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Expert Opinion on Drug Metabolism &... Nov 2013Multiple myeloma (MM) patients who relapse, or become refractory to currently available novel agents, have limited treatment options with poor outcomes. The... (Review)
Review
INTRODUCTION
Multiple myeloma (MM) patients who relapse, or become refractory to currently available novel agents, have limited treatment options with poor outcomes. The introductions of the newer proteasome inhibitor carfilzomib and the immunomodulatory agent pomalidomide have provided new treatment strategies within the relapse setting. Pomalidomide, a novel 4-amino derived from thalidomide, was recently introduced for the treatment of MM. In addition to being immune-adjuvant with anti-inflammatory properties, pomalidomide has shown several biological activities that directly and indirectly inhibit MM cells.
AREAS COVERED
Herein, the authors review the chemistry, the mechanism of action and the pharmacokinetic properties of pomalidomide. The data reviewed within this article based on the relevant literature pertaining to pomalidomide's Phase I, II and III clinical trials.
EXPERT OPINION
Pomalidomide has shown to be a safe and active agent, both alone and in combination with dexamethasone, in heavily pretreated patients. Furthermore, pomalidomide represents an effective treatment option for relapsed/refractory patients. Results from the ongoing trials evaluating the synergistic activity of pomalidomide combined with conventional chemotherapy or novel agents look promising and may prove to be viable treatment options in the future.
Topics: Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dexamethasone; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Immunologic Factors; Multiple Myeloma; Randomized Controlled Trials as Topic; Thalidomide
PubMed: 23961770
DOI: 10.1517/17425255.2013.827169 -
Therapeutics and Clinical Risk... 2015Myelofibrosis, a Philadelphia-negative myeloproliferative neoplasm, is in a new treatment era after the discovery of the JAK2V617F mutation in 2005. JAK inhibitors boast... (Review)
Review
Myelofibrosis, a Philadelphia-negative myeloproliferative neoplasm, is in a new treatment era after the discovery of the JAK2V617F mutation in 2005. JAK inhibitors boast improvements in disease-related symptoms, splenomegaly, and overall survival; however, treatment of myelofibrosis remains a challenge, given the lack of improvement in cytopenias with these agents. Second-generation immunomodulatory agents, such as pomalidomide, have shown efficacy in myelofibrosis-associated anemia within multiple clinical trials. Five major pomalido-mide clinical trials have been completed to date, and demonstrate tolerability and efficacy with low-dose pomalidomide (0.5 mg/day) in the treatment of myelofibrosis, and no clinical benefit of elevated dosing regimens (≥2.5 mg/day). Anemia responses ranged from 17% to 36% as per the International Working Group for Myelofibrosis Research and Treatment consensus guidelines, while improvements in splenomegaly were rare, and observed in <1% of most clinical trials. In comparison with earlier immunomodulatory agents, pomalidomide was associated with an improved toxicity profile, with substantially lower rates of myelosuppression and neuropathy. Given the low overall response rate to pomalidomide as a single agent, combination strategies are of particular interest for future studies. Pomalidomide is currently being tested in combination with ruxolitinib, and other novel combinations are likely on the horizon.
PubMed: 25897239
DOI: 10.2147/TCRM.S69211 -
Oncotarget Oct 2018
PubMed: 30464802
DOI: 10.18632/oncotarget.26270 -
Biomarker Research Jun 2021Immunomodulatory drugs (IMiDs) include thalidomide, lenalidomide, and pomalidomide, which have shown significant efficacy in the treatment of multiple myeloma (MM),... (Review)
Review
Immunomodulatory drugs (IMiDs) include thalidomide, lenalidomide, and pomalidomide, which have shown significant efficacy in the treatment of multiple myeloma (MM), myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)) and other hematological malignancies. IMiDs hijack the CRL4 ubiquitin ligase to target cellular proteins for ubiquitination and degradation, which is responsible for their clinical activity in MM and MDS with del(5q). However, intrinsic and acquired resistance frequently limit the efficacy of IMiDs. Recently, many efforts have been made to explore key regulators of IMiD sensitivity, resulting in great advances in the understanding of the regulatory networks related to this class of drugs. In this review, we describe the mechanism of IMiDs in cancer treatment and summarize the key regulators of IMiD sensitivity. Furthermore, we introduce genome-wide CRISPR-Cas9 screenings, through which the regulatory networks of IMiD sensitivity could be identified.
PubMed: 34090534
DOI: 10.1186/s40364-021-00297-6 -
Cancer Chemotherapy and Pharmacology Jan 2022Elotuzumab plus pomalidomide/dexamethasone (E-Pd) demonstrated efficacy and safety in relapsed and refractory multiple myeloma (RRMM). The clinical pharmacology of...
PURPOSE
Elotuzumab plus pomalidomide/dexamethasone (E-Pd) demonstrated efficacy and safety in relapsed and refractory multiple myeloma (RRMM). The clinical pharmacology of elotuzumab [± lenalidomide/dexamethasone (Ld)] was characterized previously. These analyses describe elotuzumab population pharmacokinetics (PPK), the effect of Pd, and assess elotuzumab exposure-response relationships for efficacy and safety in patients with RRMM.
METHODS
A previously established PPK model was updated with E-Pd data from the phase 2 ELOQUENT-3 study (NCT02654132). The dataset included 8180 serum concentrations from 440 patients with RRMM from 5 clinical trials. Elotuzumab PK parameter estimates were used to generate individual daily time-varying average concentrations (daily C) for multi-variable time-to-event exposure-response analyses of progression-free survival (PFS) and time to the first occurrence of grade 3 + adverse events (AEs) in RRMM.
RESULTS
Elotuzumab PK were well-described by a two-compartment model with parallel linear and Michaelis-Menten elimination from the central compartment (V) and non-renewable target-mediated elimination from the peripheral compartment (K). Co-administration with Pd resulted in a 19% and 51% decrease in elotuzumab linear clearance and K, respectively, versus Ld; steady-state exposures were similar. V increased with increasing serum M-protein. Hazard ratios (95% confidence intervals) for daily C were 0.9983 (0.9969-0.9997) and 0.9981 (0.9964-0.9998) for PFS and grade 3 + AEs, respectively.
CONCLUSIONS
The PPK model adequately described the data and was appropriate for determining exposures for exposure-response analyses. There were no clinically relevant differences in elotuzumab exposures between Pd and Ld backbones. In ELOQUENT-3, increasing elotuzumab daily C prolonged PFS without increasing grade 3 + AEs.
Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Female; Humans; Male; Middle Aged; Multiple Myeloma; Myeloma Proteins; Neoplasm Recurrence, Local; Progression-Free Survival; Thalidomide; Treatment Outcome
PubMed: 34825942
DOI: 10.1007/s00280-021-04365-4 -
BMJ Case Reports Apr 2020In patients who experience relapse of multiple myeloma, upwards of 30% can have extramedullary disease. The presence of extramedullary multiple myeloma is typically...
In patients who experience relapse of multiple myeloma, upwards of 30% can have extramedullary disease. The presence of extramedullary multiple myeloma is typically associated with adverse cytogenetics and a poor prognosis. Organs most commonly involved include the liver, skin, central nervous system, pleural effusions, kidney, lymph nodes, and pancreas. We present the case of a 53-year-old man with IgA kappa multiple myeloma with the adverse cytogenetic findings of t(4;14) and 1q21 gain who had achieved a stringent complete (sCR) response after initial therapy with carfilzomib, lenalidomide and dexamethasone. Stringent complete response is defined as the normalization of the free light chain ratio in the serum and an absence of clonal cells in the bone marrow in additiion to criteria needed to achieve complete response. Prior to undergoing a planned autologous stem cell transplant, this patient experienced cardiac tamponade secondary to extramedullary relapse of his multiple myeloma which was limited to the pericardium. In response, his treatment regimen was transitioned to pomalidomide, bortezomib, dexamethasone and cyclophosphamide for three cycles after which he again achieved sCR and ultimately underwent autologous stem cell transplant. Post-transplant consolidation therapy was administered in the form of pomalidomide, bortezomib and dexamethasone, followed by pomalidomide and bortezomib maintenance, which he has continued to receive for 3 years without evidence of disease progression.
Topics: Attitude to Health; Cardiac Tamponade; Combined Modality Therapy; Disease-Free Survival; Drug Therapy, Combination; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Pericardium; Transplantation, Autologous
PubMed: 32332043
DOI: 10.1136/bcr-2019-233340 -
Expert Review of Hematology Jun 2017Treatment of multiple myeloma has undergone profound changes in the past years thanks to the increased understanding of the biology of the disease and the new treatment... (Review)
Review
Treatment of multiple myeloma has undergone profound changes in the past years thanks to the increased understanding of the biology of the disease and the new treatment options. New drugs and effective approaches are currently available for the treatment of multiple myeloma, including immunomodulatory agents, proteasome inhibitors and autologous stem cell transplantation. Areas covered: We have described the recent updated criteria to start treatment in multiple myeloma and summarized clinical data from major studies including most recent agents. Particularly, results with pomalidomide, carfilzomib, ixazomib, monoclonal antibodies such as elotuzumab, daratumumab, and checkpoint inhibitors have been reported. Both transplant and non-transplant settings have been covered. Expert commentary: Despite the successful improvement in overall survival and time to relapse, multiple myeloma still remains incurable. Therefore, there is still an unmet need for new treatment strategies with novel mechanisms of action, like monoclonal antibodies, novel immunomodulators, and novel proteasome inhibitors. Implementation of these novel drugs in rationally designed therapies with a good balance of efficacy and safety should be carefully considered in order to improve outcome.
Topics: Autografts; Disease-Free Survival; Humans; Immunologic Factors; Multiple Myeloma; Proteasome Inhibitors; Stem Cell Transplantation; Survival Rate
PubMed: 28504554
DOI: 10.1080/17474086.2017.1326814 -
Cancers Feb 2024Multi-agent regimens incorporating immunomodulatory (IMiD) agents such as thalidomide, lenalidomide, and pomalidomide have become the preferred standard of care for the... (Review)
Review
Multi-agent regimens incorporating immunomodulatory (IMiD) agents such as thalidomide, lenalidomide, and pomalidomide have become the preferred standard of care for the treatment of patients with multiple myeloma (MM), resulting in improved survival outcomes. Currently, there are three IMiD agents approved for the treatment of MM: thalidomide, lenalidomide, and pomalidomide. Lenalidomide is commonly used to treat patients with newly diagnosed MM and as maintenance therapy following stem cell transplant or after disease relapse. Pomalidomide, the focus of this review, is approved in patients with relapsed/refractory MM (RRMM). Despite survival benefits, IMiD agents each have different safety profiles requiring consideration both prior to starting therapy and during treatment. Adverse event (AE) management is essential, not only to ensure treatment adherence and thus ensure optimal efficacy but also to maintain patient quality of life. Here, we discuss AEs associated with pomalidomide and present five clinically relevant hypothetical case studies in patients with RRMM to provide scenario-driven guidance regarding treatment selection and AE prevention and management in the clinical setting. Lastly, as new treatment approaches continue to be explored in MM, we also discuss novel cereblon E3 ligase modulator (CELMoD™) agents including iberdomide (CC-220) and mezigdomide (CC-92480).
PubMed: 38473381
DOI: 10.3390/cancers16051023 -
Scientific Reports Aug 2021This study sought to understand how the programmed death ligand 1 (PD-L1) inhibitor durvalumab and the immunomodulatory agent pomalidomide regulate immune cell... (Randomized Controlled Trial)
Randomized Controlled Trial
This study sought to understand how the programmed death ligand 1 (PD-L1) inhibitor durvalumab and the immunomodulatory agent pomalidomide regulate immune cell activation and function in patients with relapsed/refractory (RR) multiple myeloma (MM). Immunologic changes in peripheral blood and bone marrow of patients treated with durvalumab as monotherapy or in combination with pomalidomide with/without dexamethasone were characterized by assessing subsets of immune cells and gene signatures to understand the immunomodulatory effect of the treatment. Soluble PD-L1 levels were elevated at screening in patients with RRMM but did not correlate with response to durvalumab combination therapy. Immune cell subsets were increased in peripheral blood during treatment with durvalumab and pomalidomide, and combination therapy induced significant gene expression changes in the MM tumor microenvironment versus durvalumab alone. Estimation of cell populations based on RNA sequencing data revealed increased monocytes, neutrophils, and natural killer cells with the combination therapy, but not with durvalumab alone. Additionally, multiplex immunofluorescence of bone marrow demonstrated that immune populations were different in responders versus nonresponders to durvalumab plus pomalidomide with dexamethasone therapy. Overall, durvalumab effectively blocked soluble PD-L1; however, durvalumab monotherapy was not associated with immunologic changes, which were observed with combination therapy.
Topics: Antibodies, Monoclonal; Antineoplastic Agents, Immunological; B7-H1 Antigen; Drug Therapy, Combination; Gene Expression Regulation, Neoplastic; Humans; Interferon-gamma; Multiple Myeloma; Receptors, Antigen, T-Cell; Sequence Analysis, RNA; Thalidomide; Tumor Microenvironment
PubMed: 34385543
DOI: 10.1038/s41598-021-95902-x -
Contemporary Oncology (Poznan, Poland) 2014Carfilzomib (CFZ), an epoxyketone with specific chymotrypsin-like activity, is a second-generation proteasome inhibitor with significant activity in patients with... (Review)
Review
Carfilzomib (CFZ), an epoxyketone with specific chymotrypsin-like activity, is a second-generation proteasome inhibitor with significant activity in patients with relapsed and refractory multiple myeloma. On July 20, 2012, the US Food and Drug Administration approved CFZ to treat patients with multiple myeloma who have received at least two prior therapies including bortezomib (BORT) and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Cytogenetic abnormalities did not appear to have a significant impact on the CFZ activity. Carfilzomib was well tolerated and demonstrated promising efficacy in patients with renal insufficiency. Pomalidomide (POM) (CC-4047) is a novel immunomodulatory derivative (IMID) with a stronger in vitro anti-myeloma effect compared with "older" IMIDs - thalidomide and lenalidomide (LEN). On February 8, 2013, the US Food and Drug Administration approved POM (Pomalyst, Celgene) for the treatment of MM patients who have received at least two prior therapies including LEN and BORT and have demonstrated progression on or within 60 days of completion of the last therapy. Pomalidomide is a novel IMID with significant anti-myeloma activity and manageable toxicity. This compound has shown high efficacy in MM patients who were resistant to prior use of LEN/BORT as well as in patients with a high-risk cytogenetic profile. Carfilzomib and POM have very high efficacy and will be used also in first line therapy in future.
PubMed: 24876816
DOI: 10.5114/wo.2014.40175