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Journal of Korean Medical Science Jun 2024Multiple myeloma (MM) patients are at risk of skeletal-related events (SREs) like spinal cord compression, pathologic fractures, bone surgery, and radiation to bone....
BACKGROUND
Multiple myeloma (MM) patients are at risk of skeletal-related events (SREs) like spinal cord compression, pathologic fractures, bone surgery, and radiation to bone. Real-world data regarding SREs in MM are limited.
METHODS
We conducted a large, retrospective, nationwide cohort study using the Korean Health Insurance Review and Assessment Service (HIRA) database from 2007 to 2018.
RESULTS
Over a 12-year study period, we identified 6,717 patients who developed symptomatic MM. After a median follow-up of 35.1 months (interquartile range [IQR], 20.8-58.2 months), 43.6% of these patients experienced SREs, and 39.6% had four or more SREs. One in five patients (20.0%) experienced pathologic fractures within the first year of follow-up. The median time to first SRE was 9.6 months (IQR, 1.2-25.8 months), with 3.0 months in the group with prior SREs and 19.8 months in the group without prior SREs. During follow-up, 78.5% of patients received bisphosphonates. Multiple logistic regression analysis revealed several factors associated with an increased risk of SREs, including being female (odds ratio [OR], 1.44), aged 50 or older (OR, 1.87), having cerebrovascular disease (OR, 1.34), undergoing first-line chemotherapy regimens not containing bortezomib or lenalidomide (OR, 1.49), and being in the group with prior SREs and bisphosphonate use (OR, 5.63), compared to the group without prior SREs and without bisphosphonate use.
CONCLUSION
This population-based study is the first to report the incidence and risk factors of SREs in Korean MM patients, which can be used to assess their bone health.
Topics: Humans; Multiple Myeloma; Female; Male; Retrospective Studies; Middle Aged; Aged; Diphosphonates; Risk Factors; Databases, Factual; Republic of Korea; Bone Density Conservation Agents; Odds Ratio; Fractures, Spontaneous; Spinal Cord Compression; Adult; Logistic Models
PubMed: 38859738
DOI: 10.3346/jkms.2024.39.e175 -
Blood Reviews Jul 2024Patients with multiple myeloma (MM) were among the groups impacted more severely by the COVID-19 pandemic, with higher rates of severe disease and COVID-19-related... (Review)
Review
Endothelial injury and dysfunction with emerging immunotherapies in multiple myeloma, the impact of COVID-19, and endothelial protection with a focus on the evolving role of defibrotide.
Patients with multiple myeloma (MM) were among the groups impacted more severely by the COVID-19 pandemic, with higher rates of severe disease and COVID-19-related mortality. MM and COVID-19, plus post-acute sequelae of SARS-CoV-2 infection, are associated with endothelial dysfunction and injury, with overlapping inflammatory pathways and coagulopathies. Existing treatment options for MM, notably high-dose therapy with autologous stem cell transplantation and novel chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engaging antibodies, are also associated with endothelial cell injury and mechanism-related toxicities. These pathologies include cytokine release syndrome (CRS) and neurotoxicity that may be exacerbated by underlying endotheliopathies. In the context of these overlapping risks, prophylaxis and treatment approaches mitigating the inflammatory and pro-coagulant effects of endothelial injury are important considerations for patient management, including cytokine receptor antagonists, thromboprophylaxis with low-molecular-weight heparin and direct oral anticoagulants, and direct endothelial protection with defibrotide in the appropriate clinical settings.
Topics: Humans; Multiple Myeloma; COVID-19; Polydeoxyribonucleotides; SARS-CoV-2; Immunotherapy; Cytokine Release Syndrome; Endothelium, Vascular
PubMed: 38852017
DOI: 10.1016/j.blre.2024.101218 -
Biomedicine & Pharmacotherapy =... Jul 2024Multiple myeloma (MM) progression is closely dependent on cells in the bone marrow (BM) microenvironment, including fibroblasts (FBs) and immune cells. In their BM...
Multiple myeloma (MM) progression is closely dependent on cells in the bone marrow (BM) microenvironment, including fibroblasts (FBs) and immune cells. In their BM niche, MM cells adhere to FBs sustaining immune evasion, drug resistance and the undetectable endurance of tumor cells known as minimal residual disease (MRD). Here, we describe the novel bi-specific designed ankyrin repeat protein (DARPin) α-FAPx4-1BB (MP0310) with FAP-dependent 4-1BB agonistic activity. The α-FAPx4-1BB DARPin simultaneously binds to FAP and 4-1BB overexpressed by activated FBs and immune cells, respectively. Although flow cytometry analysis showed that T and NK cells from MM patients were not activated and did not express 4-1BB, stimulation with daratumumab or elotuzumab, monoclonal antibodies (mAbs) currently used for the treatment of MM, significantly upregulated 4-1BB both in vitro and in MM patients following mAb-based therapy. The mAb-induced 4-1BB overexpression allowed the engagement of α-FAPx4-1BB that acted as a bridge between FAPFBs and 4-1BBNK cells. Therefore, α-FAPx4-1BB enhanced both the adhesion of daratumumab-treated NK cells on FBs as well as their activation by improving release of CD107a and perforin, hence MM cell killing via antibody-mediated cell cytotoxicity (ADCC). Interestingly, α-FAPx4-1BB significantly potentiated daratumumab-mediated ADCC in the presence of FBs, suggesting that it may overcome the BM FBs' immunosuppressive effect. Overall, we speculate that treatment with α-FAPx4-1BB may represent a valuable strategy to improve mAb-induced NK cell activity fostering MRD negativity in MM patients through the eradication of latent MRD cells.
Topics: Killer Cells, Natural; Multiple Myeloma; Humans; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Cell Line, Tumor; Tumor Necrosis Factor Receptor Superfamily, Member 9; Membrane Proteins; Endopeptidases
PubMed: 38850654
DOI: 10.1016/j.biopha.2024.116877 -
Journal of Cancer Research and Clinical... Jun 2024Microvesicles are membraned particles produced by different types of cells recently investigated for anticancer purposes. The current study aimed to investigate the...
BACKGROUND
Microvesicles are membraned particles produced by different types of cells recently investigated for anticancer purposes. The current study aimed to investigate the effects of human bone marrow mesenchymal stem cell-derived microvesicles (BMSC-MVs) on the multiple myeloma cell line U266. BMSC-MVs were isolated from BMSCs via ultracentrifugation and characterized using transmission electron microscopy (TEM) and dynamic light scattering (DLS). U266 cells were treated with 15, 30, 60, and 120 µg/mL BMSC-MVs for three and seven days and the effects of treatment in terms of viability, cytotoxicity, and DNA damage were investigated via the MTT assay, lactate dehydrogenase (LDH) assay, and 8‑hydroxy-2'-deoxyguanosine (8‑OHdG) measurement, respectively. Moreover, the apoptosis rate of the U266 cells treated with 60 µg/mL BMSC-MVs was also assessed seven days following treatment via flow cytometry. Ultimately, the expression level of BCL2, BAX, and CCND1 by the U266 cells was examined seven days following treatment with 60 µg/mL BMSC-MVs using qRT-PCR.
RESULTS
BMSC-MVs had an average size of ~ 410 nm. According to the MTT and LDH assays, BMSC-MV treatment reduced the U266 cell viability and mediated cytotoxic effects against them, respectively. Moreover, elevated 8‑OHdG levels following BMSC-MV treatment demonstrated a dose-dependent increase of DNA damage in the treated cells. BMSC-MV-treated U266 cells also exhibited an increased apoptosis rate after seven days of treatment. The expression level of BCL2 and CCND1 decreased in the treated cells whereas the BAX expression demonstrated an incremental pattern.
CONCLUSIONS
Our findings accentuate the therapeutic benefit of BMSC-MVs against the multiple myeloma cell line U266 and demonstrate how microvesicles could be of therapeutic advantage. Future in vivo studies could further corroborate these findings.
Topics: Humans; Multiple Myeloma; Apoptosis; Mesenchymal Stem Cells; Cell Line, Tumor; Cell-Derived Microparticles; Cell Survival; DNA Damage
PubMed: 38850382
DOI: 10.1007/s00432-024-05822-2 -
Cancer Medicine Jun 2024Multiple myeloma (MM) is the leading indication of autologous hematopoietic stem cell transplantation. The aim of this study was to determine the incidence of...
OBJECTIVE
Multiple myeloma (MM) is the leading indication of autologous hematopoietic stem cell transplantation. The aim of this study was to determine the incidence of mobilization failure and characterize the risk factors associated with poor mobilization (PM) of MM patients in novel therapies era.
METHODS
We conducted a retrospective study of 211 MM patients who received their first peripheral blood stem cells (PBSC) mobilization at our single center. The following data were collected: age, gender, clinical stage, disease status, complete blood cell count, induction regimen, CD34 cell count in peripheral blood (PB), and PBSC collections.
RESULTS
In addition to conventional drugs, 22 (10.4%) patients received daratumumab containing induction, and 33 (15.6%) patients used plerixafor for poor mobilization (pre-apheresis PB CD34 cells <20/μL). Failure of collection occurred in 24 (11.4%) patients and was correlated with low white blood cell (WBC), ≥3 cycles of lenalidomide treatment before mobilization, steady-state mobilization and nouse of plerixafor are associated with mobilization failure. Daratumumab-based induction treatment ≥2 courses, albumin >41 g/L before mobilization, and steady-state mobilization were risk factors for PM in subgroups of patients treated with lenalidomide for <3 courses. In addition, Hepatitis B virus infection at baseline, thalassemia and measurable residual disease positivity were recognized as predictive factors for PM in subset of chemo-mobilization patients.
CONCLUSION
In addition to some well-recognized risk factors, baseline WBC count and daratumumab exposure ≥2 courses before mobilization were revealed as the predictive factors of mobilization failure, providing consultation for preemptive use of plerixafor.
Topics: Humans; Multiple Myeloma; Hematopoietic Stem Cell Mobilization; Female; Male; Middle Aged; Retrospective Studies; Aged; Adult; Cyclams; Benzylamines; Peripheral Blood Stem Cells; Risk Factors; Antibodies, Monoclonal; Lenalidomide; Heterocyclic Compounds; Peripheral Blood Stem Cell Transplantation; Transplantation, Autologous
PubMed: 38850125
DOI: 10.1002/cam4.7356 -
Diagnostic Pathology Jun 2024Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare plasma cell (PC) neoplasm with associated paraneoplastic syndrome.... (Review)
Review
BACKGROUND
Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare plasma cell (PC) neoplasm with associated paraneoplastic syndrome. According to the current diagnostic criteria, peripheral polyneuropathy and monoclonal PC proliferative disorder represent two mandatory criteria.
CASE PRESENTATION
We report a 54-year-old male with peripheral neuropathy of bilateral lower limbs, sclerotic bone lesions, elevated vascular endothelial growth factor (VEGF) levels, splenomegaly, extravascular volume overload, endocrinopathy, and skin hemangiomas. Of note, serum and urine protein electrophoresis (PEP) and immunofixation electrophoresis (IFE) of this patient indicated undetectable M-protein and the normal ratio of free light chains κ and λ (FLC-R (κ/λ)). No monoclonal PCs were found in bone marrow examinations or biopsy of diseased bones. However, his clinical manifestations matched most of the diagnostic criteria. After excluding other diseases that are easily confused with POEMS syndrome, the diagnosis of variant POEMS syndrome with undetectable M-protein was proposed. The patient obtained clinically significant improvement and elevated VEGF returned to normal after 6 months of treatment with lenalidomide plus dexamethasone.
CONCLUSIONS
Monoclonal PC dyscrasia (M-protein) while being a mandatory criterion for POEMS syndrome is undetectable in a considerable amount of patients that otherwise demonstrate typical symptoms. Here, we reported a case of variant POEMS syndrome with featured clinical manifestations, elevated VEGF levels, and good response to therapies targeting PCs but no evidence of M-protein. Therefore, negative results in M-protein and monoclonal PCs aren't enough to reject the diagnosis of POEMS syndrome. It is imperative to recognize the variant form of POEMS syndrome.
Topics: Humans; POEMS Syndrome; Male; Middle Aged; Lenalidomide; Thalidomide; Vascular Endothelial Growth Factor A; Dexamethasone; Treatment Outcome; Myeloma Proteins
PubMed: 38849857
DOI: 10.1186/s13000-024-01502-4 -
Journal of Translational Medicine Jun 2024Despite significant advancements in treatment strategies, multiple myeloma remains incurable. Additionally, there is a distinct lack of reliable biomarkers that can...
Progression of monoclonal gammopathy of undetermined significance to multiple myeloma is associated with enhanced translational quality control and overall loss of surface antigens.
BACKGROUND
Despite significant advancements in treatment strategies, multiple myeloma remains incurable. Additionally, there is a distinct lack of reliable biomarkers that can guide initial treatment decisions and help determine suitable replacement or adjuvant therapies when relapse ensues due to acquired drug resistance.
METHODS
To define specific proteins and pathways involved in the progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM), we have applied super-SILAC quantitative proteomic analysis to CD138 + plasma cells from 9 individuals with MGUS and 37 with MM.
RESULTS
Unsupervised hierarchical clustering defined three groups: MGUS, MM, and MM with an MGUS-like proteome profile (ML) that may represent a group that has recently transformed to MM. Statistical analysis identified 866 differentially expressed proteins between MM and MGUS, and 189 between MM and ML, 177 of which were common between MGUS and ML. Progression from MGUS to MM is accompanied by upregulated EIF2 signaling, DNA repair, and proteins involved in translational quality control, whereas integrin- and actin cytoskeletal signaling and cell surface markers are downregulated.
CONCLUSION
Compared to the premalignant plasma cells in MGUS, malignant MM cells apparently have mobilized several pathways that collectively contribute to ensure translational fidelity and to avoid proteotoxic stress, especially in the ER. The overall reduced expression of immunoglobulins and surface antigens contribute to this and may additionally mediate evasion from recognition by the immune apparatus. Our analyses identified a range of novel biomarkers with potential prognostic and therapeutic value, which will undergo further evaluation to determine their clinical significance.
Topics: Humans; Multiple Myeloma; Monoclonal Gammopathy of Undetermined Significance; Disease Progression; Proteomics; Male; Female; Protein Biosynthesis; Middle Aged; Aged; Cluster Analysis; Plasma Cells; Signal Transduction; Proteome; Quality Control
PubMed: 38849800
DOI: 10.1186/s12967-024-05345-x -
Blood Cancer Journal Jun 2024Additional copies of chromosome 1 long arm (1q) are frequently found in multiple myeloma (MM) and predict high-risk disease. Available data suggest a different outcome... (Randomized Controlled Trial)
Randomized Controlled Trial
Additional copies of chromosome 1 long arm (1q) are frequently found in multiple myeloma (MM) and predict high-risk disease. Available data suggest a different outcome and biology of patients with amplification (Amp1q, ≥4 copies of 1q) vs. gain (Gain1q, 3 copies of 1q) of 1q. We evaluated the impact of Amp1q/Gain1q on the outcome of newly diagnosed MM patients enrolled in the FORTE trial (NCT02203643). Among 400 patients with available 1q data, 52 (13%) had Amp1q and 129 (32%) Gain1q. After a median follow-up of 62 months, median progression-free survival (PFS) was 21.2 months in the Amp1q group, 54.9 months in Gain1q, and not reached (NR) in Normal 1q. PFS was significantly hampered by the presence of Amp1q (HR 3.34 vs. Normal 1q, P < 0.0001; HR 1.99 vs. Gain1q, P = 0.0008). Patients with Gain1q had also a significantly shorter PFS compared with Normal 1q (HR 1.68, P = 0.0031). Concomitant poor prognostic factors or the failure to achieve MRD negativity predicted a median PFS < 12 months in Amp1q patients. Carfilzomib-lenalidomide-dexamethasone plus autologous stem cell transplantation treatment improved the adverse effect of Gain1q but not Amp1q. Transcriptomic data showed that additional 1q copies were associated with deregulation in apoptosis signaling, p38 MAPK signaling, and Myc-related genes.
Topics: Humans; Multiple Myeloma; Female; Male; Middle Aged; Aged; Transcriptome; Chromosomes, Human, Pair 1; Plasma Cells; Adult; Gene Expression Regulation, Neoplastic; Prognosis; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38849344
DOI: 10.1038/s41408-024-01075-x -
Medicine Jun 2024Multiple myeloma (MM) was one of the hardest cancers to diagnose because of numerous nonspecific symptoms, leading to diagnostic delay. Proactive consultation of... (Observational Study)
Observational Study
Multiple myeloma (MM) was one of the hardest cancers to diagnose because of numerous nonspecific symptoms, leading to diagnostic delay. Proactive consultation of laboratory medicine (PCLM) could help timely diagnosis of blood cancers, avoiding diagnostic delay. This study aimed to evaluate the effect of PCLM on diagnosis and outcomes in MM. This retrospective study was conducted in newly diagnosed MM patients from 2011 to 2022. Implementation of PCLM initiated in 2015 with a laboratory-oriented algorithm. The annual diagnostic rate, patient demographics, the time intervals from symptom onset to diagnosis and to treatment, and clinical outcomes were analyzed. A total of 134 patients were newly diagnosed during the study interval. The diagnostic rate increased from 4.65 ± 1.59 to 7.43 ± 1.52 per million patient-visits after implementation of PCLM. The median time interval from symptom onset to diagnosis was significantly shortened after implementation of PCLM (50 days with interquartile range [IQR]: 24-136 days vs 150 days with IQR: 41-385 days, P = .003). Besides, the 1-year survival was significantly higher in patients diagnosed as MM after implementation of PCLM (72.4% vs 51.7%, P = .035). Implementation of PCLM not only increased diagnostic rate of MM and improved outcomes, but also raise awareness for MM and promote multidisciplinary collaboration in healthcare.
Topics: Humans; Multiple Myeloma; Male; Female; Retrospective Studies; Middle Aged; Referral and Consultation; Aged; Delayed Diagnosis; Adult; Algorithms
PubMed: 38847713
DOI: 10.1097/MD.0000000000038523 -
Indian Journal of Public Health Jan 2024Despite advancement in methods and application of economic evaluations (EEs), there are several uncertainties.
BACKGROUND
Despite advancement in methods and application of economic evaluations (EEs), there are several uncertainties.
OBJECTIVES
To assess the impact of alternate methodological and structural assumptions for four key principles of EE, on the results of cost-effectiveness analysis.
MATERIALS AND METHODS
Three previously published model-based EEs were used: (1) Integrated Management of Neonatal and Childhood Illnesses (IMNCIs) intervention; (2) intervention for multiple myeloma, and (3) safety-engineered syringes (SES) intervention. A series of empirical analyses was undertaken to assess the impact of alternate assumptions for discount-rate, time-horizon, study perspective, and health outcome measure, on incremental cost-effectiveness ratio (ICER), and interpretation of cost-effectiveness.
RESULTS
Increasing discount rate resulted in an increase in ICERs, for all three case-studies; however, there was no change in the conclusions. Using shorter time-horizons resulted in a significant increase in ICERs, the multiple myeloma intervention remained cost-ineffective, SES intervention became cost-ineffective, whereas IMNCI intervention remained cost-effective, despite a three-fold increase in ICER. On using disability adjusted life years instead of quality adjusted life years, ICERs increased to 0.04, 2 and 4 times for SES, IMNCI and multiple myeloma interventions, respectively. On analyzing results from a societal perspective, a decline in ICERs was observed. The decline was significant for IMNCI where the intervention turned dominant/cost-saving. In the other two case-studies decline in ICERs was modest, 32% for multiple myeloma, and 4% for SES.
CONCLUSION
We observed a significant impact of using alternate assumptions on ICERs which can potentially impact resource-allocation decisions. Our findings provide strong argument in favor of standardization of processes and development of country-specific guidelines for conduct of EE.
Topics: Cost-Benefit Analysis; Humans; India; Multiple Myeloma; Quality-Adjusted Life Years; Cost-Effectiveness Analysis
PubMed: 38847626
DOI: 10.4103/ijph.ijph_315_23