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Cancers Apr 2024FAM46C is a well-established tumour suppressor with a role that is not completely defined or universally accepted. Although FAM46C expression is down-modulated in... (Review)
Review
FAM46C is a well-established tumour suppressor with a role that is not completely defined or universally accepted. Although FAM46C expression is down-modulated in several tumours, significant mutations in the gene are only found in multiple myeloma (MM). Consequently, its tumour suppressor activity has primarily been studied in the MM context. However, emerging evidence suggests that FAM46C is involved also in other cancer types, namely colorectal, prostate and gastric cancer and squamous cell and hepatocellular carcinoma, where FAM46C expression was found to be significantly reduced in tumoural versus non-tumoural tissues and where FAM46C was shown to possess anti-proliferative properties. Accordingly, FAM46C was recently proposed to function as a pan-cancer prognostic marker, bringing FAM46C under the spotlight and attracting growing interest from the scientific community in the pathways modulated by FAM46C and in its mechanistic activity. Here, we will provide the first comprehensive review regarding FAM46C by covering (1) the intracellular pathways regulated by FAM46C, namely the MAPK/ERK, PI3K/AKT, β-catenin and TGF-β/SMAD pathways; (2) the models regarding its mode of action, specifically the poly(A) polymerase, intracellular trafficking modulator and inhibitor of centriole duplication models, focusing on connections and interdependencies; (3) the regulation of FAM46C expression in different environments by interferons, IL-4, TLR engagement or transcriptional modulators; and, lastly, (4) how FAM46C expression levels associate with increased/decreased tumour cell sensitivity to anticancer agents, such as bortezomib, dexamethasone, lenalidomide, pomalidomide, doxorubicin, melphalan, SK1-I, docetaxel and norcantharidin.
PubMed: 38730656
DOI: 10.3390/cancers16091706 -
Bone Marrow Transplantation May 2024
PubMed: 38724598
DOI: 10.1038/s41409-024-02301-7 -
Value in Health Regional Issues May 2024To present an overview of evidence of efficacy, safety, and health-related quality of life of lenalidomide or thalidomide for transplant-ineligible multiple myeloma.
OBJECTIVES
To present an overview of evidence of efficacy, safety, and health-related quality of life of lenalidomide or thalidomide for transplant-ineligible multiple myeloma.
METHODS
A literature search was performed in 5 databases until July 2022. We included systematic reviews with network meta-analyses of randomized controlled trials on the use of lenalidomide compared with thalidomide for transplant-ineligible multiple myeloma. The A Measurement Tool to Assess Systematic Reviews 2 was used to appraise the quality of included reviews. The results were focused on the lenalidomide + dexamethasone until disease progression (RDc) versus thalidomide + dexamethasone until disease progression (TDc) and induction with melphalan + prednisone + lenalidomide, followed by maintenance with lenalidomide (MPR-R) versus induction with melphalan + prednisone + thalidomide, followed by maintenance with thalidomide (MPT-T) regimens.
RESULTS
Nine studies were included. Only 1 study did not show any weakness in critical domains of A Measurement Tool to Assess Systematic Reviews 2. For overall survival, RDc proved to be superior to TDc; however, no study showed significant difference between MPR-R and MPT-T. For progression-free survival, 2 of 3 studies showed that RDc is better than TDc; however, no difference between MPR-R and MPT-T was found. Regarding safety, these lenalidomide-based regimens had a lower risk for neurologic adverse events, with an increased risk of hematologic adverse events. No health-related quality of life meta-analyses were found.
CONCLUSIONS
These findings suggest that, in terms of efficacy and safety, lenalidomide-based regimen is a good option for treatment of transplant-ineligible multiple myeloma in the public health system of Brazil, especially for those patients who develop severe neuropathy with thalidomide.
PubMed: 38718736
DOI: 10.1016/j.vhri.2024.100998 -
Transplantation and Cellular Therapy May 2024Outcomes for adults with relapsed/refractory (R/R) high-grade myeloid neoplasms remain poor, with allogeneic hematopoietic cell transplantation (HCT) the sole therapy...
Outcomes for adults with relapsed/refractory (R/R) high-grade myeloid neoplasms remain poor, with allogeneic hematopoietic cell transplantation (HCT) the sole therapy likely to result in cure. We conducted the present study to determine the feasibility of early HCT-within 60 days of beginning reinduction chemotherapy-to see whether getting patients to HCT in an expeditious manner would expand the number of patients being offered this curative option. In this proof-of-principle feasibility study, we included adults age 18 to 75 years with R/R myeloid malignancies with ≥10% blood/marrow blasts at diagnosis who were eligible for a reduced-intensity HCT. Subjects received reinduction chemotherapy with cladribine, cytarabine, mitoxantrone, and filgrastim (CLAG-M) and proceeded to HCT with reduced-intensity conditioning (fludarabine/ melphalan). We enrolled 30 subjects, all of whom received CLAG-M reinduction, although only 9 underwent HCT within 60 days (<15, the predetermined threshold for feasibility "success"), with a median time to HCT of 48 days (range, 42 to 60 days). Eleven additional subjects received HCT beyond the target 60 days (off-study), with a median time to transplantation of 83 days (range, 53 to 367 days). Barriers to early HCT included infection, physician preference, lack of an HLA-matched donor, logistical delays, and disease progression, all of which may limit the real-world uptake of such early-to-transplantation protocols.
PubMed: 38710302
DOI: 10.1016/j.jtct.2024.05.002 -
Acta Haematologica May 2024High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) has become part of standard of care (SOC) in newly diagnosed multiple myeloma. In this... (Review)
Review
BACKGROUND
High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) has become part of standard of care (SOC) in newly diagnosed multiple myeloma. In this review, we provide a historical perspective on ASCT since its introduction in the 1990s.
SUMMARY
Overall survival (OS) benefit for HDT followed by ASCT was demonstrated in studies comparing HDT with ASCT to standard-dose therapy (SDT) before the era of novel agents. Conditioning is done with melphalan 200 mg/m2. Lower doses (MEL140, MEL150) for older patients with comorbidities are safe and have comparable results. The addition of busulfan to melphalan improves progression-free survival (PFS) but not OS. HDT with ASCT after induction with novel agents prolongs PFS but not OS compared to SDT alone. The benefit is more evident in patients with high-risk cytogenetics. Mobilization can be achieved with granulocyte colony-stimulating factor alone, but is improved with the addition of chemotherapy. Plerixafor reduces mobilization failure and enables sufficient stem cell collection after induction with novel agents. ASCT is safe with a low rate of mortality (1%), and selected patients can be managed as outpatients.
KEY MESSAGES
HDT followed by ASCT remains part of SOC due to its PFS benefit and relatively low toxicity.
PubMed: 38710160
DOI: 10.1159/000539225 -
Spectrochimica Acta. Part A, Molecular... Sep 2024SERS (Surface Enhanced Raman Spectroscopy) is a new Raman spectroscopy which relies on Surface Plasmon Resonance (SPR) of metal nanoparticles. We have applied colloidal...
SERS (Surface Enhanced Raman Spectroscopy) is a new Raman spectroscopy which relies on Surface Plasmon Resonance (SPR) of metal nanoparticles. We have applied colloidal silver and gold nanoparticles as amplifier agents to enhance nucleotide Raman signals. It is observed that without these enhancing agents, it is impossible to investigate nucleotide spectrum due to weak Raman signals. Interaction mechanism of Melphalan, an anticancer drug with four nucleotides (Adenine, Cytosine, Guanine, Thymine) was investigated using SERS to detect and identify changes due to alkylating process in Raman spectra. After incubating Melphalan drug with nucleotides for 24 h at 37 °C, some changes occurred in SERS spectrum and interpretation of SERS spectra revealed the influence of the alkyl substitution on peaks and Raman shifts. After incubation of Melphalan with each nucleotide, intensity of relevant SERS signals assigned to Amid III group of Cytosine and Amid I of Thymine decreased significantly, confirming alkylating taking place. In this study, we also investigated the effect of nanoparticles type on nucleotide spectrum. We could not obtain useful information in the cases of guanine nucleotide. The SERS spectrum of Cytosine as an example of nucleotides in aqueous solution compared to solid state and results demonstrated that in solid state better signals were obtained than in liquid state.
Topics: Spectrum Analysis, Raman; Melphalan; Nucleotides; Metal Nanoparticles; Gold; Alkylating Agents; Silver
PubMed: 38704996
DOI: 10.1016/j.saa.2024.124359 -
Annals of Surgical Oncology May 2024Uveal melanoma (UM) has a poor prognosis once liver metastases occur. The melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/device combination used for...
Efficacy and Safety of the Melphalan/Hepatic Delivery System in Patients with Unresectable Metastatic Uveal Melanoma: Results from an Open-Label, Single-Arm, Multicenter Phase 3 Study.
BACKGROUND
Uveal melanoma (UM) has a poor prognosis once liver metastases occur. The melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/device combination used for liver-directed treatment of metastatic UM (mUM) patients. The purpose of the FOCUS study was to assess the efficacy and safety of melphalan/HDS in patients with unresectable mUM.
METHODS
Eligible patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of six cycles. The primary end point was the objective response rate (ORR). The secondary end points included duration of response (DOR), overall survival (OS), and progression-free survival (PFS).
RESULTS
The study enrolled 102 patients with mUM. Treatment was attempted in 95 patients, and 91 patients received treatment. In the treated population (n = 91), the ORR was 36.3 % (95 % confidence interval [CI], 26.44-47.01), including 7.7 % of patients with a complete response. Thus, the study met its primary end point because the lower bound of the 95 % CI for ORR exceeded the upper bound (8.3 %) from the benchmark meta-analysis. The median DOR was 14 months, and the median OS was 20.5 months, with an OS of 80 % at 1 year. The median PFS was 9 months, with a PFS of 65 % at 6 months. The most common serious treatment-emergent adverse events were thrombocytopenia (15.8 %) and neutropenia (10.5 %), treated mostly on an outpatient basis with observation. No treatment-related deaths were observed.
CONCLUSION
Treatment with melphalan/HDS provides a clinically meaningful response rate and demonstrates a favorable benefit-risk profile in patients with unresectable mUM (study funded by Delcath; ClinicalTrials.gov identifier: NCT02678572; EudraCT no. 2015-000417-44).
PubMed: 38704501
DOI: 10.1245/s10434-024-15293-x -
JAMA Oncology May 2024Persistence of FLT3 internal tandem duplication (ITD) in adults with acute myeloid leukemia (AML) in first complete remission (CR) prior to allogeneic hematopoietic cell...
IMPORTANCE
Persistence of FLT3 internal tandem duplication (ITD) in adults with acute myeloid leukemia (AML) in first complete remission (CR) prior to allogeneic hematopoietic cell transplant (HCT) is associated with increased relapse and death after transplant, but the association between the level of measurable residual disease (MRD) detected and clinical outcome is unknown.
OBJECTIVE
To examine the association between pre-allogeneic HCT MRD level with relapse and death posttransplant in adults with AML in first CR.
DESIGN, SETTING, AND PARTICIPANTS
In this cohort study, DNA sequencing was performed on first CR blood from patients with FLT3-ITD AML transplanted from March 2013 to February 2019. Clinical follow-up was through May 2022. Data were analyzed from October 2022 to December 2023.
EXPOSURE
Centralized DNA sequencing for FLT3-ITD in pre-allogeneic HCT first CR blood using a commercially available kit.
MAIN OUTCOMES AND MEASURES
The primary outcomes were overall survival and cumulative incidence of relapse, with non-relapse-associated mortality as a competing risk post-allogeneic HCT. Kaplan-Meier estimations (log-rank tests), Cox proportional hazards models, and Fine-Gray models were used to estimate the end points.
RESULTS
Of 537 included patients with FLT3-ITD AML from the Pre-MEASURE study, 296 (55.1%) were female, and the median (IQR) age was 55.6 (42.9-64.1) years. Using the variant allele fraction (VAF) threshold of 0.01% or greater for MRD positivity, the results closely aligned with those previously reported. With no VAF threshold applied (VAF greater than 0%), 263 FLT3-ITD variants (median [range] VAF, 0.005% [0.0002%-44%]), and 177 patients (33.0%) with positive findings were identified. Multivariable analyses showed that residual FLT3-ITD was the variable most associated with relapse and overall survival, with a dose-dependent correlation. Patients receiving reduced-intensity conditioning without melphalan or nonmyeloablative conditioning had increased risk of relapse and death at any given level of MRD compared with those receiving reduced-intensity conditioning with melphalan or myeloablative conditioning.
CONCLUSIONS AND RELEVANCE
This study provides generalizable and clinically applicable evidence that the detection of residual FLT3-ITD in the blood of adults in first CR from AML prior to allogeneic HCT is associated with an increased risk of relapse and death, particularly for those with a VAF of 0.01% or greater. While transplant conditioning intensification, an intervention not available to all, may help mitigate some of this risk, alternative approaches will be necessary for this high-risk population of patients who are underserved by the current standard of care.
PubMed: 38696205
DOI: 10.1001/jamaoncol.2024.0985 -
Transplant Infectious Disease : An... May 2024This case involves a 53-year-old female with concurrent acute myeloid leukemia (AML) and multiple myeloma. She underwent cytarabine and daunorubicin (7+3) induction...
This case involves a 53-year-old female with concurrent acute myeloid leukemia (AML) and multiple myeloma. She underwent cytarabine and daunorubicin (7+3) induction chemotherapy followed by cytarabine (HiDAC) consolidation, with an early AML relapse requiring azacitidine and venetoclax therapy. She achieved complete remission and incomplete count recovery. Following fludarabine, melphalan, and thymoglobulin induction chemotherapy, she underwent an allogeneic stem cell transplant with failure to engraft, requiring autologous stem cell rescue, buffy coat, and granulocyte transfusions, eventually presenting with a diffuse skin rash consistent with Steven-Johnson syndrome and toxic epidermal necrolysis, persistent neutropenic fevers and positive blood cultures.
PubMed: 38695847
DOI: 10.1111/tid.14273 -
The Cochrane Database of Systematic... May 2024Multiple myeloma (MM) is a haematological malignancy that is characterised by proliferation of malignant plasma cells in the bone marrow. For adults ineligible to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Multiple myeloma (MM) is a haematological malignancy that is characterised by proliferation of malignant plasma cells in the bone marrow. For adults ineligible to receive high-dose chemotherapy and autologous stem cell transplant, the recommended treatment combinations in first-line therapy generally consist of combinations of alkylating agents, immunomodulatory drugs, and proteasome inhibitors. Daratumumab is a CD38-targeting, human IgG1k monoclonal antibody recently developed and approved for the treatment of people diagnosed with MM. Multiple myeloma cells uniformly over-express CD-38, a 46-kDa type II transmembrane glycoprotein, making myeloma cells a specific target for daratumumab.
OBJECTIVES
To determine the benefits and harms of daratumumab in addition to antineoplastic therapy compared to antineoplastic therapy only for adults with newly diagnosed MM who are ineligible for transplant.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, EU Clinical Trials Register, ClinicalTrials.gov, WHO ICTRP, and conference proceedings from 2010 to September 2023.
SELECTION CRITERIA
We included randomised controlled trials that compared treatment with daratumumab added to antineoplastic therapy versus the same antineoplastic therapy alone in adult participants with a confirmed diagnosis of MM. We excluded quasi-randomised trials and trials with less than 80% adult participants, unless there were subgroup analyses of adults with MM.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the results of the search strategies for eligibility. We documented the process of study selection in a flowchart as recommended by the PRISMA statement. We evaluated the risk of bias in included studies with RoB 1 and assessed the certainty of the evidence using GRADE. We followed standard Cochrane methodological procedures.
MAIN RESULTS
We included four open-label, two-armed randomised controlled trials (34 publications) involving a total of 1783 participants. The ALCYONE, MAIA, and OCTANS trials were multicentre trials conducted worldwide in middle- and high-income countries. The AMaRC 03-16 trial was conducted in one high-income country, Australia. The mean age of participants was 69 to 74 years, and the proportion of female participants was between 40% and 54%. All trials evaluated antineoplastic therapies with or without daratumumab. In the ALCYONE and OCTANS trials, daratumumab was combined with bortezomib and melphalan-prednisone. In the AMaRC 03-16 study, it was combined with bortezomib, cyclophosphamide, and dexamethasone, and in the MAIA study, it was combined with lenalidomide and dexamethasone. None of the included studies was blinded (high risk of performance and detection bias). One study was published as abstract only, therefore the risk of bias for most criteria was unclear. The other three studies were published as full texts. Apart from blinding, the risk of bias was low for these studies. Overall survival Treatment with daratumumab probably increases overall survival when compared to the same treatment without daratumumab (hazard ratio (HR) 0.64, 95% confidence interval (CI) 0.53 to 0.76, 2 studies, 1443 participants, moderate-certainty evidence). After a follow-up period of 36 months, 695 per 1000 participants survived in the control group, whereas 792 per 1000 participants survived in the daratumumab group (95% CI 758 to 825). Progression-free survival Treatment with daratumumab probably increases progression-free survival when compared to treatment without daratumumab (HR 0.48, 95% CI 0.39 to 0.58, 3 studies, 1663 participants, moderate-certainty evidence). After a follow-up period of 24 months, progression-free survival was reached in 494 per 1000 participants in the control group versus 713 per 1000 participants in the daratumumab group (95% CI 664 to 760). Quality of life Treatment with daratumumab may result in a very small increase in quality of life after 12 months, evaluated on the EORTC QLQ-C30 global health status scale (GHS), when compared to treatment without daratumumab (mean difference 2.19, 95% CI -0.13 to 4.51, 3 studies, 1096 participants, low-certainty evidence). The scale is from 0 to 100, with a higher value indicating a better quality of life. On-study mortality Treatment with daratumumab probably decreases on-study mortality when compared to treatment without daratumumab (risk ratio (RR) 0.72, 95% CI 0.62 to 0.83, 3 studies, 1644 participants, moderate-certainty evidence). After the longest follow-up available (12 to 72 months), 366 per 1000 participants in the control group and 264 per 1000 participants in the daratumumab group died (95% CI 227 to 304). Serious adverse events Treatment with daratumumab probably increases serious adverse events when compared to treatment without daratumumab (RR 1.18, 95% CI 1.02 to 1.37, 3 studies, 1644 participants, moderate-certainty evidence). After the longest follow-up available (12 to 72 months), 505 per 1000 participants in the control group versus 596 per 1000 participants in the daratumumab group experienced serious adverse events (95% CI 515 to 692). Adverse events (Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3) Treatment with daratumumab probably results in little to no difference in adverse events (CTCAE grade ≥ 3) when compared to treatment without daratumumab (RR 1.01, 95% CI 0.99 to 1.02, 3 studies, 1644 participants, moderate-certainty evidence). After the longest follow-up available (12 to 72 months), 953 per 1000 participants in the control group versus 963 per 1000 participants in the daratumumab group experienced adverse events (CTCAE grade ≥ 3) (95% CI 943 to 972). Treatment with daratumumab probably increases the risk of infections (CTCAE grade ≥ 3) when compared to treatment without daratumumab (RR 1.52, 95% CI 1.30 to 1.78, 3 studies, 1644 participants, moderate-certainty evidence). After the longest follow-up available (12 to 72 months), 224 per 1000 participants in the control group versus 340 per 1000 participants in the daratumumab group experienced infections (CTCAE grade ≥ 3) (95% CI 291 to 399).
AUTHORS' CONCLUSIONS
Overall analysis of four studies showed a potential benefit for daratumumab in terms of overall survival and progression-free survival and a slight potential benefit in quality of life. Participants treated with daratumumab probably experience increased serious adverse events. There were likely no differences between groups in adverse events (CTCAE grade ≥ 3); however, there are probably more infections (CTCAE grade ≥ 3) in participants treated with daratumumab. We identified six ongoing studies which might strengthen the certainty of evidence in a future update of this review.
Topics: Adult; Aged; Female; Humans; Middle Aged; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bias; Bortezomib; Multiple Myeloma; Progression-Free Survival; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 38695605
DOI: 10.1002/14651858.CD013595.pub2