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Cells Dec 2019Multiple myeloma (MM) is the second-most common hematologic malignancy after diffuse large B-cell lymphoma. Despite the improvement in response and survival rates... (Review)
Review
Multiple myeloma (MM) is the second-most common hematologic malignancy after diffuse large B-cell lymphoma. Despite the improvement in response and survival rates following the introduction of novel therapies, only a few patients are cured, and the majority of MM patients experience several relapses and receive multiple lines of treatment. Currently, bortezomib and lenalidomide are the core component of treatment both at the time of diagnosis and at the relapse as well as the new proteasome inhibitors (PIs), such as carfilzomib and ixazomib, and the next-generation immunomodulatory drug, pomalidomide, are now available for patients in relapse. In addition, drugs with a different mechanism of action, such as the histone deacetylase inhibitor and the monoclonal antibodies (MoAb) targeting SLAMF7 or CD38, are a part of the anti-myeloma armamentarium and are very important for heavily pretreated or double refractory to a PI and IMiD patients. In this paper, we focus on the efficacy as well as toxicities of CD38 antibodies used both as a single agent and in combination as multiple myeloma treatment.
Topics: ADP-ribosyl Cyclase 1; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Drug Synergism; Humans; Immunotherapy; Molecular Targeted Therapy; Multiple Myeloma; Treatment Outcome
PubMed: 31842517
DOI: 10.3390/cells8121629 -
Reshaping the tumor microenvironment: The versatility of immunomodulatory drugs in B-cell neoplasms.Frontiers in Immunology 2022Immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide and pomalidomide are antitumor compounds that have direct tumoricidal activity and indirect effects... (Review)
Review
Immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide and pomalidomide are antitumor compounds that have direct tumoricidal activity and indirect effects mediated by multiple types of immune cells in the tumor microenvironment (TME). IMiDs have shown remarkable therapeutic efficacy in a set of B-cell neoplasms including multiple myeloma, B-cell lymphomas and chronic lymphocytic leukemia. More recently, the advent of immunotherapy has revolutionized the treatment of these B-cell neoplasms. However, the success of immunotherapy is restrained by immunosuppressive signals and dysfunctional immune cells in the TME. Due to the pleiotropic immunobiological properties, IMiDs have shown to generate synergetic effects in preclinical models when combined with monoclonal antibodies, immune checkpoint inhibitors or CAR-T cell therapy, some of which were successfully translated to the clinic and lead to improved responses for both first-line and relapsed/refractory settings. Mechanistically, despite cereblon (CRBN), an E3 ubiquitin ligase, is considered as considered as the major molecular target responsible for the antineoplastic activities of IMiDs, the exact mechanisms of action for IMiDs-based TME re-education remain largely unknown. This review presents an overview of IMiDs in regulation of immune cell function and their utilization in potentiating efficacy of immunotherapies across multiple types of B-cell neoplasms.
Topics: Humans; Immunomodulating Agents; Lenalidomide; Multiple Myeloma; Lymphoma, B-Cell; Immunologic Factors; Tumor Microenvironment
PubMed: 36311747
DOI: 10.3389/fimmu.2022.1017990 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Dec 2023To investigate the clinical characteristics, diagnosis, and treatment of one patient with TAFRO syndrome, and to strengthen the understanding of this rare type.
OBJECTIVE
To investigate the clinical characteristics, diagnosis, and treatment of one patient with TAFRO syndrome, and to strengthen the understanding of this rare type.
METHODS
The clinical manifestations, diagnosis and treatment process, and prognosis of the patient admitted in Gansu Provincial People's Hospital were retrospectively analyzed.
RESULTS
Combined with laboratory tests, bone marrow examination, imaging, pathology, etc, the patient was diagnosed with TAFRO syndrome. After three cycles of treatment with pomalidomide (2-3 mg/d, d1-21), cyclophosphamide (300 mg/m, 0.54 g once a week) and dexamethasone (20 mg/d, two days a week), platelet count, serum creatinine and procalcitonin returned to normal, the systemic edema disappeared, and the patient's condition was alleviated. The therapeutic effect was good.
CONCLUSION
TAFRO syndrome is rare, involves multiple systems, progresses rapidly, and has a worse prognosis. The choice of the "Pomalidomide+cyclophosphamide+dexamethasone" regimen is help to improve the survival prognosis of patient with TAFRO syndrome.
Topics: Humans; Thrombocytopenia; Retrospective Studies; Castleman Disease; Dexamethasone; Cyclophosphamide
PubMed: 38071075
DOI: 10.19746/j.cnki.issn.1009-2137.2023.06.042 -
Blood Mar 2022Immunomodulatory (IMiD) agents like lenalidomide and pomalidomide induce the recruitment of IKZF1 and other targets to the CRL4CRBN E3 ubiquitin ligase, resulting in...
Immunomodulatory (IMiD) agents like lenalidomide and pomalidomide induce the recruitment of IKZF1 and other targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and degradation. These agents are highly active in B-cell lymphomas and a subset of myeloid diseases but have compromised effects in T-cell lymphomas (TCLs). Here, we show that 2 factors determine resistance to IMiDs among TCLs. First, limited CRBN expression reduces IMiD activity in TCLs but can be overcome by newer-generation degrader CC-92480. Using mass spectrometry, we show that CC-92480 selectively degrades IKZF1 and ZFP91 in TCL cells with greater potency than pomalidomide. As a result, CC-92480 is highly active against multiple TCL subtypes and showed greater efficacy than pomalidomide across 4 in vivo TCL models. Second, we demonstrate that ZFP91 functions as a bona fide transcription factor that coregulates cell survival with IKZF1 in IMiD-resistant TCLs. By activating keynote genes from WNT, NF-kB, and MAP kinase signaling, ZFP91 directly promotes resistance to IKZF1 loss. Moreover, lenalidomide-sensitive TCLs can acquire stable resistance via ZFP91 rewiring, which involves casein kinase 2-mediated c-Jun inactivation. Overall, these findings identify a critical transcription factor network within TCLs and provide clinical proof of concept for the novel therapy using next-generation degraders.
Topics: Drug Resistance, Neoplasm; Humans; Ikaros Transcription Factor; Immunologic Factors; Lenalidomide; Lymphoma, T-Cell; Multiple Myeloma; Thalidomide; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 34936696
DOI: 10.1182/blood.2021014701 -
Investigational New Drugs Feb 2023Imnovid® is an immunomodulatory drug with antineoplastic activity. The aim of this study was to evaluate the bioequivalence and safety of the generic drug pomalidomide...
OBJECTIVE
Imnovid® is an immunomodulatory drug with antineoplastic activity. The aim of this study was to evaluate the bioequivalence and safety of the generic drug pomalidomide (Chia Tai Tianqing Pharmaceutical Group Co., Ltd) and its originator product Imnovid® (Celgene Europe Ltd) in the fasting and fed states, respectively.
METHODS
The research consisted of two parts: one with a dose of 1 mg and the other with a dose of 4 mg. 48 healthy subjects were included in each study and were divided into two groups (fasting group and fed group) at a 1:1 ratio to administrate study drugs orally. The plasma drug concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
RESULTS
The 90% CI of GMR for main pharmacokinetic (PK) parameters (C, AUC and AUC) met the requirements of bioequivalence standards. The incidence and severity of AEs associated with pomalidomide and Imnovid® were similar.
CONCLUSION
The results proved the PK parameters of pomalidomide and Imnovid® were similar and bioequivalent. Both drugs showed safety profile well.
Topics: Humans; Area Under Curve; Capsules; Chromatography, Liquid; Cross-Over Studies; East Asian People; Fasting; Healthy Volunteers; Tablets; Tandem Mass Spectrometry; Therapeutic Equivalency; Thalidomide
PubMed: 36441437
DOI: 10.1007/s10637-022-01320-9 -
European Journal of Haematology Nov 2023Although daratumumab-containing regimens improve multiple myeloma (MM) outcomes, recurrence is inevitable.
INTRODUCTION
Although daratumumab-containing regimens improve multiple myeloma (MM) outcomes, recurrence is inevitable.
METHODS AND OBJECTIVE
We performed a retrospective study using the Canadian Myeloma Research Group Database to benchmark the efficacy of carfilzomib- or pomalidomide-based therapies immediately following progression on daratumumab treatment.
RESULTS
We identified 178 such patients; median number of prior lines of therapy was 3, 97% triple-class exposed, and 60% triple-class refractory. In our cohort, 75 received a subsequent carfilzomib-based therapy, 79 received a pomalidomide-based therapy, and 24 received a treatment with both immunomodulatory drug (IMiD) and proteasome inhibitor (PI) using carfilzomib and/or pomalidomide. The median progression-free survival (PFS) and overall survival (OS) for the entire cohort were 4.5 and 14.2 months, respectively. Carfilzomib-based therapy yielded a median PFS and OS of 4.5 and 10.2 months, respectively, compared to 5.2 and 21.7 months for pomalidomide-based therapy. Patients who received both IMiD and PI with carfilzomib and/or pomalidomide had a median PFS and OS of 4.1 and 14.5 months, respectively.
CONCLUSION
Our observations demonstrate the poor outcome of MM patients when standard regimens based on carfilzomib and/or pomalidomide are utilized directly after daratumumab-based therapy given in the relapsed setting. Novel therapies, including immune therapies, are urgently needed to improve the outcomes of these daratumumab-exposed patients.
PubMed: 37574220
DOI: 10.1111/ejh.14082 -
Biomedicine & Pharmacotherapy =... Jul 2020Thalidomide was first marketed in 1957 but soon withdrawn because of its notorious teratogenicity. Studies on the mechanism of action of thalidomide revealed the... (Review)
Review
Thalidomide was first marketed in 1957 but soon withdrawn because of its notorious teratogenicity. Studies on the mechanism of action of thalidomide revealed the pleiotropic properties of this class of drugs, including their anti-inflammatory, antiangiogenic and immunomodulatory activities. Based on their notable activities, thalidomide and its analogues, lenalidomide and pomalidomide, have been repurposed to treat erythema nodosum leprosum, multiple myeloma and other haematological malignancies. Thalidomide analogues were recently found to hijack CRL4 ubiquitin ligase to target a number of cellular proteins for ubiquitination and proteasomal degradation. Thalidomide-mediated degradation of SALL4 and p63, transcription factors essential for embryonic development, very likely plays a critical role in thalidomide embryopathy. In this review, we provide a brief retrospective summary of thalidomide-induced teratogenesis, the mechanism of thalidomide activity, and the latest advances in the molecular mechanism of thalidomide-induced birth malformations.
Topics: Humans; Teratogenesis; Thalidomide; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 32304852
DOI: 10.1016/j.biopha.2020.110114 -
Life Sciences Sep 2021Medical treatment for lower urinary tract symptoms secondary to benign prostatic hyperplasia is characterized by an unfavorable balance between limited efficacy and...
AIMS
Medical treatment for lower urinary tract symptoms secondary to benign prostatic hyperplasia is characterized by an unfavorable balance between limited efficacy and pronounced side effects. We recently reported, that thalidomide reduces prostate smooth muscle contraction and inhibits cell growth. Like thalidomide, its analogs lenalidomide and pomalidomide are also in clinical use. Therefore, we investigated the effects of lenalidomide and pomalidomide on human prostate smooth muscle contraction, cytoskeletal organization, and growth-related functions in stromal cells.
MATERIALS AND METHODS
Proliferation was assessed by EdU assay and colony formation, cytoskeletal organization by phalloidin staining, cell viability by CCK8, and apoptosis and cell death by flow cytometry in cultured prostate stromal cells (WPMY-1). Contractions of human prostate tissues from radical prostatectomy were induced by methoxamine, noradrenaline, phenylephrine, endothelin-1, U46619, or electric field stimulation (EFS) in an organ bath.
KEY FINDINGS
Proliferation of WPMY-1 cells was significantly reduced by lenalidomide (5-200 μM) and pomalidomide (2.5-5 μM). In parallel, organization of actin filaments collapsed after treatment with lenalidomide and pomalidomide. Lenalidomide and pomalidomide inhibited both adrenergic contractions and non-adrenergic contractions as well as neurogenic contractions induced by EFS. Neither reduction in viability, nor increase in cell death or apoptosis was observed in WPMY-1 cells.
SIGNIFICANCE
Thalidomide-derivatives impair growth of human prostate stromal cells, without showing a decrease in cell viability and, in parallel, inhibit adrenergic, neurogenic, and non-adrenergic contractions by breakdown of the actin cytoskeleton. Urodynamic effects in vivo appear possible.
Topics: Apoptosis; Cell Line, Transformed; Humans; Lenalidomide; Male; Muscle Contraction; Muscle, Smooth; Prostate; Stromal Cells; Thalidomide
PubMed: 34186051
DOI: 10.1016/j.lfs.2021.119771 -
Journal of Oncology Pharmacy Practice :... Apr 2024Multiple myeloma cells resist standard therapies due to overexpression of the transport protein, exportin 1. Selinexor is a novel drug that targets the Exportin 1... (Review)
Review
OBJECTIVE
Multiple myeloma cells resist standard therapies due to overexpression of the transport protein, exportin 1. Selinexor is a novel drug that targets the Exportin 1 protein in these cells.
DATA SOURCE
A comprehensive search was done, and data showing the efficacy and safety of selinexor in relapsed/refractory multiple myeloma was collected using PubMed, Google Scholar, and clincialtrials.gov.
DATA SUMMARY
Results from the clinical trials STORM, BOSTON, and STOMP were included. Parts I and II of the STORM trial revealed a progression-free survival (PFS) of 4.7 and 3.7 months, a median duration of response of 6.2 and 4.4 months, and an overall survival of 7.3 and 8.4 months, respectively. BOSTON trial's SVd arm (selinexor, bortezomib, and dexamethasone) had a median follow-up period of 13.2 months and an mPFS of 13.93 months. The Vd arm (bortezomib and dexamethasone) had a median follow-up duration of 16.5 months and an mPFS of 9.46 months. The STOMP trial is still active and has limited data available. The SKd arm (selinexor, carfilzomib, and dexamethasone) reported an overall response rate of 66.7% in patients with triple refractory multiple myeloma, and 82% in patients with high-risk cytogenetics. The SPd arm (selinexor, pomalidomide, and dexamethasone) shows an overall response rate of 54.30% in pomalidomide naïve-nonrefractory, 35.70% in pomalidomide refractory and 60% in those dosed at RP2D. SRd arm (selinexor, lenalidomide, and dexamethasone) shows an overall response rate of 91.7% in lenalidomide naïve and 12.5% in lenalidomide refractory patients. SVd (selinexor, bortezomib, and dexamethasone) arm reported an overall response rate of 63% in all patients while the SDd arm (selinexor, daratumumab, and dexamethasone) showed an overall response rate of 73%.
CONCLUSION
To improve the outcome of patients with relapsed/refractory multiple myeloma, it is critical to develop new therapies, assess potential therapeutic synergies, and overcome drug resistance by determining the efficacy of multiple myeloma therapies across multiple disease subgroups.
Topics: Humans; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Drug Resistance, Neoplasm; Exportin 1 Protein; Hydrazines; Karyopherins; Multiple Myeloma; Neoplasm Recurrence, Local; Progression-Free Survival; Receptors, Cytoplasmic and Nuclear; Triazoles; Clinical Trials as Topic
PubMed: 38454813
DOI: 10.1177/10781552241235902 -
Cancers Oct 2023Daratumumab-based combinations with pomalidomide/dexamethasone (DPd), or bortezomib/dexamethasone (DVd), have shown activity in relapsed/refractory multiple myeloma...
Efficacy and Safety of Daratumumab, Pomalidomide, and Dexamethasone (DPd) Compared to Daratumumab, Bortezomib, and Dexamethasone (DVd) in Daratumumab-Naïve Relapsed Multiple Myeloma.
Daratumumab-based combinations with pomalidomide/dexamethasone (DPd), or bortezomib/dexamethasone (DVd), have shown activity in relapsed/refractory multiple myeloma (RRMM) patients. However, no direct comparisons of safety or efficacy of the two regimens have been published to date. We conducted a retrospective study to compare the safety and efficacy of DPd and DVd in daratumumab-naïve RRMM patients. We included 140 daratumumab-naïve patients who had received DPd or DVd for RRMM. Overall, the DPd group had a greater number of patients who had high-risk disease characteristics. Although response was deeper in the DPd group, the median progression-free survival (PFS) and overall survival (OS) were similar between the two groups. The DPd group exhibited a higher incidence of hematologic toxicities, whereas the DVd group had a higher incidence of peripheral neuropathy. The study results showed that while DPd may provide a deeper response, there was no significant difference in PFS or OS compared to DVd. For the high proportion of difficult-to-treat patients, duration of treatment may have contributed to these results, indicating that patient and disease characteristics should be considered when selecting salvage treatments.
PubMed: 37835587
DOI: 10.3390/cancers15194894