The
`,t'Wiiiil::.1d6i'>rf~<
`, - z's9tlr /.- 1~-~ -
`~ew Englanu
`Journal of Medicine
`
`/
`
`L,,
`
`/
`✓
`
`1,
`
`I
`
`Established in 1812 as THE NEW ENGLAND JOURNAL OF MEDICINE AND SURGERY
`
`VOLUME 341
`
`NOVEMBER 18, 1999
`
`NUMBER 21
`
`,
`~-1
`
`EDITORIALS
`ORIGINAL ARTIC:LES
`Alcohol for Stroke Prevention! .......... ..... ............... 16':f
`Light-To-Moderate Alcohol Consumption
`and the Risk of Stroke among
`M. HOMMEL AND A. }AILLARD
`•
`Thalidomide - A Revival Story ...................... ~
`U.S. Male Physicians ............................................. 1557
`N. R.AJE AND K. ANDERSON C.-7
`K. BERGER AND OTHERS
`Antitumor Activity of Thalidomide
`Firearms and Suicide .................................... ,. ............ 1609
`in Refractory Multiple MyeJoma ..................... ~
`M.L. ROSENBERG, J.A. MERCY,
`L_...1/"
`S. SINGHAL AND OTHERS
`AND L.B. POTTER
`Reduction of False Negative Results in
`~
`Screening of Newborns for Homocystinuria 1572
`M.J. PETERSCHMITT, J .R. SIMMONS,
`AND H.L. LEVY
`Brief Report: Leuprolide Acetate Therapy
`in Luteinizing Hormone-Dependent
`Cushing's Syndrome .............................................. 1577
`A. LACROIX, P. HAMET, AND J.-M. BOUTIN
`
`SOUNDING BOARD
`Medical Professionalism in Society ...................... 1612
`M.K. WYNIA, S.R. LATHAM, A.C. KAo,
`J.W. BERG, AND L.L. EMANUEL
`
`INFORMATION FOR AUTHORS ......................... 1617
`
`C:ORRESPONDENCE
`Authors' Conflicts of Interest: A Disclosure
`and Editors' Reply ..................................................... 1618
`Reimbursement for Evaluation
`and Management Services ........................................ 161r
`Neostigmine for Acute Colonic Pseudo-Obstruction 1622
`DNA Vaccines ................................................................. 1623
`The Effects ofVam:omycin and /J-Lactam
`Antibiotics on Vancomycin·Resistant
`Staphylococcus ,iureus .......................... ............. ......... .. 1624
`Priming with Human Chorionic Gonadotropin
`before Retrieval of Immature Oocytcs
`in Women with Infertility Due to the
`Polycystic Ovary Syndrome ...................................... 1624
`
`IMAGES IN C:LINICAL MEDIC:INE
`Gangrene and Type I Cryoglobulinemia
`in Multiple Myeloma ............................................. 1582
`L. CIRASINO AND P.R. BARBANO
`
`SPEC:IAL ARTIC:LE
`
`M~r:::=:~.~~~~~.~~:~.~.~~·····················6583
`
`G.J. WINTEMUTE, C.A. PARHAM,
`J.J. BEAUMONT, M. WRIGHT, AND C. DRAKE
`
`REVIEW ARTIC:LE
`Benign Paroxysmal Positional Vertigo ................. 1590
`J.M. FURMAN AND S.P. CASS
`
`CASE RECORDS OF THE
`MASSACHUSETTS GENERAL HOSPITAL
`CORRECTIONS
`A Five-Month-Old Girl
`Treatment of Asthma with Drugs Modifying
`with Coffee-Grounds Vomitus ........................... ~
`the Leukotriene Pathway ........................................ 1632
`Zolpidem in Progressive Supranuclear Palsy .............. 1632
`S. HARDY AND S.B. KEEL
`/
`
`BOOK REVIEWS
`
`....................................................... 1627
`NOTICES ..................................................................... 1629
`
`Owned, ,,.1,1;,h,J, '"'" C e,pyrighte,l, 1999, by nm MASSACHUSE'ITS MEDICAL SOCIETY
`
`p
`E
`ll
`l
`0
`
`D l 0024
`A
`L s
`
`Univ. Of Minn -
`BiD-MBdlcal .
`UIIP8PJ
`11 19 99
`
`N
`E
`w
`s
`p
`A
`p
`E
`R
`
`THE NEW ENGLAND JOURNAL OF MEDICINE (ISSN 0028·4793) is published weekly
`from editorial offic .. at 10 Shattuck Street, Boston, MA 02115-6094. Subscription price:
`5129.00 per year. Periodicals postage paid at Boston and at additional mailing offices.
`POSTMASTER: Send address changes to P.O. Box 540803, Waltham, MA 02454-0803.
`
`DOES1VOT
`LEA VE LIBRA.1?. Y
`
`Dr. Reddy’s Laboratories, Inc. v. Celgene Corp.
`IPR2018-01504
`Exhibit 2023, Page 1
`
`

`

`ANTITUMOR ACTIVITY OF THALIDOMIDE IN REFRACTORY MULTIPLE MVELOMA
`
`ANTITUMOR ACTIVITY OF THALIDOMIDE IN REFRACTORY
`MULTIPLE MYELOMA
`
`SEEMA StNGHAL, M.D., JAYESH MEHTA, M.0., RAMAN DESIKAN, M.0., DAN AYERS, M.S., PAULA ROBERSON, PH.D.,
`PAUL EDDLEMON, B.S., N1KHIL MUNSHI, M.0., ELIAS ANAISSIE, M.0., CARLA WILSON, M.0., PH.O.,
`MADHAV OHO0APKAR, M.D., JEROME ZELDIS, M.D., AND BART BARLOGIE, M.D., PH.D.
`
`ABSTRACT
`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.
`Methods Eighty-four previously treated patients
`with refractory myeloma (76 with a relapse after high(cid:173)
`dose chemotherapy) receiveu 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
`BOO mg per day. Response was assessed on the ba(cid:173)
`sis of a reduction of the myeloma protein in serum
`or Bence Jones protein in urine that lasted for at least
`six weeks.
`Resuln 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(cid:173)
`tein levels were apparent within two months in 78
`percent of the -patients with a response and were as(cid:173)
`sociated with decreased numbers of plasma cells in
`bone marrow and increased hemoglobin levels. The
`microvascular 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(cid:173)
`tion, weakness or fatigue, or somnolence. More se(cid:173)
`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(cid:173)
`tients had died (30 with no response and 6 with a re(cid:173)
`sponse). After 12 months of follow-up, Kaplan-Meier
`estimates of the mean (±SE) rates of event-free sur(cid:173)
`vival and overall survival for all patients were 22±5
`percent and 58::!::5 percent, respectively.
`Conclusions Thalidomide is active against ad(cid:173)
`vanced myeloma. It can induce marked and durable
`responses in some patients with multiple myeloma,
`including those who relapse after high-dose chemo(cid:173)
`therapy. (N Engl J Med 1999;341:1565-71.I
`Cl1999, Massachusetts Medical Society.
`
`M ULTIPLE myeloma accounts for ap(cid:173)
`
`proximately 1 percent of all cancers and
`H1 percent of hematologic cancers. It
`is incurable with conventional chemo(cid:173)
`therapy.1 Melphalan-based high-dose chemotherapy
`with .hematopoietic stem-cell support increases the
`rate of complete remission and extends event-free and
`overall survival.24 However, many patients still relapse,
`and options for salvage therapy are limited.5,6
`Angiogenesis is important in embryogenesis, wound
`healing, diabetic retinopathy, and twnor progression.7.S
`The immunomodulatory drug thalidomide can inhib(cid:173)
`it angiogenesis and induce apoptosis of established
`neovasculature in experimental models.9,1° For these
`reasons, angiogenesis-inhibiting drugs such as tha(cid:173)
`lidomide may be useful for treating cancers that de(cid:173)
`pend on neovascularization.
`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
`prognosis.11-16 Plasma levels of various angiogenic cy(cid:173)
`tokines, such as basic fibroblast growth factor and
`vascular endothelial growth factor, are elevated in pa(cid:173)
`tients with active myeloma_ll·13,16 In 1965, Olson et al.
`reported slowing of disease progression in one pa(cid:173)
`tient who was treated with thalidomide.17 These con(cid:173)
`siderations led us to administer thalidomide to five
`patients with end-stage myeloma through a compas(cid:173)
`sionate-use protocol. One patient with a large tumor
`burden ( as indicated by an IgA level of 8.4 g per dec(cid:173)
`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(cid:173)
`servation prompted a phase 2 investigation of tha-
`
`From the Myeloma and Lymphoma Program, South Carolina Cancer
`Center, University of South Carolina, Columbia (S-S., J.M.); the Myeloma
`and Transplantation Research Center, University of Arkansas for Medical
`Sciences, Little lwck (R.D., D.A., P.R., P.E., N.M., E.A., C.W., J.Z., B.B-);
`and the Laboratory of Cellular Physiology and Immunology, Rockefeller
`University, New York (M.D.). Address reprint requests ro Dr. Barlogie at
`the Myeloma and Transplantation Research Center, University of Arkansas
`for Medical Sciences, 4301 W. Markham, Slot 623, Little Rock, AR 72205.
`Other authors were David Siegel, M.D., Ph.D., University of Arkansas
`for Medical Sciences, Little Rock, and John Crowley, Ph.D., Fred Hutch(cid:173)
`inson Cancer Research Center, Seattle.
`
`Volume 341 - Number 21
`
`1565
`
`Dr. Reddy’s Laboratories, Inc. v. Celgene Corp.
`IPR2018-01504
`Exhibit 2023, Page 2
`
`

`

`The New England Journal of Medicine
`
`lidomide in patients with advanced and refractory
`myeloma.
`
`TABLE 1. CHARACfERISTICS OF THE PATIENTS.
`
`METHODS
`
`Patients and'Treatments
`
`Between December 1997 and June 1998, 84 consecutive, eligi(cid:173)
`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 of normal levels. All patients were treated at a single
`center according to a phase 2 protocol approved by the institution(cid:173)
`al review board and the Food and Drug Administration (FDA).
`Thalidomide was supplied in 50-mg capsules by Celgene (War(cid:173)
`ren, NJ) and was administered nightly at a dose of 200 mg. The
`dose was increased by 200 mg every twO weeks for six weeks, so
`that the final dose was 800 mg per day. Data were analyzed as of
`June 17, 1999, when the duration of treatment ranged from 2 to
`465 days (median, 80) and the median Collow-up of surviving
`patients was 13 months.
`Table 1 summarizes the characteristics of the patients and de(cid:173)
`tails of prior therapy. Seventy-six patients (90 percent) had received
`at least one cycle of high-dose chemotherapy with autologous hem(cid:173)
`atopoietic stem-cell suppon, 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(cid:173)
`genetic abnormality (deletion of chromosome 13) was present in
`35 patients (42 percent).i0 One patient had received an allograft
`as a second intervention, with evidence of full donor-type chi(cid:173)
`merism in normal lymphohematopoietic cells. At the time of en(cid:173)
`rollment, all patients had progressive disease, with an increase in
`paraprotein levels of at least 25 percent or at least 50 percent plas(cid:173)
`ma cells in bone marrow. Approximately half the patients had been
`retreated with dexamethasone or other regimens, but the disease
`had progressed before th,alidomide treatment was begun.
`
`Evaluation
`
`The pretreatment evaluation included complete blood counts,
`tests of renal and liver function, serum and urine protein electro(cid:173)
`phoresis, and measurements of serum levels ofimmunoglobulins,
`beta,-mkroglobulin, ap.d C-reactive protein. Bone marrow aspi(cid:173)
`rates were obtained and biopsies were performed to determine
`the percentage of plasma cells in bone marrow, to identify kary(cid:173)
`otypic abnormalities (Giemsa-banded cells in metaphase), and to
`assess the proliferative activity in plasma cells according to the
`bromodeoxyuridine method to derive the plasma-cell-labeling
`index.18 Follow-up studies included a weekly estimation of para(cid:173)
`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(cid:173)
`quantitative fashion in biopsy samples that were obtained with
`a trephine and stained with an anti-CD34 monoclonal antibody
`(prediluted 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 levd of paraprotein 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(cid:173)
`sis of the component showing the smaller decline. Patients with
`
`1566
`
`November 18, 1999
`
`Male sex
`Durie-Salmon stage III multiple myeloma
`[gG paraprotcin
`Duration of prior therapy >60 mo
`Prior high-dose chemotherapy
`Receipt of> l cycle of high-dose chemotherapy
`Interval between last cycle of fugh-dosc chemotherapy
`and initiation of thalidomide > 12 mo
`Age >60 yr
`Hemoglobin <9 g/dl
`Plarelcr count <50 x 10'/mm•
`Scrum albumin <3.5 g/dl
`Serum crcatininc > 1.5 mg/dl (133 µ,mol/liter)
`Scrum beca2-microglobulin >6 mg/liter
`Serum C-rcactivc protein >3 mg/liter
`Serum monoclonal immunoglobulin > 1 g/dl
`Urine Bence Jones protein > 1 g/day
`> 50% Plasma cells in bone marrow on biopsy
`Plasma-cdl-labeling index > l %*
`Bartl grade Ut
`Deletion of chromosome 13
`Outcome
`Completion of study
`Withdrawal from study
`Progression
`Intolerance of thalidomide
`Death of patient with a responsc;t
`Personal reasons
`Final dose of thalidomide
`400 mg/day
`600 mg/day
`800 mg/day
`
`No. o•
`PATIEr.rrs I"-)
`
`61 (73)
`51 (61)
`51 (61)
`18 (21)
`76 (90)
`58 (69)
`43 (57)
`
`32 (38)
`19 (23)
`17 (20)
`22 (26)
`22 (26)
`24 (29)
`20 (24)
`51 (61)
`44 (52)
`18 (21)
`13 (15)
`19 (23)
`35 (42)
`
`19 (23)
`
`54 (64)
`9 (11)
`1 (l)
`1 (1)
`
`72 (86)
`57 (68)
`46 (55)
`
`*The plasma-ccll-labeling index represents the percentage oflighr-chain(cid:173)
`restricted plasma cells incorporating bromodeoxyuridine. 18
`tThe Bartl grading system distinguishes myeloma cells according ro their
`morphologic maturation.'9 Grade II refers to immature plasma cells of
`cleaved, asynchronous, or polymorphous appearance.
`;f:This patient had a response to treatment but died on day 37 of treatment.
`
`a reduction of Jess 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(cid:173)
`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(cid:173)
`gence of the monoclonal protein ( determined by irnmunofixation)
`on at least two occasions was considered to indicate a relapse. 1n
`patients who had a complete remission .or a nearly complete re(cid:173)
`mission (;;a,90 percent reduction in serum or urine paraprotein lev(cid:173)
`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(cid:173)
`age of plasma cells had to decrease by at least 50 percent to qual(cid:173)
`ify as a bone marrow response.
`
`Assessment of Adverse Effects
`
`All patients, irrespective of the duration of therapy, were in(cid:173)
`cluded in the evaluation of adverse effects. All patients received
`diaries after providing infonned consent, and 83 patients (99 per-
`
`cen
`of 1
`pro
`ing
`dat
`He
`ver:
`me
`
`St,
`
`in
`Be•
`sp<
`SUI
`otl
`iab
`vai
`ex:
`gn
`od
`th•
`or
`pe
`wi
`trt
`it)
`to
`re:
`di
`pr
`ve
`ar
`K
`st
`ar e,
`ol
`01
`le
`ai
`V\I
`ti
`u
`SJ
`p
`a
`s,
`a
`
`11
`V
`r
`r
`t
`s
`<
`j
`I
`
`Dr. Reddy’s Laboratories, Inc. v. Celgene Corp.
`IPR2018-01504
`Exhibit 2023, Page 3
`
`

`

`ANTITUMOR ACTIVITY OF THALIDOMIDE IN REFRACTORY MULTIPLE MVELOMA
`
`cent) reported having adverse effects. A comprehensive checklist
`of the adverse effects associated with thalidomide therapy was
`provided by Celgene; it was based on previous experience in treat(cid:173)
`ing patients with leprosy and had been reviewed by the FDA. The
`data were verified by the patients by direct or telephone interviews.
`Hematologic values and other laboratory-based measures of ad(cid:173)
`verse effects were assessed at least monthly by the data-manage(cid:173)
`ment office.
`
`Statistical Analysis
`
`The primary end point for this phase 2 study was a diminution
`in the plasma level of the myeloma protein or the urine level of
`Bence Jones protein. Other end points included the time to a re(cid:173)
`sponse, the time to disease progression, event-free survival, overall
`survival, the microvascularity of bone marrow, and improvements in
`other laboratory values. Response was treated as a categorical var(cid:173)
`iable. Comparisons of the response according to other categorical
`variables were assessed with use of the chi-square test or Fisher's
`exact test, as appropriate. The times to response and disease pro(cid:173)
`gression were calculated with the use of the competing-risk meth(cid:173)
`ods.21 The time to response was defined as the interval between
`the start of therapy and a given respo~ (i.e., a decline in the serum
`or urine level of paraprotein of at least 25 percent, 50 percent, 75
`percent, or 90 percent or a complete remission). Competing risks
`with respect to the time to response included discontinuation of
`treatment because of progression or a lack of response, an inabil(cid:173)
`ity to tolerate thalidomide, or death or personal reasons. The time
`to progres~ion was calculated only for patients with a paraprotein
`response and was defined as the time from the start of therapy to
`disease progression. Competing risks with respect to the time to
`progression included discontinuation of treatment because of ad(cid:173)
`verse effects or death or for personal reasons. Event-free survival
`and overall survival were estimated according to the method of
`Kaplan and Meier. 22 Event-free survival was calculated from the
`start of therapy to disease progression, removal from the study for
`any reason, death from any cause, or the last follow-up visit, which(cid:173)
`ever occurred first. Overall survival was calculated from the start
`of therapy to death ,from any cause or the last follow-up visit. Data
`on patients who had not had an event by the time of the last fol(cid:173)
`low-up were censored at that time with respect to times to response
`and progression, event-free survival, and overall survival. Survival
`was compared with use of the log-rank test. 23 Univariate and mul(cid:173)
`tivariate (stepwise) logistic-regression methods were used to eval(cid:173)
`uate the prognostic importance of various characteristics with re(cid:173)
`spect to the likelihood of achieving at least a 25 percent or 50
`percent reduction in serum or urine paraprotein levels. Univariate
`and multivariate (stepwise) proportional-hazards regression analy(cid:173)
`ses were used to evaluate the prognostic importance of various char(cid:173)
`acteristics with respect to event-free survival and overall survival.
`Since the microvascular density of bone marrow was used as a
`measure of the antiangiogenic action of thalidomide, this variable
`was extensively modeled. To account for the need for multiple
`measurements of each patient over time and missing data, we used
`mixed-models repeated-measures analysis of variance to evaluate
`the microvascular density of bone marrow. 24 The use of compound
`symmetry and first-order autoregressive covariance structures was
`compared, and the results were found to be similar according to
`Akaike's criterion. Therefore, the values obtained with the com(cid:173)
`pound-symmetry models are reported. Measurements of the mi(cid:173)
`crovascular density of bone marrow were grouped according to
`the length of treatment, and values were measured every 50 days
`for a total of seven times, including the pretreatment value. The
`natural logarithm of the values for the microvascular density of
`bone marrow was used in the analysis. Estimates for patients with
`no response and patients with a complete or nearly complete re(cid:173)
`sponse (;;<,90 percent reduction in serum or urine paraprotein lev(cid:173)
`els) were used to predict the response in terms of the microvas(cid:173)
`cular density of bone marrow over time.
`Improvements in important clinical measures were evaluated on
`the basis of the percent change from base line to the time of the
`
`maximal response or, for those without a response, the time at
`which treatment was discontinued. Spearman correlations were
`used to assess whether the changes within response groups were
`significant. For variables with no significant correlations, the signed(cid:173)
`rank test was used to test the hypothesis within response groups
`that the change was significantly different from zero. All statistical
`tests were two-sided.
`
`RESULTS
`Decline in Paraproteln Levels
`Timely escalations in the daily dose of thalidomide
`to 400 mg, 600 mg, and 800 mg were possible in 83
`percent, 62 percedt, and 47 percent of the patients, re(cid:173)
`spectively; the proportions of patients who eventually
`reacp.ed these levels were 86 percent, 68 percent, and
`55 percent, respectively (Table 1). In 27 patients (32
`percent), the serum or urine paraprotein level declined
`by at least 25 percent, including 7 (8 percent) with a
`decline of at least 50 percent, 6 (7 percent) with a de(cid:173)
`cline of at least 75 percent, and 6 (7 percent) with a
`decline of at least 90 percent; 2 patients had a com(cid:173)
`plete remission (Table 2). The median interval be(cid:173)
`tween the start of treatment and a decrease in the
`paraprotein level of at least 25 percent was 29 days
`( range, 4 days to 6 months) (Fig. 1). Seventy-eight
`percent of the responses of this magnitude were ap(cid:173)
`parent within two months; they were observed with(cid:173)
`in four months in all but two patients with a re(cid:173)
`sponse. More marked reductions in paraprotein, by at
`least 50 percent and 75 percent, occurred after a me(cid:173)
`dian of two and three months of therapy, respectively.
`A low plasma-cell-labeling index (assessed as a con(cid:173)
`tinuous variable) was the only statistically significant
`variable associated with a response among both the
`group with at least a 25 percent decrease in parapro(cid:173)
`tein levels (P=0.01) and the group with at least a 50
`percent decrease (P=0.01). Using the median plasma(cid:173)
`cell-labeling index of 0.2 percent as a cutoff value,
`we found that 46 percent of patients with values be(cid:173)
`low the median had a reduction in paraprotein levels
`of at least 25 percent, as compared with 9 percent
`of patients with higher values (P<0.05). On univari(cid:173)
`ate analysis, deletion of chromosome 13 wa3 predic(cid:173)
`tive of an unfavorable response, but not on multi(cid:173)
`variate analysis.
`
`Bone Marrow Response
`Bone marrow samples were obtained after one to
`nine months of therapy ( median, three) in 48 patients.
`A paraprotein response was associated with a bone
`marrow response in 81 percent of the patients who
`could be evaluated (Table 2). In seven of the eight
`patients with at least a 90 percent reduction in para(cid:173)
`protein levels, the concurrently examined bone mar(cid:173)
`row specimens contained less than 5 percent plasma
`cells. A decline in the percentage of plasma cells in
`bone marrow by at least 50 percent occurred in only
`4 of 27 patients with no paraprotein response (15 per(cid:173)
`cent) who had follow-up bone marrow examinations.
`
`Volume 341 Numbc:r 21
`
`1567
`
`Dr. Reddy’s Laboratories, Inc. v. Celgene Corp.
`IPR2018-01504
`Exhibit 2023, Page 4
`
`

`

`ere
`els
`car
`lev
`res
`cei
`
`Ad
`
`tie
`ad
`2
`w
`or
`m
`ef
`ca
`SU
`p,
`d<
`2
`C)
`Ir
`tr
`S<
`le
`ti
`SJ
`tJ
`2
`n
`p
`t,
`s
`t
`C
`
`l
`E
`
`The New England Journal of Medicine
`
`TABLE 2. PARAPROTEIN R.EsPONSE AND BONE MARROW REsPONSE.,
`
`PARAPROTEIN RHPONSE
`
`No.OF
`PATIENTS
`(%OF TOTAL)
`
`AssESSMENT OF 8oNE
`MARROW RESPONSE
`
`CURRENT STATIIS
`
`TOTAL
`NO.*
`
`NO. WITI!
`RESPONSE (%)t
`
`NO.WHO
`NO, WITH
`RELAPSE(%) DIED(%)
`
`0
`2
`
`2(100)
`2
`2 (2)
`Complete remission
`5 (83)
`6
`6 (7)
`;,,90% decrease in paraprotcin
`3 (60}
`5
`6 (7)
`,a,75% decrease in paraprotein
`0
`4(100)
`4
`7 (8)
`il>50% decrease in paraprotcin
`3
`3 (75}
`4
`6 (7)
`;,, 25% decrease in paraprotcin
`6 (22}
`17 (81)
`21
`27 (32)
`Total
`30 (53)
`4 (15)
`27
`57 (68)
`No response
`*The response could not be evaluated in 6 of the patients with a paraprotein response and in 30
`of the patients with no paraprotcin response.
`t A bone marrow response was defined as the presence of less than 5 percent plasma cells in bone
`marrow in patients who had a complete paraprotein response or at least a 90 percent reduction in
`paraprotein levds and as a reduction in plasma cells of at least 50 percent in patients with all othe;r
`types of paraprotein re;sponses.
`
`0
`2
`3
`3,
`4
`12 (44}
`
`~_..,.-..r------ ;;.25% reduction in paraprotein
`
`: ................... il>50% reduction in paraprotein
`,:·r:··:"'""·:·~::~·::::::::::.::::::::::::::.1•"""""··· .... >75% reduction in paraprotein
`r · - · - · - · - · - ii<90% reduction in paraprotein
`....... ,....
`.}
`_ •• r_:::.+ r
`___ ..r - - - - - - - - - Complete response
`
`: · , :
`
`:
`
`(cid:127)(cid:127) :·:
`
`,.. -
`
`-
`
`-
`
`-
`
`-
`
`-
`
`•
`
`0.5
`
`(I)
`0
`C: 0.4
`(I)
`'O
`·13
`..5. 0.3
`a.,
`>
`·~ (ti
`:i
`E 0.1
`:::, u
`
`0.2
`
`0.0
`
`0
`
`12
`14
`10
`4
`8
`6
`2
`Months after the Start of Thalidomide
`
`16
`
`Figure 1. Times to Various Paraprotein Responses.
`Among patients with a response, the median times to a reduction in the serum or urine paraprotein
`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 (..,25 percent reduc(cid:173)
`tion) were apparent within two months after the initiation of treatment.
`
`Microvascular 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(cid:173)
`ue. Ar least one measurement of the microvascular
`density of bone marrow was made in 7 4 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(cid:173)
`row and the percentage of plasma cells in bone mar(cid:173)
`row correlated significantly at all times except the last
`(r>0.5, P=-,,0,01). Although the microvascular den(cid:173)
`sity of bone marrow decreased markedly in some pa-
`
`tients with a complete or nearly complete remission,
`estimates of the slope 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 beta2-micro(cid:173)
`globulin, C-reactive 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 beta2-microglobulin rose (median in-
`
`1568
`
`• November 18, 1999
`
`Dr. Reddy’s Laboratories, Inc. v. Celgene Corp.
`IPR2018-01504
`Exhibit 2023, Page 5
`
`

`

`ANTITUMOR ACTIVITY OF THALIDOMIDE IN REFRACTORY MULTIPLE MYELOMA
`
`crease, 43 percent; P<0.001) and serum albumin lev(cid:173)
`els fell (median decrease, 4 percent; P<0.001) signifi(cid:173)
`cantly in patients with no response. Serum creatinine
`levels did not change significantly in patients with a
`response, and they increased by a median of 13 per(cid:173)
`cent in those witl1out a response (P<0.001).
`
`Adverse Effects
`Side effects reported by at least 10 percent of pa(cid:173)
`tients at most dose levels are listed in Table 3. Most
`adverse effects were mild or moderate (grade 1 or
`2 according to the system of classification of the
`World Health Organization). Constipation, weakness
`or fatigue, and somnolence occurred in one third or
`more of the patients. Reports of grade 3 or 4 adverse
`effects were infrequent (less than 10 percent in all
`cases). One quarter of the patients had no appreciable
`side effects at the 200-mg dose, whereas virtually all
`patients had adverse effects of grade 1 or 2 at higher
`doses. Fewer than 5 percent of patients had grade 1 or
`2 leukopenia at any dose, and grade 3 or 4 thrombo(cid:173)
`cytopenia or anemia occurred in only three patients.
`In most of the patients who had no response, pre(cid:173)
`treatment anemia or thrombocytopenia did not wor(cid:173)
`sen, whereas significant increases in the hemoglobin
`levels occurred in patients with a response. Nine pa(cid:173)
`tients could not tolerate thalidomide (four with a re(cid:173)
`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(cid:173)
`nine levels of more than 50 percent was related to
`progressive disease, with increasing Bence Jones pro(cid:173)
`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.
`
`Time to Progression, Event-free Survival,
`and Overall Survival
`Of 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 ofl4.5 months
`(range, 12 to 16 ), the median time to progression
`had not been reached. The disease in a mean (:!:SE)
`of 44 ::!: 10 percent of patients was judged to have pro(cid:173)
`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 58±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)
`
`TABLE 3. INCIDENCE OF GRADE 1 OR 2 ADVERSE EFFECTS.*
`
`ADVERSE EFFECT
`
`DosE OF THAUOOMOE
`_ 200mg/DAY 400mg/DAY 600mg/DAY 800mg/DAY
`(N=57)
`(N=46)
`(N""72)
`(N""83)
`
`I
`
`percentage of patientst
`
`Constipation
`Weakness or
`fatigue
`Somnolence
`Tingling or
`numbness
`Dizziness
`Rash
`Mood chang~
`or depression
`lncoordination
`Tremors
`Edema
`Nausea
`Headache
`
`35
`29
`
`34
`12 •
`17
`16
`16
`
`16
`10
`6
`12
`12
`
`44
`31
`
`43
`14
`
`25
`18
`24
`
`17
`13
`10
`15
`10
`
`44
`39
`
`40
`19
`
`23
`21
`23
`
`14
`19
`12
`23
`14
`
`59
`48
`
`43
`28
`
`28
`26
`22
`
`22
`22
`22
`11
`11
`
`*The classification system of the World Health Organization was used.
`Grade 1 cffecrn are mild, and grade 2 arc moderate.
`tValues arc the percentages of patients at each dose level.
`
`were all predictive of a brief period of event-free sur(cid:173)
`vival, whereas low albumin levels (P<0.001), the de(cid:173)
`letion of chromosome 13 (P=0.004), and high num(cid:173)
`bers of plasma cells in bone marrow (P=0.05) were
`associated with a relative