Dataset Information

In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma.

ABSTRACT:

Background

Combinations of drug treatments based on bortezomib or lenalidomide plus steroids have resulted in very high response rates in multiple myeloma. However, most patients still relapse, indicating the need for novel combination partners to increase duration of response or to treat relapsed disease. We explored the antimyeloma activity of triple combinations of these well-established schemes with panobinostat, a novel deacetylase inhibitor with a multi-targeted profile.

Design and methods

The activity of these combinations was explored in vitro in cell lines by using MTT and annex-in V, ex vivo by flow cytometry, and in vivo using two different murine models of human myeloma: one bearing a subcutaneous plasmacytoma and another with a disseminated myeloma. Moreover, gene expression profiling and immunohistochemical studies were performed.

Results

The addition of panobinostat (LBH589) to dexamethasone and either bortezomib or lenalidomide resulted in clear potentiation in multiple myeloma cell lines, freshly isolated plasma cells, and murine models of multiple myeloma. The quantification of the potency of these combinations by using the Chou-Talalay method showed synergistic combination indices for all of them. This effect derived from the deregulation of a cluster of genes that was completely different from the sum of genes affected by the single agents (895 and 1323 genes exclusively deregulated by panobinostat and dexamethasone plus bortezomib or lenalidomide, respectively). Functional experiments, such as annexin V staining, cell cycle analysis, and immunohistochemical studies also supported this potentiation. Anti-myeloma efficacy was confirmed in an extramedullary plasmacytoma model and a disseminated luciferized model, in which panobinostat also provided a marked benefit in bone disease.

Conclusions

The potent activity, together with the exclusive mechanistic profile, provides the rationale for the clinical evaluation of these drug combinations in multiple myeloma.

SUBMITTER: Ocio EM

PROVIDER: S-EPMC2864386 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma.

Ocio Enrique M EM Vilanova David D Atadja Peter P Maiso Patricia P Crusoe Edvan E Fernández-Lázaro Diego D Garayoa Mercedes M San-Segundo Laura L Hernández-Iglesias Teresa T de Alava Enrique E Shao Wenlin W Yao Yung-Mae YM Pandiella Atanasio A San-Miguel Jesús F JF

Haematologica 20091130 5

<h4>Background</h4>Combinations of drug treatments based on bortezomib or lenalidomide plus steroids have resulted in very high response rates in multiple myeloma. However, most patients still relapse, indicating the need for novel combination partners to increase duration of response or to treat relapsed disease. We explored the antimyeloma activity of triple combinations of these well-established schemes with panobinostat, a novel deacetylase inhibitor with a multi-targeted profile.<h4>Design ...[more]

PMID: 19951978

Similar Datasets

Project description:BackgroundHigh-dose chemotherapy plus autologous stem-cell transplantation has been the standard treatment for newly diagnosed multiple myeloma in adults up to 65 years of age. However, promising data on the use of combination therapy with lenalidomide, bortezomib, and dexamethasone (RVD) in this population have raised questions about the role and timing of transplantation.MethodsWe randomly assigned 700 patients with multiple myeloma to receive induction therapy with three cycles of RVD and then consolidation therapy with either five additional cycles of RVD (350 patients) or high-dose melphalan plus stem-cell transplantation followed by two additional cycles of RVD (350 patients). Patients in both groups received maintenance therapy with lenalidomide for 1 year. The primary end point was progression-free survival.ResultsMedian progression-free survival was significantly longer in the group that underwent transplantation than in the group that received RVD alone (50 months vs. 36 months; adjusted hazard ratio for disease progression or death, 0.65; P<0.001). This benefit was observed across all patient subgroups, including those stratified according to International Staging System stage and cytogenetic risk. The percentage of patients with a complete response was higher in the transplantation group than in the RVD-alone group (59% vs. 48%, P=0.03), as was the percentage of patients in whom minimal residual disease was not detected (79% vs. 65%, P<0.001). Overall survival at 4 years did not differ significantly between the transplantation group and the RVD-alone group (81% and 82%, respectively). The rate of grade 3 or 4 neutropenia was significantly higher in the transplantation group than in the RVD-alone group (92% vs. 47%), as were the rates of grade 3 or 4 gastrointestinal disorders (28% vs. 7%) and infections (20% vs. 9%). No significant between-group differences were observed in the rates of treatment-related deaths, second primary cancers, thromboembolic events, and peripheral neuropathy.ConclusionsAmong adults with multiple myeloma, RVD therapy plus transplantation was associated with significantly longer progression-free survival than RVD therapy alone, but overall survival did not differ significantly between the two approaches. (Supported by Celgene and others; IFM 2009 Study ClinicalTrials.gov number, NCT01191060 .).

Dataset Information

In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma.

Background

Design and methods

Results

Conclusions

Publications

In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets