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`IPR2018-01714
`Celgene Ex. 2011, Page 1
`
`

`

`
`
`JOURNAL OF
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`THE AMERICAN
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`SOCIETY OF
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`HEMATOLOGY
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`‘4‘
`
`IPR2018-01714
`Celgene Ex. 2011, Page 2
`
`

`

`PROGRAM OF THE 45“l ANNUAL MEETING OF
`
`THE AMERICAN SOCIETY OF HEMATOLOGY
`
`
`
`December 6-9, 2003
`
`San Diego, California
`
`
`
`Printed in_ the USA
`Copyright © 2003, The Amerlcan Socxety ofHematology, Washington, DC.
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`This material wast-timed
`atthe NLM a d may be-
`Subjact USEprright Laws
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`IPR2018'01714
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`Celgene EX. 201 1, Page 3
`
`IPR2018-01714
`Celgene Ex. 2011, Page 3
`
`

`

`
`This material may be protected by Copyright law (Title 17 0.5. Code)
`
`
`
`
`450a
`
`mAb 13-134, targeting CD138, conjugated with DMl (B-B4-DM1) against a panel ofCD138+
`MM cells (MM.IS, OCI-MyS and MM.1R) and CD138~ cells (the Waldenstrom’s
`macroglobulinemia cell line WSU-WM and the lymphoma line SUDHL4) in vitro.
`Following 48 h of treatment, B-B4-DM1 significantly decreased survival ofCD138+ MM
`cells (IC50: 10-50 nM), assessed by viable cell number, MTT and proliferation assays,
`compared to CD138- WSU-WM or SUDHL4 cells (IC50 not reached). In contrast,
`cytotoxicity of unconjugated DMl was equivalent in both CD138+ and CD138- cells
`(IC50 < 10 nM). The exposure of cells to equimolar concentrations ofunconjugated mAb B-
`B4 alone for 96 11 did not induce any cytotoxicity. We examined the effects induced by B-B4,
`B-B4—DM1 and DM1 on proliferation of OCI-My5 and SuDllL4 cells adherent to bone
`marrow stromal cells (BMSCs). Unconjugated mAb did not induce any detectable effect,
`whereas B-B4-DM1 showed specific activity against CD138+ cells. DMl alone induced
`toxicity in both lines including BMSC. We further evaluated activity of BB4-DM1 against
`CD138+ MM cells cultured with CD138- cell lines or peripheral blood cells, or against
`CD138+ primary MM cells adherent to patient BMSCs. B-B4-DM1 was selectively able to
`deplete CD138+ tumor cells. Propidium iodide profiling confirmed that B-B4-DM1
`treatment of MM cells results in reduction of S-phase, G2 arrest, and apoptotie cell death.
`Finally, antitumor activity ofB-B4-DM1 was evaluated in vivo in a murine MM xenograft
`model. Mice bearing OI’MZ human MM cells were treated with B-B4-DM1 (75 rig/Kg or
`150 rig/Kg), huC242-DM1 (150 rig/Kg) unreactivc with MM cells or vehicle only for a
`total of5 days. Inhibition oftumor growth and improvement in median overall survival were
`observed in B-B4-DM l-treatcd mice (p<0.005) compared to control groups. In conclusion,
`our data demonstrate that B-B4-DM1 has in vitro and in vivo anti-MM activity, suggesting
`its potential utility for treatment ofMM.
`
`Abstract# 1642
`
`Poster Board #-Session: 754-I
`
`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 Therapy for Multiple Myeloma (MM). Maurizio Zangari,'
`Bart Barlogie,l Joth Jacobson’“,2 Jerome B. Zeldis,3 Elias J. Anaissie,l
`Raymond Thertulicn,l Athanasios Fassas,1 Choon-Kee Lee,I John D.
`Sha'ughncssy,l Guido J. Trieot.l ’Myeloma Institutefor Research and Therapy,
`University ofArkansas for Medical Sciences, Little Rock, AR, USA; ’Cancer
`Research And Biostatistics, Seattle, WA, USA; 3Celgene Corporation, Warren.
`NJ, USA.
`
`.58 patients with advanced and refractory MM were enrolled in this randomized phase
`II trial. Patient characteristics included age 2 ()0 in 54%, abnormal cytogcnetics 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 response rates after monthly REV cycles are depicted according to 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=0.04l).
`
`Best 2 MProtein Response by Oyvch:
`50.0%
`
`40.0%
`
`20.0%
`
`0.0%
`
`60.0%
`
`40.0%
`
`20.0%
`
`0.0%
`
`
`
`
`a
`50°
` I g??? u 90%
`121257: 0
`
`A
`
`DOSC limiting toxicity was cytopenia, especially thrombocytopenia with 55% ofpatients
`with pre-REV platelet levels 2 100,000/uL developing grade > 2 thrombocytopenia (<
`50.000/HL) as Opposed to 90% when Dre-REV platelet levels were < 100,000411. (p=.001).
`
`Event-Free Survival by Cytoganefim: UARK Quit-44
`my.
`12-Hour:
`
`Emu IN Equine
`325 (1253)
`——No Q 10 l 21
`
`22 (32
`31% (15.07)
`- -Q
`Lord P-value : t3
`
`Overall Survival by Cyoqendica: UAHK 2001-44
`r--_u
`my.
`
`my.
`
`m.
`
`
`
`6:!"
`
`40$
`
`20%
`
`0%
`
`‘07.
`
`12-an
`Darwin
`Euimne
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`(559)
`23‘
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`is
`
`THERAPEUTICS FOR PLASMA CELL DYSCRASIA
`
`REV was not associated with sedative or neurotoxic side effects. Estimated 12-month
`EFS and OS rates are 30% and 61%, respectively, independent of cytogenetic abnormalities
`(CA) and REV dose. Serial gene expression profiling (GEP) studies prior to and 48 hr after
`REV revealed similar but not identical GEP changes as 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, Liposornal Doxorubicin and Dexamethasone (T-VAD
`Doxil): A Phase II Multicenter Study. Konstantinos Zervas", Meletios
`Athanasios Dimopoulos, Eleni Hatziharisi“, Athanasios Anagnostopoulos*,
`Maria Papaioannou“, Chrisanthi Mitsouli*, Panos Panagiotidis", loannis
`Korantzis“, Michael Tzilianos*, Alice Maniatis“. Greek Myeloma Study
`Group, Athens, Greece.
`Introduction: We and others have shown that VAI)-doxil is an outpatient regimen
`which is effective in two-thirds of previously untreated patients with multiple myeloma.
`Recent data also indicate that thalidomide with dexamethasone is a highly active primary
`treatment for myeloma patients. Thus, we studied the efficacy and toxicity ofthe combination
`of VAD-doxil with thalidomide as initial 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 l, and dexamethasone 40mg
`PO daily for 4 days. Dexamethasone was also given on days 15-18 of the first cycle of
`treatment. The regimen was administered every 4 weeks for 4 courses. Thalidomide was
`given daily at a dose of 200 mg at bedtime. Response to treatment was evaluated after 4
`cycles oftrcatment. After completion of4 cycles the patients were allowed to proceed to
`high dose chemotherapy or to receive two additional cycles of the same treatment.
`Results: Thirty-nine previously untreated patients were included in this phase II
`multicenter trial. Their median age was 68 years, median serum albumin 3.2g/dl and median
`serum b2 microglobulin 3.9mg/d10n an intention-to-treat basis, 29 ofthe 39 patients (74%)
`responded to treatment. Four patients (10%) achieved complete and 25 (64%) partial response.
`Three patients (8%) showed minor response and 7 (18%) were rated as non responders. The
`time to response was short and at least 50% reduction of monoclonal protein was noted
`within 2 months oftrcatment in 80% of responding patients. Major grade 3 or 4 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 thalidomide is an effective and relatively well tolerated
`initial cytoreductive treatment for symptomatic patients with multiple myelorna. Prospective
`randomized studies are required in order to assess the effect of this regimen on the long-tenn
`outcome of this disease.
`
`Abstracttte
`
`1644
`
`Poster Board #-Session: 756-1
`
`Doxorubicin and Dcxamcthasone (AD) Followed by Thalidomide
`and Dexamethasone (TD) as Initial Therapy for Symptomatic
`Patients with Multiple Myeloma. Raymond L. Comenzo,l
`IIani
`llassoun,l Lilian Reieh*,' Virginia Klimek,l Tarun chalramani,I Madhav
`Dhodapkar,‘ Lisa Drake"‘,l Cyrus Iledvat"‘,2 Julie Tcruya-Fcldstcitt*,2 Martin
`Flcisher*,3 Daniel A. Filippa”:2 Stephen D. Nirner.l ’Meclicine, Memorial
`Sloan-Kettering Cancer Center, New York, NY, USA; 3Patliology, Memorial
`Sloan-Kettering Cancer Center, New York. NY. USA; ’Clinicul Lalwratories,
`Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
`The addition of thalidomide to doxorubicin-containing regimens has been associated
`with high response rates and a 25% incidence ofvcnous thromboembolie complications in
`patients with multiple myeloma (NEJM 2001;344:195l-2; Blood 2001;98:1614-5; Blood
`2002;100:1168-71). This risk has been increased in patients with myeloma exhibiting the
`11q+ chromosome abnormality. To maintain the beneficial ctlects ofthese agents and minimize
`thromboembolic complications, we are examining the use of these agents in a temporally
`separated fashion for symptomatic stage II and 111 patients. Doxorubicin and dexamethasone
`(AD;A=9mg/m3/day, Days 1—4; D=40mg/day, Days 1-4, 9-12, 17-20) are given for} 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 stem cell transplantation
`(SCT). As of 7/03 we have enrolled 27 patients (16M, 1 1W) with a median age of58 years
`(range, 38-79); 10 had myeloma with plasmaeytomas extending into soft tissues. Median [52
`microglobulin was 2.2mg/L (ND-10.5) and hemoglobin 11.3g/dl (81.3-14.3). Fluorescent
`in situ hybridization (FISH) studies ofbaseline bone marrows, searching for abnormalities
`of chromosomes 11, 13 and 14, are available for 23 patients. Abnormalities of 14 were
`detectedin seven patients, of] l in live patients,ofl 1, l3 and 14 intwo,of 11 and 13 in one,
`and of 11 and 14 in one. Seven patients had no abnormalities of l l, 13 or 14 by FISH. Five
`patients are currently in treatment and two have been removed from study, one for a DVT that
`occurred during cycle 5 and the other for a myocardial infarction after cycle 1. Two patients
`developed DVT on or just after therapy with thalidomide (2/21; 10%; 1/2 with 1111+),
`which seems to be less than the incidence of DVT (6/21; 29%; 4/6 with llqt) 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" u)
`and 8 partial responses (40%). One patient had stable disease (5%). Two patients achieved
`CR after 3 cycles of AD and underwent SCT, and 16 patients in toto have undergone SCT
`
`This material was copied
`at: the N Ltd a rid may be
`Eubject LIE Empyright‘ Laws
`
`|PR2018—01714
`
`Celgene Ex. 2011, Page 4
`
`IPR2018-01714
`Celgene Ex. 2011, Page 4
`
`