovative quadruplet regimen as well as daratumumab, bortezomib, and prednisone make this old drug current yet. Melflufen is a peptide-conjugated alkylator belonging to a novel class of compounds, representing an overcoming of L-PAM in terms of mechanism of action and effectiveness. The improved melflufen cytotoxicity is related to aminopeptidase activity, notably present in normal and neoplastic cells and remarkably heavily overexpressed in MM cells. Upon entering a cell, melflufen is cleaved by aminopeptidases, ultimately releasing the L-PAM payload and eliciting further the inflow and cleavage of the conjugated peptide. This virtuous loop persists until all extracellular melflufen has been utilized. The aminopeptidase-driven accumulation results in a 50-fold increase in L-PAM cell enrichment as compared with free alkylator. This condition produces selective cytotoxicity, increased on-target cell potency, and decreased off-target cell toxicity, ultimately overcoming resistance pathways triggered by previous treatments, including alkylators. Due to its distinct mechanism of action, melflufen plus dexamethasone as a doublet, and in combination with other novel drugs, has the potential to be beneficial for a broad range of patients with relapsed/refractory (RR) MM in third- or even in second-line therapy. The safety profile of melflufen has been consistent across studies, and no new safety concerns have been identified when melflufen was administered in doublet and triplet combinations. Based on growing clinical evidence, melflufen could be not only a good addition in the fight against RRMM but also a drug with a very favorable tolerability profile.
Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Humans; Melphalan; Multiple Myeloma; Phenylalanine
PubMed: 34262262
DOI: 10.2147/DDDT.S295215