2011多发性骨髓瘤进展ccohematology2011mmslidescme（论文资料）课件

December 10-13, 2011 San Diego, California Update on Multiple Myeloma CCO Independent Conference Coverage of the 2011 Annual Meeting of the American Society of Hematology* This program is supported by educational grants from *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. Jointly sponsored/coprovided by Annenberg Center for Health Sciences at Eisenhower and Clinical Care Options, LLC /oncology Update on Multiple Myeloma About These Slides Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options (email ) Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials. /oncology Update on Multiple Myeloma Faculty Kenneth Anderson, MD Kraft Family Professor of Medicine Harvard Medical School Director, Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute Boston, Massachusetts Sagar Lonial, MD Professor of Hematology and Oncology Director, Translational Research B-Cell Malignancy Program The Winship Cancer Institute Emory University Atlanta, Georgia Amitabha Mazumder, MD Professor of Medicine Director, Multiple Myeloma Program New York University Medical Center New York, New York /oncology Update on Multiple Myeloma Faculty Disclosures Kenneth Anderson, MD, has disclosed that he has served on advisory boards for Bristol-Myers Squibb, Celgene, Merck, Millennium, Novartis, and Onyx and owns stock in Acetylon. Sagar Lonial, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Celgene, Merck, Millennium, Novartis, and Onyx. Amitabha Mazumder, MD, has disclosed that he has received fees for non-CME services from Celgene and Millennium. Thank you for accessing CCO Independent Conference Coverage of the 2011 Annual Meeting of the American Society of Hematology from San Diego, California. In the following slides, you will find highlights of the key studies from this meeting. Be sure to review the slide notes field for each slide for insightful commentary from our expert faculty. Overview of Update on Multiple Myeloma /oncology Update on Multiple Myeloma Overview of Update on Multiple Myeloma Preclinical studies and studies in smoldering MM Role of cereblon protein expression in IMiD-treated disease QuiRedex: lenalidomide plus dexamethasone vs lenalidomide alone in smoldering MM Newly diagnosed and previously untreated MM MM-015 update: lenalidomide, melphalan, and prednisone with lenalidomide maintenance VISTA final results : bortezomib, melphalan, and prednisone vs melphalan and prednisone Phase I/II study of MLN9708 combined with lenalidomide and dexamethasone Phase I/II study of carfilzomib, lenalidomide, and dexamethasone /oncology Update on Multiple Myeloma Overview of Update on Multiple Myeloma Relapsed and refractory MM Phase I study of marizomib PX-171-004: final results with carfilzomib in the bortezomib-naive group Phase I expansion study of MLN9708 MM-002: phase II results of pomalidomide alone or combined with dexamethasone Vantage 088: vorinostat combined with bortezomib PANORAMA 2: panobinostat combined with bortezomib and dexamethasone Phase II study of elotuzumab combined with lenalidomide and dexamethasone Preclinical Studies and Studies in Smoldering MM /oncology Update on Multiple Myeloma Cereblon Protein Expression: Background Cereblon protein recently identified as primary target mediating thalidomide-related teratogenicity Forms E3 ubiquitin ligase complex Cereblon function in complex inhibited by thalidomide Low levels of cereblon expression observed in lenalidomide-resistant cell lines Ito T, et al. Science. 2010;327:1345-1350. Cereblon DDB1 Cul4 Protein degradation Thalidomide /oncology Update on Multiple Myeloma Cereblon Protein Expression: Study Design Investigation of role of cereblon in antimyeloma activity of IMiDs Preclinical in vitro study using cell lines and MM patient samples Lentiviral shRNA constructs used for gene knockdown Nontargeted (control) Cereblon targeted Assays to measure cell viability (MTT) and cell death (annexin V and cell cycle) Zhu YX, et al. ASH 2011. Abstract 127. Zhu YX, et al. Blood. 2011;118:4771-4779. /oncology Update on Multiple Myeloma Cereblon Protein Expression: Effect in MM Cell Lines and Patient Samples Decreased cereblon expression in lenalidomide-resistant vs lenalidomide-sensitive MM cells Due to homozygous deletions of cereblon gene Exogenous cereblon expression restored lenalidomide sensitivity Cereblon IMiD-binding mutant unable to restore sensitivity Cereblon mRNA knockdown cytotoxic in MM cells Viable cells reduced from 81% to 35% with cereblon knockdown Up to 30% of MM cells survived cereblon knockdown Resistant to lenalidomide, but sensitive to melphalan, dexamethasone, and bortezomib Decreased cereblon gene expression in 8 of 9 relapsed MM patient samples Zhu YX, et al. ASH 2011. Abstract 127. Zhu YX, et al. Blood. 2011;118:4771-4779. /oncology Update on Multiple Myeloma Cereblon Protein Expression: Effect on Gene Expression Impaired transcriptional response to lenalidomide in cereblon-depleted MM cells Decreased IRF4 expression with cereblon knockdown, similar to lenalidomide treatment Zhu YX, et al. ASH 2011. Abstract 127. Zhu YX, et al. Blood. 2011;118:4771-4779. Gene Expression, nOPM2 Lenalidomide-Sensitive MM Cell Line Nontargeted RNA Control Knockdown Cereblon-Targeted RNA Knockdown Down-regulated genes63630 Up-regulated genes637150 /oncology Update on Multiple Myeloma Binding to Cereblon Critical for IMiD Antimyeloma Activity IMiDs bind to cereblon through a common glutarimide moiety Correlative effect between cereblon expression and lenalidomide response in MM cell lines Reduced cereblon protein levels in lenalidomide-resistant MM cell lines Lenalidomide and pomalidomide exhibit both shared and unique substrate profiles Model suggests cereblon is a single IMiD target that can mediate the pleiotropic activities of lenalidomide Lopez-Girona A, et al. ASH 2011. Abstract 738. Zhu YX, et al. ASH 2011. Abstract 127. /oncology Update on Multiple Myeloma Cereblon Protein Expression: Conclusions Cereblon protein expression necessary for IMiD antimyeloma activity Possible mechanism of action for IMiDs in MM Reduced cereblon expression evident in lenalidomide-resistant MM patients vs levels at diagnosis Cereblon likely critical but not only source of IMiD resistance Reduced expression of IRF4 gene is common effect of both IMiD treatment and reduced cereblon expression Cereblon is potentially a new target in MM Novel cereblon-targeted agents with improved efficacy and fewer toxicities Inducing cereblon expression may improve lenalidomide sensitivity Zhu YX, et al. ASH 2011. Abstract 127. Zhu YX, et al. Blood. 2011;118:4771-4779. /oncology Update on Multiple Myeloma QuiRedex: Study Design Multicenter, open-label, randomized phase III trial Evaluated new treatment regimen for smoldering MM vs current standard of care Mateos MV, et al. ASH 2011. Abstract 991. Patients with high-risk smoldering MM (N = 126) Lenalidomide 25 mg/day on Days 1-21 + Dexamethasone 20 mg/day on Days 1-4, 12-15 No TreatmentNo Treatment Lenalidomide 10 mg/day on Days 1-21 (Low-dose dexamethasone added at time of biologic progression) Induction 9 x 28-day cycles Maintenance 28-day cycles 2 yrs Primary endpoint: TTP to symptomatic MM Secondary endpoints: response, duration of response, safety and tolerability, PFS, OS /oncology Update on Multiple Myeloma QuiRedex: Response Majority of patients responded to lenalidomide plus dexamethasone Responses improved with maintenance 12 of 14 patients either improved to PR or had SD after receiving low- dose dexamethasone during lenalidomide maintenance Mateos MV, et al. ASH 2011. Abstract 991. Response, % ITT Population With Median of 9 Induction Cycles (Range: 1-9) (n = 57) After Completion of 9 Induction Cycles (n = 51) After Median of 15 Maintenance Cycles (Range: 2-31) (n = 50) ORR869696 Stringent CR7816 CR7812 VGPR111216 PR616852 SD1444 /oncology Update on Multiple Myeloma QuiRedex: TTP to Symptomatic MM and OS Significant increase in TTP with vs without treatment Significantly prolonged OS with vs without treatment Median 3-yr OS (from study inclusion): 93% vs 76%; P = .04 Median 5-yr OS (from diagnosis): 94% vs 79%; P = .03 Mateos MV, et al. ASH 2011. Abstract 991. Median TTP Lenalidomide + dexamethasone: NR No treatment: 23 mos HR: 6.0 (95% CI: 2.9-12.6; P 75 yrs), response (PR vs VGPR), ISS stage (I/II vs III) No effect on OS and TTP with maintenance lenalidomide Palumbo A, et al. ASH 2011. Abstract 475. OutcomeMPR-R (n = 152) MPR (n = 153) MP (n = 154) Median PFS, mos HR vs MP P value vs MP 31 0.395 95% MM patients Current study randomized relapsed/refractory MM patients to different schedules of elotuzumab plus lenalidomide and dexamethasone High ORR in both groups Median time to response: 1.0 mos (range: 0.7-4.3) Median PFS not reached after median follow-up of 14 mos Similar safety profiles between groups ResponseElotuzumab 10 mg/kg (n = 36) Elotu