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Proceedings of the Japan Academy.... 2020Thalidomide, originally developed as a sedative drug, causes multiple defects due to severe teratogenicity, but it has been re-purposed for treating multiple myeloma,...
Thalidomide, originally developed as a sedative drug, causes multiple defects due to severe teratogenicity, but it has been re-purposed for treating multiple myeloma, and derivatives such as lenalidomide and pomalidomide have been developed for treating blood cancers. Although the molecular mechanisms of thalidomide and its derivatives remained poorly understood until recently, we identified cereblon (CRBN), a primary direct target of thalidomide, using ferrite glycidyl methacrylate (FG) beads. CRBN is a ligand-dependent substrate receptor of the E3 ubiquitin ligase complex cullin-RING ligase 4 (CRL4). When a ligand such as thalidomide binds to CRBN, it recognizes various 'neosubstrates' depending on the shape of the ligand. CRL4 binds many neosubstrates in the presence of various ligands. CRBN has been utilized in a novel protein knockdown technology named proteolysis targeting chimeras (PROTACs). Heterobifunctional molecules such as dBET1 are being developed to specifically degrade proteins of interest. Herein, we review recent advances in CRBN research.
Topics: Animals; Drug Repositioning; Humans; Molecular Targeted Therapy; Thalidomide
PubMed: 32522938
DOI: 10.2183/pjab.96.016 -
Blood Nov 2015Treatment options for patients with heavily pretreated relapsed and/or refractory multiple myeloma remain limited. We evaluated a novel therapeutic regimen consisting of...
Treatment options for patients with heavily pretreated relapsed and/or refractory multiple myeloma remain limited. We evaluated a novel therapeutic regimen consisting of carfilzomib, pomalidomide, and dexamethasone (CPD) in an open-label, multicenter, phase 1, dose-escalation study. Patients who relapsed after prior therapy or were refractory to the most recently received therapy were eligible. All patients were refractory to prior lenalidomide. Patients received carfilzomib IV on days 1, 2, 8, 9, 15, and 16 (starting dose of 20/27 mg/m(2)), pomalidomide once daily on days 1 to 21 (4 mg as the initial dose level), and dexamethasone (40 mg oral or IV) on days 1, 8, 15, and 22 of 28-day cycles. The primary objective was to evaluate the safety and determine the maximum tolerated dose (MTD) of the regimen. A total of 32 patients were enrolled. The MTD of the regimen was dose level 1 (carfilzomib 20/27 mg/m(2), pomalidomide 4 mg, dexamethasone 40 mg). Hematologic adverse events (AEs) occurred in ≥60% of all patients, including 11 patients with grade ≥3 anemia. Dyspnea was limited to grade 1/2 in 10 patients. Peripheral neuropathy was uncommon and limited to grade 1/2. Eight patients had dose reductions during therapy, and 7 patients discontinued treatment due to AEs. Two deaths were noted on study due to pneumonia and pulmonary embolism (n = 1 each). The combination of CPD is well-tolerated and highly active in patients with relapsed/refractory multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT01464034.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Multiple Myeloma; Oligopeptides; Pneumonia; Pulmonary Embolism; Recurrence; Thalidomide; Time Factors
PubMed: 26384354
DOI: 10.1182/blood-2015-05-643320 -
Journal of Clinical Oncology : Official... Jan 2023In the phase II ELOQUENT-3 trial (ClinicalTrials.gov identifier: NCT02654132), elotuzumab combined with pomalidomide/dexamethasone (EPd) significantly improved... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
In the phase II ELOQUENT-3 trial (ClinicalTrials.gov identifier: NCT02654132), elotuzumab combined with pomalidomide/dexamethasone (EPd) significantly improved progression-free survival (PFS) versus pomalidomide/dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma (RRMM) previously treated with lenalidomide and a proteasome inhibitor (PI). Here, we present the final overall survival (OS) results.
METHODS
Patients with RRMM who had received ≥ 2 prior lines of therapy, with disease refractory to last therapy and either refractory or relapsed and refractory to lenalidomide and a PI were randomly assigned (1:1) to receive EPd or Pd. The primary end point was PFS per investigator assessment. ORR and OS were secondary end points planned to be tested hierarchically.
RESULTS
A total of 117 patients were randomly assigned to EPd (n = 60) and Pd (n = 57). Among treated patients (EPd 60, Pd 55), there were 37 (61.7%) deaths in the EPd group and 41 (74.5%) in the Pd group, most commonly because of disease progression (EPd 41.7%, Pd 49.1%). Median (95% CI) OS was significantly improved with EPd (29.8 [22.9 to 45.7] months) versus Pd (17.4 [13.8 to 27.7] months), with a hazard ratio of 0.59 (95% CI, 0.37 to 0.93; = .0217). OS benefit with EPd was observed in most patient subgroups. The safety profile of EPd was consistent with prior reports with no new safety signals detected.
CONCLUSION
EPd demonstrated a statistically significant improvement in OS versus Pd in patients with RRMM previously treated with lenalidomide and a PI who had disease refractory to last therapy. In this setting, ELOQUENT-3 is the first randomized study of a triplet regimen incorporating a monoclonal antibody and Pd to improve both PFS and OS significantly.
Topics: Humans; Multiple Myeloma; Lenalidomide; Antineoplastic Combined Chemotherapy Protocols; Survival Analysis; Dexamethasone
PubMed: 35960908
DOI: 10.1200/JCO.21.02815 -
Clinical Lymphoma, Myeloma & Leukemia Jul 2022Despite the increasing number of treatment options available for multiple myeloma, relapse is still inevitable and there remains a critical unmet need for treatments for... (Review)
Review
Despite the increasing number of treatment options available for multiple myeloma, relapse is still inevitable and there remains a critical unmet need for treatments for patients with late-stage, highly refractory disease. In this review, we discuss currently approved treatment options for heavily pretreated patients with relapsed and refractory multiple myeloma, with a focus on the optimal management of patients with MM refractory to lenalidomide, bortezomib, and in some cases, daratumumab or an anti-CD38 monoclonal antibody. Data from recent clinical trials of immunomodulatory agents (pomalidomide), proteasome inhibitors (PIs; carfilzomib and ixazomib), monoclonal antibodies (elotuzumab, daratumumab, and isatuximab), and other novel therapies (including panobinostat-based therapy) are summarized. We also provide potential therapeutic strategies for patients according to different treatment histories, and include case studies to illustrate the practical use of various treatment options in a clinical setting. Regimens containing pomalidomide, elotuzumab, next-generation PIs, panobinostat, or selinexor may provide effective treatment options in patients with triple-refractory disease. The choice of agents used, and combinations thereof should be individualized as well as strategically planned from early- to late-stage relapse.
Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Lenalidomide; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat; Proteasome Inhibitors
PubMed: 35148975
DOI: 10.1016/j.clml.2022.01.011 -
Endocrinology, Diabetes & Metabolism... 2017Hypothyroidism is a recognized side effect of thalidomide drugs. We herein report a case of 83-year-old Irish female with a diagnosis of multiple myeloma and a...
UNLABELLED
Hypothyroidism is a recognized side effect of thalidomide drugs. We herein report a case of 83-year-old Irish female with a diagnosis of multiple myeloma and a background history of type 2 diabetes mellitus and hypertension. Our patient received pomalidomide and multiple courses of chemotherapy and achieved very good initial response for her multiple myeloma but subsequently she relapsed. She did not have any past history of thyroid disease or family history of thyroid disorders. Prior to treatment with pomalidomide, her thyroid function test was completely normal. She was commenced on pomalidomide in February 2017. Four weeks post treatment, she presented with worsening fatigue, and as a part of her workup, a thyroid function test was performed. Her free T4 was low at 7.2 pmol/L (reference range: 9.0-20.0) while her TSH was elevated at 44.7 mIU/L (reference range: 0.35-4.94). Pomalidomide treatment was terminated, and she was commenced on thyroid hormonal therapy replacement therapy with thyroxine with good clinical and biochemical response. Practitioners prescribing pomalidomide should be aware of this potential complication and patients who are receiving immunomodulatory drugs like pomalidomide should undergo regular thyroid hormone levels screen.
LEARNING POINTS
Overt hypothyroidism is a side effect of pomalidomide.Thyroid function test should be included as a screening test with regular review in patients receiving pomalidomide.Unexplained worsening fatigue in patients receiving pomalidomide should raise the possibility of overt hypothyroidism.
PubMed: 29302330
DOI: 10.1530/EDM-17-0110 -
Leukemia Jun 2021In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone (PVd) demonstrated superior efficacy vs bortezomib and dexamethasone (Vd) in patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone (PVd) demonstrated superior efficacy vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma previously treated with lenalidomide, including those refractory to lenalidomide. This analysis evaluated outcomes in patients at first relapse (N = 226) by lenalidomide-refractory status, prior bortezomib exposure, and prior stem cell transplant (SCT). Second-line PVd significantly improved PFS vs Vd in lenalidomide-refractory (17.8 vs 9.5 months; P = 0.0276) and lenalidomide-nonrefractory patients (22.0 vs 12.0 months; P = 0.0491), patients with prior bortezomib (17.8 vs 12.0 months; P = 0.0068), and patients with (22.0 vs 13.8 months; P = 0.0241) or without (16.5 vs 9.5 months; P = 0.0454) prior SCT. In patients without prior bortezomib, median PFS was 20.7 vs 9.5 months (P = 0.1055). Significant improvement in overall response rate was also observed with PVd vs Vd in lenalidomide-refractory (85.9% vs 50.8%; P < 0.001) and lenalidomide-nonrefractory (95.7% vs 60.0%; P < 0.001) patients, with similar results regardless of prior bortezomib or SCT. No new safety signals were observed. These data demonstrate the benefit of PVd at first relapse, including immediately after upfront lenalidomide treatment failure and other common first-line treatments.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Lenalidomide; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Prognosis; Salvage Therapy; Survival Rate; Thalidomide
PubMed: 32895455
DOI: 10.1038/s41375-020-01021-3 -
Leukemia Aug 2018
Topics: Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Dexamethasone; Follow-Up Studies; Humans; Multiple Myeloma; Oligopeptides; Prognosis; Survival Rate; Thalidomide
PubMed: 29479061
DOI: 10.1038/s41375-018-0024-1 -
Blood Jun 2016The International Myeloma Working Group consensus updates the definition for high-risk (HR) multiple myeloma based on cytogenetics Several cytogenetic abnormalities such...
The International Myeloma Working Group consensus updates the definition for high-risk (HR) multiple myeloma based on cytogenetics Several cytogenetic abnormalities such as t(4;14), del(17/17p), t(14;16), t(14;20), nonhyperdiploidy, and gain(1q) were identified that confer poor prognosis. The prognosis of patients showing these abnormalities may vary with the choice of therapy. Treatment strategies have shown promise for HR cytogenetic diseases, such as proteasome inhibition in combination with lenalidomide/pomalidomide, double autologous stem cell transplant plus bortezomib, or combination of immunotherapy with lenalidomide or pomalidomide. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. Cross-trial comparisons may provide insight into the effect of new drugs in patients with cytogenetic abnormalities. However, to achieve this, consensus on definitions of analytical techniques, proportion of abnormal cells, and treatment regimens is needed. Based on data available today, bortezomib and carfilzomib treatment appear to improve complete response, progression-free survival, and overall survival in t(4;14) and del(17/17p), whereas lenalidomide may be associated with improved progression-free survival in t(4;14) and del(17/17p). Patients with multiple adverse cytogenetic abnormalities do not benefit from these agents. FISH data are implemented in the revised International Staging System for risk stratification.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Chromosome Aberrations; Combined Modality Therapy; Consensus; Cytogenetics; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Multiple Myeloma; Prognosis; Risk Factors; Thalidomide; Transplantation, Autologous
PubMed: 27002115
DOI: 10.1182/blood-2016-01-631200