95 research outputs found
Phase 3 randomised study of daratumumab, bortezomib and dexamethasone (DVd) vs bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR
Novel Therapeutic Agents for the Management of Patients with Multiple Myeloma and Renal Impairment
Cancer cell sensitivity to bortezomib is associated with survivin expression and p53 status but not cancer cell types
<p>Abstract</p> <p>Background</p> <p>Survivin is known playing a role in drug resistance. However, its role in bortezomib-mediated inhibition of growth and induction of apoptosis is unclear. There are conflicting reports for the effect of bortezomib on survivin expression, which lacks of a plausible explanation. Methods: In this study, we tested cancer cells with both p53 wild type and mutant/null background for the relationship of bortezomib resistance with survivin expression and p53 status using MTT assay, flow cytometry, DNA fragmentation, caspase activation, western blots and RNAi technology.</p> <p>Results</p> <p>We found that cancer cells with wild type p53 show a low level expression of survivin and are sensitive to treatment with bortezomib, while cancer cells with a mutant or null p53 show a high level expression of survivin and are resistant to bortezomib-mediated apoptosis induction. However, silencing of survivin expression utilizing survivin mRNA-specific siRNA/shRNA in p53 mutant or null cells sensitized cancer cells to bortezomib mediated apoptosis induction, suggesting a role for survivin in bortezomib resistance. We further noted that modulation of survivin expression by bortezomib is dependent on p53 status but independent of cancer cell types. In cancer cells with mutated p53 or p53 null, bortezomib appears to induce survivin expression, while in cancer cells with wild type p53, bortezomib downregulates or shows no significant effect on survivin expression, which is dependent on the drug concentration, cell line and exposure time.</p> <p>Conclusions</p> <p>Our findings, for the first time, unify the current inconsistent findings for bortezomib treatment and survivin expression, and linked the effect of bortezomib on survivin expression, apoptosis induction and bortezomib resistance in the relationship with p53 status, which is independent of cancer cell types. Further mechanistic studies along with this line may impact the optimal clinical application of bortezomib in solid cancer therapeutics.</p
In Support of a Patient-Driven Initiative and Petition to Lower the High Price of Cancer Drugs
Comment in
Lowering the High Cost of Cancer Drugs--III. [Mayo Clin Proc. 2016]
Lowering the High Cost of Cancer Drugs--I. [Mayo Clin Proc. 2016]
Lowering the High Cost of Cancer Drugs--IV. [Mayo Clin Proc. 2016]
In Reply--Lowering the High Cost of Cancer Drugs. [Mayo Clin Proc. 2016]
US oncologists call for government regulation to curb drug price rises. [BMJ. 2015
Novel therapeutic agents for the management of patients with multiple myeloma and renal impairment
Renal impairment is a major complication of multiple myeloma. Patients presenting with severe renal impairment represent a greater therapeutic challenge and generally have poorer outcome. However, once patients with renal impairment achieve remission, their outcomes are comparable with those of patients without renal impairment. Therapies that offer substantial activity in this setting are needed. Bortezomib, thalidomide, and lenalidomide have substantially improved the survival of patients with multiple myeloma. Here we review the pharmacokinetics, activity, and safety of these agents in patients with renal impairment. Bortezomib can be administered at the full approved dose and schedule in renally impaired patients; similarly, no dose reductions are required with thalidomide. The pharmacokinetics of lenalidomide is affected by its renal route of excretion, and dose adjustments are recommended for moderate/severe impairment. Substantial evidence has emerged showing that these novel agents improve outcomes of patients with renal impairment, including impairment reversal. Bortezomib, thalidomide, and lenalidomide (at the recommended doses) are active options for patients with mild to moderate impairment, although limited data are available for thalidomide. Information on lenalidomide-based combinations is still emerging, but the available data indicate considerable activity. Substantial evidence indicates that bortezomib-high-dose dexamethasone with or without a third drug (e.g., cyclophosphamide, thalidomide, or doxorubicin) is an appropriate option for patients with any degree of renal impairment. ©2012 AACR.Peer Reviewe
Lenalidomide-Associated Tumor Flare Reaction Is Manageable in Patients With Chronic Lymphocytic Leukemia
Novel therapeutic agents for the management of patients with multiple myeloma and renal impairment
Renal impairment is a major complication of multiple myeloma. Patients presenting with severe renal impairment represent a greater therapeutic challenge and generally have poorer outcome. However, once patients with renal impairment achieve remission, their outcomes are comparable with those of patients without renal impairment. Therapies that offer substantial activity in this setting are needed. Bortezomib, thalidomide, and lenalidomide have substantially improved the survival of patients with multiple myeloma. Here we review the pharmacokinetics, activity, and safety of these agents in patients with renal impairment. Bortezomib can be administered at the full approved dose and schedule in renally impaired patients; similarly, no dose reductions are required with thalidomide. The pharmacokinetics of lenalidomide is affected by its renal route of excretion, and dose adjustments are recommended for moderate/severe impairment. Substantial evidence has emerged showing that these novel agents improve outcomes of patients with renal impairment, including impairment reversal. Bortezomib, thalidomide, and lenalidomide (at the recommended doses) are active options for patients with mild to moderate impairment, although limited data are available for thalidomide. Information on lenalidomide-based combinations is still emerging, but the available data indicate considerable activity. Substantial evidence indicates that bortezomib-high-dose dexamethasone with or without a third drug (e.g., cyclophosphamide, thalidomide, or doxorubicin) is an appropriate option for patients with any degree of renal impairment. ©2012 AACR
An Investigational Proteasome Inhibitor MLN9708 (MLN2238) Induces Apoptosis In Human Multiple Myeloma Cells In Vitro
Lenalidomide in combination with dexamethasone improves survival and time-to-progression in patients≥ 65 years old with relapsed or refractory multiple myeloma
Two pivotal, phase III, randomised, placebo-controlled, registration
trials (MM-009 and MM-010) showed that lenalidomide plus dexamethasone
was more effective than placebo plus dexamethasone in the treatment of
patients with relapsed or refractory multiple myeloma. This pooled,
retrospective subanalysis of MM-009 and MM-010 analysed outcomes
according to patient age. A total of 704 patients (390 aged < 65 years,
232 aged 65-74 years, and 82 aged >= 75 years) received lenalidomide or
placebo, both in combination with dexamethasone. The overall response
rate (ORR) was significantly higher in patients treated with
lenalidomide plus dexamethasone versus placebo plus dexamethasone in all
age groups (P < 0.0001 for all). Median progression-free survival (PFS)
and median time-to-progression (TTP) were similar, and both were
significantly longer with lenalidomide plus dexamethasone in all age
groups (P < 0.001 for all). Median overall survival (OS) favoured
lenalidomide plus dexamethasone in all age groups, although the
difference was not statistically significant. Adverse events of anaemia,
febrile neutropenia, deep-vein thrombosis, neuropathy, and
gastrointestinal disorders increased with age. Lenalidomide combined
with dexamethasone improved the ORR and prolonged PFS, TTP, and OS
compared with placebo plus dexamethasone, irrespective of age. This
finding was consistent with the overall MM-009 and MM-010 populations
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