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Cancers Sep 2020Immunomodulatory drugs (IMiDs) are analogs of thalidomide. They have immunomodulatory, antiangiogenic and proapoptotic properties and exert a role in regulating the... (Review)
Review
Immunomodulatory drugs (IMiDs) are analogs of thalidomide. They have immunomodulatory, antiangiogenic and proapoptotic properties and exert a role in regulating the tumor microenvironment. Recently IMiDs have been investigated for their pleiotropic properties and their therapeutic applications in both solid tumors (melanoma, prostate carcinoma and differentiated thyroid cancer) and hematological malignancies. Nowadays, they are applied in de novo and relapsed/refractory multiple myeloma, in myelodysplastic syndrome, in del5q syndrome with specific use of lenalidomide and B-cell lymphoma. Several studies have been conducted in the last few years to explore IMiDs possible use in acute myeloid leukemia treatment. Here we report the mechanisms of action of IMiDs in acute myeloid leukemia and their potential future therapeutic application in this disease.
PubMed: 32899586
DOI: 10.3390/cancers12092528 -
Hematology (Amsterdam, Netherlands) Dec 2022Extramedullary disease (EMD) is characterized by plasma cells outside of bone marrow in multiple myeloma (MM) patients, which results in an adverse prognosis. EMD...
OBJECTIVES
Extramedullary disease (EMD) is characterized by plasma cells outside of bone marrow in multiple myeloma (MM) patients, which results in an adverse prognosis. EMD treatment is yet challenging even in the era of novel drugs. Only limited data are available on pomalidomide-based therapy for EMD patients. The purpose of the current study was to assess the efficacy of pomalidomide-based therapy in EMD.
METHODS
The current retrospective analysis of six patients assessed the utility of pomalidomide-based therapy in the treatment of EMD.
RESULTS
The median age at diagnosis was 55 (47-70) years. A serological response was observed: 16% ( = 1) complete response (CR), 67% ( = 4) partial response (PR), and 16% ( = 1) progressive disease (PD). Extramedullary overall response rate (ORR) was 83% ( = 5), with 50% ( = 3) CR, 33% ( = 2) PR, and extramedullary progression in one patient. The median progression-free survival (PFS) was 5 months and the median overall survival (OS) was 8 months from diagnosis of EMD.
DISCUSSION AND CONCLUSION
Pomalidomide-based therapy showed efficacy in these previously treated patients with EMD.
Topics: Aged; Angiogenesis Inhibitors; Female; Humans; Male; Middle Aged; Multiple Myeloma; Progression-Free Survival; Retrospective Studies; Thalidomide; Treatment Outcome
PubMed: 35068387
DOI: 10.1080/16078454.2021.2019364 -
Hematology/oncology Clinics of North... Apr 2024Despite improved treatments, most patients with multiple myeloma (MM) will experience relapse. Several novel agents have demonstrated activity and tolerability in early... (Review)
Review
Despite improved treatments, most patients with multiple myeloma (MM) will experience relapse. Several novel agents have demonstrated activity and tolerability in early phase clinical trials. Venetoclax is a B-cell lymphoma 2 (Bcl-2) inhibitor with activity in patients with t(11;14) and/or Bcl-2 expression. Iberdomide and mezigdomide are cereblon E3 ligase modulators with higher potency, immunomodulatory, and antiproliferative activity compared with lenalidomide and pomalidomide. They have shown promising activity in heavily pretreated patients. Modakafusp alfa is an immunocytokine that targets interferons to CD38+ cells. It has demonstrated single agent activity in relapsed/refractory MM in the phase 1 setting.
Topics: Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Antineoplastic Agents; Lenalidomide; Proto-Oncogene Proteins c-bcl-2; Dexamethasone; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38216384
DOI: 10.1016/j.hoc.2023.12.013 -
European Journal of Haematology Jan 2022We evaluated the efficacy and safety of pomalidomide, bortezomib, and dexamethasone (PVd) vs bortezomib and dexamethasone (Vd) by age, renal function, and high-risk... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
We evaluated the efficacy and safety of pomalidomide, bortezomib, and dexamethasone (PVd) vs bortezomib and dexamethasone (Vd) by age, renal function, and high-risk cytogenetic abnormalities in lenalidomide-pretreated patients with multiple myeloma at first relapse.
METHODS
OPTIMISMM was a phase 3, multicenter, open-label, randomized study (NCT01734928; N = 559). The primary endpoint was progression-free survival (PFS).
RESULTS
Overall, 226 patients had received one prior line of therapy. PVd significantly prolonged PFS vs Vd in patients aged ≤65 years (median, 22.0 vs 13.1 months; P = .0258) and >65 years (median, 17.6 vs 9.9 months; P = .0369). Median PFS in patients with renal impairment (RI; creatinine clearance <60 mL/min) was 15.1 months with PVd vs 9.5 months with Vd (hazard ratio [HR], 0.67 [95% CI, 0.34-1.34]). In patients without RI, median PFS was 22.0 vs 13.1 months (HR, 0.45 [95% CI, 0.27-0.76]). In patients with high-risk cytogenetics, median PFS was 14.7 vs 9.9 months (HR, 0.39 [95% CI, 0.13-1.17]). PVd significantly improved overall response rate vs Vd in all subgroups. The safety profile of PVd was consistent with previous reports.
CONCLUSIONS
These findings confirmed the benefits of PVd at first relapse, including in patients with poor prognostic factors.
Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Drug Resistance, Neoplasm; Female; Humans; Lenalidomide; Male; Middle Aged; Multiple Myeloma; Prognosis; Recurrence; Retreatment; Thalidomide; Treatment Outcome
PubMed: 34496096
DOI: 10.1111/ejh.13706 -
BioRxiv : the Preprint Server For... Mar 2023Cas9 is a programmable nuclease that has furnished transformative technologies, including base editors and transcription modulators (e.g., CRISPRi/a), but several...
Cas9 is a programmable nuclease that has furnished transformative technologies, including base editors and transcription modulators (e.g., CRISPRi/a), but several applications of these technologies, including therapeutics, mandatorily require precision control of their half-life. For example, such control can help avert any potential immunological and adverse events in clinical trials. Current genome editing technologies to control the half-life of Cas9 are slow, have lower activity, involve fusion of large response elements (> 230 amino acids), utilize expensive controllers with poor pharmacological attributes, and cannot be implemented on several CRISPR-based technologies. We report a general platform for half-life control using the molecular glue, pomalidomide, that binds to a ubiquitin ligase complex and a response-element bearing CRISPR-based technology, thereby causing the latter's rapid ubiquitination and degradation. Using pomalidomide, we were able to control the half-life of large CRISPR-based technologies (e.g., base editors, CRISPRi) and small anti-CRISPRs that inhibit such technologies, allowing us to build the first examples of on-switch for base editors. The ability to switch on, fine-tune and switch-off CRISPR-based technologies with pomalidomide allowed complete control over their activity, specificity, and genome editing outcome. Importantly, the miniature size of the response element and favorable pharmacological attributes of the drug pomalidomide allowed control of activity of base editor using AAV as the delivery vehicle. These studies provide methods and reagents to precisely control the dosage and half-life of CRISPR-based technologies, propelling their therapeutic development.
PubMed: 36945568
DOI: 10.1101/2023.03.12.531757 -
Elotuzumab in combination with pomalidomide and dexamethasone for the treatment of multiple myeloma.Expert Review of Anticancer Therapy Nov 2019: Despite major advances in the therapeutic management of multiple myeloma (MM), it remains an incurable disease. Several combinations of monoclonal antibodies with... (Review)
Review
: Despite major advances in the therapeutic management of multiple myeloma (MM), it remains an incurable disease. Several combinations of monoclonal antibodies with novel agents are being investigated with promising results in order to prolong progression-free and overall survival.: This paper aims to critically present available data from clinical trials investigating the combination of elotuzumab with pomalidomide and dexamethasone in refractory/relapsed MM patients and determine its current role in clinical practice.: Pomalidomide-based combinations with monoclonal antibodies have been shown to be effective in patients with MM who are refractory to or have relapsed following treatment with lenalidomide and/or a proteasome inhibitor (PI). These regimens seem to be more effective than the standard combination of pomalidomide with dexamethasone alone. Taking into consideration that the vast majority of MM patients will receive upfront treatment including a PI and lenalidomide in the near future, pomalidomide-based triplets, such as elotuzumab-pomalidomide-dexamethasone, will become the standard of care in the second line of therapy.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Multiple Myeloma; Progression-Free Survival; Survival Rate; Thalidomide; Treatment Outcome
PubMed: 31679403
DOI: 10.1080/14737140.2019.1685879 -
Medicine Jan 2023Pomalidomide is an immunomodulatory imide drug used in multiple myeloma and in Kaposi sarcoma.
RATIONALE
Pomalidomide is an immunomodulatory imide drug used in multiple myeloma and in Kaposi sarcoma.
PATIENT CONCERNS
A 72-years-old male, treated for multiple myeloma with dexamethasone, pomalidomide and daratumumab, presented dyspnea, hypoxemia, biological inflammatory syndrome, ground glass opacities on computed tomography scan (CT-scan) and lymphocytic and eosinophilic alveolitis, with no specific cytologic or microbiological findings, 2 months after pomalidomide initiation.
INTERVENTION AND OUTCOME
Antibiotics were started after bronchoscopy. No improvement was noted in dyspnea and biological inflammatory syndrome after 5 days of treatment. Pomalidomide was then discontinued, with continuation of Daratumumab-Dexamethasone, resulting in a rapid recovery of symptoms and CT-scan anomalies. No recurrence of dyspnea was observed during the 15 months of follow-up.
DIAGNOSES
Pomalidomide-induced lung injury.
LESSONS
Pomalidomide-induced lung injury is a rare and serious adverse event that can occur early after Pomalidomide introduction. As pomalidomide use is increasing, the identification of drug toxicity as a possible cause of lung injury appears important. We report a rapid recovery of symptoms and CT-scan anomalies after pomalidomide discontinuation.
Topics: Male; Humans; Aged; Multiple Myeloma; Lung Injury; Dexamethasone; Dyspnea; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36637962
DOI: 10.1097/MD.0000000000032473 -
European Review For Medical and... Nov 2022Triplet regimens based on pomalidomide and dexamethasone have been applied to treat relapsed/refractory multiple myeloma, but the safety and efficacy are not yet very... (Meta-Analysis)
Meta-Analysis
The efficacy and safety of triplet regimens based on pomalidomide and dexamethasone for treatment of relapsed/refractory multiple myeloma: a systematic review and meta-analysis.
OBJECTIVE
Triplet regimens based on pomalidomide and dexamethasone have been applied to treat relapsed/refractory multiple myeloma, but the safety and efficacy are not yet very clear. This meta-analysis aimed at comparing the safety and efficacy of different triplet therapies and analyzing the best therapy regimen.
MATERIALS AND METHODS
A comprehensive literature search identified a total of 615 studies, and 22 studies assessing 1,889 subjects met the inclusion criteria of this meta: phase II/III trial, over 2 median lines of prior therapy, and detailed efficacy outcomes like overall response rate (ORR), overall survival, and progression-free survival (PFS). All statistical analyses were performed by Revman version 5.3, and the heterogeneity was tested by I2 (25% indicating low heterogeneity, 50% moderate, and 75% high). For those with less heterogeneity, fixed-effect model was used. With a significant high heterogeneity, a random-effect model was used.
RESULTS
Pooled analysis showed ORR 66.2% across all triplet regimens based on pomalidomide and dexamethasone. Among all triplet regimens, therapy containing bortezomib showed the highest ORR (90.3%), and the one containing elotuzumab showed the lowest ORR (41.2%). The pooled ORRs for the remaining treatment regimens are as follows: cyclophosphamide (70.1%), isatuximab (66.3%), daratumumab (61.2%), clarithromycin (60.0%), pembrolizumab (47.3%). A total of 21 adverse events appeared in the included studies, with neutropenia being the highest incidence of hematologic adverse events (32.1%) and cough being the highest incidence of non-hematologic adverse events (43.3.%).
CONCLUSIONS
Three-drug regimens based on pomalidomide and dexamethasone could yield excellent overall response rate to relapsed/refractory multiple myeloma, but there are still various adverse events; therefore, consequent studies should address these adverse events.
Topics: Humans; Multiple Myeloma; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Thalidomide
PubMed: 36394758
DOI: 10.26355/eurrev_202211_30162 -
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 -
Expert Opinion on Emerging Drugs Sep 2020Systemic AL amyloidosis is a protein-misfolding disorder that is characterized by the deposition of insoluble amyloid fibrils derived from kinetically unstable light... (Review)
Review
INTRODUCTION
Systemic AL amyloidosis is a protein-misfolding disorder that is characterized by the deposition of insoluble amyloid fibrils derived from kinetically unstable light chains. Achieving a rapid and deep hematologic response is critical for long-term survival.
AREAS COVERED
This review covers the existing and emerging treatment options for systemic AL, divided into anti-plasma cell and fibril-directed therapies. The anti-CD38 monoclonal antibody daratumumab has demonstrated an unprecedented hematologic response rate and will become the new standard-of-care in newly diagnosed patients in combination with CyBorD/VCD. Other plasma cell-directed drugs that have prospective data on safety and efficacy in AL include proteasome inhibitors [bortezomib and ixazomib], immunomodulatory drugs [lenalidomide and pomalidomide], and alkylating agents [melphalan and bendamustine]. A major unmet need is the development of fibril-directed therapies with the goal of eliminating amyloid fibrils that are already deposited in vital organs.
EXPERT OPINION
The treatment of newly diagnosed AL in the future will likely include daratumumab-based therapy in conjunction with fibril-directed therapy. The most promising second line drugs are venetoclax [for t(11;14)] and pomalidomide, with several others in the pipeline, including antibody-drug conjugates. Minimal residual disease will emerge as a new endpoint for drug development and will potentially guide treatment duration.
Topics: Animals; Antibodies, Monoclonal; Bridged Bicyclo Compounds, Heterocyclic; Drug Development; Humans; Immunoglobulin Light-chain Amyloidosis; Immunologic Factors; Sulfonamides; Thalidomide
PubMed: 32731778
DOI: 10.1080/14728214.2020.1803829