Bortezomib: a new paradigm for treatment of multiple myeloma

Bortezomib: a new paradigm for treatment of multiple myeloma

Bortezomib: a new paradigm for treatment of multiplemyelomaMichael W. Schuster, M.D.

Historical PerspectiveThe first well-known case of multiple myelomawas that of Mr. McBean described in 1846, 1847,and 1850 by John Darlympe, Henry Bence Jones,and William MacIntyre Mr. McBean, a highly respectable tradesman fromLondonThe term multiple myeloma dates from 1873and was introduced by von Rusitzky

The Proteasome and Its Function The proteasome, present and abundant in all cells,degrades ubiquitinated proteins The ubiquitin-proteasome pathway controls proteinhomeostasis in the cell Ubiquitin “tags” proteins for degradation by theproteasome The ubiquitination process is specific and regulated

BortezomibPotency, Ki = 0.6 nMReversible inhibition ofthe proteasomeHighly selectiveNNONHOHNOHBOH

BORTEZOMIB –One Target, Multiple PathwaysProteasome inhibition mediated cytotoxicity involvesmultiple downstream mechanismsIn non-clinical studies bortezomib:Stabilized cell-cycle regulatory proteinsInhibited NF-κB activationInhibited Anti-angiogenicInduced apoptosisWas not susceptible to multipleresistance mechanisms tested

BORTEZOMIB MOA: ProteasomeInhibition, NF-κB, and Multiple Myeloma(Microenvironment)VELCADEX XX(Microenvironment)

VELCADE (bortezomib) forInjection

SUMMIT (025):A Phase II Study ofVELCADE(bortezomib) for InjectionPaul G. Richardson, 1 Bart Barlogie, 2 James Berenson, 3 Seema Singhal, 4 Ann Traynor, 4 Sundar Jagannath, 5 David Irwin, 6Vincent Rajkumar, 7 Gordan Srkalovic, 8 Melissa Alsina, 9 Raymond Alexanian, 10 David Siegel, 11 Robert Orlowski, 12 DavidKuter, 13 Steven Limentani, 14 Dixie Esseltine, 15 Gretchen Richards, 15 Michael Kauffman, 15 Julian Adams, 15 David P.Schenkein, 15 and Kenneth C. Anderson 11 Dana-Farber Cancer Institute, 2 University of Arkansas, 3 Cedars-Sinai Medical Center, 4 NorthwesternUniversity Medical Center, 5 St Vincent’s Comprehensive Cancer Center, 6 Alta Bates Cancer Center, 7 Mayo Clinic, 8 Cleveland Clinic Foundation, 9 H.Lee Moffitt Cancer Center, 10 M.D. Anderson Cancer Center, 11 Carol G. Simon Cancer Center, 12 University of North Carolina at Chapel Hill,3 Massachusetts General Hospital, 14 Charlotte Medical Clinic, 15 Millennium Pharmaceuticals, Inc

SUMMIT: Study Design Open-label, single-arm, multi-center phase II study in 202patients Overall response rate determined by an IndependentReview Committee using criteria by Bladé et al Response rate also evaluated using SWOG criteria

SUMMIT: Entry Criteria Relapsed following at least 2 prior therapies for multiplemyeloma and refractory to most recent therapy (N=202) Measurable disease– Or non-measurable disease (nonsecretory or oligosecretory) Karnofsky Performance Status score >60 Hematologic status:– Platelets >30 x 10 9 /L– Hemoglobin >8 g/dL– ANC >1.0 x 10 9 /L Creatinine clearance >30 ml/minute Liver enzymes

SUMMIT: Treatment Plan Bortezomib 1.3 mg/m 2 IV push over 3-5 seconds 21-day cycle– Administered on days 1, 4, 8, and 11 with a 10-day restperiod (days 12-21)– 72 hours between doses 8-cycle study period– For CR patients, 2 cycles beyond confirmed CR– Extension protocol available for patients experiencing benefit

SUMMIT:Patient/Disease CharacteristicsTotal EnrolledMedian duration of multiple myeloma sincediagnosis (years)Median age, yearsM protein: IgG / IgA / Light ChainMedian creatinine clearance (mL/min)Karnofsky PerformanceStatus score ≤70Hemoglobin

SUMMIT: Prior Therapies ReceivedPrior Therapies(N=202)Any prior steroids, e.g., dexamethasone, VAD 99%Any prior alkylating agents, e.g., MP, VBMCP 92%Any prior thalidomide therapy 83%Any prior anthracyclines, e.g., VAD, mitoxantrone 81%Received at least 2 of the above 98%Received at least 3 of the above 92%Received all 4 of the above 66%High-dose therapy, including stem cell transplant 64%Prior experimental or other types of therapy 44%.

Response RatesBortezomib Alone (n=188) *CategoryComplete Response + Partial Response>50% Reduction in M protein (Bladé et al)N (%)27.7%(95% CI=21, 35)Clinical remission (SWOG)>75% Reduction in M protein17.6%(95% CI=12, 24)Complete Response100% Reduction in M protein by immunofixation(Bladé et al)2.7%(95% CI=1, 6)Kaplan-Meier EstimatedMedian Duration of Response365 days(95% CI= 224, NE † )*188/202 patients were evaluable for response.† NE= Not Estimable

Response RatesBortezomib Alone (n=188) *130%25%20%27.7%(95% CI = 21, 35)17.6%(95% CI = 12, 24) 2.7% CR(95% CI = 1, 6)in heavily pretreatedpatientpopulation15%10%5%0%CR+PRSWOG Clinical Remission>50% >75% Reduction in M protein*188/202 patients were evaluable for response1. Millennium Pharmaceuticals, Inc., 2003.

SUMMIT: Duration of Responsewith Bortezomib (CR+PR) *1Percent patients maintaining response over time (n=52)1009080706050403020100%0 2 4 6 8 10 12 14 16 18Months Median time to response was 38 days(range 30-127 days)Median duration of response = 12 months(365 days; 95% CI = 224, NE)*188/202 patients were evaluable for response.NE = not estimable.1. Millennium Pharmaceuticals, Inc., 2003.

1009080706050403020100%SUMMIT: Overall SurvivalCurves with Bortezomib *1Percent overall survival over time (N=202)MonthsMedian overall survival = 16 months*(range

Duration of Response and SurvivalResponse independent of number and typesof prior therapiesMedian time to response– 38 days (range 30 to 127 days)Median duration of response– 365 days (95% CI 224, NE)Median survival– 16 months (range

A Phase II Multicenter Randomized Study of the ProteasomeInhibitor Bortezomib (VELCADE, formerly PS-341) in MultipleMyeloma (MM) Patients (Pts) Relapsed After Front-line TherapySundar Jagannath 1 , Bart Barlogie 2 , James Berenson 3 , David Siegel 4 , David Irwin 5 *, Paul G. Richardson 6 ,Michael Schuster, 7 Raymond Alexanian 8 , Steven A. Limentani 9 , Melissa Alsina 10 , Dixie-Lee Esseltine 11 , MichaelKauffman 11 , Julian Adams 11 , David P. Schenkein 11 and Kenneth C. Anderson 6 . 1 St. Vincent's Catholic MedicalCenter, New York, NY; 2 University of Arkansas, Little Rock, AR; 3 Cedars-Sinai Medical Center, Los Angeles, CA;4Carol G. Simon Cancer Center, Morristown, NJ; 5 Alta Bates Comprehensive Cancer Center, Berkeley, CA; 6 Dana-Farber Cancer Institute, Boston, MA; 7 New York Presbyterian Hospital, New York, NY; 8 M.D. Anderson CancerCenter, Houston, TX; 9 Charlotte Medical Clinic, Charlotte, NC; 10 H. Lee Moffitt Cancer Center, Tampa, FL and11Millennium Pharmaceuticals, Inc., Cambridge, MA.

Clinical RationaleDemonstrated activity seen in advancedrelapsed and refractory myelomaSeveral doses and schedules tested inPhase I/II trialsCurrent trial designed as a pilot study toexplore the activity of two dose levels in anearlier patient population (relapsed myeloma)

Study DesignOpen-label, multicenter, randomized phase IItrial (10 sites in USA)– Bortezomib 1.0 and 1.3 mg/m 2 /dosePrimary endpoint: overall response rate (CR,PR, MR)– Independent review committee (IRC) usingBladé criteriaSecondary endpoints:– Response rate with dexamethasone,safety/tolerability, pharmacodynamics, QOL,pharmacogenomics

Entry CriteriaInclusion– History of relapse or failure to respond to front-linetherapy for myeloma– Measurable disease– KPS ≥ 60–Platelets ≥ 30 x 10 9 /L , Hgb ≥ 8 g/dL, ANC ≥ 1.0 x10 9 /L– Creatinine clearance ≥ 30 mL/min– Liver enzyme: ≤3 x ULNExclusion– No POEMS or plasma cell leukemia– Impaired kidney function requiring dialysis

Treatment PlanBortezomib 1.0 or 1.3 mg/m 2 IV push, no premedicationTwice weekly x2 weeks followed by 1-week rest– Administered on days 1, 4, 8, and 11Dexamethasone permitted if suboptimal response after2 cycles (PD patients) or 4 cycles (SD patients)– 20 mg PO on days 1-2, 4-5, 8-9, 11-12Maximum of 8 cycles– For CR patients, 2 cycles beyond confirmed CR– Extension protocol for responding patients

IRC AssessmentsObjective cycle-by cycle assessmentsConfirmed response– 6 weeks following initial assessmentPrevention of potential bias– IRC members unaware whether dexamethasoneadded to treatmentResponse data following administration ofdexamethasone not included in bortezomib aloneanalysis– Analysis for response to bortezomib alone and alltreatment

Patient CharacteristicsTotal1.0 mg/m 2 1.3 mg/m 2N=28 N=26 N=54Age in Years (median) 65 61 63Range (39-82) (30-84) (30-84)KPS ≤ 70 11% 16% 13%Hemoglobin

Disease Characteristics1.0 mg/m 2 1.3 mg/m 2TotalN=28N=26 N=54Myeloma: IgG, IgA, Other(%) 54/29/17 65/23/12 59/26/15Yrs from initial Dx (median) 2.0 2.0 2.0Creatinine clearance (median) 71 82 75β2-microglobulin (mg/L) (median) 8.4 3.6 4.3Abnormal cytogenetics 29% 48% 38%

Previous TherapiesPrior SCT48%Median number ofprior therapies, 3(range 1-7)Thalidomide30%Anthracyclines54%Alkylators72%Steroids98%0% 20% 40% 60% 80% 100%

Response (%) to Bortezomib AloneOverall a(CR+PR+MR)1.0 mg/m 2(N=27)33 b1.3 mg/m 2(N=26)50CR IF- 44CR IF+ 70PR1935MR412SD2619PD3019a 1 pt with nonsecretory myeloma inevaluable for responseb11% and 12% were not IRC evaluable in 1.0 and 1.3 dose groups, respectively; numbers rounded to the nearest integer

Response (%) to Bortezomib Alone orwith Dexamethasone1.0 mg/m 2(N=27: 16 combination)1.3 mg/m 2(N=26: 12 combination)Overall a4462CR IF- 44(CR+PR+MR)CR IF+ 15-PRMRSDPD1971930a1 pt with nonsecretory myeloma inevaluable for response;b7% and 8% were not IRC evaluable in 1.0 and 1.3 dose groups, respectively; numbers rounded to the nearest integer46121219

Time to Progressionon Bortezomib Alone (n=54)Median follow-up: 8.8 monthsMedian TTP 321 days (11months)

Overall Survival (n=54)Median survival, not reachedat 8.8 months follow-up

Most Common Adverse Events(1.0 mg/m 2 )NauseaDiarrheaConstipationG1-2G3G4ThrombocytopeniaNeutropeniaAnemiaFatigueArthralgiaInsomniaHeadachePer. Neuropathy• No deaths within 20days of last dose0 10 20 30 40 50 60 70 80

Most Common Adverse Events(1.3 mg/m 2 )NauseaDiarrheaConstipationThrombocytopeniaNeutropeniaAnemiaFatigueG1-2G3G4ArthralgiaInsomniaHeadachePer. Neuropathy• 1 death within 20days of last dose(pneumonia withsepsis); unlikelyrelated to studydrug0 10 20 30 40 50 60 70 80

CREST Study A small, dose-response study in 54 patients Responses observed with 1.0 mg/m 2 and 1.3 mg/m 2 doses– 1 CR observed at both 1.3 and 1.0 mg/m 2– Overall response (CR + PR):• 38% at 1.3 mg/m 2• 30% at1.0 mg/m 2

Bortezomib Versus Dexamethasone inRelapsed Multiple Myeloma:A Phase 3 Randomized Study (APEX)A Report of the Interim AnalysisPaul G. Richardson, 1 Pieter Sonneveld, 2 Michael W. Schuster, 3 David Irwin, 4Edward A. Stadtmauer, 5 Thierry Facon, 6 Jean-Luc Harousseau, 7 Dina Ben-Yehuda, 8 Sagar Lonial, 9Hartmut Goldschmidt, 10 Donna Reece, 11 Jesus F. San Miguel, 12Joan Bladé, 13 Mario Boccadoro, 14 Jamie Cavenagh, 15 William S. Dalton, 16Anthony L. Boral, 17 David Schenkein, 17 Kenneth C. Anderson 11Dana-Farber Cancer Institute, 2 University Hospital Rotterdam, 3 New York-Presbyterian Hospital, 4 Alta Bates CancerCenter, 5 University of Pennsylvania Cancer Center, 6 Hospital Claude Huriez, 7 Hotel Dieu Hospital, 8 HadassahUniversity Hospital, 9 Emory University, 10 Universitaetsklinikum Heidelberg, 11 Princess Margaret Hospital, 12 HospitalUniversitario de Salamanca, 13 Universitario de Barcelona 14 Università di Torino, 15 St. Bartholomew’s Hospital, 16 H.Lee Moffitt Cancer Center, 17 Millennium Pharmaceuticals, Inc.

Bortezomib8 cycles1.3 mg/m 2 IV pushD 1, 4, 8, 11 q 3-wk cycleTreatment PlanRandomizationInductionDexamethasone4 cycles40 mg POD 1–4, 9–12, 17–20 q 5-wk cycle3 cycles1.3 mg/m 2 IV pushD 1, 8, 15, 22 q 5-wk cycleMaintenance40 mg POD 1–4 q 4-wk cycle5 cycles273 treatment days 280 treatment daysRichardson et al. ASCO 2004; Abstract 6511

Time to Progression (Interim Analysis)58% improvement in median TTPBortezomib(n = 327)P < 0.0001Proportion of PatientsDexamethasone(n = 330)MonthsMedian TTP: Bortezomib 5.7 mosDexamethasone 3.6 mosRichardson et al. ASCO 2004; Abstract 6511

Results of Interim Analysis (APEX)Significant TTP benefit (P < 0.0001) withbortezomib vs dexamethasone– 58% increase in median TTPEarly survival advantage prior tocrossoverTrend toward lower incidence of severeand life-threatening infectionsNo difference in TSE (small Richardson number et al. ASCO 2004; of Abstract 6511

Adverse Events(Interim Analysis)Bortezo DexamethaAdverse events ≥mib% sone%66 56Adverse G3* events11 13Serious G4* adverseDiscontinuation40 39events †due to adverse 22 23events* Treatment-related< 1 3mortality †*Safety population.†ITT population.Richardson et al. ASCO 2004; Abstract 6511

Mean Platelet Count During Treatment250DexamethasoneMean Platelet Count, × 10 9 /L20015010050Bortezomib0BL 3 6 9 12 15 18 21 24Week• Bortezomib arm: platelet counts measured on days 1, 4, 8, 11 of each 21-day cycle• Dexamethasone arm: platelet counts measured every 3 weeksRichardson et al. ASCO 2004; Abstract 6511

APEX Survival at Final Analysis*(Includes Crossover)Bortezomib (n = 333)Proportion of PatientsOverall survival, P < 0.011-year survival, P < 0.01Median follow-up in survivors approx 8 mo1 yearDexamethasone (n = 336)(412) (115) (6)Days (Patients at Risk)*January 13, 2004Richardson et al. ASCO 2004; Abstract 6511

First-line Therapy With Bortezomib(VELCADE ® , Formerly PS-341) in Patients WithMultiple Myeloma (MM)Sundar Jagannath, 1 Brian G.M. Durie, 1 Jeffrey Wolf, 1Elber Camacho, 1David Irwin, 1 Jose Lutzky, 1 Marti McKinley, 1 Eli Gabayan, 1Amitabha Mazumder, 1 John Crowley, 2 David Schenkein 31Salick Health Care Research Network, Los Angeles, CA; 2 Center for Research &Biostatistics, Seattle, WA; 3 Millennium Pharmaceuticals, Inc., Cambridge, MA

Treatment PlanBortezomib 1.3 mg/m 2 2x/week x2 q 3 weeks for amaximum of 6 cyclesPatients received bortezomib alone for the first 2cyclesDex 40 mg on day of and after each bortezomibdose was added if–After 2 cycles for patients who achieve less than aPR–After 4 cycles for patients who achieve less than aCR (immunofixation negative)–Dex dose was twice the dose used in the phase 2bortezomib trials (SUMMIT/CREST) 5,6Jagannath et al. ASCO 2004; Abstract 6551

Current Best Overall Responses(n = 24)Response*CRPRMRSDPDn (%)2 (8)4 (17)13 (54)4 (17)0 (0)1 (4)NCR Overall CR/NCR/PR 79%*Responses based on paraprotein.> SD 96%• Bortezomib alone induced CR/NCR in 6 patients;2 of these NCR patients received dexamethasone and responsestatus remained unchangedJagannath et al. ASCO 2004; Abstract 6551

Cycle 2 Response and Best Overall Response(n = 24)Cycle 2Response*Best Overall Response*Bortezomibn = 24, n (%)Bortezomibn = 10, n (%)Bortezomib +dexamethasonen = 14 (%)CRNCRPR1 (4)1 (4)8 (33)2 (8)2 (8)4 (17)0 (0)2 (8)9 (38)OverallCR/NCR/PR79%MR8 (33)1 (4)3 (13)SD5 (21)0 (0)0 (0)PD1 (4)1 (4)0 (0)*Responses based on paraprotein.Jagannath et al. ASCO 200; Abstract 6551

Confirmation of Remission:PET ScanPlasmacytomasPretreatmentAfter 4 CyclesJagannath et al. ASCO 2004; Abstract 6551

Peripheral Neuropathy (N=24)Painful neuropathy per NCI CTC v2– Grade 2: 3 patients– Grade 3: 2 patients, both off studyGrade 3 neuropathy resolved completely 4months post-treatmentJagannath et al. ASCO 2004; Abstract 6551

A Randomized phase III trial ofthalidomide plus dexamethasone versusdexamethasone in newly diagnosedmultiple myeloma (E1A00): A trialcoordinated by the Eastern CooperativeOncology GroupS.V. Rajkumar, E, 1 E. Blood, 2 D.H. Vesole, 3 R. Shepard, 4P.R. Greip, 11Mayo Clinic, 2 Dana Farber Cancer Institute, 3 Medical College of Wisconsin,4University of Virginia

Treatment PlanRandomizationThalidomide +DexamethasoneThal 200 mg PO QDDex D1-4, 9-12, 17-204 cyclesDexamethasone40 mg POD 1–4, 9–12, 17–20RR 80% RR 53%RR = ≥ 50% decrease M-proteinRajkumar et al. ASCO 2004; Abstract 6508

Adverse EventsThal/DeNeuropathyx5%DVT14%Rash4%Sinus Bradycardia 1%DeathToxicity ≥ G46%31%Dexamethasone3%3%0%0%8%15%Rajkumar et al. ASCO 2004; Abstract 6508

Oral melphalan, prednisone andthalidomide for newly diagnosedmyeloma patientsA.Palumbo, A. Bertoli, P. Musto, M. Nunzi,V. De Stefano, L. Catalano, T. Caravita, C. Cangialosi, S. Bringen, M.BoccadoroItalian Multiple Myeloma Study Group

Treatment PlanThalidomide 100mg PO QDMelphalan 4mg/m2 PO D1-7, QmoPrednisone 40mg/m2 PO D1-7, QmoPalumbo et al. ASCO 2004; Abstract 6549

Best Overall ResponsesResponse*CRNCRPRNR%2619937*Responses based on paraprotein.Palumbo et al. ASCO 2004; Abstract 6549

DeathToxicity/Adverse EventsNeuropathyNeutropenia ≥G3ConstipationInfectionDVTN=4238%14%28%26%19%0.5%Palumbo et al. ASCO 2004; Abstract 6549

PAD Combination Therapy(Bortezomib/Adriamycin and Dexamethasone) for Untreated MultipleMyelomaJ. D. Cavenagh, 1 N. Curry, 1 J. Stec, 2 C.Morris, 3 M. Drake, 3 S. Agrawal, 1 D.Schenkein, 2 D. Esseltine, 2 H. Oakervee 11St Bartholomew’s Hospital, London, UK2Millennium Pharmaceuticals, Inc., Cambridge, MA,USA;3Belfast City Hospital, Belfast, UK

Primary objectivesObjectives– Evaluate feasibility of collecting peripheralblood stem cells (PBSCs) after PAD– Assess engraftment after high-dosetherapy (HDT)Secondary objectives– Assess safety and toxicity– Determine response rates, progressionfreesurvival, and overall survival– Perform pharmacodynamic assessmentsCavenagh et al. ASCO 2004; Abstract 6550

TreatmentCycle 1 1 4 8 11 15 18 21Bortezomib 1.3 mg/m 2Dexamethasone 40 mgAdriamycinCycles 2–4Bortezomib 1.3 mg/m 2 1 4 8 11 15 18 21Dexamethasone 40 mgAdriamycinInduction (4 cycles prior to transplantation)– Bortezomib 1.3 mg/m 2 by IV bolus on days 1, 4, 8, and 11– Doxorubicin administered by continuous infusion or IV push tocohorts at escalating dose levels (0, 4.5, 9.0 mg/m 2 /day) on days 1–4– Dexamethasone 40 mg p.o• Cycle 1: days 1–4, 8–11, and 15–18• All subsequent cycles: days 1–4DayDayCavenagh et al. ASCO 2004; Abstract 6550

Responses95% CR/PR after ≥ 1 cycle of treatment(n = 21)–1 CR after bortezomib + dexamethasonealone–2 CRs after PAD94% CR/PR rate after 4 cycles (n = 18)Cavenagh et al. ASCO 2004; Abstract 6550

Serum/Urinary Myeloma Protein Responseby PAD CycleMyeloma Protein (g/L)90807060504030IsotypeIgAκIgAλIgGκIgGλκ-LCλ-LCMean ±SEM20100Pre-Rx #1 #2 #3 #4Treatment Cycle• Mean M-protein levels decreased significantly following cycle 1 oftreatment and continued to decrease after subsequent cyclesCavenagh et al. ASCO 2004; Abstract 6550

Outcome after PBSCT– 11 of 15 mobilized patients have receivedMEL200/PBSCT– 8 of 11 assessed 3 months post MEL200• 5 improved response• 2 PR unchanged• 1 VGPR unchanged– Hematopoietic recovery (n = 11)• Median days until neutrophil count > 0.5 x 10 6 /L = 17(range, 1–24)• Median days until platelet count > 20 x 10 9 /L = 13(range, 10–33)Cavenagh et al. ASCO 2004; Abstract 6550

ConclusionsPAD combination therapy demonstratedencouraging activity in previously untreatedpatients with multiple myeloma– 94% CR/PR rate after 4 cycles– 15 of 16 patients successfully mobilized– 11 of 15 successfully transplanted thus far– All 8 evaluable patients achieved PR or betterfollowing PBSCT (2 CR, 4 VGPR, 2 PR), some hadimproved responseMajor toxicity is painful neuropathy– Primarily grade 1– Generally appeared in cycle 3 or 4– Neuropathic symptoms are improving in allCavenagh et al. ASCO 2004; Abstract 6550patients after completion of therapy

Chemotherapy with fludarabine (F),cyclophosphamide (C), and rituximab (R)improves complete response (CR),remission duration and survival as initialtherapy of chronic lymphocytic leukemia(CLL)M.J. Keating, S. O’Brien, S. Lerner, W. Wierda,H. KantajarianMD Anderson Cancer Center

Fludarabine, Cyclophosphamide,and Rituximab (FCR) in Untreated CLLTreatment Course 1 Courses 2-6Rituximab 375 mg/m 2 day 1* 500 mg/m 2 day 1*Fludarabine 25 mg/m 2 days 2-4 † 25 mg/m 2 days 1-3 †Cyclophosphamide 250 mg/m 2 days 2-4 † 250 mg/m 2 days 1-3 † Treatment repeated q 28 days for 6 cycles of therapy.*Prophylaxis with TMP/SMX + valacyclovir optional.† Allopurinol/tumor lysis precautions required.Keating et al. ASCO 2004; Abstract 6565

Response, Response Duration,SurvivalTreatment# Pts %CR %PR RDOSF+P 137 31 54 30mo74moF+C/M 135 32 55 43mo92moFCR 224 71 24 NR NRKeating et al. ASCO 2004; Abstract 2565

Conclusions: Study 024Bortezomib was active in relapsed MM pts– Overall response 33% and 50% at 1.0 and1.3 mg/m 2Additional responses seen with addition ofDex– Overall response 44% and 62% respectivelyCRs observed at both 1.0 and 1.3 mg/m 2

Conclusions: Study 024Possible dose response observed for bothclinical benefit and toxicityClinically significant toxicity included diarrhea,fatigue and peripheral neuropathy– 15% of pts discontinued due to a treatmentrelatedadverse eventDefinitive Phase III trial (APEX) is activelyrecruiting pts

Combined Velcade & ChemotherapyPre-clinical experiments show that Bortezomib cankill myeloma cell lines at lower doses whencombined with chemotherapyPhase I/II study presented at ASH from Cedars-Sinai group, combining Bortezomib with MelphalanBortezomib given days 1,4,8, & 11 @ 0.7 mg/M2Melphalan given po d1-4 q 28 days @0.025-0.25mg/kg Yang et al, Abstract #826 appears in Blood, Volume 102, issue 11,November 16, 2003

Combined Velcade & Chemotherapy15 pre-treated pts. ages 33-702-7 prior therapiesGrade III myelosuppression67% PR13% MR20% SD

Combined Velcade and ThalidomideLittle Rock group presented Phase I/II trial at ASHVelcade given days 1,4,8,11 q 21 days @ 1 mg/M2+ Thalidomide 50-100 mgDex could be added if no PR after 2 cycles78% resistant to Thalidomide72% had prior tandem transplant22% CR rate after 8 cycles53% MPR > 50%Zangari et al, Abstract #830 appears in Blood, Volume 102, issue 11,November 16, 2003

Combine Velcade/Thalidomide

Reduction in Myeloma Protein byCycle

Trial of Velcade/DoxilChapel Hill group presented Phase I/II data at ASHVelcade given d1,4,8,& 11 q 21 days @ 0.9-1.5mg/M2Doxil given day 4 @ 30 mg/M2Grade ¾ toxicities included fatigue,cytopenias,neuropathy, Gi problems, palmer erythrodysesthesiaMTD 1.5 mg/M2 of VelcadeOrlowski et al, Abstract #1639 appears in Blood, Volume 102, issue 11,November 16, 2003

Trial of Velcade/Doxil5/22 myeloma pts. With CR, 2 pts with near-CR, and 8 pts with PRNo cardiac toxicitiesDose reductions ocurred frequently at 1.4and 1.5 mg/M2 of Velcade

Safety and Tolerability of VELCADE TM(bortezomib) for Injection

Pooled Safety Results in Phase II MultipleMyeloma Studies with Bortezomib 1 N=228– Includes patients receiving 1.3 mg/m 2 starting dose inSUMMIT and CREST Phase II trials Median number of prior therapies– SUMMIT was 6 (n=202)– CREST was 3 (n=26)

Combined Safety Data fromSUMMIT and CREST Trials *1On-Study adverse events (>30% overall)in Phase II clinical trials at 1.3 mg/m 2 dose (N=228)Nausea64%DiarrheaDecreased appetite & anorexiaConstipationVomitingThrombocytopeniaAnemia51%43%43%36%43%32%Asthenia (fatigue, malaise, weakness)65%Grades 1-2†Peripheral NeuropathyPyrexia37%36%Grade 3†Grade 4†0 10 20 30 40 50 60 70 80 90 100%

Combined Safety Data fromSUMMIT and CREST Trials * At baseline, more than 80% of patients had signs ofperipheral neuropathy Incidence of febrile neutropenia was

Bortezomib: Indication and Usage Bortezomib is indicated for the treatment of multiplemyeloma patients who have received at least two priortherapies and have demonstrated disease progressionon the last therapy.The effectiveness of bortezomib is based on responserates. There are no controlled trials demonstrating aclinical benefit, such as an improvement in survival.

Bortezomib:Contraindications and WarningsContraindication Bortezomib is contraindicated in patients withhypersensitivity to bortezomib, boron, or mannitol.Warnings Bortezomib should be administered under the supervisionof a physician experienced in the use of antineoplastictherapy. Pregnancy Category D: Women of childbearing potentialshould avoid becoming pregnant while being treated withbortezomib.

Bortezomib: Precautions Peripheral Neuropathy: Treatment with bortezomib may be associatedwith a peripheral neuropathy that is predominately sensory, althoughrare cases of mixed sensorimotor neuropathy have been reported.Patients with pre-existing symptoms and/or signs of peripheralneuropathy may experience worsening during treatment withbortezomib. Patients should be monitored for symptoms of neuropathy,such as numbness, a burning sensation, hyperesthesia, hypoesthesia,paresthesia, discomfort, or neuropathic pain. Hypotension: Treatment with bortezomib may be associated withorthostatic/postural hypotension throughout therapy. Caution should beused when treating patients with a history of syncope, patients receivingmedications known to be associated with hypotension, and patientswho are dehydrated. Gastrointestinal Adverse Events: Nausea, diarrhea, constipation,and vomiting may occur during treatment with bortezomib.

Bortezomib: Precautions (cont.) Thrombocytopenia: Complete blood counts including platelet countsshould be frequently monitored throughout treatment with bortezomib.Thrombocytopenia was maximal at Day 11 and usually recovered by thenext cycle. Onset is most common in Cycles 1 and 2 but can continuethroughout therapy. There have been reports of gastrointestinal andintracerebal hemorrhage in association with thrombocytopenia inducedby bortezomib. Patients with Hepatic or Renal Impairment: Patients with renal andhepatic impairment should be closely monitored for toxicities. Animal Toxicity Findings: Toxicities observed with chronicadministration in animals included severe anemia and thrombocytopenia;gastrointestinal, neurological and lymphoid system toxicities; andmultifocal hemorrhage in the brain, eye and heart. At doses twice therecommended clinical dose, animals experienced profound hypotensionand bradycardia resulting in myocardial damage and death.

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