Dataset Information

Rational combination treatment with histone deacetylase inhibitors and immunomodulatory drugs in multiple myeloma.

ABSTRACT: Immunomodulatory drugs (IMiDs) thalidomide, lenalidomide (Len) and pomalidomide trigger anti-tumor activities in multiple myeloma (MM) by targetting cereblon and thereby impacting IZF1/3, c-Myc and IRF4. Histone deacetylase inhibitors (HDACi) also downregulate c-Myc. We therefore determined whether IMiDs with HDACi trigger significant MM cell growth inhibition by inhibiting or downregulating c-Myc. Combination treatment of Len with non-selective HDACi suberoylanilide hydroxamic acid or class-I HDAC-selective inhibitor MS275 induces synergic cytotoxicity, associated with downregulation of c-Myc. Unexpectedly, we observed that decreased levels of cereblon (CRBN), a primary target protein of IMiDs, was triggered by these agents. Indeed, sequential treatment of MM cells with MS275 followed by Len shows less efficacy than simultaneous treatment with this combination. Importantly ACY1215, an HDAC6 inhibitor with minimal effects on class-I HDACs, together with Len induces synergistic MM cytotoxicity without alteration of CRBN expression. Our results showed that only modest class-I HDAC inhibition is able to induce synergistic MM cytotoxicity in combination with Len. These studies may provide the framework for utilizing HDACi in combination with Len to both avoid CRBN downregulation and enhance anti-MM activities.

SUBMITTER: Hideshima T

PROVIDER: S-EPMC4476017 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Rational combination treatment with histone deacetylase inhibitors and immunomodulatory drugs in multiple myeloma.

Hideshima T T Cottini F F Ohguchi H H Jakubikova J J Gorgun G G Mimura N N Tai Y-T YT Munshi N C NC Richardson P G PG Anderson K C KC

Blood cancer journal 20150515

Immunomodulatory drugs (IMiDs) thalidomide, lenalidomide (Len) and pomalidomide trigger anti-tumor activities in multiple myeloma (MM) by targetting cereblon and thereby impacting IZF1/3, c-Myc and IRF4. Histone deacetylase inhibitors (HDACi) also downregulate c-Myc. We therefore determined whether IMiDs with HDACi trigger significant MM cell growth inhibition by inhibiting or downregulating c-Myc. Combination treatment of Len with non-selective HDACi suberoylanilide hydroxamic acid or class-I H ...[more]

PMID: 25978432

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Project description:Carfilzomib, a selective proteasome inhibitor (PI), is approved for the treatment of patients with relapsed or refractory multiple myeloma (MM). Combination regimens incorporating a PI and immunomodulatory drug (IMiD) have been associated with deep responses and extended survival in patients with newly diagnosed MM (NDMM). Carfilzomib-based combinations with immunomodulators are being extensively studied in the frontline setting. The objective of this review was to describe efficacy and safety data for carfilzomib-based, PI/immunomodulatory combinations in NDMM. Information sources were articles indexed in PubMed and abstracts from key hematology/oncology congresses published between January 2012 and December 2018. PubMed and congresses were searched for prospective clinical studies assessing the combination of carfilzomib with an IMiD for NDMM treatment. Retrospective and preclinical reports, case reports/series, reviews, and clinical studies not evaluating carfilzomib-immunomodulator combinations in NDMM were excluded based on review of titles and abstracts. A total of nine articles and 72 abstracts were deemed relevant and included in the review. A total of six distinct carfilzomib-based, PI/immunomodulator combination regimens have been evaluated in 12 clinical trials. Overall, treatment with these regimens has resulted in deep responses, including high rates of negativity for minimal residual disease. These deep responses have translated to long progression-free survival and overall survival rates. Efficacy results for these regimens have generally been consistent across subgroups defined by age, transplant eligibility, and cytogenetic risk. The safety profile of carfilzomib in NDMM is consistent with that observed in the relapsed-refractory MM setting. Clinical studies have found that carfilzomib-based combinations with immunomodulators are highly active with a favorable safety profile in NDMM. The carfilzomib, lenalidomide, and dexamethasone (KRd) drug backbone is a promising foundation for treatment strategies aimed at achieving long-term, deep responses (functional cures) in the frontline setting. Several ongoing studies are evaluating KRd, with or without anti-CD38 monoclonal antibodies.

Project description:BACKGROUND:Immunomodulatory drugs (thalidomide, lenalidomide and pomalidomide; IMID) are widely used in the treatment of multiple myeloma patients. To date, few data are available on IMID adherence in multiple myeloma patients. The aim of our study was to evaluate IMID adherence and to compare two indirect methods to measure IMID adherence in multiple myeloma patients: a specific questionnaire and the medication possession ratio (MPR). Another aim was to explore this specific questionnaire for the assessment of IMID adherence in multiple myeloma patients. METHODS:All consecutive multiple myeloma patients, with at least two consecutive dispensations of thalidomide, lenalidomide or pomalidomide in our hospital were included in this prospective study. IMID adherence was measured using a specific questionnaire and the medication possession ratio. Relationship between the questionnaire scores and variables of interest was evaluated by multiple linear regression with a robust variance estimator. FINDINGS:Sixty-three patients were included in our study. The mean questionnaire score was 8.2±1.2 and the mean medication possession ratio value was 0.97±0.06. A total of 76% of patients were considered adherent according to the questionnaire (i.e. score ≥ 8), 94% according to the medication possession ratio (i.e. MPR ≥ 0.90), and 70% according to the questionnaire and the medication possession ratio. No statistically significant linear association was observed between the questionnaire score and any variables of interest including medication possession ratio. All Cronbach's alpha were relatively low (range 0.0342-0.2443), showing a low correlation of the different questions with the questionnaire score. CONCLUSIONS:Our study is the first prospective study evaluating IMID adherence in multiple myeloma patients in real life. The high adherence to IMIDs reported here, regardless of the drug, is encouraging considering the efficacy, toxicity and elevated cost of IMIDs. The specific questionnaire should be used with caution to evaluate IMID adherence.

Dataset Information

Rational combination treatment with histone deacetylase inhibitors and immunomodulatory drugs in multiple myeloma.

Publications

Rational combination treatment with histone deacetylase inhibitors and immunomodulatory drugs in multiple myeloma.

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