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The Lancet. Haematology Mar 2024Chimeric antigen receptor T-cell therapy idecabtagene vicleucel (ide-cel) showed significantly improved progression-free survival compared with standard regimens in... (Randomized Controlled Trial)
Randomized Controlled Trial
Health-related quality of life in patients with triple-class exposed relapsed and refractory multiple myeloma treated with idecabtagene vicleucel or standard regimens: patient-reported outcomes from the phase 3, randomised, open-label KarMMa-3 clinical trial.
BACKGROUND
Chimeric antigen receptor T-cell therapy idecabtagene vicleucel (ide-cel) showed significantly improved progression-free survival compared with standard regimens in adults with relapsed and refractory multiple myeloma who had received two to four previous regimens in the ongoing phase 3 KarMMa-3 trial (NCT03651128). This study analysed patient-reported outcomes (PROs), a KarMMa-3 secondary endpoint.
METHODS
In the randomised, open-label, phase 3 KarMMa-3 trial, 386 patients in hospitals (≥18 years of age, with measurable disease and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who had received two to four previous regimens-including an immunomodulatory agent, a proteasome inhibitor, and daratumumab-and had documented disease progression after receiving their last dose of the last therapy) were randomly assigned to ide-cel (n=254) or standard regimens (daratumumab, pomalidomide, and dexamethasone; daratumumab, bortezomib, and dexamethasone; ixazomib, lenalidomide, and dexamethasone; carfilzomib and dexamethasone; or elotuzumab, pomalidomide, and dexamethasone; n=132). Patients were expected to complete the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life C30 Questionnaire (QLQ-C30), Multiple Myeloma Module (QLQ-MY20), EQ 5 dimensions (EQ-5D), and EQ-5D visual analogue scale (VAS) at baseline and follow-up timepoints (data cutoff April 18, 2022). PROs included nine prespecified primary domains: EORTC QLQ-C30 GHS-quality of life (QoL), physical functioning, cognitive functioning, fatigue, and pain; QLQ-MY20 disease symptoms and side effects of treatment; and five-level EQ-5D (EQ-5D-5L) index score and EQ-5D visual VAS. Differences in overall least-squares mean changes from baseline to month 20 were analysed using post-hoc constrained longitudinal data analysis. Time to confirmed improvement or deterioration from baseline was analysed using Cox proportional hazard models.
FINDINGS
Patients were randomly assigned between May 6, 2019, and April 8, 2022. Overall, the median age was 63 years (IQR 55-68); 151 (39%) patients were female; and 250 (65%) patients were White, 36 (9%) Black or African American, 19 (5%) Hispanic or Latino, 12 (3%) Asian, and seven (2%) of other race. The median follow-up was 18·6 months (IQR 14·0-26·4). PRO compliance was higher than 75% throughout. Overall least-squares mean changes from baseline favoured ide-cel with Hedges' g effect sizes from 0·3 to 0·7 for most domains. Patients in the ide-cel group showed statistically significant and clinically meaningful improvements across the primary PRO domains of interest, with the exception of QLQ-MY20 disease symptoms, side effects of treatment, and EQ-5D-5L index score, which showed improvement across assessment visits but did not exceed the within-group minimally important difference thresholds. The ide-cel group had shorter times to clinically meaningful improvement than the standard regimens group in QLQ-C30 domains except in role functioning, diarrhoea, and financial difficulties; in QLQ-MY20 domains except body image; and in EQ-5D-VAS.
INTERPRETATION
Ide-cel offers improved health-related quality of life compared with standard regimens for patients with relapsed and refractory multiple myeloma after previous lines of therapy. The PRO data highlight the extended QoL benefits of a one-time infusion with ide-cel compared with continuous treatment with standard regimens in the treatment of triple-class exposed patients with relapsed and refractory multiple myeloma.
FUNDING
2seventy bio and Celgene, a Bristol Myers Squibb Company.
Topics: Female; Humans; Male; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Multiple Myeloma; Patient Reported Outcome Measures; Quality of Life; Receptors, Chimeric Antigen; Thalidomide; Aged
PubMed: 38423700
DOI: 10.1016/S2352-3026(24)00005-X -
Expert Review of Hematology 2024To evaluate the efficacy and safety of pomalidomide in combination treatment of relapsed/refractory multiple myeloma (RRMM). (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
To evaluate the efficacy and safety of pomalidomide in combination treatment of relapsed/refractory multiple myeloma (RRMM).
METHODS
Published clinical trials were searched in the Cochrane Library, PubMed, EMBASE to February 2023. The literature was screened and evaluated according to the inclusion criteria, and the data were analyzed by a random effect model. Overall response rate (ORR), overall survival (OS), progression-free survival (PFS) and full grade or ≥ 3 adverse events (AEs) were the outcomes.
RESULTS
This study included 31 clinical trials, which included 4776 patients. The pooled ORR of the doublet regimens was 33.3% (95%CI: 27-39%) and the triplet regimens was 66% (95%CI: 58-74%). Among the 25 included studies, the median PFS was 8.29 months (95%CI: 7.27-9.31), and nine studies reported median OS of 19.43 months (95%CI: 14.56-24.30). In terms of safety, the most common hematologic AEs of grade ≥ 3 were neutropenia (41%) and anemia (20%); Non-hematologic AEs were pneumonia (14%) and infection/febrile neutropenia (14%).
CONCLUSIONS
Pomalidomide combined treatment regimens have shown good clinical efficacy, especially in pomalidomide + dexamethasone combined with other drugs. In terms of safety, it's important to pay attention to the likelihood of hematological adverse events when used clinically.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO: CRD42023420644.
Topics: Multiple Myeloma; Humans; Thalidomide; Dexamethasone; Antineoplastic Combined Chemotherapy Protocols; Recurrence; Treatment Outcome
PubMed: 38421372
DOI: 10.1080/17474086.2024.2326219 -
Hematology Reports Aug 2023Relapsed/refractory extramedullary myeloma (RREMM) is an uncommon and aggressive subtype of multiple myeloma defined by plasma cell proliferation outside the bone...
Efficacy of Bendamustine, Pomalidomide, and Dexamethasone (BPD) Regimen in Relapsed/Refractory Extramedullary Myeloma: A Retrospective Single-Centre Study, Real-Life Experience.
BACKGROUND AND OBJECTIVES
Relapsed/refractory extramedullary myeloma (RREMM) is an uncommon and aggressive subtype of multiple myeloma defined by plasma cell proliferation outside the bone marrow. Therapeutic options for RREMM are limited, and the prognosis is generally unfavorable. This research aimed to assess the effectiveness of the bendamustine, pomalidomide, and dexamethasone (BPD) regimen in patients with RREMM.
MATERIAL AND METHODS
We carried out a retrospective investigation of 11 RREMM patients who underwent BPD treatment. The primary endpoint was progression-free survival. The secondary endpoints of the study were two-year survival and overall response rate (ORR). We analyzed the sociodemographic and clinical features of the patients.
RESULTS
The average age of the patients was 62 years. They had a median of four prior treatment lines, and eight patients had previously received autologous stem-cell transplantation. After eight BPD treatment cycles, the ORR stood at 54%, with one very good partial response (VGPR), five partial responses (PR), three progressive diseases (PD), and two stable diseases (SD). The median follow-up was 15 months, with a two-year PFS rate of 71.3% and a two-year survival rate of 81.8%.
CONCLUSIONS
The BPD regimen demonstrated promising effectiveness in RREMM patients, yielding favorable ORR and survival rates. To corroborate these findings and explore additional treatment alternatives for this patient group, larger prospective studies are required.
PubMed: 37606493
DOI: 10.3390/hematolrep15030048 -
Leukemia & Lymphoma Jun 2024Once-weekly carfilzomib at 56 mg/m plus immunomodulatory drugs and dexamethasone has shown efficacy and tolerability treating early relapsed/refractory multiple...
Once-weekly carfilzomib at 56 mg/m plus immunomodulatory drugs and dexamethasone has shown efficacy and tolerability treating early relapsed/refractory multiple myeloma (RRMM). The phase 2 SELECT study (NCT04191616) evaluated efficacy/safety of weekly carfilzomib, pomalidomide, and dexamethasone (KPd) in early RRMM patients refractory to lenalidomide. All 52 treated patients were refractory to prior treatment, and 19 (37%) were triple-class refractory. Overall response rate (ORR; primary endpoint) was 58% (35% ≥ very good partial response, 6% ≥ complete response); median response duration was 20.3 months. Minimal residual disease negativity (10) was achieved in 10% of patients. Median progression-free survival was 11.1 months; median overall survival was 18.8 months. Adverse events (AEs) were consistent with the known safety profile including grade ≥3 treatment-emergent AEs reported in 67% of patients. Although the primary endpoint of ORR was not met, KPd showed meaningful clinical benefits in lenalidomide-refractory RRMM patients, including those who were daratumumab-refractory and/or triple-class refractory.
Topics: Humans; Multiple Myeloma; Thalidomide; Oligopeptides; Dexamethasone; Male; Female; Aged; Antineoplastic Combined Chemotherapy Protocols; Middle Aged; Aged, 80 and over; Treatment Outcome; Neoplasm Recurrence, Local; Adult; Drug Resistance, Neoplasm; Recurrence
PubMed: 38497533
DOI: 10.1080/10428194.2024.2322030 -
Blood Jun 2024Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) affects 1 in 5,000 persons, making it the second most common inherited bleeding disorder...
Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) affects 1 in 5,000 persons, making it the second most common inherited bleeding disorder worldwide. Telangiectatic bleeding, primarily causing recurrent epistaxis and chronic gastrointestinal bleeding, is the most common and most important manifestation of this multisystem vascular disorder. HHT-associated bleeding results in substantial psychosocial morbidity and iron deficiency anemia that may be severe. Although there remain no regulatory agency-approved therapies for HHT, multiple large studies, including randomized controlled trials, have demonstrated the safety and efficacy of antifibrinolytics for mild-to-moderate bleeding manifestations and systemic antiangiogenic drugs including pomalidomide and bevacizumab for moderate-to-severe bleeding. This has led to a recent paradigm shift away from repetitive temporizing procedural management towards effective systemic medical therapeutics to treat bleeding in HHT. In this article, 4 patient cases are used to illustrate the most common and most challenging presentations of HHT-associated bleeding that hematologists are likely to encounter in daily practice. Built on a framework of published data and supported by extensive clinical experience, guidance is given for modern evidence-based approaches to antifibrinolytic therapy, antiangiogenic therapy, and iron deficiency anemia management across the HHT disease severity spectrum.
PubMed: 38864625
DOI: 10.1182/blood.2023021765 -
Chemical Communications (Cambridge,... Dec 2023Optimisation of protein degraders requires balancing multiple factors including potency, cell permeability and solubility. Here we show that the fluorescence of...
Optimisation of protein degraders requires balancing multiple factors including potency, cell permeability and solubility. Here we show that the fluorescence of pomalidomide can be used in high-throughput screening assays to rapidly assess cellular penetration of degrader candidates. In addition, this technique can be paired with endocytosis inhibitors to gain insight into potential mechanisms of candidates entering a target cell. A model library of pomalidomide conjugates was synthesised and evaluated using high-throughput fluorescence microscopy. This technique based on intrinsic fluorescence can be used to guide rational design of pomalidomide conjugates without the need for additional labels or tags.
Topics: Thalidomide; Microscopy, Fluorescence
PubMed: 38019727
DOI: 10.1039/d3cc04314b -
Cureus Feb 2024Lenalidomide and Pomalidomide are chiral immunomodulatory drugs (IMiDs) and have antiangiogenic and anti-immunomodulatory activity. Each enantiomer may have distinct...
Computational Analysis of Lenalidomide and Pomalidomide Enantiomers' Binding Interactions With Prostaglandin (PG)-Protein: Implications for Inflammatory Activity in Cancer.
BACKGROUND
Lenalidomide and Pomalidomide are chiral immunomodulatory drugs (IMiDs) and have antiangiogenic and anti-immunomodulatory activity. Each enantiomer may have distinct binding and biological activity. This study aimed to explore the in-silico binding of both enantiomers of Lenalidomide and Pomalidomide with Prostaglandin and its potential impact on persisting inflammatory activity in cancer. This can further provide insight into the transport of pro-inflammatory mediators and their potential implications for the inflammatory microenvironment within tumors.
MATERIALS AND METHODS
Molecular docking studies were performed to explore the binding potential of both enantiomers of Lenalidomide and Pomalidomide with Pg protein. The crystal structure of Pg-protein (PDB ID: 1IW7) was obtained from the Protein Data Bank.
RESULTS
The binding energies for (-)-Lenalidomide and (+)-Lenalidomide were -6.7 and -7.2 kcal/mol, respectively, while the binding energies for (-)-Pomalidomide and (+)-Pomalidomide were -7.8 and -8.1 kcal/mol, respectively. The binding mode analysis revealed that all four compounds formed hydrogen bonds with key amino acid residues of Pg-protein. The hydrogen bond distances for (-)-Lenalidomide, (+)-Lenalidomide, (-)-Pomalidomide, and (+)-Pomalidomide were 2.1 Å, 2.0 Å, 2.2 Å, and 2.1 Å, respectively.
CONCLUSIONS
The present study suggests that both enantiomers of Lenalidomide and Pomalidomide have a high affinity for Pg-protein and can effectively target the Pg-protein pathway to persist inflammatory activity in cancer. By targeting inflammation-mediated processes, these drugs may offer a novel strategy to combat tumor progression.
PubMed: 38558718
DOI: 10.7759/cureus.55294 -
ACS Omega Aug 2023High-performance thin-layer chromatographic (HPTLC) assays for pomalidomide (PMD) measurement are lacking in the published database. Furthermore, eco-friendly...
High-performance thin-layer chromatographic (HPTLC) assays for pomalidomide (PMD) measurement are lacking in the published database. Furthermore, eco-friendly stability-indicating analytical assays for PMD measurement are also lacking in the published database. In order to detect PMD in commercial products more accurately and sustainably than the conventional normal-phase HPTLC (NP-HPTLC) assay, an effort was made to design and verify a sensitive and eco-friendly reversed-phase HPTLC (RP-HPTLC) assay. The silica gel 60 NP-18F254S and 60 RP-18F254S plates were used as the stationary phases for NP-HPTLC and RP-HPTLC methods, respectively. The solvent system for NP-HPTLC was chloroform-methanol (90:10 v/v). However, the solvent system for RP-HPTLC was ethanol-water (75:25 v/v). The greenness scores for both assays were measured by AGREE approach. PMD measurement was performed for both assays at 372 nm. In the 50-600 and 20-1000 ng/band ranges, the NP-HPTLC and RP-HPTLC methods were linear for PMD measurement. The RP-HPTLC assay was superior to the NP-HPTLC method for measuring PMD in terms of sensitivity, accuracy, precision, and robustness. The ability of both methods to identify PMD in the presence of its degradation products suggests that both methods have stability-indicating features. When employing the NP-HPTLC and RP-HPTLC assays, respectively, the assay for PMD in commercial capsules was 88.68 and 98.83%. The AGREE scores for NP-HPTLC and RP-HPTLC assays were calculated to be 0.44 and 0.82, respectively, suggesting an outstanding greenness characteristic of the RP-HPTLC method than the NP-HPTLC method. The RP-HPTLC method was found to be superior to the NP-HPTLC method based on these findings. Therefore, the RP-HPTLC method could be successfully applied for the determination of PMD in pharmaceutical products.
PubMed: 37636909
DOI: 10.1021/acsomega.3c04382 -
Cancer Medicine May 2024Comparative investigations evaluating the efficacy of pomalidomide-based (Pom-based) versus daratumumab-based (Dara-based) therapies in patients with relapsed/refractory...
BACKGROUND
Comparative investigations evaluating the efficacy of pomalidomide-based (Pom-based) versus daratumumab-based (Dara-based) therapies in patients with relapsed/refractory multiple myeloma (RRMM) remain scarce, both in randomized controlled trials and real-world studies.
METHODS
This retrospective cohort study included 140 RRMM patients treated with Pom-based or Dara-based or a combination of pomalidomide and daratumumab (DPd) regimens in a Chinese tertiary hospital between December 2018 and July 2023.
RESULTS
The overall response rates (ORR) for Pom-based (n = 48), Dara-based (n = 68), and DPd (n = 24) groups were 57.8%, 84.6%, and 75.0%, respectively (p = 0.007). At data cutoff on August 1, 2023, the median progression-free survival (PFS) was 5.7 months (95% CI: 5.0-6.5) for the Pom-based group, 10.5 months (5.2-15.8) for the Dara-based group, and 6.7 months (4.0-9.3) for the DPd group (p = 0.056). Multivariate analysis identified treatment regimens (Dara-based vs. Pom-based, DPd vs. Pom-based) and Eastern Cooperative Oncology Group performance status (ECOG PS) as independent prognostic factors for PFS. In the subgroups of patients aged >65 years, with ECOG PS ≥2, lines of therapy ≥2, extramedullary disease or double-refractory disease (refractory to both lenalidomide and proteasome inhibitors), the superiority of Dara-based regimens over Pom-based regimens was not evident. A higher incidence of infections was observed in patients receiving Dara-based and DPd regimens (Pom-based 39.6% vs. Dara-based 64.7% vs. DPd 70.8%, p = 0.009).
CONCLUSIONS
In real-world settings, Pom-based, Dara-based, and DPd therapies exhibited favorable efficacy in patients with RRMM. Dara-based therapy yielded superior clinical response and PFS compared to Pom-based therapy.
Topics: Humans; Multiple Myeloma; Thalidomide; Male; Female; Retrospective Studies; Middle Aged; Aged; China; Antineoplastic Combined Chemotherapy Protocols; Antibodies, Monoclonal; Progression-Free Survival; Aged, 80 and over; Treatment Outcome; Adult; Neoplasm Recurrence, Local; Drug Resistance, Neoplasm
PubMed: 38698679
DOI: 10.1002/cam4.7232 -
Cell Transplantation 2024Neuronal damage resulting from traumatic brain injury (TBI) causes disruption of neuronal projections and neurotransmission that contribute to behavioral deficits....
Pomalidomide Improves Motor Behavioral Deficits and Protects Cerebral Cortex and Striatum Against Neurodegeneration Through a Reduction of Oxidative/Nitrosative Damages and Neuroinflammation After Traumatic Brain Injury.
Neuronal damage resulting from traumatic brain injury (TBI) causes disruption of neuronal projections and neurotransmission that contribute to behavioral deficits. Cellular generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is an early event following TBI. ROS often damage DNA, lipids, proteins, and carbohydrates while RNS attack proteins. The products of lipid peroxidation 4-hydroxynonenal (4-HNE) and protein nitration 3-nitrotyrosine (3-NT) are often used as indicators of oxidative and nitrosative damages, respectively. Increasing evidence has shown that striatum is vulnerable to damage from TBI with a disturbed dopamine neurotransmission. TBI results in neurodegeneration, oxidative stress, neuroinflammation, neuronal apoptosis, and autophagy in the striatum and contribute to motor or behavioral deficits. Pomalidomide (Pom) is a Food and Drug Administration (FDA)-approved immunomodulatory drug clinically used in treating multiple myeloma. We previously showed that Pom reduces neuroinflammation and neuronal death induced by TBI in rat cerebral cortex. Here, we further compared the effects of Pom in cortex and striatum focusing on neurodegeneration, oxidative and nitrosative damages, as well as neuroinflammation following TBI. Sprague-Dawley rats subjected to a controlled cortical impact were used as the animal model of TBI. Systemic administration of Pom (0.5 mg/kg, intravenous [i.v.]) at 5 h post-injury alleviated motor behavioral deficits, contusion volume at 24 h after TBI. Pom alleviated TBI-induced neurodegeneration stained by Fluoro-Jade C in both cortex and striatum. Notably, Pom treatment reduces oxidative and nitrosative damages in cortex and striatum and is more efficacious in striatum (93% reduction in 4-HNE-positive and 84% reduction in 3-NT-positive neurons) than in cerebral cortex (42% reduction in 4-HNE-positive and 55% reduction in 3-NT-positive neurons). In addition, Pom attenuated microgliosis, astrogliosis, and elevations of proinflammatory cytokines in cortical and striatal tissue. We conclude that Pom may contribute to improved motor behavioral outcomes after TBI through targeting oxidative/nitrosative damages and neuroinflammation.
Topics: Rats; Animals; Rats, Sprague-Dawley; Reactive Oxygen Species; Neuroinflammatory Diseases; Brain Injuries, Traumatic; Oxidative Stress; Cytokines; Cerebral Cortex; Disease Models, Animal; Thalidomide
PubMed: 38483119
DOI: 10.1177/09636897241237049