1、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
2、-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,About These Slides,Users are encouraged to use these slides in their own
3、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 Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options (email ),Disclaimer The materials published on the Clinical Care Options Web site
4、 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 Adminis
5、tration. 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.,Faculty,Kenneth Anderson, MD Kraft Family Professor of Medicin
6、e 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
7、Amitabha Mazumder, MD Professor of Medicine Director, Multiple Myeloma Program New York University Medical Center New York, New York,Faculty Disclosures,Kenneth Anderson, MD, has disclosed that he has served on advisory boards for Bristol-Myers Squibb, Celgene, Merck, Millennium, Novartis, and Onyx
8、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 a
9、ccessing 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 comm
10、entary from our expert faculty.,Overview of 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
11、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
12、 study of carfilzomib, lenalidomide, and dexamethasone,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 alo
13、ne 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,Cereblon Protein Expressio
14、n: Background,Cereblon protein recently identified as primary target mediating thalidomide-related teratogenicity Forms E3 ubiquitin ligase complex Cereblon function in complex inhibited by thalidomideLow levels of cereblon expression observed in lenalidomide-resistant cell lines,Ito T, et al. Scien
15、ce. 2010;327:1345-1350.,Cereblon,DDB1,Cul4,Protein degradation,Thalidomide,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 knockdo
16、wn 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.,Cereblon Protein Expression: Effect in MM Cell Lines and Patient Samples,Decreased cereblon exp
17、ression 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 redu
18、ced 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, e
19、t al. Blood. 2011;118:4771-4779.,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,
20、et al. Blood. 2011;118:4771-4779.,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
21、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.,Cereblon Pro
22、tein 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 resistan
23、ce 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, e
24、t al. ASH 2011. Abstract 127. Zhu YX, et al. Blood. 2011;118:4771-4779.,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 smolderin
25、g MM(N = 126),Lenalidomide 25 mg/day on Days 1-21 + Dexamethasone 20 mg/day on Days 1-4, 12-15,No Treatment,No 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: TT
26、P to symptomatic MM Secondary endpoints: response, duration of response, safety and tolerability, PFS, OS,QuiRedex: Response,Majority of patients responded to lenalidomide plus dexamethasone Responses improved with maintenance12 of 14 patients either improved to PR or had SD after receiving low-dose
27、 dexamethasone during lenalidomide maintenance,Mateos MV, et al. ASH 2011. Abstract 991.,QuiRedex: TTP to Symptomatic MM and OS,Significant increase in TTP with vs without treatmentSignificantly prolonged OS with vs without treatment Median 3-yr OS (from study inclusion): 93% vs 76%; P = .04 Median
28、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 .0001) Median follow-up: 32 mos (range: 12-49),1.0,0.8,0.6,0.4,0.2,0,Proportion of Patients Alive,Mos From Inclusion,0
29、,45,5,10,15,20,25,30,35,40,Lenalidomide + dexamethasone No treatment,QuiRedex: Safety,3 cases of second primary malignancies reported in treatment arm,Mateos MV, et al. ASH 2011. Abstract 991.,QuiRedex: Conclusions,Improved outcomes with lenalidomide and dexamethasone induction plus maintenance lena
30、lidomide vs no treatment in smoldering MM1 Significantly prolonged TTP, OS Addition of low-dose dexamethasone to maintenance lenalidomide maintained disease stabilization in most cases of biologic progression1 Well tolerated, with most adverse events grade 1/21 Drug-related toxicities should be cons
31、idered when evaluating risk/benefit Question remains regarding effect of treatment at this disease stage Delay progression only or alter natural history also Ongoing phase II/III ECOG trial evaluating single-agent lenalidomide vs observation in smoldering MM; suspended in December 20112,1. Mateos MV
32、, et al. ASH 2011. Abstract 991. 2. ClinicalTrials.gov. NCT01169337.,Studies in Newly Diagnosed and Previously Untreated MM,MM-015: Study Design,Updated analysis of randomized, multicenter, placebo-controlled phase III trial,Palumbo A, et al. ASH 2011. Abstract 475.,Newly diagnosed transplantation-i
33、neligible MM patients 65 yrs of age or older(N = 459),MPR-R Melphalan 0.18 mg/kg on Days 1-4 + Prednisone 2 mg/kg on Days 1-4 + Lenalidomide 10 mg/day on Days 1-21,MPR Melphalan 0.18 mg/kg on Days 1-4 + Prednisone 2 mg/kg on Days 1-4 + Lenalidomide 10 mg/day on Days 1-21,MPR Melphalan 0.18 mg/kg on
34、Days 1-4 + Prednisone 2 mg/kg on Days 1-4 + Lenalidomide 10 mg/day on Days 1-21,Continued lenalidomide,Discontinued lenalidomide, placebo added,Continued placebo,Disease progression,Lenalidomide 25 mg/day Dexamethasone,Cycles 1-9 (28-day cycles),Cycles 10+,Double-blind treatment phase,Open-label ext
35、ension/ follow-up phase,Stratified by age and disease stage,Primary endpoint: PFS,MM-015: Outcomes in Patients in Overall Population (65 Yrs of Age and Older),Continued lenalidomide significantly improves PFS vs placebo PFS benefit extended through patient subgroups in landmark analysis Age (65-75 v
36、s 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.,MM-015: Outcomes in Patients Aged 65-75 Yrs,Superior response rates and shorter median time to response in MPR-R and MPR arms vs MP Analysis of ti
37、me to PR/VGPR showed minimum of 9 cycles of induction therapy needed for maximal response Improved median PFS with lenalidomide maintenance in patients 65-75 yrs of age, similar to overall population MPR-R vs MP, HR: 0.301; P .001 MPR vs MP, HR: 0.618; P = .006 Trend for improved OS with lenalidomid
38、e treatment (HR: 0.70),Palumbo A, et al. ASH 2011. Abstract 475.,0,10,20,30,40,50,60,70,80,90,Response Rate (%),MPR-R (n = 116),MPR (n = 116),MP (n = 116),Treatment,79.3,73.3,47.4,44.0,35.3,37.9,35.3,36.2,11.2,PR VGPR,MM-015: Conclusions,Addition of lenalidomide to MP significantly prolongs PFS and
39、improves response rates in newly diagnosed MM patients aged 65-75 yrs1 Both induction and maintenance phases Trend for improved OS with MPR-R Secondary malignancy incidence slightly higher in MPR-R and MPR vs MP arms Not significantly increased in patients aged 65-75 yrs Supports recently published
40、age-adjusted dose modification guidelines2 Role of lenalidomide in transplantation-eligible patients still under investigation Updated phase III trial results suggest significant increase in PFS in favor of transplantation vs MPR after induction3,1. Palumbo A, et al. ASH 2011. Abstract 475. 2. Palum
41、bo A, et al. N Engl J Med. 2011;364:1046-1060. 3. Palumbo A, et al. ASH 2011. Abstract 3069.,VISTA: Study Design,Final analysis of randomized, international phase III clinical trial Median follow-up: 60.1 mos,San Miguel JF, et al. ASH 2011. Abstract 476.,Patients with previously untreated MM(N = 682
42、),VMP Bortezomib 1.3 mg/m2 on Days 1, 4, 8, 11, 22, 25, 29, 32 for 4 cycles; Days 1, 8, 22, 29 for 5 cycles + Melphalan 9 mg/m2 QD on Days 1-4 + Prednisone 60 mg/m2 QD on Days 1-4 (n = 344),MP Melphalan 9 mg/m2 QD on Days 1-4 + Prednisone 60 mg/m2 QD on Days 1-4 (n = 338),Nine 6-wk cycles,VISTA: OS
43、and Posttreatment Outcomes,Addition of bortezomib to frontline MP significantly prolongs OS OS benefit observed in most subgroups, except patients with high-risk cytogenetics May be due to fewer patients receiving subsequent bortezomib-based therapy in VMP group compared with MP group (38% vs 60%),S
44、an Miguel JF, et al. ASH 2011. Abstract 476.,*P = .0004; P .0001,VISTA: Conclusions,Final analysis confirms significant OS benefit with addition of bortezomib to frontline MP 13.3-mo OS improvement Justifies incorporation of bortezomib into initial MM therapy Favorable compared with delaying bortezo
45、mib in the relapsed/refractory MM setting Validates efficacy of bortezomib combination with previous standard of care (MP),San Miguel JF, et al. ASH 2011. Abstract 476.,MLN9708 Phase I/II Study: Design,MLN9708: investigational, orally available proteasome inhibitor Hydrolyzes to biologically active
46、MLN2238 (dipeptidyl leucine boronic acid), which has faster proteasome dissociation and greater tissue penetration vs bortezomib1 Current study: open-label, multicenter, dose-escalation phase I/II trial2 Primary endpoints: safety, MTD, recommended phase II dose Secondary endpoints: MLN2238 pharmacok
47、inetics, treatment response Patients: previously untreated with measurable disease (n = 15) Treatment: 28-day cycles for up to 12 mos MLN9708: started at 1.68 mg/m2, increased in 33% increments based on dose-limiting toxicities in cycle 1, on Days 1, 8, 15 Dexamethasone: 40 mg/day on Days 1, 8, 15,
48、22 Lenalidomide: 25 mg/day on Days 1-21,1. Kupperman E, et al. Cancer Res. 2010;70:1970-1980. 2. Berdeja JG, et al. ASH 2011. Abstract 479.,MLN9708 Phase I/II Study: Response and Safety,Rapid responses observed in all patients (N = 15), generally in cycle 1 CR (n = 4), VGPR (n = 5), and PR (n = 6) N
49、o dose-limiting toxicities observed up to 2.23 mg/m2 MLN9708 MTD: 2.97 mg/m2/wk Recommended phase II dose: 2.23 mg/m2/wk As effective as MTD, but with better toxicity profile Well tolerated, with transient adverse events Grade 1 peripheral neuropathy (n = 3) Grade 3: vomiting (n = 2), deep vein thro
50、mbosis (n = 2), anemia (n = 2), rash (n = 2) Grade 4: thrombocytopenia (n = 1),Berdeja JG, et al. ASH 2011. Abstract 479.,MLN9708 Phase I/II Study: Conclusions,Novel proteasome inhibitor MLN9708 appears safe and active in previously untreated MM Manageable toxicity profile Dose-limiting toxicities p
51、rimarily gastrointestinal Infrequent and low-grade peripheral neuropathy Rapid responses ( PR) observed in all patients Validates strategy of combining a proteasome inhibitor with lenalidomide/dexamethasone Recommended phase II dosing of 2.23 mg/m2/wk when combined with lenalidomide and dexamethasone,
