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Journal of Clinical Pharmacology May 2015A population pharmacokinetic (PPK) model of pomalidomide was developed and the influence of demographic and disease-related covariates on PPK parameters was assessed...
A population pharmacokinetic (PPK) model of pomalidomide was developed and the influence of demographic and disease-related covariates on PPK parameters was assessed based on data from 6 clinical trials of pomalidomide (dose range, 0.5-10 mg) in healthy participants (n = 96) and patients with multiple myeloma (MM; n = 144). PPK data described herein suggest that systemic clearance of pomalidomide is comparable between healthy study participants and patients with MM. However, apparent peripheral volume of distribution and apparent intercompartmental clearance between central and peripheral compartments were 8- and 3.7-fold higher in patients with MM vs. healthy subjects, suggesting drug exposure is higher in peripheral compartments of patients with MM vs. healthy subjects. Covariate analysis suggested pomalidomide clearance is not affected by demographic factors except for gender, and it is unlikely this factor is clinically relevant. In addition, renal function as measured by creatinine clearance or renal impairment (RI) does not significantly affect clearance of pomalidomide. In conclusion, pomalidomide has robust pharmacokinetic exposure, not affected by demographic factors or renal impairment. Pomalidomide is preferentially taken up by tumors over healthy tissues in patients with MM.
Topics: Adult; Age Factors; Aged; Aged, 80 and over; Clinical Trials as Topic; Female; Humans; Immunologic Factors; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Multiple Myeloma; Renal Insufficiency; Sex Factors; Thalidomide
PubMed: 25556560
DOI: 10.1002/jcph.455 -
Blood Cancer Journal Mar 2023Bortezomib, lenalidomide, and dexamethasone induction chemotherapy (VRd), followed by autologous stem cell transplantation (ASCT), are the standard of care for patients...
Bortezomib, lenalidomide, and dexamethasone induction chemotherapy (VRd), followed by autologous stem cell transplantation (ASCT), are the standard of care for patients with newly diagnosed multiple myeloma (NDMM). Pomalidomide is currently approved for relapsed-refractory multiple myeloma. This single-arm, open-label, phase 2 study was the prospective evaluation of the efficacy and safety of bortezomib, pomalidomide, and dexamethasone (VPd) induction for NDMM. We used Fleming's two-stage design for sample size calculation. We included transplant-eligible and ineligible patients aged 18-75 years in the study. The patients received four cycles of VPd induction followed by response assessment. Thirty-four patients were included in the study, of which 31 completed all four cycles of induction. The median age was 52 years (32-72). Thirty (91%) patients had multiple myeloma, and three had multiple plasmacytomas with less than 10% bone marrow involvement. Nine (27%) had ISS-I, 9 (27%) had ISS-II, and 15 (46%) had ISS-III myeloma. Three patients had high-risk cytogenetic abnormalities. After four cycles of VPd induction, ten patients (32%) achieved stringent CR, nine had CR (29%), eight (26%) had VGPR, and 4 (13%) had PR. Fifteen (48%) had a complete metabolic response (CMR) on PET-CT. Two patients developed SAEs. Anemia was the most common hematological toxicity. Peripheral neuropathy and constipation were the most common non-hematological toxicities. Patients with ≥VGPR had significantly better 12-month PFS than those with PR. Patients with ≥VGPR and CMR on PET-CT had significantly better 12-month OS. Our study showed VPd induction is safe and efficacious in NDMM. Further Phase 3 studies are necessary to establish the superiority and survival benefits.
Topics: Humans; Middle Aged; Multiple Myeloma; Bortezomib; Hematopoietic Stem Cell Transplantation; Positron Emission Tomography Computed Tomography; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Transplantation, Autologous
PubMed: 36964143
DOI: 10.1038/s41408-023-00816-8 -
Hematology. American Society of... Dec 2017The approach to the patient with relapsed or relapsed/refractory multiple myeloma requires a careful evaluation of the results of previous treatments, the toxicities... (Review)
Review
The approach to the patient with relapsed or relapsed/refractory multiple myeloma requires a careful evaluation of the results of previous treatments, the toxicities associated with it, and an assessment of prognostic factors. The majority of patients will have received prior therapy with drug combinations, including a proteasome inhibitor and an immune-modulatory agent. It is the physician's task to choose the right moment for the start of therapy and decide with the patient which goals need to be achieved. The choice of regimen is usually based on prior response, drugs already received, adverse effects, comorbidities of the patient, and expected efficacy and tolerability. Many double and triple drug combinations are available. In addition, promising new drugs such as pomalidomide, carfilzomib, and monoclonal antibodies are or will be available shortly, and other options can be explored in clinical trials. Finally, supportive care and palliative options need to be considered in later relapsed disease. Increasingly, it becomes important to consider the therapeutic options for the whole duration of the disease and integrate a systematic approach for the patient.
Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Humans; Immunologic Factors; Multiple Myeloma; Oligopeptides; Proteasome Inhibitors; Recurrence; Thalidomide
PubMed: 29222299
DOI: 10.1182/asheducation-2017.1.508 -
American Journal of Hematology Jan 2016There have been major advances in the diagnosis, staging, risk-stratification, and management of multiple myeloma (MM). In addition to established CRAB (hypercalcemia,... (Review)
Review
There have been major advances in the diagnosis, staging, risk-stratification, and management of multiple myeloma (MM). In addition to established CRAB (hypercalcemia, renal failure, anemia, and lytic bone lesions) features, new diagnostic criteria include three new biomarkers to diagnose the disease: bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain ratio ≥100, and >1 focal lesion on magnetic resonance imaging. MM can be classified into several subtypes based on baseline cytogenetics, and prognosis varies according to underlying cytogenetic abnormalities. A Revised International Staging System has been developed which combines markers of tumor burden (albumin, beta-2 microglobulin) with markers of aggressive disease biology (high-risk cytogenetics and elevated serum lactate dehydrogenase). Although the approach to therapy remains largely the same, the treatment options at every stage of the disease have changed. Carfilzomib, pomalidomide, panobinostat, daratumumab, elotuzumab, and ixazomib have been approved for the treatment of the disease. These drugs combined with older agents such as cyclophosphamide, dexamethasone, thalidomide, bortezomib, and lenalidomide dramatically increase the repertoire of regimens available for the treatment of MM. This review provides a concise overview of recent advances in MM, including updates to diagnostic criteria, staging, risk-stratification, and management.
Topics: Antineoplastic Agents; Consolidation Chemotherapy; Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Humans; Maintenance Chemotherapy; Multiple Myeloma; Neoplasm Staging; Recurrence
PubMed: 26565896
DOI: 10.1002/ajh.24236 -
Current Opinion in HIV and AIDS Jan 2017This review discusses the pathogenesis and recent advances in the management of Kaposi sarcoma herpesvirus (KSHV)-associated diseases. (Review)
Review
PURPOSE OF REVIEW
This review discusses the pathogenesis and recent advances in the management of Kaposi sarcoma herpesvirus (KSHV)-associated diseases.
RECENT FINDINGS
KSHV, a gammaherpesvirus, causes several tumors and related diseases, including Kaposi sarcoma, a form of multicentric Castleman disease (KSHV-MCD), and primary effusion lymphoma. These most often develop in patients infected with human immunodeficiency virus (HIV). KSHV inflammatory cytokine syndrome (KICS) is a newly described syndrome with high mortality that has inflammatory symptoms-like MCD but not the pathologic lymph node findings. KSHV-associated diseases are often associated with dysregulated human interleukin-6, and KSHV encodes a viral interleukin-6, both of which contribute to disease pathogenesis. Treatment of HIV is important in HIV-infected patients. Strategies to prevent KSHV infection may reduce the incidence of these tumors. Pomalidomide, an immunomodulatory agent, has activity in Kaposi sarcoma. Rituximab is active in KSHV-MCD but can cause Kaposi sarcoma exacerbation; rituximab plus liposomal doxorubicin is useful to treat KSHV-MCD patients with concurrent Kaposi sarcoma.
SUMMARY
KSHV is the etiological agents of all forms of Kaposi sarcoma and several other diseases. Strategies employing immunomodulatory agents, cytokine inhibition, and targeting of KSHV-infected cells are areas of active research.
Topics: Antineoplastic Agents; Castleman Disease; Herpesvirus 8, Human; Humans; Immunologic Factors; Lymphoma, Primary Effusion; Sarcoma, Kaposi
PubMed: 27662501
DOI: 10.1097/COH.0000000000000330 -
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 -
Life (Basel, Switzerland) Nov 2023This review discusses immunomodulatory drug (IMiDs) sequencing and IMiD-free interval strategies for lenalidomide-refractory myeloma. IMiDs and proteasome inhibitors... (Review)
Review
This review discusses immunomodulatory drug (IMiDs) sequencing and IMiD-free interval strategies for lenalidomide-refractory myeloma. IMiDs and proteasome inhibitors (PIs) improve clinical outcomes in patients with myeloma; however, refractoriness to lenalidomide, a category of IMiD, predicts poor outcomes. Next-generation IMiDs, such as pomalidomide, are effective even for lenalidomide-refractory myeloma. Therefore, an IMiD-sequencing strategy from lenalidomide to pomalidomide would be desirable. PIs are an antimyeloma therapeutic agent with another mode of action that might restore cereblon, a target of IMiDs; therefore, an IMiD-free interval via class switching from lenalidomide to PIs may be a promising alternative for lenalidomide-refractory myeloma. Additionally, the anti-CD38 monoclonal antibody is a key drug for salvage therapy in anti-CD38 monoclonal antibody-naïve patients. In clinical practice, safety profiles and social convenience can play important roles in the choice of combination therapy. In the future, the selection of optimal treatments should be based on the status of the immunological environment and genetic alterations. This review aims to discuss IMiDs sequencing and IMiD-free interval strategies for lenalidomide- refractory myeloma.
PubMed: 38004369
DOI: 10.3390/life13112229 -
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 -
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 -
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