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`
`MEDICINE Celgene Ex. 2011, Page 1
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`PROGRAM OF THE 45" ANNUAL MEETING OF
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`THE AMERICAN SOCIETY OF HEMATOLOGY
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`December 6-9, 2003
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`San Diego, California
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`

`

`
`This material may beprotected by Copyrightlaw(Title 17 U.S. Code)
`
`
`
`450a
`
`mAb b-B4,targeting CD 138, conjugated with DM! (B-B4-DM 1) againsta panel ofCD138+
`MM cells (MM.1S, OCI-My5 and MM.1R) and CD138- cells (the Waldenstrom’s
`macroglobulinemia cell line WSU-WM and the lymphoma line SUDHL4)in vitro.
`Following 48h oftreatment, B-B4-DM1 significantly decreased survival of CD138+ MM
`cells (IC50: 10-50 nM), assessed by viable cell number, MTT andproliferation assays,
`compared to CD138- WSU-WM or SUDHL4cells (1C50 not reached). In contrast,
`cytotoxicity of unconjugated DMI was equivalent in both CD138+ and CD138- cells
`(IC50 < 10 nM). The exposureof cells to equimolar concentrations ofunconjugated mAb B-
`B4alonefor 96 hdid not induce any cytotoxicity. We examinedtheeffects induced by B-B4,
`B-B4-DM1 and DMI onproliferation of OCI-My5 and SuDHL4cells adherent to bone
`marrowstromal cells (BMSCs). Unconjugated mAb did not induce any detectable effect,
`whereas B-B4-DM1 showedspecific activity against CD138+ cells. DMI alone induced
`toxicity in bothlines including BMSC. Wefurther evaluated activity of BB4-DM1 against
`CD138+ MMcells cultured with CD138- cell lines or peripheral blood cells, or against
`CD138+ primary MM cells adherentto patient BMSCs. B-B4-DM1 wasselectively able to
`deplete CD138+ tumorcells. Propidium iodide profiling confirmed that B-B4-DM1
`treatment of MM cellsresults in reduction of S-phase, G2 arrest, and apoptotic cell death.
`Finally, antitumoractivity of B-B4-DM1 wasevaluated in vivo in a murine MM xenograft
`model. Mice bearing OPM2 human MMcells were treated with B-B4-DM1 (75 pe/Kg or
`150 e/Kg), huC242-DM1 (150 Hg/Kg) unreactive with MM cells or vehicle only for a
`total of5 days.Inhibitionoftumor growth and improvementin median overall survival were
`observed in B-B4-DM I-treated mice (p<0.005) compared to control groups. In conclusion,
`our data demonstrate that B-B4-DM1 hasinvitro and in vivo anti-MM activity, suggesting
`its potential utility for treatment of MM.
`
`Poster Board #-Session: 754-I
`Abstract# 1642
`Revimid 25 mg (REV 25) x 20 Versus 50 mg (REV 50) x 10 q 28 Days
`with Bridging of 5 mg x 10 Versus 10 mg x 5 as Post-Transplant
`Salvage Therapyfor Multiple Myeloma (MM). Maurizio Zangari,!
`Bart Barlogie,' Joth Jacobson*,? Jerome B. Zeldis,> Elias J. Anaissie,!
`Raymond Thertulien,’ Athanasios Fassas,! Choon-Kee Lee,! John D.
`Shaughnessy, GuidoJ. Tricot.' ‘MyelomaInstitutefor Research and Therapy,
`University ofArkansas Jor Medical Sciences, Little Rock, AR, USA; ?Cancer
`Research AndBiostatistics, Seattle, WA, USA; 4Celgene Corporation, Warren,
`NJ, USA.
`58 patients with advanced and refractory MM wereenrolled in this randomized phase
`YW trial. Patient characteristics included age 2 60 in 54%, abnormal cytogenetics in 54%
`including del 13 in 33%; prior therapy > 5 years in 41%: prior autotransplants in 86%
`including tandem transplant in 48%; prior thalidomide exposure in 93% of patients.
`Cumulative responserates after monthly REVcycles are depicted accordingto the levels of
`M protein reduction specified, which were higher with REV 25 than REV 50 (Cycle 8 50%
`or greater response: 40% vs 15% p=0.041).
`
`Best % M-Protein Response by Cycle
`60.0%
`
`40.0%
`
`20.0%
`
`0.0%
`
`60.0%
`
`40.0%
`
`20.0%
`
`0.0%
`
`Doselimiting toxicity was cytopenia, especially thrombocytopenia with 55% ofpatients
`with pre-REVplatelet levels 2 100,000/UL developing grade > 2 thrombocytopenia (<
`50,000/1L) as opposed to 90% when pre-REVplatelet levels were < 100,000/1L (p=.001).
`
`THERAPEUTICS FOR PLASMA CELL DYSCRASIA
`
`REV wasnotassociated with sedative or neurotoxic side effects, Estimated 12-month
`EFSand OSratesare 30% and 61%,respectively, independentof cytogenetic abnormalities
`(CA) and REVdose.Serial gene expression profiling (GEP) studies prior to and 48 hr after
`REVrevealedsimilar but not identical GEP changesas observed after thalidomide. Clinical
`outcome data will be presented in the context of these GEP data.
`
`Abstract# 1643
`Poster Board #-Session: 755-1
`
`Primary Treatment of Mutiple Myeloma with Thalidomide,
`Vincristine, Liposomal Doxorubicin and Dexamethasone (T-VAD
`Doxil): A Phase II Multicenter Study. Konstantinos Zervas*, Melctios
`Athanasios Dimopoulos, Eleni Hatziharisi*, Athanasios Anagnostopoulos*,
`Maria Papaioannou*, Chrisanthi Mitsouli*, Panos Panagiotidis*, Ioannis
`Korantzis*, Michael Tzilianos*, Alice Maniatis*, Greek Myeloma Study
`Group, Athens, Greece.
`Introduction: We and others have shown that VAD-doxil is an outpatient regimen
`whichis effective in two-thirds of previously untreated patients with multiple myeloma.
`Recentdata also indicate that thalidomide with dexamethasoneis a highly active primary
`treatment for myelomapatients. Thus, we studied the efficacy and toxicity ofthe combination
`of VAD-doxil with thalidomide asinitial cytoreductive treatment in previously untreated
`patients with symptomatic myeloma.
`Patients and methods: The treatment consisted of vincristine 2mg IV, liposomal
`doxorubicin 40mg/m2 IV, administered as single dose on day 1, and dexamethasone 40mg
`PO daily for 4 days. Dexamethasone was also given on days 15-18 ofthe first cycle of
`treatment. The regimen was administered every 4 weeks for 4 courses. Thalidomide was
`given daily at a dose of 200 mgat bedtime. Responseto treatment was evaluated after 4
`cycles oftreatment, After completion of 4 cycles the patients were allowed to proceed to
`high dose chemotherapy orto receive two additional cycles of the same treatment.
`Results: Thirty-nine previously untreated patients were included in this phase II
`multicentertrial. Their median age was 68 years, median serum albumin 3.2g/dl and median
`serum b2 microglobulin 3.9mg/dlOnan intention-to-treat basis, 29 of the 39 patients (74%)
`respondedto treatment. Fourpatients (10%) achieved complete and 25 (64%)partial response.
`Three patients (8%) showed minorresponse and7 (18%) were rated as non responders. The
`time to response was short and at least 50% reduction of monoclonal protein was noted
`within 2 monthsoftreatment in 80% ofresponding patients, Major grade 3 or4 toxicities
`consisted of neutropenia (15%), thrombocytopenia (15%), deep vein thrombosis (10%),
`constipation (10%), skin rash (5%) and peripheral neuropathy (5%). Two patients (5%)
`experienced early death due to infection. Event-free and overall survival at 22 months were
`55% and 74% respectively.
`Conclusions: The combination of vincristine, liposomal doxorubicin, and
`dexamethasone (VAD doxil) with thalidomideis an effective and relatively well tolerated
`initial cytoreductive treatmentfor symptomatic patients with multiple myeloma.Prospective
`randomizedstudies are required in orderto assess the effect of this regimen on the long-term
`outcomeofthis discase.
`
`Abstract# 1644
`
`Poster Board #-Session: 756-1
`
`Doxorubicin and Dexamethasone (AD) Followed by Thalidomide
`and Dexamethasone (TD) as Initial Therapy for Symptomatic
`Patients with Multiple Myeloma. Raymond L. Comenzo,' Hani
`Hassoun,! Lilian Reich*,' Virginia Klimek,' Tarun Kewalramani,' Madhav
`Dhodapkar,' Lisa Drake*,' Cyrus Hedvat*,? Julie Teruya-Feldstein*,? Martin
`Fleisher*,? Dantel A. Filippa*,? Stephen D. Nimer.! ‘Medicine, Memorial
`Sloan-Kettering Cancer Center, New York, NY, USA; ?Pathology, Memorial
`Sloan-Kettering Cancer Center, New York, NY, USA; 3Clinical Laboratories,
`Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
`The addition of thalidomide to doxorubicin-containing regimens has becn associated
`with high response rates and a 25% incidence of venous thromboembolic complications in
`patients with multiple mycloma (NEJM 2001;344:1951-2; Blood 2001;98:1614-5; Blood
`2002; 100:1168-71). This risk has been increased in patients with myeloma exhibiting the
`11q+ chromosomeabnormality. To maintain the beneficial effects ofthese agents and minimize
`thromboembolic complications, we are examining the use of these agents in a temporally
`separated fashion for symptomatic stage [Land III patients. Doxorubicin and dexamethasone
`(AD; A=9mg/m*/day, Days 1-4; D=40mg/day, Days 1-4, 9-12, 17-20) are given for 3 months
`followed by thalidomide and dexamethasone (TD; T=200mg nightly; D=as above) for 2
`months with prophylactic antibiotics and daily aspirin (325g). At any point in therapy
`patients achieving complete responses (CR; immunofixation negative) are permitted to
`forgo further induction therapy and proceed with autologous stemcell transplantation
`(SCT). As of 7/03 we have enrolled 27patients (16M, 11W) with a median age of 58 years
`(range, 38-79); 10 had myeloma with plasmacytomasextending into soft tissues. Median B2
`microglobulin was 2.2mg/L (ND-10,5) and hemoglobin 11.3g/dl (8.3-14.3). Fluorescent
`in situ hybridization (FISII) studies of baseline bone marrows,searching for abnormalities
`of chromosomes [1, 13 and 14, are available for 23 patients, Abnormalities of 14 were
`detected in sevenpatients, of [1 in five patients, of 11, 13 and 14 in two, of 11 and 13 in one,
`and of {1 and 14 in one. Sevenpatients had no abnormalities of 11, 13 or 14 by FISH. Five
`patients are currently in treatment and two have been removed from study, one fora DVTthat
`occurred during cycle 5 and the other for a myocardialinfarction after cycle 1. Two patients
`developed DVT onorjust after therapy with thalidomide (2/21; 10%; 1/2 with I1q+),
`which scemsto be less than the incidence of DVT (6/21; 29%; 4/6 with I1q+) noted in
`initial versions of this trial incorporating thalidomide and doxorubicin together in each
`cycle. Twenty patients are currently evaluable for response. Nineteen have responded to
`therapy (95%), including 5 complete responses (25%), 6 very good partial responses (30%)
`and 8 partial responses (40%), Onepatient had stable disease (5%). Two patients achieved
`CRafter 3 cycles of AD and underwent SCT,and 16 patientsi? tofo have undergone SCT
`
`Overall Survival by Cogenetice: UARK 200144
`00%
`
`aS
`
`on
`
`htt,'
`
`ne
`
`0%
`WeMorth
`
` Extimae
`Deahy {N
`—a
`8/32
`72% GSe)
`
`—~No CA
`112 GO% (58H)
`Logark Povale = 57
`
`9
`2
`6
`9
`2
`Mocthe trem Stat d Pratoool Therapy
`
`This material was copied
`atthe NLM and may be
`Subject US Copyright Laws
`
`IPR2018-01714
`Celgene Ex. 2011, Page 4
`
`Event—Free Survival by Cytogenetics: UARK 2001—44
`1%
`TeeMorah,
`Evertu/N Eamae
`S27 RM (1259)
`No CA
`227m He 1547
`mh
`Logrank Pewaive = 49
`
`
`
`0%
`
`
`
`OO
`
`0%
`
`2%
`
`0%
`
`2
`9
`8
`3
`Morths from Start od Protocol Therapy
`
`8
`
`IPR2018-01714
`Celgene Ex. 2011, Page 4
`
`