The European Medicines Agency Review of Carfilzomib for the Treatment of Adult Patients with Multiple Myeloma Who Have Received at Least One Prior Therapy

Tzogani, Kyriaki; Jiménez, Jorge Camarero; García, Isabel; Sancho-Lopez, Arantxa; Martin, Marc Pujalte; Moreau, Alexandre; Démolis, Pierre; Salmonson, Tomas; Bergh, Jonas; Laane, Edward; Ludwig, Heinz; Gisselbrecht, Christian; Pignatti, Francesco

doi:10.1634/theoncologist.2017-0184

Cited by 13 publications

(12 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also treatment of isolated fibroblasts from IPF-patients with the pan-HDAC inhibitor panobinostat/LBH589 reduced significantly profibrotic genes and also diminished the synthesis of anti-apoptosis molecules [ 31 ]. Thus, these anticancer agents hold great promise and could be readily progressed into an IPF clinical trial, as SAHA (vorinostat) and romidepsin are licensed and established therapies for cutaneous T-cell lymphoma (CTCL) [ 39 ], and LBH589 for multiple myeloma [ 34 – 36 ]. LBH589 is an orally available, novel hydroxamic acid pan-HDAC inhibitor that potently inhibits all class I, -II and IV HDAC enzymes at low nanomolar concentrations [ 34 , 38 , 39 ], and is reported to be at least 10-fold more potent than SAHA [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

“…Panobinostat (Farydak ® ) was developed by Novartis for the treatment of various cancers, and in February 2015 it received accelerated approval by the US Food and Drug Administration (FDA) for treatment of adult patients with multiple myeloma. In August 2015 it was approved by the European Medicines Agency for the same use [ 34 – 36 ]. Currently, this neoplastic drug is along with other HDAC inhibitors also being studied in patients with HIV for potential to affect latent HIV viral reservoirs, as it has demonstrated effective disruption of HIV latency in these patients [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Comparison of the antifibrotic effects of the pan-histone deacetylase-inhibitor panobinostat versus the IPF-drug pirfenidone in fibroblasts from patients with idiopathic pulmonary fibrosis

et al. 2018

View full text Add to dashboard Cite

BackgroundIdiopathic pulmonary fibrosis (IPF) is a devastating lung disease with a poor prognosis. Pirfenidone is the first antifibrotic agent to be approved for IPF-treatment as it is able to slow down disease progression. However, there is no curative treatment other than lung transplantation. Because epigenetic alterations are associated with IPF, histone deacetylase (HDAC)-inhibitors have recently been proven to attenuate fibrotic remodeling in vitro and in vivo. This study compared the effects of pirfenidone with the pan-HDAC-inhibitor panobinostat/LBH589, a FDA-approved drug for the treatment of multiple myeloma, head-to-head on survival, fibrotic activity and proliferation of primary IPF-fibroblasts in vitro.MethodsPrimary fibroblasts from six IPF-patients were incubated for 24h with vehicle (0.25% DMSO), panobinostat (LBH589, 85 nM) or pirfenidone (2.7 mM), followed by assessment of proliferation and expression analyses for profibrotic and anti-apoptosis genes, as well as for ER stress and apoptosis-markers. In addition, the expression status of all HDAC enzymes was examined.ResultsTreatment of IPF-fibroblasts with panobinostat or pirfenidone resulted in a downregulated expression of various extracellular matrix (ECM)-associated genes, as compared to vehicle-treated cells. In agreement, both drugs decreased protein level of phosphorylated (p)-STAT3, a transcription factor mediating profibrotic responses, in treated IPF-fibroblasts. Further, an increase in histone acetylation was observed in response to both treatments, but was much more pronounced and excessive in panobinostat-treated IPF-fibroblasts. Panobinostat, but not pirfenidone, led to a significant suppression of proliferation in IPF-fibroblasts, as indicated by WST1- and BrdU assay and markedly diminished levels of cyclin-D1 and p-histone H3. Furthermore, panobinostat-treatment enhanced α-tubulin-acetylation, decreased the expression of survival-related genes Bcl-XL and BIRC5/survivin, and was associated with induction of ER stress and apoptosis in IPF-fibroblasts. In contrast, pirfenidone-treatment maintained Bcl-XL expression, and was neither associated with ER stress-induction nor any apoptotic signaling. Pirfenidone also led to increased expression of HDAC6 and sirtuin-2, and enhanced α-tubulin-deacetylation. But in line with its ability to increase histone acetylation, pirfenidone reduced the expression of HDAC enzymes HDAC1, -2 and -9.ConclusionsWe conclude that, beside other antifibrotic mechanisms, pirfenidone reduces profibrotic signaling also through STAT3 inactivation and weak epigenetic alterations in IPF-fibroblasts, and permits survival of (altered) fibroblasts. The pan-HDAC-inhibitor panobinostat reduces profibrotic phenotypes while inducing cell cycle arrest and apoptosis in IPF-fibroblasts, thus indicating more efficiency than pirfenidone in inactivating IPF-fibroblasts. We therefore believe that HDAC-inhibitors such as panobinostat can present a novel therapeutic strategy for IPF.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparison of the antifibrotic effects of the pan-histone deacetylase-inhibitor panobinostat versus the IPF-drug pirfenidone in fibroblasts from patients with idiopathic pulmonary fibrosis

et al. 2018

View full text Add to dashboard Cite

show abstract

“…1,2 The accelerated approval of carfilzomib in July 2012 was based on the promising results of a single-arm multicenter trial enrolling 266 patients with recurrent and/or refractory multiple myeloma. The next-generation proteasome inhibitor carfilzomib is reported to increase the frequency and depth of responses, and improves survival in heavily pretreated patients with multiple myeloma.…”

Section: Introductionmentioning

confidence: 99%

“…The next-generation proteasome inhibitor carfilzomib is reported to increase the frequency and depth of responses, and improves survival in heavily pretreated patients with multiple myeloma. 1,2 The accelerated approval of carfilzomib in July 2012 was based on the promising results of a single-arm multicenter trial enrolling 266 patients with recurrent and/or refractory multiple myeloma. The overall response rate in this heavily pretreated population was 23%, with a median duration of response of 7.8 months.…”

Section: Introductionmentioning

confidence: 99%

Measuring cardiopulmonary complications of carfilzomib treatment and associated risk factors using the SEER‐Medicare database

Fakhri

Fiala

Shah

et al. 2019

Cancer

View full text Add to dashboard Cite

BACKGROUND: Carfilzomib improves survival in patients with recurrent myeloma. Given the strict eligibility criteria in clinical trials, the actual frequency of cardiac adverse events (CAEs) and pulmonary adverse events (PAEs) and the risk factors associated with these AEs in the general population need to be established. METHODS: The authors extracted myeloma cases in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database from 2000 through 2013 and corresponding claims through 2014. They then identified patients who received carfilzomib during their disease course. Subsequently, the International Classification of Diseases, Ninth Revision (ICD-9) was used to identify all the codes for CAEs, PAEs, and respiratory infections associated with carfilzomib use. Preexisting diagnoses corresponding to the CAEs and PAEs of interest were excluded to distinguish toxicity from comorbidity. Multivariate Cox regression was performed to determine those variables independently associated with the development of CAEs and PAEs. RESULTS: Of the 635 patients analyzed, the median age was 72 years (range, 36-94 years); 55% of the patients were male and 79% were white. The median duration of carfilzomib treatment was 58 days (range, 1-716 days). Overall, approximately 66% of the patients had codes for either CAEs or PAEs. In terms of CAEs, approximately 22% of patients developed hypertension, 15% developed peripheral edema, and 14% experienced heart failure. With regard to PAEs, approximately 28% of patients developed dyspnea, 15% developed cough, and 15% developed pneumonia. Only chronic obstructive pulmonary disease (COPD) was found to be independently associated with the development of CAEs. Patients with preexisting COPD were found to have a 40% increase in their hazard of developing CAEs (adjusted hazard ratio, 1.40; 95% CI, 1.03-1.90). CONCLUSIONS: In older adults with myeloma who are undergoing treatment with carfilzomib, new cardiac and pulmonary diagnoses were common. Patients with preexisting COPD were found to be at an increased risk of developing CAEs. Cancer 2020;126:808-813.

show abstract

“…herpes zoster in patients treated with proteasome inhibitors or high-dose dexamethasone, for which effective antiviral prophylaxis is mandatory). Some recent papers show a possible association of some novel drugs with infection 16 - 25 . Thus, a possible causative link between certain drugs and infection occurrence must be investigated in further clinical studies, and the results can be incorporated into a subsequent modification of the proposed index.…”

Section: Discussionmentioning

confidence: 99%

Multiple Myeloma Index for Risk of Infection

Valković¹,

Gacic²,

Načinović-Duletić³

2018

J. Cancer

View full text Add to dashboard Cite

Based on our earlier research into the main characteristics and risk factors for infections in hospitalized patients with multiple myeloma, we created the numerical Multiple Myeloma Index for Risk of Infection (MMIRI) to predict infection in myeloma patients. The included factors that could influence the pathogenesis and incidence of infections were sex, performance status, Durie Salmon stage of disease, International Staging System, serum creatinine level, immune paresis, neutropenia, serum ferritin level, the presence of any catheters, disease duration, stable/progressive disease, and type of therapy. For each of these parameters, the strength of association with infection was statistically estimated and specific number of points was assigned to each of these parameters, proportional to the strength of the association. When designing the MMIRI, we included only those parameters that we determined were pathophysiologically associated with the infection. After further statistical analysis, we identified an optimal cutoff score of 6 or above as indicating a significant risk for infection, with a sensitivity of 93.2% and specificity of 80.2%. The scoring system in the retrospective receiver operating characteristic analysis showed an area under the curve of 0.918. The potential value of the MMIRI is the possibility of identifying those patients who would benefit from the prophylactic administration of antibiotics and other anti-infective measures while minimizing the contribution to antibiotic resistance related to the overuse of these drugs. As far as we know, this index represents the first attempt to create such an instrument for predicting the occurrence of infections in myeloma patients.

show abstract

The European Medicines Agency Review of Carfilzomib for the Treatment of Adult Patients with Multiple Myeloma Who Have Received at Least One Prior Therapy

Abstract: This article summarizes the scientific review of the application leading to regulatory approval of carfilzomib in combination with lenalidomide and dexamethasone in the European Union.

Cited by 13 publications

References 21 publications

Comparison of the antifibrotic effects of the pan-histone deacetylase-inhibitor panobinostat versus the IPF-drug pirfenidone in fibroblasts from patients with idiopathic pulmonary fibrosis

Comparison of the antifibrotic effects of the pan-histone deacetylase-inhibitor panobinostat versus the IPF-drug pirfenidone in fibroblasts from patients with idiopathic pulmonary fibrosis

Measuring cardiopulmonary complications of carfilzomib treatment and associated risk factors using the SEER‐Medicare database

Multiple Myeloma Index for Risk of Infection

Contact Info

Product

Resources

About