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Clinical Lymphoma, Myeloma & Leukemia Jun 2021Treatment of relapsed/refractory multiple myeloma (RRMM) is highly challenging, especially for patients with disease refractory to initial therapy, and in particular for...
INTRODUCTION
Treatment of relapsed/refractory multiple myeloma (RRMM) is highly challenging, especially for patients with disease refractory to initial therapy, and in particular for disease developing refractoriness to lenalidomide. Indeed, with currently approved treatments, median progression-free survival (PFS) in the lenalidomide-refractory setting is less than 10 months, reflecting the difficulty in treating this patient population. Pomalidomide is a second-generation immunomodulatory drug that has shown activity in lenalidomide-refractory disease in the setting of different combinations.
PATIENTS AND METHODS
A real-world study was conducted by the Spanish Myeloma group in a cohort of patients with RRMM treated with pomalidomide, cyclophosphamide, and dexamethasone (PomCiDex). One hundred patients were treated with a median of 3 prior lines of therapy.
RESULTS
Overall response rate was 39%, with a clinical benefit rate of 93%. Median PFS was 7.6 months; median overall survival (OS) was 12.6 months. Median PFS and OS survival were consistent across the different subgroups analyzed. Prolonged PFS and OS were found in patients with responsive disease.
CONCLUSION
Our results compared favorably with those obtained with different pomalidomide-based combinations in a similar patient population. PomCiDex remains a manageable, cost-effective, and all-oral triplet combination for RRMM patients.
Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dexamethasone; Disease Management; Drug Resistance, Neoplasm; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Multiple Myeloma; Proportional Hazards Models; Recurrence; Retreatment; Thalidomide; Treatment Outcome
PubMed: 33741302
DOI: 10.1016/j.clml.2021.02.004 -
Clinical Cancer Research : An Official... Nov 2020Addition of daratumumab to pomalidomide and low-dose dexamethasone (LoDEX) is a safe and effective combination for relapsed/refractory multiple myeloma treatment. We...
PURPOSE
Addition of daratumumab to pomalidomide and low-dose dexamethasone (LoDEX) is a safe and effective combination for relapsed/refractory multiple myeloma treatment. We sought to better understand immune combinational benefit of pomalidomide and daratumumab with LoDEX.
PATIENTS AND METHODS
Immunophenotypic changes were analyzed in peripheral blood from longitudinal sampling of patients treated with this triplet regimen from cohort B of the CC4047-MM-014 phase II trial (NCT01946477).
RESULTS
Consistent with the daratumumab mechanism, treatment led to decreased natural killer (NK) and B cells. In contrast, pronounced increases occurred in activated and proliferating NK and T cells, appreciably in CD8 T cells, along with reduction in naïve and expansion of effector memory compartments. Timing of T-cell changes correlated with pomalidomide dosing schedule. Enhanced activation/differentiation did not result in increased exhausted T-cell phenotypes or increases in regulatory T cells. Similar immune enhancements were also observed in patients previously refractory to lenalidomide.
CONCLUSIONS
These data support a potential mechanism for enhanced immune-mediated cytotoxicity in which daratumumab-mediated NK-cell diminution is partially offset by pomalidomide effects on the remaining NK-cell pool. Furthermore, daratumumab antimyeloma activity and elimination of CD38 T cells (regulatory/activated) provide a rationale for therapeutic combination with direct tumoricidal activity and immunomodulation of pomalidomide-directed T-cell enhancements. These data highlight enhancements in immune subpopulations for the combination of daratumumab with pomalidomide and potentially with next-generation cereblon-targeting agents.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; CD8-Positive T-Lymphocytes; Cell Proliferation; Dexamethasone; Female; Humans; Immunomodulation; Immunophenotyping; Killer Cells, Natural; Lenalidomide; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; T-Lymphocytes, Regulatory; Thalidomide
PubMed: 32928795
DOI: 10.1158/1078-0432.CCR-20-1781 -
British Journal of Haematology Feb 2020Patients with relapsed/refractory multiple myeloma (RRMM) for whom the benefits of lenalidomide have been exhausted in early treatment lines need effective therapies. In...
Patients with relapsed/refractory multiple myeloma (RRMM) for whom the benefits of lenalidomide have been exhausted in early treatment lines need effective therapies. In cohort A of the phase 2 MM-014 trial, we examined the safety and efficacy of pomalidomide plus low-dose dexamethasone immediately after lenalidomide-based treatment failure in patients with RRMM and two prior lines of therapy. Pomalidomide 4 mg was given on days 1 to 21 of 28-day cycles. Dexamethasone 40 mg (20 mg for patients aged >75 years) was given on days 1, 8, 15 and 22 of 28-day cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. The intention-to-treat population comprised 56 patients; all received prior lenalidomide (87·5% lenalidomide refractory) and 39 (69·6%) received prior bortezomib. ORR was 32·1% (28·2% in the prior-bortezomib subgroup). Median PFS was 12·2 months (7·9 months in the prior-bortezomib subgroup). Median OS was 41·7 months (38·6 months in the prior-bortezomib subgroup). The most common grade 3/4 treatment-emergent adverse events were anaemia (25·0%), pneumonia (14·3%) and fatigue (14·3%). These findings support earlier sequencing of pomalidomide-based therapy in lenalidomide-pretreated patients with RRMM, including those who have become refractory to lenalidomide. Trial registration: www.ClinicalTrials.gov identifier NCT01946477.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disease-Free Survival; Female; Humans; Lenalidomide; Male; Middle Aged; Multiple Myeloma; Survival Rate; Thalidomide
PubMed: 31588567
DOI: 10.1111/bjh.16213 -
Leukemia Aug 2014In this report, a panel of European myeloma experts discuss the role of pomalidomide in the treatment of relapsed and refractory multiple myeloma (RRMM). Based on the... (Review)
Review
In this report, a panel of European myeloma experts discuss the role of pomalidomide in the treatment of relapsed and refractory multiple myeloma (RRMM). Based on the available evidence, the combination of pomalidomide and low-dose dexamethasone is a well-tolerated and effective treatment option for patients with RRMM who have exhausted treatment with lenalidomide and bortezomib. The optimal starting dose of pomalidomide is 4 mg given on days 1-21 of each 28-day cycle, whereas dexamethasone is administered at a dose of 40 mg weekly (reduced to 20 mg for patients aged >75 years). The treatment should continue until evidence of disease progression or unacceptable toxicity. Dose-modification schemes have been established for patients who develop neutropenia, thrombocytopaenia and other grade 3-4 adverse events during pomalidomide therapy. Guidance on the prevention and management of infections and venous thromboembolism is provided, based on the available clinical evidence and the experience of panel members. The use of pomalidomide in special populations, such as patients with advanced age, renal impairment or unfavourable cytogenetic features, is also discussed.
Topics: Age Factors; Clinical Trials as Topic; Dexamethasone; Drug Administration Schedule; Humans; Immunologic Factors; Infections; Multiple Myeloma; Neutropenia; Peripheral Nervous System Diseases; Quality of Life; Thalidomide; Venous Thromboembolism
PubMed: 24496300
DOI: 10.1038/leu.2014.60 -
Leukemia Dec 2020Patients with multiple myeloma who have relapsed after or become refractory to lenalidomide in early treatment lines represent a clinically important population in need...
Patients with multiple myeloma who have relapsed after or become refractory to lenalidomide in early treatment lines represent a clinically important population in need of effective therapies. The safety and efficacy of pomalidomide, low-dose dexamethasone, and daratumumab was evaluated in lenalidomide-pretreated patients with relapsed or refractory multiple myeloma (RRMM) after one to two prior treatment lines in the phase 2 MM-014 study. Patients received pomalidomide 4 mg daily from days 1-21 and dexamethasone 40 mg weekly (28-day cycles). Daratumumab 16 mg/kg was administered per label. Primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS) and safety. Per protocol, all patients (N = 112) had received lenalidomide in their most recent prior regimen (75.0% lenalidomide refractory). ORR was 77.7% (76.2% in lenalidomide-refractory patients); median follow-up was 17.2 months. Median PFS was not reached (1-year PFS rate 75.1%). The most common hematologic grade 3/4 treatment-emergent adverse event was neutropenia (62.5%). Grade 3/4 infections were reported in 31.3% of patients, including 13.4% with grade 3/4 pneumonia. These results demonstrate the safety and efficacy of pomalidomide-based therapy as early as second line in patients with RRMM, even immediately after lenalidomide failure, indicating that switching from the immunomodulatory agent class is not necessary.
Topics: Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Female; Humans; Lenalidomide; Male; Multiple Myeloma; Neoplasm Recurrence, Local; Progression-Free Survival; Thalidomide
PubMed: 32376855
DOI: 10.1038/s41375-020-0813-1 -
Transplantation and Cellular Therapy Dec 2023Second autologous hematopoietic cell transplantation (AHCT2) is a useful therapeutic modality for fit patients with multiple myeloma who have durable remission after...
Continuous Elotuzumab, Pomalidomide, and Dexamethasone Maintenance Following Second Autologous Transplantation for Multiple Myeloma: Results of a Prospective Phase 2 Multicenter Trial.
Second autologous hematopoietic cell transplantation (AHCT2) is a useful therapeutic modality for fit patients with multiple myeloma who have durable remission after upfront AHCT. Retrospective studies have suggested a significant benefit of incorporating maintenance therapy post-AHCT2, but prospective data on specific regimens are lacking. The purpose of this study was to investigate the use of elotuzumab, pomalidomide, and dexamethasone (EPd) as salvage therapy prior to and maintenance after AHCT2 for relapsed multiple myeloma. This prospective single-arm phase II trial investigating the use of EPd in combination with AHCT2 in patients with relapsed multiple myeloma was conducted at 2 academic centers in North America. The primary outcome was 1-year progression-free survival (PFS). Twenty-five patients were enrolled on the study. Sixteen patients received EPd induction; six patients (38%) progressed during salvage therapy and were removed from the trial prior to AHCT2. Following a planned safety analysis, the protocol was amended, and EPd induction was removed from the study schema. An additional 9 patients underwent induction off-study and were enrolled on trial for AHCT2 and EPd maintenance. A total of 18 patients underwent AHCT2 and received EPd maintenance. Two patients discontinued treatment because of toxicity, one attributed to elotuzumab and the other to pomalidomide. The 1-year PFS was 72%, and the median PFS was 19 months. The study was closed early owing to poor accrual; 6 patients remained on therapy at time of analysis. EPd maintenance after AHCT2 was safe and tolerable. The 1-year PFS and median PFS were similar to values in previous retrospective reports of outcomes following AHCT2. Further studies are needed to define the optimal use of and protocol for AHCT2 in fit patients with relapsed multiple myeloma.
Topics: Humans; Multiple Myeloma; Prospective Studies; Transplantation, Autologous; Retrospective Studies; Dexamethasone
PubMed: 37741459
DOI: 10.1016/j.jtct.2023.09.014 -
PloS One 2022In the backdrop of rapidly changing relapsed/refractory (RR) multiple myeloma (MM) treatment schema that mainly evolves around immunotherapies, it is easy to disregard... (Comparative Study)
Comparative Study
In the backdrop of rapidly changing relapsed/refractory (RR) multiple myeloma (MM) treatment schema that mainly evolves around immunotherapies, it is easy to disregard more traditional drugs. Finding the best partner for pomalidomide, a potent third-generation immunomodulatory drug, is an important agenda we face as a community and cyclophosphamide addition has been used for outcomes augmentation. We carried out this real-world study to identify patients who will show durable response to pomalidomide and those who will benefit from cyclophosphamide addition. A total of 103 patients (57 in pomalidomide-dexamethasone [Pd] group versus 46 in pomalidomide-cyclophosphamide-dexamethasone [PCd]) were studied. They were previously treated with bortezomib (98.1%) or lenalidomide (100%) and previous lines of therapy were median 3 lines. Significantly better overall response rate (ORR) was seen in the PCd (75.6%) than Pd (41.7%) group (p = 0.001), but no differences in survival outcomes. Subgroup analysis revealed that high-risk myeloma features, poor response to lenalidomide or bortezomib had superior ORRs when cyclophosphamide was added. Also, long-term responders for pomalidomide were associated with excellent response to previous IMiD treatments. Pomalidomide-based therapy was discontinued in five patients due to intolerance or adverse events, but there was no mortality during treatment. In conclusion, we showed that pomalidomide-based treatment is still relevant and can ensure durable response in RRMM setting, especially for patients who responded well to previous lenalidomide. Addition of cyclophosphamide to Pd is associated with better ORR, and can be positively considered in fit patients with high-risk MM, extramedullary disease, and less-than-satisfactory response to previous lenalidomide treatment.
Topics: Administration, Intravenous; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dexamethasone; Female; Humans; Longitudinal Studies; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Retrospective Studies; Survival Analysis; Thalidomide; Treatment Outcome
PubMed: 35085238
DOI: 10.1371/journal.pone.0260113 -
Blood Mar 2016Current therapeutic strategies for sickle cell anemia are aimed at reactivating fetal hemoglobin. Pomalidomide, a third-generation immunomodulatory drug, was proposed to...
Current therapeutic strategies for sickle cell anemia are aimed at reactivating fetal hemoglobin. Pomalidomide, a third-generation immunomodulatory drug, was proposed to induce fetal hemoglobin production by an unknown mechanism. Here, we report that pomalidomide induced a fetal-like erythroid differentiation program, leading to a reversion of γ-globin silencing in adult human erythroblasts. Pomalidomide acted early by transiently delaying erythropoiesis at the burst-forming unit-erythroid/colony-forming unit-erythroid transition, but without affecting terminal differentiation. Further, the transcription networks involved in γ-globin repression were selectively and differentially affected by pomalidomide including BCL11A, SOX6, IKZF1, KLF1, and LSD1. IKAROS (IKZF1), a known target of pomalidomide, was degraded by the proteasome, but was not the key effector of this program, because genetic ablation of IKZF1 did not phenocopy pomalidomide treatment. Notably, the pomalidomide-induced reprogramming was conserved in hematopoietic progenitors from individuals with sickle cell anemia. Moreover, multiple myeloma patients treated with pomalidomide demonstrated increased in vivo γ-globin levels in their erythrocytes. Together, these data reveal the molecular mechanisms by which pomalidomide reactivates fetal hemoglobin, reinforcing its potential as a treatment for patients with β-hemoglobinopathies.
Topics: Adult; Anemia, Sickle Cell; Carrier Proteins; Erythroid Precursor Cells; Erythropoiesis; Fetal Hemoglobin; Gene Expression Regulation, Developmental; Genetic Vectors; Hematopoietic Stem Cells; Histone Demethylases; Humans; Ikaros Transcription Factor; Kruppel-Like Transcription Factors; Lentivirus; Multiple Myeloma; Neoplasm Proteins; Nuclear Proteins; Proteasome Endopeptidase Complex; RNA Interference; RNA, Small Interfering; Repressor Proteins; SOXD Transcription Factors; Thalidomide; Transcription, Genetic; beta-Globins; gamma-Globins
PubMed: 26679864
DOI: 10.1182/blood-2015-09-667923 -
Communications Biology Nov 2021Pomalidomide and lenalidomide are immunomodulatory agents that were derived from thalidomide. Cereblon (CRBN) is a common direct target of thalidomide and related...
Pomalidomide and lenalidomide are immunomodulatory agents that were derived from thalidomide. Cereblon (CRBN) is a common direct target of thalidomide and related compounds and works as a Cullin Ring 4 E3 ubiquitin ligase (CRL4) with DDB1, CUL4, and ROC1. The substrate specificity of CRL4 is modulated by thalidomide-related compounds. While lenalidomide is approved for the treatment of several diseases including multiple myeloma, 5q- syndrome, mantle cell lymphoma, and follicular lymphoma, pomalidomide is approved only for the treatment of lenalidomide-resistant multiple myeloma. Here we show that PLZF/ZBTB16 and its fusion proteins are pomalidomide-dependent neosubstrates of CRL4. PLZF joins to RARα or potentially other partner genes, and the translocation causes leukemias, such as acute promyelocytic leukemia and T-cell acute lymphoblastic leukemia. We demonstrate that pomalidomide treatment induces PLZF-RARα degradation, resulting in antiproliferation of leukemic cells expressing PLZF-RARα. This study highlights a potential therapeutic role of pomalidomide as a degrader of leukemogenic fusion proteins.
Topics: Adaptor Proteins, Signal Transducing; Amino Acid Sequence; HEK293 Cells; Humans; Promyelocytic Leukemia Zinc Finger Protein; Sequence Alignment; Thalidomide; Ubiquitin-Protein Ligases
PubMed: 34764413
DOI: 10.1038/s42003-021-02801-y -
Bioorganic Chemistry Jun 2019As the first intracellular signaling molecule and the most frequently mutated oncogene, B-Raf represents an important target in cancer therapy. Here we report several...
As the first intracellular signaling molecule and the most frequently mutated oncogene, B-Raf represents an important target in cancer therapy. Here we report several pomalidomide hybrids acting as proteolysis targeting chimeras (PROTACs) for the degradation of B-Raf. Due to its high expression of B-Raf, MCF-7 cells are sensitive to these compounds. Among them, compound 2 can effectively kill cancer cells via inducing cells apoptosis. As a B-Raf degrader, compound 2 can accelerate the degradation of B-Raf by recruiting ubiquitin-proteasome system, and further affects the expression of Mcl-1, a downstream protein of B-Raf. The anticancer mechanism of compound 2 is quite different from its mother compound and cancer cells seem to be more sensitive to the degrader, hinting that degradation of B-Raf by PROTAC is a potential way for cancer treatment.
Topics: Antineoplastic Agents; Cell Line; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Hep G2 Cells; Humans; MCF-7 Cells; Molecular Structure; Myeloid Cell Leukemia Sequence 1 Protein; Protein Kinase Inhibitors; Proteolysis; Proto-Oncogene Proteins B-raf; Structure-Activity Relationship; Thalidomide
PubMed: 30901674
DOI: 10.1016/j.bioorg.2019.03.035