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Steroid-sparing Therapy After Hsp90 Inhibitor Clinical Study

Steroid-sparing Therapy After Hsp90 Inhibitor Clinical Study. Asher A. Chanan-Khan, MD Roswell Park Cancer Institute Buffalo, NY. Patient Has Poor Prognostic Indicators. IgA isotype del(13q) t(4;14). IgA = immunoglobulin A; del(13q) = deletion of the long arm of chromosome 13.

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Steroid-sparing Therapy After Hsp90 Inhibitor Clinical Study

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  1. Steroid-sparing Therapy After Hsp90 Inhibitor Clinical Study Asher A. Chanan-Khan, MDRoswell Park Cancer InstituteBuffalo, NY

  2. Patient Has Poor Prognostic Indicators • IgA isotype • del(13q) • t(4;14) IgA = immunoglobulin A; del(13q) = deletion of the long arm of chromosome 13

  3. Prognostic Features • Karyotype analysis: del(13q) and t(4;14) are associated with a poor outcome • Supported by FISH analysis: FISH = fluorescence in situ hybridization; OS = overall survival Chang et al. Bone Marrow Transplant. 2005;36(9):793-796.

  4. Author Regimen ORR Padmanabhan* Bortezomib, pegylated doxorubicin, thalidomide 65% Terpos† Bortezomib, melphalan, dexamethasone, thalidomide 64% Palumbo † Bortezomib, melphalan, prednisone, thalidomide 80% Hollmig‡ Bortezomib, doxorubicin, dexamethasone, thalidomide 50% Kropff † Bortezomib, dexamethasone, cyclophosphamide 88% Reece † Bortezomib, dexamethasone, prednisone 56% Bortezomib Combination Regimens Relapsed/Refractory Disease ORR = Overall response rate * EHA 2006 Absract; † ASH 2005 Abstract;‡ASH 2004 Abstract

  5. Why Does It Make Sense to Consider a Clinical Trial at This Point? • No standard approach has been shown to improve prognosis • Patient is still in good condition • Multiple relapses and/or multiple lines of therapy may prohibit enrollment into a clinical trial due to marrow dysplasia • Standard treatment options remain possibilities for later on

  6. Hsp90 Phase 1 Study • Geldanamycin (17-AAG or KOS-953) • Small-molecule inhibitor of hsp90 • Hsp90 is upregulated in myeloma cells and inhibits myeloma cell apoptosis • Preclinical studies • Geldanamycin induces apoptosis of drug-sensitive and -resistant myeloma cells Mitsiades et al. Blood 2006;107(3):1092-1100.

  7. A Second Clinical Trial • Disease has significantly advanced • Platelet count is low • Thus, this patient may not be eligible for most clinical studies

  8. Treatment Recommendation • Bortezomib, pegylated doxorubicin, thalidomide (VDT) • Can optimize benefit of current bortezomib • Steroid-sparing • Benefit still derived for pts who had single-agent bortezomib

  9. Geldanamycin + Bortezomib • Ongoing phase 1 study • Gene profiling studies have shown: • Bortezomib induces hsp90 expression • Bortezomib/geldanamycin augments cytotoxicity in myeloma cells Mimnaugh et al. Mol Cancer Ther. 2004;3(5):551-566.

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