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Measurement of overall survival (OS) remains the gold standard for interpreting the impact of new therapies for multiple myeloma in phase 3 trials. However, as outcomes have improved, it is increasingly challenging to use OS as the primary endpoint if timely approval of novel agents is to be ensured to enable maximum benefit for patients. Surrogate endpoints of OS, such as progression-free survival (PFS) and response to treatment, have contributed to approval decisions by the Food and Drug Administration (FDA) and European Medicines Agency as endpoints demonstrating clinical benefit, and the FDA has recently supported the use of minimal residual disease (MRD) as an accelerated approval endpoint in multiple myeloma. This review aims to address situations in which the use of PFS as a surrogate endpoint warrants careful interpretation especially for specific subgroups of patients and considers ways to ensure that studies can be designed to account for possible discordance between PFS and OS. The utility of subgroup analyses, including the potential for those not pre-specified, to identify target populations for new agents is also discussed.
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Mieloma Múltiplo , Intervalo Livre de Progressão , Humanos , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Mieloma Múltiplo/tratamento farmacológico , Ensaios Clínicos como Assunto , Neoplasia Residual , BiomarcadoresRESUMO
Photoelectrochemical (PEC) technology is a promising approach for converting solar energy into chemical energy, offering significant potential for renewable energy applications. In this work, the CuO thin film was fabricated with different pH value in between 8.5 ± 0.1 and 10.5 ± 0.1 via Successive Ionic Layer Adsorption and Reaction (SILAR) method. The Effect of pH on thickness, structural, morphological, elemental composition and optical properties were investigated by using stylus profilometry, XRD, SEM, TEM, EDX, UV-vis and PL. The XRD results showed that as the pH increased, the crystallite size increased from 19.24 nm to 25.62 nm, with a monoclinic phase along the (111) direction. The CuO film deposited at pH value 10.5 ± 0.1 exhibit well defined identical particle with its size in the range between 200 and 300 nm was confirmed by SEM and TEM analysis. As the pH increased from 8.5 ± 0.1 to 10.5 ± 0.1, the CuO film bandgap (Eg) value reduced from 1.52 eV to 1.42 eV with indirect transition. The CuO photocathode deposited at pH 10.5 ± 0.1 shows maximum photocurrent density of 1.45 mA/cm2 at -0.1 V vs. RHE in 0.5 M Na2SO4 solution. Furthermore, the Electrochemical Impedance Spectroscopy (EIS) analysis shows, the CuO (pH 10.5 ± 0.1) electrode have higher conductivity value of 0.6862 S/cm compared CuO at pH 8.5 ± 0.1 (0.2779 S/cm) and CuO at pH 9.5 ± 0.1 (0.4646 S/cm) electrodes.
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Three classes of BCMA-directed therapy (BDT) exist: antibody drug-conjugates (ADCs), CAR-T, and T-cell engagers (TCEs), each with distinct strengths and weaknesses. To aid clinicians in selecting between BDTs, we reviewed myeloma patients treated at Mayo Clinic with commercial or investigational BDT between 2018-2023. We identified 339 individuals (1-exposure = 297, 2-exposures = 38, 3-exposures = 4) who received 385 BDTs (ADC = 59, TCE = 134, CAR-T = 192), with median follow-up of 21-months. ADC recipients were older, with more lines of therapy (LOT), and penta-refractory disease. Compared to ADCs, CAR-T (aHR = 0.29, 95%CI = 0.20-0.43) and TCEs (aHR = 0.62, 95%CI = 0.43-0.91) had better progression-free survival (PFS) on analysis adjusted for age, the presence of extramedullary (EMD), penta-refractory disease, multi-hit high-risk cytogenetics, prior BDT, and the number of LOT in the preceding 1-year. Likewise, compared to ADCs, CAR-T (aHR = 0.28, 95%CI = 0.18-0.44) and TCEs (aHR = 0.60, 95%CI = 0.39-0.93) had superior overall survival. Prior BDT exposure negatively impacted all classes but was most striking in CAR-T, ORR 86% vs. 50% and median PFS 13-months vs. 3-months. Of relapses, 54% were extramedullary in nature, and a quarter of these cases had no history of EMD. CAR-T demonstrates superior efficacy and where feasible, should be the initial BDT. However, for patients with prior BDT or rapidly progressive disease, an alternative approach may be preferable.
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Antígeno de Maturação de Linfócitos B , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/terapia , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/tratamento farmacológico , Antígeno de Maturação de Linfócitos B/antagonistas & inibidores , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Imunoterapia Adotiva , Adulto , Imunoconjugados/uso terapêutico , Idoso de 80 Anos ou mais , Recidiva Local de Neoplasia/terapia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva , Estudos RetrospectivosRESUMO
DISEASE OVERVIEW: Multiple myeloma accounts for approximately 10% of hematologic malignancies. DIAGNOSIS: The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE): CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) attributable to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L and urine monoclonal protein is ≥200 mg/24 h), or >1 focal lesion on magnetic resonance imaging. RISK STRATIFICATION: The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation is considered high-risk multiple myeloma. Presence of any two high risk factors is considered double-hit myeloma; three or more high risk factors is triple-hit myeloma. RISK-ADAPTED INITIAL THERAPY: In patients who are candidates for autologous stem cell transplantation, induction therapy consists of anti-CD38 monoclonal antibody plus bortezomib, lenalidomide, dexamethasone (VRd) followed by autologous stem cell transplantation (ASCT). Selected standard risk patients can delay transplant until first relapse. Frail patients who not candidates for transplant are treated with VRd for approximately 8-12 cycles followed by maintenance or alternatively with daratumumab, lenalidomide, dexamethasone (DRd) until progression. MAINTENANCE THERAPY: Standard risk patients need lenalidomide maintenance, while bortezomib plus lenalidomide maintenance is needed for high-risk myeloma. MANAGEMENT OF RELAPSED DISEASE: A triplet regimen is usually needed at relapse, with the choice of regimen varying with each successive relapse. Chimeric antigen receptor T (CAR-T) cell therapy and bispecific antibodies are additional options.
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Mieloma Múltiplo , Humanos , Mieloma Múltiplo/terapia , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Medição de Risco , Transplante Autólogo , Transplante de Células-Tronco Hematopoéticas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gerenciamento Clínico , Fatores de RiscoRESUMO
Smoldering multiple myeloma (SMM) is a precursor stage that precedes multiple myeloma (MM). SMM is heterogenous with nearly 40% of patients progressing to MM in the first 5 years. The high rate of progression of SMM patients highlights the need for early intervention, which underscores the importance of identifying SMM patients with the highest risk of progression. Several risk stratification models showed utility in identifying high-risk SMM patients; however, these systems showed limited sensitivity. To date, identifying high-risk SMM patients remains an important clinical need. In this study, we present the 3-dimensional telomere profiling as a structural biomarker capable of stratifying SMM patients as a function of genomic instability. Quantifying telomere dysfunction using the TeloView technology showed utility in risk stratification of cancer patients, particularly hematological malignancies. In this study, we analyzed 168 SMM patients. We report an AUC in ROC analysis of 0.8 using a subset of the patients as a training dataset. We then conducted a blind validation on a different cohort and demonstrated a positive predictive value of 85% and negative predictive value of 73%, with sensitivity and specificity of 83% and 76%, respectively. We examined the correlation between the TeloView prediction and the 20-2-20 scoring system, and cytogenetic abnormalities. We report a correlation of 53% with the 20-2-20 scores and over 60% correlation with cytogenetic abnormalities. The result of this study presents the telomere profiling as an effective biomarker able to stratify SMM patients to their respective risk groups with high sensitivity and specificity.
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Progressão da Doença , Mieloma Múltiplo Latente , Telômero , Humanos , Mieloma Múltiplo Latente/genética , Mieloma Múltiplo Latente/diagnóstico , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Mieloma Múltiplo/genética , Mieloma Múltiplo/diagnóstico , Valor Preditivo dos TestesRESUMO
PURPOSE: Patients with Waldenström macroglobulinemia (WM) have disparate outcomes. Newer therapies have emerged since the development of International Prognostic Scoring System, and MYD88L265P mutation is now frequently assessed at diagnosis, warranting reexamination of the prognostic parameters. PATIENTS AND METHODS: We reviewed records of 889 treatment-naïve patients with active WM, consecutively seen between January 01, 1996, and December 31, 2017, to identify clinical predictors of overall survival (OS) in univariate analyses. Patients with complete data for the parameters significant on the univariate analyses (n = 341) were included in a multivariable analysis to derive a prognostic model, subsequently validated in a multi-institutional cohort. RESULTS: In the derivation cohort (n = 341), age (hazard ratio [HR], 1.9 [95% CI, 1.2 to 2.1]; P = .0009), serum lactate dehydrogenase (LDH) above upper limit of normal (HR, 2.3 [95% CI, 1.3 to 4.5]; P = .007), and serum albumin <3.5 g/dL (HR, 1.5 [95% CI, 0.99 to 2.3]; P = .056) were independently prognostic. By assigning a score of 1 point each to albumin <3.5 g/dL (HR, 1.5) and age 66-75 years (HR 1.4) and 2 points for age >75 years (HR, 2.6) or elevated LDH (HR, 2.3), four groups with distinct outcomes were observed on the basis of the composite scores. Five-year OS was 93% for the low-risk (score 0), 82% for low-intermediate risk (score 1), 69% for intermediate-risk (score 2), and 55% for the high-risk (score ≥3; P < .0001) groups. In the validation cohort (N = 335), the model maintained its prognostic value, with a 5-year OS of 93%, 90%, 75%, and 57% for the four groups, respectively (P < .0001). CONCLUSION: Modified Staging System for WM (MSS-WM), utilizing age, albumin, and LDH is a simple, clinically useful, and externally validated prognostic model that reliably risk-stratifies patients with symptomatic WM into four groups with distinct prognosis.
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Macroglobulinemia de Waldenstrom , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/mortalidade , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Medição de Risco , Prognóstico , L-Lactato Desidrogenase/sangue , Estudos Retrospectivos , Idoso de 80 Anos ou maisRESUMO
INTRODUCTION: Tracking insulin-like growth factor-1 (IGF-1) level alongside the middle phalanx of the third finger (MP3) staging modification could provide valuable insights into the relationship between hormonal factors and skeletal maturation during different stages of growth. Longitudinal studies indeed play a crucial role in understanding these complex relationships over time, allowing for a more comprehensive assessment of how IGF-1 might serve as a marker for pubertal growth stages. METHODOLOGY: The present longitudinal prospective cohort study was done among 26 boys and 26 girls. For each child, once in every 6 months for 3 years, blood samples (to estimate IGF-1 level) and X-rays of the left hand middle finger were taken. DRG IGF-1 600 Human Enzyme-Linked Immunosorbent Assay kit was used for the quantitative measurement of IGF1 from serum. The MP3 stages of the middle phalanx of the middle finger were evaluated using a modified MP3 system. The collected data were subjected to suitable descriptive and inferential statistics. RESULTS: The mean IGF1 levels were significantly higher in girls compared to boys across all the stages of MP3 skeletal maturity indicators. However, in both boys and girls, IGF-1 levels showed increasing trends from Stage F to H where it peaked and showed deceleration to Stage I (P < 0.05). CONCLUSION: The observed increase in serum IGF-1 levels during pubertal stages, followed by a decline in late puberty, aligning with the stages of skeletal maturation, suggests a close relationship between hormonal changes and bone development.
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Fator de Crescimento Insulin-Like I , Criança , Feminino , Humanos , Masculino , Estudos Longitudinais , Estudos ProspectivosAssuntos
Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Ciclofosfamida , Dexametasona , Amiloidose de Cadeia Leve de Imunoglobulina , Humanos , Bortezomib/administração & dosagem , Bortezomib/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Ciclofosfamida/administração & dosagem , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Amiloidose de Cadeia Leve de Imunoglobulina/mortalidade , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Masculino , Feminino , Idoso , Falha de Tratamento , Pessoa de Meia-IdadeRESUMO
Tributyltin (TBT), an organotin endocrine-disrupting substance, is recognized as one of the important toxic environmental pollutants. The present study was carried out to investigate the toxic effects of TBT on behavior and the ovary of adult zebrafish with a focus on oxidative stress markers and oocyte maturation. Adult zebrafish were exposed to three different concentrations (125, 250, and 500â¯ng/L of water) of TBT for 28 days. TBT exposure produced a concentration-dependent negative effect on the body weight and behavior (anxiety-like symptoms) of adult zebrafish. Alterations in the activity of superoxide dismutase (SOD) and catalase (CAT), the total antioxidant capacity of ovarian tissue by the highest exposure level of TBT resulted in lipid peroxidation as indicated by increased malondialdehyde (MDA) level. The numbers of early-vitellogenic oocytes were significantly increased in zebrafish exposed to TBT as low as 125â¯ng/L. However, the numbers and size of fully-grown (mature) oocytes were significantly reduced in the highest exposure group only. Correlation between the MDA level and pre-vitellogenic oocytes in the 500â¯ng/L group indicated that lipid peroxidation prevented the maturation of pre-vitellogenic oocytes. TBT exposure produced significant histological changes in the ovary as evidenced by disturbed maturation of oocytes. In conclusion, TBT adversely affected the maturation of oocytes in zebrafish ovary through oxidative stress-mediated mechanisms.
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Comportamento Animal , Catalase , Peroxidação de Lipídeos , Malondialdeído , Oócitos , Ovário , Estresse Oxidativo , Superóxido Dismutase , Compostos de Trialquitina , Poluentes Químicos da Água , Peixe-Zebra , Animais , Compostos de Trialquitina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Feminino , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovário/patologia , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Superóxido Dismutase/metabolismo , Comportamento Animal/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Malondialdeído/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Catalase/metabolismo , Disruptores Endócrinos/toxicidadeRESUMO
Background: Arthroscopic knee procedures are one amongst the common surgical interventions for problems in the knee. It is technically more demanding than an open procedure and is associated with several potential complications. During arthroscopy procedures, several technical challenges may arise, and even experienced surgeons may encounter new issues. However, careful attention to the surgical technique can help prevent or resolve them. Methodology: The study was conducted on all patients who underwent knee arthroscopy procedure during study period. We recorded details of the implants used and any unexpected situations related to them, as well as how they were managed. Instrumentation-related parameters such as screwdriver issues, radiofrequency ablator issues, scope damages, shaver complications, probe complications, and meniscus suture passing devices were also assessed. Results: In total, there were 12 (3.73%) implant and instrument-related incidents and complications, of which 5 (1.55%) were implant-related and 7 (2.17%) were instrument related. Among the instrumentation-related incidents and complications, two (0.62%) were screwdriver breakage incidents, two (0.62%) were radiofrequency ablator-related incidents, one was arthroscopic probe (0.31%) related incident, one (0.31%) was meniscus suture passing device related complication and one (0.31%) was arthroscope related incident. Conclusion: Surgeons must be ready to anticipate and effectively manage any technical difficulties that may arise during the procedure, maintaining composure in the face of unexpected challenges and guiding the team. In most cases, incidents can be addressed intra operatively and may not have long-term effects on patient outcomes. It is crucial to have multiple implant and instrument backup options available for successful surgery.
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Induction regimens for multiple myeloma (MM) commonly include bortezomib, which has typically been administered twice weekly despite studies demonstrating comparable efficacy and less peripheral neuropathy (PN) with once-weekly bortezomib. We aimed to analyze the real-world prevalence and efficacy of once-weekly versus twice-weekly bortezomib regimens in newly diagnosed MM. We analyzed 2497 US patients aged 18-70 years treated with commercial first-line bortezomib using nationwide Flatiron Health electronic health record-derived data, including 910 (36.4%) patients who received twice-weekly and 1522 (63.2%) who received once-weekly bortezomib. Once-weekly bortezomib use increased over time, from 57.7% in 2017 to 73.1% in 2022. Multivariate analysis identified worsened performance status and more recent year of diagnosis with higher odds of receiving once-weekly bortezomib. Real-world progression-free survival (median 37.2 months with once-weekly versus 39.6 months with twice-weekly, p = 0.906) and overall survival (medians not reached in either cohort, p = 0.800) were comparable. PN rates were higher in patients receiving twice-weekly bortezomib (34.7% versus 18.5%, p < 0.001). In conclusion, once-weekly bortezomib is clearly associated with similar efficacy and fewer toxicities compared to twice-weekly bortezomib. Our findings support once-weekly bortezomib as a standard-of-care regimen for newly diagnosed patients with MM.
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Mieloma Múltiplo , Humanos , Bortezomib/efeitos adversos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/etiologia , Esquema de Medicação , Resultado do Tratamento , Intervalo Livre de Doença , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/uso terapêuticoRESUMO
Refractoriness to lenalidomide is an important factor determining the choice of therapy at first relapse in multiple myeloma (MM). It remains debatable if resistance to lenalidomide varies among MM refractory to standard doses vs low dose maintenance doses. In this study, we assessed the outcomes with subsequent therapies in patients with MM refractory to standard dose vs low dose lenalidomide. We retrospectively reviewed all patients with MM at our institution who received first line therapy with lenalidomide containing regimens, and assessed progression free survival (PFS) and overall survival for these patients for second line therapy, and with lenalidomide retreatment. For second line therapy, we found no difference in the PFS between standard dose refractory and low dose refractory groups (median PFS 14 months vs 14 months, p = 0.95), while the PFS for both these groups was inferior to the not refractory group (median PFS 30 months, p < 0.001 for both pairs). Similar trends were seen among these groups on lenalidomide retreatment, and on multivariable analysis. These data suggest that refractoriness to lenalidomide is not dose dependent, and definition of lenalidomide refractoriness should not depend on the dose of lenalidomide to which the disease was considered refractory.