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Clinical Lymphoma, Myeloma & Leukemia Mar 2024A proportion of patients with multiple myeloma (MM) are older and/or have comorbidities, requiring dose adjustments. Data from OPTIMISMM (NCT01734928) supported the use...
INTRODUCTION
A proportion of patients with multiple myeloma (MM) are older and/or have comorbidities, requiring dose adjustments. Data from OPTIMISMM (NCT01734928) supported the use of pomalidomide, bortezomib, and dexamethasone (PVd) for treating relapsed/refractory MM. This subanalysis of OPTIMISMM assessed outcome by frailty and/or bortezomib dose adjustment.
METHODS
Patient frailty (nonfrail vs. frail) was classified using age, Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status. Data from patients requiring a bortezomib dose reduction, interruption, and/or withdrawal during PVd treatment were assessed.
RESULTS
Among 559 patients, 93 of 281 (33.1%) and 93 of 278 (33.5%) patients who received PVd and bortezomib and dexamethasone (Vd), respectively, were frail. Overall response rate (ORR) and median progression-free survival (PFS) were higher in nonfrail vs. frail with PVd treatment (ORR, 82.8% vs. 79.6%; PFS, 14.7 vs. 9.7 months); significantly higher than with Vd regardless of frailty. Grade ≥ 3 treatment-emergent adverse events (TEAEs) were higher with PVd vs. Vd, regardless of frailty. Discontinuations of PVd were lower in nonfrail vs. frail patients (19.2% vs. 30.1%); the median duration of treatment was similar (DoT; 8.8 vs. 8.9 months, respectively). Patients who received PVd with a bortezomib dose adjustment (n = 240) had a longer median DoT (9.3 vs. 4.5 months) and PFS (12.1 vs. 8.4 months) vs. those without.
CONCLUSION
Frail patients treated with PVd demonstrated a higher ORR and a longer PFS and DoT vs. Vd, despite a higher frequency of grade ≥ 3 TEAEs leading to pomalidomide, bortezomib, and/or dexamethasone discontinuation. Therefore, PVd treatment may improve patient outcomes, regardless of frailty.
Topics: Humans; Multiple Myeloma; Bortezomib; Lenalidomide; Frailty; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Thalidomide
PubMed: 38072743
DOI: 10.1016/j.clml.2023.10.009 -
Blood Research Jul 2020The therapeutic strategy for relapsed and refractory multiple myeloma (RRMM) integrates a holistic approach regarding patient, disease, and drug-related factors.... (Review)
Review
The therapeutic strategy for relapsed and refractory multiple myeloma (RRMM) integrates a holistic approach regarding patient, disease, and drug-related factors. Patient-related factors include age, frailty status, and underlying comorbidities, especially cardiovascular and renal diseases and peripheral neuropathies that affect tolerability to multiple drug combinations or transplantations. Disease-related factors encompass these multiple patient-related factors, particularly the aggressiveness of the disease and cytogenetics. Regarding drug-related factors, the approval of novel proteasome inhibitors (such as carfilzomib and ixazomib), immunomodulatory agents (such as pomalidomide), monoclonal antibodies (such as daratumumab and elotuzumab), and new classes of drugs increasingly makes the choice treatment more complex and necessitates a comprehensive summary and an update of the efficacy and toxicities of each antimyeloma drug and its combinations. Further, careful monitoring of the side effects and supportive care throughout the course of treatment are important to achieve better outcomes for patients with RRMM.
PubMed: 32719176
DOI: 10.5045/br.2020.S008 -
Blood Jul 2019
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Dexamethasone; Humans; Lenalidomide; Multiple Myeloma; Thalidomide
PubMed: 31296539
DOI: 10.1182/blood-2019-04-901157 -
ImmunoTargets and Therapy 2021Whereas the treatment of MM was dependent solely on alkylating agents and corticosteroids during the prior three decades, the landscape of therapeutic measures to treat... (Review)
Review
Whereas the treatment of MM was dependent solely on alkylating agents and corticosteroids during the prior three decades, the landscape of therapeutic measures to treat the disease began to expand enormously early in the current century. The introduction of new classes of small-molecule drugs, such as proteasome blockers (bortezomib and carfilzomib), immunomodulators (lenalidomide and pomalidomide), nuclear export inhibitors (selinexor), and histone deacetylase blockers (panobinostat), as well as the application of autologous stem cell transplantation (ASCT), resulted in a seismic shift in how the disease is treated. The picture changed dramatically once again starting with the 2015 FDA approval of two monoclonal antibodies (mAbs) - the anti-CD38 daratumumab and the anti-SLAMF7 elotuzumab. Daratumumab, in particular, has had a great impact on MM therapy and today is often included in various regimens to treat the disease, both in newly diagnosed cases and in the relapse/refractory setting. Recently, other immunotherapies have been added to the arsenal of drugs available to fight this malignancy. These include isatuximab (also anti-CD38) and, in the past year, the antibody-drug conjugate (ADC) belantamab mafodotin and the chimeric antigen receptor (CAR) T-cell product idecabtagene vicleucel (ide-cel). While the accumulated benefits of these newer agents have resulted in a doubling of the disease's five-year survival rate to more than 5 years and improved quality of life, the disease remains incurable. Almost without exception patients experience relapse and/or become refractory to the drugs used, making the search for innovative therapies all the more essential. This review covers the current scope of anti-myeloma immunotherapeutic agents, both those in clinical use and on the horizon, including naked mAbs, ADCs, bi- and multi-targeted mAbs, and CAR T-cells. Emphasis is placed on the benefits of each along with the challenges that need to be overcome if MM is to be considered curable in the future.
PubMed: 34527606
DOI: 10.2147/ITT.S306103 -
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 -
Oncotarget Mar 2018Chemotherapy with gemcitabine and nab-paclitaxel (gemcitabine/nab-paclitaxel) is recommended for unresectable pancreatic cancer. However, the therapeutic efficacy is...
BACKGROUND
Chemotherapy with gemcitabine and nab-paclitaxel (gemcitabine/nab-paclitaxel) is recommended for unresectable pancreatic cancer. However, the therapeutic efficacy is attenuated by the antitumor agent-induced activation of nuclear factor-κB (NF-κB). Thalidomide inhibits NF-κB activation, therefore, we hypothesized that pomalidomide, a third-generation IMiD, would also inhibit NF-κB activation and enhance the antitumor effects of gemcitabine/nab-paclitaxel.
METHODS
, we assessed NF-κB activity and apoptosis in response to pomalidomide alone, gemcitabine/nab-paclitaxel, or combination of pomalidomide and gemcitabine/nab-paclitaxel in human pancreatic cancer cell lines (PANC-1 and MIA PaCa-2). , we established orthotopic model and the animals were treated with oral pomalidomide and injection of gemcitabine/nab-paclitaxel.
RESULTS
In pomalidomide and gemcitabine/nab-paclitaxel group, gemcitabine/nab-paclitaxel-induced NF-κB activation was inhibited and apoptosis was enhanced in comparison with those in the other groups both and . Especially, this study revealed for the first time that pomalidomide enhances p53 on pancreatic cancer cells. The tumor growth in the pomalidomide and gemcitabine/nab-paclitaxel group was significantly slower than that in the gemcitabine/nab-paclitaxel group. Moreover, pomalidomide induced G0/G1 cell cycle arrest and suppressed angiogenesis.
CONCLUSIONS
Pomalidomide enhanced the antitumor effect of gemcitabine/nab-paclitaxel by inhibition of NF-κB activation. This combination regimen would be a novel strategy for treating pancreatic cancer.
PubMed: 29644009
DOI: 10.18632/oncotarget.24608 -
Discovery of Novel Bruton's Tyrosine Kinase PROTACs with Enhanced Selectivity and Cellular Efficacy.Journal of Medicinal Chemistry Jun 2023Bruton's tyrosine kinase (BTK) is a target for treating B-cell malignancies and autoimmune diseases, and several BTK inhibitors are already approved for use in humans....
Bruton's tyrosine kinase (BTK) is a target for treating B-cell malignancies and autoimmune diseases, and several BTK inhibitors are already approved for use in humans. Heterobivalent BTK protein degraders are also in development, based on the premise that proteolysis targeting chimeras (PROTACs) may provide additional therapeutic benefits. However, most BTK PROTACs are based on the BTK inhibitor ibrutinib raising concerns about their selectivity profiles, given the known off-target effects of ibrutinib. Here, we disclose the discovery and characterization of BTK PROTACs based on the selective BTK inhibitor and the cereblon recruitment ligand pomalidomide. is a highly potent BTK degrader (DC 0.5 nM) that inhibited cell growth and induced apoptosis at lower concentrations than the two parent molecules, as well as three previously reported BTK PROTACs, and had improved selectivity compared to ibrutinib-based BTK PROTACs.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; B-Lymphocytes; Cell Proliferation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proteolysis Targeting Chimera
PubMed: 37195170
DOI: 10.1021/acs.jmedchem.3c00176 -
American Society of Clinical Oncology... 2015Recent developments in the treatment of multiple myeloma (MM) have led to improvements in response rates and to increased survival. A major advance in the last decade... (Review)
Review
Recent developments in the treatment of multiple myeloma (MM) have led to improvements in response rates and to increased survival. A major advance in the last decade has been the introduction of the novel agents thalidomide, bortezomib, and lenalidomide as part of front-line treatment in both the transplant and nontransplant settings. However, disease relapse is inevitable for the majority of patients and myeloma typically recurs more aggressively with each relapse, eventually leading to the development of treatment-refractory disease. Several phase II and III trials have demonstrated the efficacy of recently approved agents in the setting of relapsed and relapsed and refractory MM, including pomalidomide and carfilzomib. Ixazomib, an oral proteasome inhibitor, and multiple other novel classes of agents are being investigated. These include monoclonal antibodies and histone deacetylase inhibitors, which may further add to the therapeutic armamentarium for this malignancy. Therefore, in a disease characterized by multiple relapses, the optimal sequencing of the different effective options is an important consideration in attempting to prolong survival.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Resistance, Neoplasm; Humans; Methotrexate; Multiple Myeloma; Neoplasm Recurrence, Local; Oligopeptides; Randomized Controlled Trials as Topic; Salvage Therapy; Stem Cell Transplantation; Thalidomide; Transplantation, Autologous; Vincristine
PubMed: 25993216
DOI: 10.14694/EdBook_AM.2015.35.e504 -
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 -
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