`
`
`
`The
`L13cw Englanu
`Journal of Medicine
`
`
`
`Established in 1812 as THE New ENGLAND JOURNAL OF MEDICINE AND SURGERY
`
`VOLUME 341
`
`NOVEMBER 18, I999
`
`NUMBER 21
`
`ORIGINAL ARTICLES
`
`light-To-Moderate Alcohol Consumption
`and the Risk of Stroke among
`US. Male Physicians
`1L BERGER AND OTHERS
`
`. EDITORIAL:
`\,
`Alcohol for Stroke Prevention? .............................. I60?"
`M. HOMMEL AND A. IAILLARD
`-
`
`1557 K .J
`
`Thalidomide -— A Revival Story ......................
`N. RAH: AND K. ANDERSON
`
`Antitumor Activity of Thalidomide
`
`in Refractory Multiple Myeloma .....................@
`
`S. SINGHAL AND OTHERS
`
`/
`Reduction of False Negative Results in
`Screening of Newborns for Homocysu'nuria I572
`MJ. Pernnscumrr, LR. SIMMONS,
`AND H.L. LEVY
`
`Brief Report: Leuprolide Acetate Therapy
`in Luteinizing Hormone-Dependent
`Cushing’s Syndrome .............................................. 1577
`A. LACROIX, P. HAMET, AND ].-M. BOUTIN
`
`IMAGIS IN CLINICAL MEDICINI
`
`Gangrene and Type I Cryoglobulinemia
`in Multiple Myeloma ............................................. I582.
`L. CIRASINO AND LR. BARBANO
`
`SPECIAL ARTICLE
`
`Mortality among Recent Purchasers
`of Handguns ...........................................................
`GJ. WINTEMUTE, C.A. PARIIAM,
`1.]. BEAUMONT, M. WRIGHT, AND C. DRAKE
`
`REVIEW ARTICLE
`
`Benign Paroxysmal Positional Vertigo ................. I590
`I.M. FURMAN AND S.P. CASS
`
`CASE RECORDS OF THE
`MASSACHUSETTS GENERAL HOSPITAL
`
`Firearms and Suicide ................................................. 1609
`ML ROSENBERG, LA. MERCY,
`AND LB. POTTER
`
`SOUNDING BOARD
`
`Medical Professionalism in Society ...................... 1612
`M.K. WYNIA, S.R. LA'I'HAM, A.C. KAO,
`LW. BERG, AND L.L. EMANUEL
`
`INFORMATION FOR AUTHORS ......................... 1617
`
`CORRISPON DENCE
`
`Authors’ Conflicts of Interest: A Disclosure
`
`and Editors’ Reply ..................................................... I618
`Reimbursement for Evaluation
`
`and Management Services ........................................ Iéuf"
`Neostigmine for Acute Colonic Pseudo~0bstruction 1612
`DNA Vaccines ................................................................. 1623
`The Effects of Vancomyein and B-Lactam
`Antibiotics on Vancomydn’Resistant
`Staphylococcus aurm .................................................. 162.4
`Priming with Human Char-ionic Gonadotropin
`before Retrieval of Immature Oocytes
`in Women with Infertility Due to the
`Polyeystie Ovary Syndrome ...................................... I624
`
`BOOK REVIEWS ....................................................... 1627
`
`NOTICES ..................................................................... 1629
`CORRECTIONS
`A Five-Month-Old Girl
`Treatment of Asthma with Drugs Modifying
`With Coffee-Grounds Vomitus ........................... I
`the Leukotriene Pathway ........................................ 1632
`S. HARDY AND S.B. KEEL
`Zolpidem in Progressive Supranuclear Palsy
`I632
`
`Owned, gamut. ul Ocopyrubud, 1999, by TH: MASSACHUSETTS MEDICAL SOCIETY
`
` mt‘bOI-‘UCHFH’U
`
`0024 & :4
`71 1.9 99
`a
`
`1m NEW ENGLAND IOURNAL or Mwlcm: (ISSN 0028-4793) iI published weekly
`from editorial office: i 10 Shamxk Street. Bonon, MA 02115-6094‘ Subscription price'
`$129.00 per yur. Periodical: W paid at Boston and at additional mailing offices
`POSTMASTER: Send address changes In ROI Box 540803, WIldIam, MA 02454-0803.
`
`DOES NOT
`
`LEA VE £13m;
`
`Dr. Reddy's Laboraton’os, Inc. v. Celgene Corp,
`IPR2018-01509
`Exhibit 2023, Page 1
`
`.
`
`
`
`

`

`
`
`ANTITUMOH ACTIVITY OF THALIDOMIDE IN REFRACTORY MULTIPLE MYELOMA ur.v--¢‘ '3‘." ' ‘ i
`
`
`
`3" f»-
`..‘,‘.“.‘t
`'tt:
`.
`\
`
`
` .‘.'53.,» . ‘
`I
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`-‘ <;~ 'I‘."
`:‘T'fifiii
`" ' U" ‘7' Cir
`
`
`
`ANTITUMOR ACTIVITY OF THALIDOMIDE IN REFRACTORY
`MULTIPLE MYELOMA
`
`SEEMA SINGHAL, M.D., JAYESH MEHTA, M.D., RAMAN DesmAN, M.D., DAN AYERS, M.S., PAULA Roarnson, PH.D.,
`'
`PAUL EDDLEMON, B.S., NIKHIL MUNSHl, M.D., ELIAS ANAlSSlE. M.D., CARLA WILSON, M.D., PH.D.,
`MADHAV DHODAPKAR, M.D., JEROME ZELDIS, M.D., AND BART BARLOGIE, M.D., PHD.
`
`AesTnAcr
`
`Background Patients with myeloma who relapse
`after high-dose chemotherapy have few therapeutic
`options. Since increased bone marrow vascularity
`imparts a poor prognosis in myeloma, we evaluated
`the efficacy of thalidomide, which has antiangiogenic
`properties, in patients with refractory disease.
`Method: Eighty—four previously treated patients
`with refractory myeloma (76 with a relapse after high
`dose chemotherapy) received oral thalidomide as a
`single agent for a median of 80 days (range, 2 to 465).
`The starting dose was 200 mg daily, and the dose was
`increased by 200 mg every two weeks until it reached
`800 mg per day. Response was assessed on the ba-
`sis of a reduction of the myeloma protein in serum
`or Bence Jones protein in urine that lasted for at least
`six weeks.
`
`Results The serum or urine levels of paraprotein
`were reduced by at least 90 percent in eight patients
`(two had a complete remission), at least 75 percent
`in six patients, at least 50 percent in seven patients,
`and at least 25 percent in six patients, for a total rate
`of response of 32 percent. Reductions in the parapro-
`tein levels were apparent within two months in 78
`percent of the patients with a response and were as-
`sociated with decreased numbers of plasma cells in
`bone marrow and increased hemoglobin levels. The
`microvasculer density of bone marrow did not change
`significantly in patients with a response. At least one
`third of the patients had mild or moderate constipa-
`tion, weakness or fatigue, or somnolence. More se-
`vere adverse effects were infrequent (occurring in less
`than 10 percent of patients), and hematologic effects
`Were rare. As of the most recent follow-up, 36 pa-
`tients had died (30 with no response and 6 with a re-
`sponse). After 12 months of follow—up, Kaplen—Meier
`estimates of the mean (:SE) rates oi event-free sur-
`vival and overall survival for all patients were 2215
`percent and 58:5 percent, respectively.
`ad—
`Conclusion: Thalidomide is active against
`vanced myeloma, It can induce marked and durable
`responses in some patients with multiple myeloma,
`including those who relapse after high-dose chemo-
`therapy. (N Engl J Med 1999;341:1565-71.)
`01999, Massachusetts Medical Society.
`
`ULTIPLE myeloma accounts for ap-
`proximately 1 percent of all cancers and
`10 percent of hematologic cancers. It
`is incurable with conventional chemo—
`therapy.l Mclphalan-bascd high-dose chemotherapy
`with hcmatoPOictic stcm~ccll support incrcaScs the
`rate of complete remission and extends event-free and
`overall survival.H However, many patients still relapse,
`and options for salvage therapy are limited.5)6
`Angiogcncsis is important in cmbryogcnesis, wound
`healing, diabetic rctinopathy, and tumor progression."
`The immunomodulatory drug thalidomide can inhib-
`it angiogcncsis and induce apoptosis of established
`ncovasculaturc in experimental models.’-)0 For these
`reasons, angiogcncsis-inhibiting drugs such as tha-
`lidomide may be useful for treating cancers that dc-
`pcnd on ncovascularizau'on.
`Prominent bone marrow vascularization occurs in
`
`multiple myeloma. It correlates positively with a high
`plasma-cell—labeling index (a poor prognostic Sign)
`and disease activity and independently confers a poor
`prognosisll-l" Plasma levels of various angiogcnic cy-
`tokincs, such as basic fibroblast growth factor and
`vascular cndothclial growth factor, are elevated in pa-
`tients with active myelornafl'nv16 In 1965, Olson er al.
`reported slowing of disease progression in one pa-
`tient who was treated with thalidomide.17 Thcsc con—
`siderations led us to administer thalidomide to five
`
`patients with end-stage myeloma through a compas-
`sionate-use protocol. One patient with a large tumor
`burden (as indicated by an IgA level of 8.4 g per dec-
`iliter, the presence of more than 95 percent plasma
`cells in bone marrow, and the need for transfusion),
`who had had no response to two cycles of high-dose
`chemotherapy followed by multiple salvage therapies,
`had a nearly complete remission within three months
`after the initiation of thalidomide therapy. This ob-
`servation prompted a phase 2 investigation of tha-
`
`
`
`From the Myclom and Lymphoma Program, South Carolina Cancer
`Center, University of South Carolina, Columbia (5.5., }.M.); the Myeloma
`and Transplantation Research Center, University of Arkansas for Medical
`Sciences, Little Rock (R.D., D.A., Rik, BIL, N.M., E.A., C.W., 12., 8.3.);
`and the Labommory of Cellular Physiology and immunology, Rockefeller
`Univusiry, New York (MD). Addnm reprint requests to Dr. Barlogie II
`the Mycloma and Transplantation Research Center, University of Arkansas
`for Medical Sciences, i301 W. Markham, Slot 623. Little Rock, AR 72105.
`Other authors were David Siegel. M.D., Ph.D., University of Arkansas
`for Medical Sdenccs. Little Rock‘ and John Cch, Ph.D., Fred Hutch»
`inson Cancer Research Center, Seattle.
`
`Dr. Retir’fl‘éltnséflnei? chélbené car?“
`lPR2018-01509
`Exhibit 2023, Page 2
`
`

`

`The New England Journal of Medicine
`
`lidomide in patients with advanced and refractory
`myeloma.
`
`TAILE 1. Cmcmmsnos or THE PATIENTS.
`
`Grammar:
`
`No. or
`Parents (95)
`
`METHODS
`
`Patients and'Ttootmonts
`
`Between December 1997 and June 1998, 84 consecutive, eligi-
`ble patients with previously treated and progressive myeloma began
`treatment with oral thalidomide as a single agent after providing
`written informed consent. No patients were excluded on the basis
`of renal or cardiopulmonary function, whereas patients could be
`excluded if the results of liver-function tests were more than twice
`the upper limit 0f normal levels. All patients were trmtod at a single
`center according to a phase 2 protocol approved by the institution-
`al review board and the Food and Drug Administration (FDA).
`Thalidomide was supplied in 50-mg capsules by Celgene (War-
`ren, NJ.) and was administered nightly at a dose of 200 mg. The
`‘dOsewasincreasedbyZOOmgeverymweeksforsixweeks.so
`that the final dose was 800 mg per day. Data were analyzed as of
`lune 17. 1999, when the duration of treatment ranged from 2 to
`465 days (median, 80) and the median fiollow-up of surviving
`patients was 13 months.
`Table 1_ summarizes the characteristics of the patients and de-
`tails ofprior therapy. Seventy-six patients (90 percent) had received
`at least one cydc of high-dose chemotherapy with autologous hem-
`aropoietic stem-cell support, and 58 (69 percent) had received two
`or more cycles of intensive chemotherapy. The median time from
`the last course ,of high—dose chemotherapy to the beginning of
`treatment with thalidomide was 14 months. A high—risk cyto-
`genetic abnormality (deletion of chromosome 13) was present in
`35 patients (42 percent).20 One padent had received an allograft
`as a second intervention, with evidence of full donor—type chi-
`merisrn in normal lyrnphohematopoietie cells. At the time of en-
`rollment, all patients had progressive disease, with an increase in
`paraprorein levels of at least 25 percent or at least 50 percent plas—
`ma cells in bone marrow. Approximately halfthc patients had been
`retreated with dcxamethasone or other regimens, but the disease
`had progressed before thalidomide treatment was begun.
`
`Evaluation
`
`The pretreatment evaluation included complete blood counts,
`tests of renal and liver function, serum and urine protein electro-
`phoresis, and measurements of serum levels of immunoglobulins,
`beraz-microglohulin, and C-reactive protein Bone marrow aspi-
`rates were obtained and biopsies were performed to determine
`the percentage of plasma cells in bone marrow, to identify kary—
`otypic abnormalities (Giemsa-banded cells in metaphase), and to
`assess the proliferative activity in plasma cells according to die
`bromodeoxyuridine method to derive the plasma-cell—labeling
`index.13 Follow-up studies included a weekly estimation of para-
`protein levels — the myeloma protein in serum and Bence Jones
`protein in urine — for the first two months, followed thereafter
`by monthly measurements. Whenever possible, bone marrow was
`examined at the time of the maximal response or when patients
`with no response left the study.
`The microvascularity of bone marrow was studied in a semi-
`quantitative fashion in biopsy samples that were obtained with
`a trephinc and stained with an anti~CD34 monoclonal antibody
`(prediluned Clone QBEnd/ 10, Cell Marque, Austin, Tex.) The
`results were expressed as the number of vessels per high-power
`field (400X).
`
`Assessment of Response
`
`The primary end point of the study was the finding of a decline
`in the level ofparaprotcin in serum or urine of at least 25 percent,
`50 percent, 75 percent, or 90 percent on two occasions at least
`six weeks apart. Among patients with detectable levels of both
`urine and serum paraprotein, the response was judged on the ba-
`sis of the component showing the smaller decline. Patients with
`
`1556 - November 18, 1999
`
`61 (73)
`51 (6])
`51 (61)
`18 (21)
`76 (90)
`58 (69)
`43 (57)
`
`32 (38)
`19 (23)
`17 (20)
`22 (26)
`22 (26)
`24 (29)
`20 (24)
`5] (61)
`44 (52)
`18 (21)
`13 (15)
`19 (23)
`35 (42)
`
`"
`Male wt
`Dorie—Salmon stage III multiple myeloma
`IgG paraprotein
`Duration 13pr therapy >60 mo
`Prior high-dose chemotherapy
`Receipt of >1 cycle of high-dose chemotherapy
`Interval between last cycle offiigh-dosc chemotherapy
`and initiation of thalidomide >12 mo
`Age >60 yr
`Hemoglobin <9 g/dl
`Platelet count <50X lol/mm’
`Serum albumin <3.5 g/dl
`Serum creatinine >r.s mg/dl (133 patrol/liter)
`Serum beuz-rnlcroglobulin >6 mg/liter
`Serum C-rcaetive protein >3 mg/liter
`Serum monoclonal immunoglohulin >1 g/dl
`Urine Bence Iones protein >l g/day
`>5096 Plasma cells in bone marrow on biopsy
`Plasma-cefl‘labeling index >19t-
`Bartl grade 111
`Deletion of chromosome 13
`Outcome
`Completion of study
`Withdrawal from study
`Progression
`Intolerance of thalidomide
`Deathofpalientwitharesponset
`Personal masons
`Final dose of thalidomide
`72 (86)
`400 rug/day
`57 (68)
`600 trig/day
`
`800 mg/day 46 (55)
`
`_
`
`19 (23)
`
`54: (64)
`9 (11)
`1(1)
`l (1)
`
`‘The plmna-ccll—labeling index represents the percentage of light-chain—
`restricted plasma cells incorporating bromodeoxyuridlne.”
`(The Bartlgrsdiugsystemdisringuishesmyelomaedlsaccordingtotheir
`morphologic maturation." Grade I] refer: to immature plasma cells of
`cleaved, asynchronous, or polymorphous appearance.
`zmrpatimthadarespomemneaunembutdiedomhyvofueammu
`
`a reduction of less than 25 percent and those who discontinued
`treatment before a response could be assessed were considered to
`have had no response to thalidomide. Thus, the results were eval-
`uated on an intention-to-treat basis. In patients with a response,
`an increase in serum or urine paraprotein levels by more than 25
`percent above the nadir value was considered evidence of relapse.
`In patients who had a complete remission, evidence of reemer-
`gence of the monoclonal protein (detemiined by immunofixation)
`on at least two occasions was considered to indimte a relapse. In
`patients who had a complete remission or a nearly complete re—
`mission (k90 percent reduceion in serum or urine paraprotein lev-
`els), a bone marrow response was defined as the finding of less
`than 5 percent plasma cells in the biopsy specimen or aspirate. For
`the remaining patients with a paraprotein response, the percent-
`age of plasma cells had to decrease by at least 50 percent to qual-
`ify as a bone marrow response.
`
`Assessment of Adverse Elfom
`
`All patients, irrespective of the duration of therapy, were in-
`cluded in the evaluation of adverse effects. All patients received
`diaries after providing informed consent, and 83 patients (99 per-
`
`Dr. Reddy’s Laboratories, Inc. v. Oelgene Corp.
`IPR2018-01509
`Exhibit 2023, Page 3
`
`cen
`
`W1
`
`povvsflc.éflfi'993fil
`..-—~—.unm~.nunfih<3
`
`

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`
`Dr. Reddy’s Laboratories, Inc. v. Celgene Corp.
`IPR2018-01509
`Exhibit 2023, Page 4
`
`

`

`
`The New England Journal owedicine
`
`_——
`__________—__—__—.——u—-———————-
`
`TABLE 2. Pamnon-zm Pompous: AND BONE MARROW murmur:
`____________.__———.—_-——————-—
`
`PW Rem
`
`No. or
`PATENTS
`(96 or mml
`
`Worm
`Mm Rem:
`TOTAL
`NO. WITH
`N0.‘
`REPONSE(%)1
`
`MM Sum-
`NO. WITH
`NO. WHO
`lawsuit) man“)
`
`o
`o
`2 (100)
`2
`2 (2)
`Complete remission
`2
`2
`5 (33)
`a
`6 (7)
`)90% decrease in paraprotein
`1
`3
`3 (so)
`5
`6 (7)
`375% decrease in panprotein
`7 (8)
`350% decrease in parapmtein
`o
`3.
`4 (100)
`4
`3
`4
`3 (75)
`4
`6 (7)
`325% decrease in paraprotein
`6 (22)
`12 (44)
`17 (81)
`21
`27 (32)
`Total
`
`
`
`—4 (15)27 30 (53)
`57 (68)
`No response
`
`"l‘he response could not be evaluated in 6 of the patients with a paraprotein response and in 30
`of the patients with no paraprotein response.
`1A bone marrow retponse was defined as the presence of 13: than 5 percent plasma cells in bone
`marrow in patients who had a complete pmpmtein response or at least a 90 percent reduction in
`paraprotein levels anda: a reduction in plasma cells of at last 50 percent in patients with all other
`rypm of paraprotein responses.
`
`0.6
`
`0.4
`
`0.3
`
`
`
`
`
`'-CumulativeIncidence
`
`1'
`
`
`
`>25% reduction in paraprotein
`..............
`:................... >5°% reduction In par.pro‘°in
`
`
`r", ..... -.r'-'
` :4"
`___..r---
`------ Complete response
`
`10
`12
`14
`16
`O
`2
`4
`6
`8
`
`"J...............n.....
`
`....'------------- >75% reduction in paraprotein
`
`------- 390% reduction in paraprotein
`
`Months after the Start of Thalidomide
`
`Figure 1. Times to Various Paraproteln Responses.
`Among patients with a response, the median times to a reduction In the serum or urine paraproteln
`level of at least 25 percent, 50 percent, 75 percent, and 90 percent were one, two, four, and four
`months. respectively. Seventy-eight percent of the responses at the lowest level (3:26 percent reduc-
`tlon) were apparent within two months after the lnltiation of treatment.
`
`Microvmulnr Density of Bone Marrow
`
`The microvascular density of bone marrow was
`scheduled to be assessed every 50 days for a total of
`seven measurements, including the pretreatment val—
`ue. At least one measurement of the microvascular
`
`density of bone marrow was made in 74 patients (88
`percent); two or more measurements were made in
`37 patients (44 percent). In all, measurements were
`made in 69 patients before treatment and (in 50-
`day increments) in 17 at time 2, in 22 at time 3, in
`11 at time 4, in 12 at time 5, in 4 at time 6, and in
`3 at time 7. The microvascular density of bone mar-
`row and the percentage of plasma cells in bone mar-
`row correlated significantly at all times except the last
`(r>0.5, PS0.01). Although the microvascular den-
`sity of bone marrow decreased markedly in some pa-
`
`tients with a complete or nearly complete remissiOn,
`estimates of the lepe were not significantly different
`from zero among those with a response (P=0.39)
`and those without a response (P=0.22).
`
`Other Changes
`
`The percent changes from base line to the time of
`the maximal response among patients with a response
`and the time of the last follow-up visit among those
`without a response were assessed for betaz-micro-
`globulin, C-reactivc protein, lactic dehydrogenase,
`creatinine, albumin, and hemoglobin levels and the
`platelet count. Hemoglobin levels increased only in
`patients with a response (median increase, 11 percent;
`P<0.001 for the comparison with base-line values).
`Serum levels of betaz-microglobulin rose (median in-
`
`1568 . Novembcrls, 1999
`
`Dr. Reddy's Laboratories, Inc. v. Celgene Corp.
`IPR2018—01509
`Exhibit 2023, Page 5
`
`car
`
`lev
`res
`cei
`
`nnmmmauaz’
`
`m-l
`
`.-‘-——‘——.
`
`
`
`._.______.__.._.._.—-————._.—.—————-———
`
`

`

`
`
`ANTITUMOR ACTIVITY OF THALIDOMIDE IN REFRACTORY MULTIPLE MYELOMA
`
`crease, 43 percent; P<0.001) and serum albumin lev-
`els fell (median decrease, 4 percent; P<0.001) signifi-
`cantly in patients with no response. Serum creatinine
`levels did not change significantly in patients with a W Em
`response, and they increased by a median of 13 per-
`cent in those without a response (P<0.001),
`
`TABLE 3. INCIDENCE 0F GRADE 1 on 2 ADVERSE Emacrs.‘
`
`DulcFTW
`_ zoo mg/DM 400mg/DAY 600mg/DAY 800mg/DAY
`(“33)
`("‘72)
`("'57)
`("““l
`percentage 0' patient"
`44
`44
`31
`39
`
`59
`48
`
`35
`29
`
`‘
`
`34
`12
`17
`16
`16
`
`16
`10
`6
`12
`12
`
`43
`14
`25
`,8
`24
`
`17
`13
`1°
`15
`10
`
`40
`19
`23
`21
`23
`
`14
`19
`12
`23
`14
`
`43
`23
`as
`' as
`22
`
`22
`22
`22
`11
`11
`
`Constipation
`Mum Effects
`Side effects reported by at least 10 percent of pa- Wan“, o,
`tients at most dose levels are listed in Table 3. Most
`fads»:
`adverse effects were mild or moderate (grade 1 or
`Sonmfficncc
`2 according to the system of classification of the Twat;
`World Health Organization). Constipation, weakness Dim“
`or fatigue, and somnolence occurred in one third or
`Rash
`more of the patients. Reports of grade 3 or 4 adverse M Chang“
`effects were infrequent (less than 10 percent in all
`«depression
`cases). One quarter of the patients had no appreciable
`Mordimfion
`side effects at the ZOO-mg dose, whereas virtually all mm“
`patients had adverse effects of grade 1 or 2 at higher
`Edam
`doses. Fewer than 5 percent of patients had grade 1 or
`NM“
`Headache
`2 leukopenia at any dose, and grade 3 or 4 thrombo-
`cytopenia or anemia occurred in only three patients.
`In most of the patients who had no response, pre-
`treatment anemia or thrombocytopcnia did nor wor-
`sen, Whereas significant increases in the hemoglobin
`levels occurred in patients with a response. Nine pa-
`tients could not tolerate thalidomide (four with a re-
`sponse and five with no response) and discontinued
`treatment after a median of 36 days (range, 10 to
`241). In eight patients, an increase in serum creati-
`nine levels of more than 50 percent was related to
`progressive disease, with increasing Bence Jones pro-
`teinuria. One of the patients with a response died
`suddenly on day 37 of treatment. The death was
`thought to be related to sepsis, although a possible
`contribution of thalidomide could not be ruled out.
`
`'The classification system of the World Health Organization was used.
`Gnde 1 effects are mild, and grade 2 are moderate.
`1’Values are the percentages of patients at each dose level.
`
`were all predictive of a brief period of event-free sur—
`vival, whereas low albumin levels (P<0.001), the de-
`letion of chromosome 13 (P=0.004), and high num-
`bers of plasma cells in bone marrow (P=0.05) were
`associated with a relatively short overall survival.
`Thalidomide was discontinued after a median of
`
`52 days (range, 2 to 286) because of a lack of response
`in 53 patients (4 patients continued to receive the
`drug without a response) and because of relapse in
`12 patients who had had a response. One patient who
`had a decrease in the paraprotein level of at least 25
`percent and who had not previously received high-
`dose therapy subsequently underwent autologous
`stem-cell transplantation at his owu request. As of
`June 17, 1999, 36 patients had died, including 30 pa-
`tients without a response who died of progressive
`disease or complications of Subsequent salvage ther—
`apy, as well as 6 patients with a response who subse-
`quently relapsed and died of progressive disease (3) or
`toxicity from salvage therapy (3).
`
`DISCUSSION
`
`We found that thalidomide had substantial antitu-
`mor activity in patients with advanced myeloma. Ten
`percent of patients had complete or nearly complete
`remission, and 32 percent had a reduction in serum
`or urine paraprotein levels of at least 25 percent. In
`most patients, the decline in paraprotein levels was
`accompanied by a reduction in the percentage of plas-
`ma cells in bone marrow and an increase in hemo-
`
`globin levels, both of which are consistent with the
`
`1569
`Volume 341 Number 21
`Dr. Reddy's Laboratories, Inc. v. Celgene Corp.
`IPR2018-01509
`Exhibit 2023, Page 6
`
`Time to Progression, Event-free Survival,
`and Overall Survival
`
`0f the 27 patients with a decrease in paraprotein
`levels of at least 25 percent, 12 had a recurrence of
`the disease. After a median follow-up of 14.5 months
`(range, 12 to 16), the median time to progression
`had not been reached. The disease in a mean (:SE)
`of 4-4: 10 percent of patients was judged to have pro-
`gressed at 12 months. The median event-free survival
`for all 84 patients was three months (Fig. 2). After 12
`months of follow-up, 22:5 percent of the 84 patients
`remained event-free and 581-5 percent Were alive.
`Nineteen patients were still receiving thalidomide 4 to
`15 months after starting the treatment (median, 13),
`including 15 patients with a response and 4 with no
`response who had had some improvement in various
`disease indicators but who had not had a decrease in
`
`paraprotein levels of at least 25 percent. Multivariate
`analysis indicated that increases in lactic dehydrogen-
`ase levels (P=0.001), the plasma—cell—labeling index
`(P=0.006), and C-reactive protein levels (P=0.007)
`
`
`
`

`

`dr(
`ucr
`865
`1
`tip
`re;
`stu
`l‘ul
`> pa.
`cm
`Ch-
`tip
`
`5
`(g
`I
`Sin
`__
`
`.3!
`riptea
`Mt
`W
`
`
`
`
`
`
`
`
`
`-c:eta-Zen":asewe=29:seer-295393.:93'33‘3"2"
`
`The New England Journal of MedicineW
`
`1.0
`
`0.8
`
`0.6
`
`2
`(1:)
`33
`.2".
`
`0 C
`
`0.4
`
`.12:
`a
`e 0.2
`0.
`
`0.0
`
`
`
`
`Overall survival
`
`Eventvjree survival
`-----------------
`
`0
`
`2
`
`14.
`12
`10
`8
`4
`Months after the Start of Thalidomide
`
`16
`
`18
`
`No. Ar Rust
`84
`Overall survival
`Event-free survival 84
`
`78
`65
`
`as
`39
`
`58
`24
`
`55
`19
`
`51
`18
`
`34
`11
`
`Figure 2. Kaplan-Msier Estimates of Overall Survival and Event—free Survival.
`Event-free survival was calculated from the start of thalidomide therapy to progression. removal from
`. the study for any reason, death from any cause, or the last follow-up visit, whichever occurred first 1 bars
`indicate standard errors at 12 months.
`
`presence of atrue antitumor efi‘ect. Although not ex-
`amined quantitatively, bone pain decreased markedly
`in patients with a response. We did not evaluate lyric
`bone lesions, which seldom heal,even in patients with
`a sustained complete remission.
`Thalidomide has a number of properties that could
`explain its activity in myeloma; it can alter the expres~
`sion of adhesion molecules}5 suppress the production
`of tumor necrosis factor a,” increase the production
`of interleukin-10,37 'and enhance cell—mediated im-
`munity by directly sfimuladng cytotoxic T cells.” Its
`interactions with type 1 and type 2 helper T cells pro-
`duce complex effects on the levels of cytokines such as
`interleukin-4, interleukin-5, and interferon-y.” Tha~
`lidomide also increases the total number of lympho~
`cytes as well as CD8+ and CD4+ T-cell counts, along
`with substantially increasing mean plasma levels of
`soluble interleukin—2 receptor.29
`Thalidomide has been shown to inhibit angiogenv
`esis induced by fibroblast growth factor and vascular
`endothelial growth factor in a rabbit-cornea micro-
`pocket assay9 and a murine model of corneal vascu-
`larization.lo It has also been shown to cause apoptosis
`of established mum-associated angiogenesis in expero
`imemal models.10 The bone marrow of patients with
`hematologic cancers shows extensive vascularityflzv13
`which has prognostic implications in myeloma.“ The
`apparent lack of a consistent decrease in the microvas-
`cular density of bone marrow in patients in whom
`thalidomide had a marked antitumor effect requires
`further study. The persistence of extensive vascular-
`ization in some patients with a response is consistent
`with the finding of persistent neovascularity in pa-
`tients with multiple myeloma who had a response to
`high-dose chemotherapy.15 The production of an-
`
`1570 - November 18,1999
`
`giogenic cytokincs such as fibroblast growth factor
`and vascular endothelial growth factor by undetect-
`able residual myeloma cells may sustain the increased
`microvascular density of bone marrow in patients con-
`sidered to be in remission on the basis of bone mar-
`
`row findings. The persistence of extensive vasculariza-
`tion in patients with a response makes it seem likely
`that the antimyeloma action of thalidomide depends
`on more than one of the actions of the drug out-
`lined above. The mouse model of severe combined
`
`immunodeficiency, which can be used for the in vivo
`growth of primary human myeloma cells, is ideally
`suited to study the mechanisms by which thalidomide
`induces responses in myeloma.‘o
`The antitumor properties of thalidomide are being
`evaluated in various malignant diseases,“as although
`only limited efficacy data are available so far. Pro-
`longed responses to thalidomide in some patients with
`advanced refractory disease suggest that the mecha-
`nism of action of thalidomide is distinctly different
`from that of the other agents active against mycloma.
`The absence of myelosuppressive and other impor-
`tant adverse effects suggests that thalidomide could
`be an ideal agent for use in combination with che-
`motherapy. Indeed, a complete remission has been
`achieved with such an approach. in several patients
`with myeloma who had no response to treatment with
`either regimen alone.“ This approach has also been
`shown to have greater antitumor activity than chemo-
`therapy alone in a murine model of breast cancer.”
`In our study, most patients had adverse effects,
`but the majority of these reactions were mild or mod-
`erate. Reducing the dose of thalidomide alleviated the
`effects in most cases, and only nine patients discon-
`tinued therapy altogether. The gradual reduction in
`
`Dr. Reddy’s Laboratories, Inc. v. Celgene Corp.
`IPR2018—01509
`Exhibit 2023, Page 7
`
`

`

`ANTITUMOR ACTIVITY OF THALIDOMIDE IN REFRACTORY MULTIPLE MYELOMA
`
`drowsiness and fatigue insome patients with contin-
`ued treatment at the same dose (data not showu) sug~
`gests the occurrence of tachyphylaxis.
`We conclude that thalidomide is active against mul-
`tiple mycloma, even in patients who relapsed after
`repeated cycles of high--dose chemotherapy Larger
`studies of thalidomide, its analogues, and otherin-
`hibitors of angiogenesis are therefore warranted in
`patients with myeloma an