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Blood Science (Baltimore, Md.) Apr 2024Relapsed and refractory multiple myeloma (RRMM) and B-cell leukemia/lymphoma with extramedullary disease (EMD) have poor prognosis and high mortality, lack of effective...
Relapsed and refractory multiple myeloma (RRMM) and B-cell leukemia/lymphoma with extramedullary disease (EMD) have poor prognosis and high mortality, lack of effective therapeutic approaches. We reported for the first time that 6 patients with malignant hematological diseases with EMD received chimeric antigen receptor (CAR)-T treatment combined with pomalidomide, and CAR-T cells were treated with pomalidomide in vitro to determine its killing activity and cytokine secretion. Three patients with RRMM were given B cell maturation antigen (BCMA)-CAR-T therapy. All 3 patients with B-cell leukemia/lymphoma received CD19/22-CAR-T sequential infusion. There were no treatment-related deaths. The maximum overall response rate (ORR) was 100%. Median follow-up was 211.5 days (75-407 days). Three patients (50%) experienced cytokine release syndrome, all of which were grade 1, and no neurotoxicity was observed. In vitro experiments showed that the killing activity did not differ significantly between BCMA-CAR-T cells with and without pomalidomide (10, 25, or 50 μg/mL) in 8226/U266 cell cocultures ( > .05). Tumor necrosis factor (TNF)-α and interferon (IFN)-γ secretion was significantly higher from 8226 and Raji cells cocultured with BCMA-CAR-T and cluster of differentiation (CD)19-CAR-T cells ( < .05). Based on the cocultures, adding pomalidomide significantly promoted IFN-γ and TNF-α secretion ( < .05). Based on the above clinical and in vitro studies demonstrating the co-administration of pomalidomide with CAR-T cell treatment demonstrated favorable tolerability and therapeutic effectiveness in RRMM or B-cell leukemia/lymphoma.
PubMed: 38433987
DOI: 10.1097/BS9.0000000000000184 -
Blood Mar 2011It is currently assumed that myelofibrosis (MF) originates from acquired mutations that target the hematopoietic stem cell and induce dysregulation of kinase signaling,... (Review)
Review
It is currently assumed that myelofibrosis (MF) originates from acquired mutations that target the hematopoietic stem cell and induce dysregulation of kinase signaling, clonal myeloproliferation, and abnormal cytokine expression. These pathogenetic processes are interdependent and also individually contributory to disease phenotype-bone marrow stromal changes, extramedullary hematopoiesis, ineffective erythropoiesis, and constitutional symptoms. Molecular pathogenesis of MF is poorly understood despite a growing list of resident somatic mutations that are either functionally linked to Janus kinase (JAK)-signal transducer and activator of transcription hyperactivation (eg JAK2, MPL, and LNK mutations) or possibly involved in epigenetic dysregulation of transcription (TET2, ASXL1, or EZH2 mutations). Current prognostication in primary MF is based on the Dynamic International Prognostic Scoring System-plus model, which uses 8 independent predictors of inferior survival to classify patients into low, intermediate 1, intermediate 2, and high-risk disease groups; corresponding median survivals are estimated at 15.4, 6.5, 2.9, and 1.3 years. Such information is used to plan a risk-adapted treatment strategy for the individual patient, which might include observation alone, conventional or investigational (eg, JAK inhibitors, pomalidomide) drug therapy, allogenic stem cell transplantation with reduced- or conventional-intensity conditioning, splenectomy, or radiotherapy. I discuss these treatment approaches in the context of who should get what and when.
Topics: Algorithms; Hematologic Tests; Humans; Models, Biological; Polycythemia Vera; Primary Myelofibrosis; Prognosis; Risk Assessment; Thrombocythemia, Essential; World Health Organization
PubMed: 21200024
DOI: 10.1182/blood-2010-11-315614 -
Oncology (Williston Park, N.Y.) Nov 2011In the past decade we have seen four new agents approved by the US Food and Drug Administration for treatment of multiple myeloma: the proteasome inhibitor (PI)... (Review)
Review
In the past decade we have seen four new agents approved by the US Food and Drug Administration for treatment of multiple myeloma: the proteasome inhibitor (PI) bortezomib (Velcade), the immunomodulatory agents lenalidomide (Revlimid) and thalidomide (Thalomid), and liposomal doxorubicin. These are commonly used in the treatment of relapsed/refractory (R/R) multiple myeloma (MM), but there is no universally accepted standard treatment. Salvage therapy must be tailored according to an individual patient's clinical profile, with the risks and potential effects of treatment-related adverse events being major determinants of the choice of therapy. Two novel agents in phase II studies to investigate their potential for the treatment of R/R MM are carfilzomib, a selective, irreversible next-generation PI, and pomalidomide, a next-generation thalidomide analog. This review will discuss the side-effect profiles of the currently approved immunomodulatory agents and bortezomib, as well as those of the newer agents, carfilzomib and pomalidomide.
Topics: Antineoplastic Agents; Boronic Acids; Bortezomib; Humans; Kidney; Multiple Myeloma; Nervous System Diseases; Oligopeptides; Pyrazines; Recurrence; Thalidomide; Venous Thromboembolism
PubMed: 25188481
DOI: No ID Found -
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 -
Australian Prescriber Feb 2015
Review
PubMed: 26648609
DOI: 10.18773/austprescr.2015.012 -
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 -
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 -
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 -
Frontiers in Pharmacology 2022To explore the effect of pomalidomide on the maturation of monocyte-derived dendritic cells (moDCs) from healthy donors (HDs) and multiple myeloma (MM) patients. MoDCs...
To explore the effect of pomalidomide on the maturation of monocyte-derived dendritic cells (moDCs) from healthy donors (HDs) and multiple myeloma (MM) patients. MoDCs were generated by the incubation of monocytes from peripheral blood mononuclear cells (PBMCs) for 7 days in a medium consisting of 800 U/ml granulocyte-macrophage colony stimulating factor (GM-CSF), 500 U/ml interleukin-4 (IL-4), RPMI 1,640 medium, 5% human serum, 100 U/ml penicillin and 0.1 mg/ml streptomycin. Meanwhile, the incubation system was administrated with 10 µM pomalidomide or 1 × PBS as the control group. On the eighth day, cells were harvested and analyzed by flow cytometry. The CD80CD86 cell population in total cells was gated as moDCs in the FACS analyzing system. After that, the expression of CD40 and HLA-DR on moDCs was analyzed. Meanwhile, the supernatant from the incubation system was evaluated for the secretion of cytokines interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein 1α (MIP-1α) by enzyme-linked immunosorbent assay (ELISA). When analyzing all the HD-moDCs together ( = 15), pomalidomide significantly increased the mean fluorescence intensity (MFI) of CD40 expression and HLA-DR expression on moDCs compared with the control group ( = 0.003, = 0.040). Meanwhile, the proportion of CD40 moDCs and HLA-DR moDCs in total moDCs was significantly higher in the pomalidomide group than in the control group ( = 0.008, = 0.032). When analyzing all MM patient-moDCs together ( = 11), pomalidomide significantly increased the MFI of CD40 expression and HLA-DR expression on moDCs compared with the control group ( = 0.047, = 0.006). Meanwhile, the proportion of HLA-DR moDCs in total DCs was significantly higher in the pomalidomide group than in the control group ( < 0.001). Moreover, HD-moDCs ( = 8) treated with pomalidomide secreted 192% IL-12, 110% TNF-α, and 112% MIP-1α of the untreated moDCs ( = 0.020, = 0.006, = 0.055). However, when analyzing MM patient-moDCs ( = 10) together, the secretion of IL-12, TNF-α and MIP-1α from moDCs showed no significant difference between the pomalidomide group and the control group ( = 0.458, = 0.377, = 0.248). , 10 µM pomalidomide enhances the maturation of moDCs derived from both HDs and MM patients. Pomalidomide shows potential to be applied as a DC adjuvant for DC-based immunotherapy, such as the DC vaccine and DC cell therapy in MM.
PubMed: 36545316
DOI: 10.3389/fphar.2022.1076096