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Australian Prescriber Feb 2015
Review
PubMed: 26648609
DOI: 10.18773/austprescr.2015.012 -
Journal of Oncology 2019The treatment options in multiple myeloma (MM) has changed dramatically over the past decade with the development of novel agents such as proteasome inhibitors (PIs);... (Review)
Review
The treatment options in multiple myeloma (MM) has changed dramatically over the past decade with the development of novel agents such as proteasome inhibitors (PIs); bortezomib and immunomodulatory drugs (IMiDs); thalidomide, and lenalidomide which revealed high efficacy and improvement of overall survival (OS) in MM patients. However, despite these progresses, most patients relapse and become eventually refractory to these therapies. Thus, the development of novel, targeted immunotherapies has been pursued aggressively. Recently, next-generation PIs; carfilzomib and ixazomib, IMiD; pomalidomide, histone deacetylase inhibitor (HDADi); panobinostat and monoclonal antibodies (MoAbs); and elotuzumab and daratumumab have emerged, and especially, combination of mAbs plus novel agents has led to dramatic improvements in the outcome of MM patients. The field of immune therapies has been accelerating in the treatment of hematological malignancies and has also taken center stage in MM. This review focuses on an overview of current status of novel MoAb therapy including bispecific T-cell engager (BiTE) antibody (BsAb), antibody-drug conjugate (ADC), and chimeric antigen receptor (CAR) T cells, in relapsed or refractory MM (RRMM). Lastly, investigational novel MoAb-based therapy to overcome immunotherapy resistance in MM is shown.
PubMed: 31781214
DOI: 10.1155/2019/6084012 -
BMC Cancer Jul 2022Pomalidomide in combination with dexamethasone has demonstrated positive results in patients with relapsed or refractory multiple myeloma (RRMM), but no data are...
Efficacy and safety of pomalidomide and low-dose dexamethasone in Chinese patients with relapsed or refractory multiple myeloma: a multicenter, prospective, single-arm, phase 2 trial.
BACKGROUND
Pomalidomide in combination with dexamethasone has demonstrated positive results in patients with relapsed or refractory multiple myeloma (RRMM), but no data are available in China. We conducted a multicenter, single-arm trial to examine the efficacy and safety of bioequivalent generic pomalidomide plus low-dose dexamethasone in Chinese RRMM patients.
METHODS
Adult (≥ 18 years of age) RRMM patients who progressed after at least two previous treatments, including bortezomib and lenalidomide, were eligible. Pomalidomide was given orally at 4 mg/day on days 1 to 21 of a 28-day cycle. Dexamethasone was given at 40 mg/day (either orally or intravenously; 20 mg/day at 75 years or older) on days 1, 8, 15, and 22 of each cycle. Treatment continued until disease progression or intolerable adverse events (AEs). The primary end point was objective response rate (ORR).
RESULTS
Seventy-four patients were enrolled between February 2017 and February 2019. All patients had progressed within 60 days of their last therapy. 74.3% of the patients were resistant to lenalidomide, 31.1% had renal insufficiency and 33.8% had high-risk cytogenetic RRMM. The median follow-up duration was 33.0 months (range 31.1-34.8 months). The ORR was 37.8% in the overall analysis, 32.7% in lenalidomide-refractory patients, 36.0% in patients with high-risk cytogenetics and 34.8% in RRMM patients with renal impairment. The median progression-free survival was 5.7 months (95% CI 3.7-8.8 months). The median overall survival was 24.3 months (95% CI 14.4-41.1 months). The most common grade 3 and 4 treatment-emergent adverse events (TEAEs) were neutropenia (63.5%), leukopenia (37.8%), thrombocytopenia (28.4%), and anemia (31.1%). Pulmonary infection (27.0%) was the most frequent grade 3 and 4 nonhematologic TEAE. No previously unreported AEs were observed. No venous thromboembolism was reported.
CONCLUSIONS
Pomalidomide in combination with low-dose dexamethasone is effective and safe in Chinese RRMM patients.
TRIAL REGISTRATION
The study is registered at Chinese Clinical Trial Registry (ChiCTR) ( ChiCTR-OIC-17013234 , first registered on 03/11/2017).
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Lenalidomide; Leukopenia; Multiple Myeloma; Prospective Studies; Thalidomide
PubMed: 35778685
DOI: 10.1186/s12885-022-09802-y -
Clinical Lymphoma, Myeloma & Leukemia Sep 2023Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS) but...
INTRODUCTION
Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS) but directionally different overall survival (OS) favoring pomalidomide (hazard ratio [HR], 1.10) in OCEAN.
METHODS
These analyses further investigated prognostic subgroups impacting survival in updated data from the randomized, phase 3 OCEAN study (NCT03151811; date: February 3, 2022) and the phase 2 HORIZON study (NCT02963493; date: February 2, 2022).
RESULTS
In OCEAN, subgroups prognostic for OS were age (P = .011; <65 years favored pomalidomide) and no previous autologous stem cell transplant (ASCT) or progression >36 months after ASCT (P = .001; favored melflufen). Overall, 245 of 495 (49%) patients randomized had received a previous ASCT, of which 202 (82%) had progressed within 36 months following their ASCT. When excluding patients who had progressed <36 months post-ASCT (melflufen group, n = 145; pomalidomide group, n = 148), median OS was 23.6 months with melflufen and 19.8 months with pomalidomide (HR, 0.83 [95% CI, 0.62-1.12]; P = .22). Among patients with triple-class refractory disease in HORIZON, patients who had progressed <36 months post-ASCT (n = 58) had a lower response rate and shorter duration of response and PFS than the remaining patients (n = 52). Safety was consistent with previous reports.
CONCLUSION
These analyses demonstrate a consistent benefit for melflufen and dexamethasone in patients with relapsed/refractory multiple myeloma who have not received an ASCT or progressed >36 months after receiving an ASCT (ClinicalTrials.gov identifier: NCT03151811).
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Follow-Up Studies; Melphalan; Multiple Myeloma; Risk Assessment; Transplantation, Autologous; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Randomized Controlled Trials as Topic
PubMed: 37355418
DOI: 10.1016/j.clml.2023.05.004 -
Blood Research Jul 2020Since the introduction of an alkylator to the treatment of multiple myeloma (MM), new effective agents have been developed, such as immunomodulatory drugs including... (Review)
Review
Since the introduction of an alkylator to the treatment of multiple myeloma (MM), new effective agents have been developed, such as immunomodulatory drugs including thalidomide, lenalidomide, and pomalidomide; proteasome inhibitors including bortezomib, carfilzomib, and ixazomib; monoclonal antibodies including daratumumab and elotuzumab; and deacetylase inhibitors including panobinostat. Numerous regimens with these new agents have been developed and they have contributed in improving survival outcomes in MM patients. In addition, the recommended therapies for newly diagnosed MM change every year based on the results of clinical trials. This review will discusses the appropriate induction therapies based on recent clinical trials for patients with newly diagnosed MM.
PubMed: 32719175
DOI: 10.5045/br.2020.S007 -
Oncotarget Jun 2017The use of carfilzomib/pomalidomide single-agent or in combination with other agents in patients with refractory/relapsed multiple myeloma (RRMM) was not clearly... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
The use of carfilzomib/pomalidomide single-agent or in combination with other agents in patients with refractory/relapsed multiple myeloma (RRMM) was not clearly clarified in clinical practice. We sought to compile the available clinical reports to better understand the efficacy and safety of carfilzomib (CFZ) and pomalidomide (POM).
RESULTS
Based on our research criteria, we identified 37 prospective studies that evaluated 1160 patients. Analysis of subgroup differences between carfilzomib single-agent and CFZ/DEX dual combination showed significantly(P < 0.001, I2 = 96.3%), suggesting the overall response rate (ORR) of 66% attained from CFZ/DEX dual combination seemed to be higher than that of 28% from carfilzomib single-agent. And, the same trend favoring CFZ/DEX dual combination was found in ≥VGPR and CBR analysis. The ORR of 31% attained from POM/DEX dual combination was superior to that of 19% from pomalidomide single-agent(P < 0.001, I2 = 94.4%). And, the same trend favoring POM/DEX dual combination was found in ≥VGPR and CBR analysis. However, the ORR of 83% attained from POM/BOR/DEX triplet combination was superior to that of 31% from POM/DEX dual combination(P < 0.001, I2 = 99.1%). And, the same trend favoring POM/BOR/DEX triplet combination was found in ≥VGPR analysis.
METHODS
We searched published reports including carfilzomib and (or) pomalidomide therapy for RRMM who had received bortezomib and (or) lenalidomide.
CONCLUSION
Pomalidomide/Carfilzomib plus dexamethasone seemed to attain a superior response rate compared with pomalidomide/carfilzomib single-agent. Furthermore, the combination of pomalidomide, bortezomib and dexamethasone resulted in a much higher response rate compared with pomalidomide plus dexamethasone regimen. These results needed more validation in future trials.
Topics: Antineoplastic Combined Chemotherapy Protocols; Disease Management; Drug Resistance, Neoplasm; Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Oligopeptides; Prospective Studies; Salvage Therapy; Thalidomide
PubMed: 27458170
DOI: 10.18632/oncotarget.10768 -
Revista Medica de Chile Dec 2018Thalidomide changed the treatment of patients with multiple myeloma, however, its effectiveness has been compromised due to its side effects. New strategies are needed... (Review)
Review
Thalidomide changed the treatment of patients with multiple myeloma, however, its effectiveness has been compromised due to its side effects. New strategies are needed to specifically target the challenges of multiple myeloma through innovative, more effective, and less toxic therapy. The new immunomodulatory (IMiDs) compounds are structural and functional analogs of thalidomide, which were designed to improve the immunomodulatory and anticancer properties and tolerability profiles. We review the development of second generation IMiDs, lenalidomide and pomalidomide, their immunomodulatory and tumoricidal effects, their mechanisms of action, as well as the influence of dexamethasone on their effect and pharmacological resistance. In conclusion, lenalidomide and pomalidomide demonstrate a powerful activity and they are highly effective and well-tolerated treatment options for patients with myeloma, used alone or in combination with dexamethasone.
Topics: Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Immunologic Factors; Immunomodulation; Lenalidomide; Multiple Myeloma; Thalidomide
PubMed: 30848748
DOI: 10.4067/s0034-98872018001201444 -
Journal of Cellular Biochemistry Jan 2017Multiple myeloma (MM) is a malignant plasma cell disorder, clinically characterized by osteolytic lesions, immunodeficiency, and renal disease. Over the past decade, MM... (Review)
Review
Multiple myeloma (MM) is a malignant plasma cell disorder, clinically characterized by osteolytic lesions, immunodeficiency, and renal disease. Over the past decade, MM therapy is significantly improved by the introduction of novel therapeutics such as immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide), proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), monoclonal antibodies (daratumumab and elotuzumab), histone deacetylase (HDAC) inhibitors (Panobinostat). The clinical success of these agents has clearly identified vulnerabilities intrinsic to the MM cell, as well as targets that emanate from the tumor microenvironment. Despite these significant improvements, MM remains incurable due to the development of drug resistance. This perspective will discuss more recent strategies which take advantage of multiple targets within the proteome recycling pathway, chromatin remodeling, and disruption of nuclear export. In addition, we will review the development of strategies designed to block opportunistic survival signaling that occurs between the MM cell and the tumor microenvironment including strategies for inhibiting myeloma-induced immune suppression. It has become clear that MM tumors continue to evolve on therapy leading to drug resistance. It will be important to understand the emerging drug resistant mechanisms and additional vulnerabilities that occur due to the development of clinical resistance. J. Cell. Biochem. 118: 15-25, 2017. © 2016 Wiley Periodicals, Inc.
Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Humans; Multiple Myeloma; Neoplasm Proteins; Proteome; Signal Transduction
PubMed: 27261328
DOI: 10.1002/jcb.25617 -
Pharmaceutics Apr 2022() An important concomitant of stroke is neuroinflammation. Pomalidomide, a clinically available immunomodulatory imide drug (IMiD) used in cancer therapy, lowers...
() An important concomitant of stroke is neuroinflammation. Pomalidomide, a clinically available immunomodulatory imide drug (IMiD) used in cancer therapy, lowers TNF-α generation and thus has potent anti-inflammatory actions. Well-tolerated analogs may provide a stroke treatment and allow evaluation of the role of neuroinflammation in the ischemic brain. () Two novel pomalidomide derivatives, 3,6'-dithiopomalidomide (3,6'-DP) and 1,6'-dithiopomalidomide (1,6'-DP), were evaluated alongside pomalidomide in a rat middle cerebral artery occlusion (MCAo) stroke model, and their anti-inflammatory actions were characterized. () Post-MCAo administration of all drugs lowered pro-inflammatory TNF-α and IL1-β levels, and reduced stroke-induced postural asymmetry and infarct size. Whereas 3,6'- and 1,6'-DP, like pomalidomide, potently bound to cereblon in cellular studies, 3,6'-DP did not lower Ikaros, Aiolos or SALL4 levels-critical intermediates mediating the anticancer/teratogenic actions of pomalidomide and IMiDs. 3,6'-DP and 1,6'-DP lacked activity in mammalian chromosome aberration, AMES and hERG channel assays -critical FDA regulatory tests. Finally, 3,6'- and 1,6'-DP mitigated inflammation across rat primary dopaminergic neuron and microglia mixed cultures challenged with α-synuclein and mouse LPS-challenged RAW 264.7 cells. () Neuroinflammation mediated via TNF-α plays a key role in stroke outcome, and 3,6'-DP and 1,6'-DP may prove valuable as stroke therapies and thus warrant further preclinical development.
PubMed: 35631536
DOI: 10.3390/pharmaceutics14050950 -
Discovery of Novel Bruton's Tyrosine Kinase PROTACs with Enhanced Selectivity and Cellular Efficacy.Journal of Medicinal Chemistry Jun 2023Bruton's tyrosine kinase (BTK) is a target for treating B-cell malignancies and autoimmune diseases, and several BTK inhibitors are already approved for use in humans....
Bruton's tyrosine kinase (BTK) is a target for treating B-cell malignancies and autoimmune diseases, and several BTK inhibitors are already approved for use in humans. Heterobivalent BTK protein degraders are also in development, based on the premise that proteolysis targeting chimeras (PROTACs) may provide additional therapeutic benefits. However, most BTK PROTACs are based on the BTK inhibitor ibrutinib raising concerns about their selectivity profiles, given the known off-target effects of ibrutinib. Here, we disclose the discovery and characterization of BTK PROTACs based on the selective BTK inhibitor and the cereblon recruitment ligand pomalidomide. is a highly potent BTK degrader (DC 0.5 nM) that inhibited cell growth and induced apoptosis at lower concentrations than the two parent molecules, as well as three previously reported BTK PROTACs, and had improved selectivity compared to ibrutinib-based BTK PROTACs.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; B-Lymphocytes; Cell Proliferation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proteolysis Targeting Chimera
PubMed: 37195170
DOI: 10.1021/acs.jmedchem.3c00176