Thalidomide in the Management of Multiple Myeloma
`
`Bart Barlogie, Maarizio Zangrzri, Trey Spencer, Atbanaiiw Farms, Elia; Amisrz'e,
`Arbraf Badroi, jeamz Cromer, and Guido Tricot
`
`Thalidomide has recently been shown to have significant activity In refractory multiple myeloma (MM). A
`follow-up of the original phase II trial, expanded to 169 patients, shows 2-year survival of 60%; patients
`receiving 242 g over 3 months had a higher response rate and superior survival than those receiving lower
`doses. The addition of thalidomide to dexamethasone and chemotherapy for the management of post-
`transpiant relapses results In higher response rates. The early results of the Total Therapy II trial for newly
`diagnosed MM patients show an unprecedented complete remission (OR) and near-CR rate of 69% after two
`melphalan—based transplants (whether or not receiving thalidomide).
`In addition, available clinical trial
`Inforrnatlon Involving at least 20 patients conflmis that thalidomide is active in one third of patients in
`single-agent trials for refractory disease, with response rates increasing to 50% to 60% in combination with
`dexamethasone and to as high as 80% in combination with dexamethasone and chemotherapy. When applied
`as primary therapy In smoldering myeloma, one third of patients experienced 50% paraproteln reduction (PPR);
`in combination with dexamethasone pulsing, 70% to 80% of symptomatic patients responded. Thus,
`thalidomide is a major new tool in the treatment armamentarium of MM. The virtual lack of myelosuppression
`makes It an Ideal agent for combination with cytotoxic chemotherapy. Newer, more potent. and less toxic
`derivatives of thalidomide are being evaluated.
`Semln Hematol 38:250-259. Copyright © 2001 by W.B. Saunders Company.
`
`ADVANCES IN THE management of multiple
`
`myelomn (MM) can be traced to two seminal
`observations. First, increasing close intensity of glucocor—
`ticoids, mainly in the form of dexamethasone pulsing as
`realized in the vincristine, doxorubicin, and dexametha-
`sone (VAD) regimen, was shown to overcome resistance
`to standard alkylating agent—prednisone combinations
`when applied in the setting of primary unresponsive and
`resistant relapse.” Similarly, dose escalation of the key
`alkylating agent melphalan to myeloablative intensity,
`facilitated by autologous hematopoietic stem cell support,
`was shown to overcome resistance to both alkylating
`agents in standard doses and high—dose glucocorticoid—
`containing regimens."-"~26 Historically controlled and
`subsequently randomized trials demonstrated that high~
`dose melphalan-based regimens, especially with periph-
`eral blood stem cell (PBSC) support, when applied in the
`setting of newly diagnosed symptomatic MM, increased
`the incidence of true complete remission (CR) from 5%
`with standard regimens to 50% with high—dose therapy
`and markedly extended both event-free (EFS) and overall
`survival (OS).'-'-"“’-” This progress is closely linked to the
`recognition that mobilized PBSC, with the use of either
`stem cell—sparing chemotherapy (such as cyclophospha-
`
`Fmm the Myriam: and Tranrp/anrarion Rereurrb Center, Unir'enity
`of Arkmuai for Medical Srimm, Little Rock, AR.
`Supported in part by Gran! Na. CA558I9 from II): National
`Canrer Inuit/(Ir, Ber/mda. MD.
`Adi/rm reprint reg/(em It) Bar! Bar/ogre, MD, PhD, 4301 W
`Markham, Mail 5/0! 623, Little Rock, AR 72205.
`Copyright © 2001 by “7.8. Salmdmr Company
`0037-1963/01/3803’0011535.00“)
`doi:10.1053/1/12111200126014
`
`mide) or hematopoietic growth factors alone, facilitated
`brisket hematopoietic engraftmenr with earlier neutro-
`phil and platelet recovery than had been the case with
`autologous bone marrow.“5 Thus,
`the duration at risk,
`especially in elderly and frail patients, could be reduced
`from 3 weeks to 7 days with a decrease in treatment-
`related mortality to 1% to 2%. An important consider-
`ation for successful high-dose therapy was the recognition
`that stem cell—toxic agents such as melphalan. nitro—
`soureas, and ionizing radiation to marrow-containing
`bone sites needed to be avoided in order
`to obtain
`
`hematopoietic stem cells of sufficient quantity and quality
`to facilitate rapid engraftmentn'“ and avoid secondary
`acute myelodysplasia syndrome (MDS)/acute myeloge-
`nous leukemia (A.l\rfl.).22 Single-agent melphalan, usually
`at 200 mg/mz, as conditioning results in superior out-
`come with less toxicity than regimens containing toral-
`body irradiation.“19 With appropriate dose modifications
`of melphalan, such autocransplants can also be applied to
`the elderly (>65 and >70 years)3-“° and in the setting of
`renal
`failure.“~43 Post«transplantation management had
`relied mainly on interferon33 and in recent years on
`consolidation chemotherapy with dexamethasone. cyclo-
`phosphamide, etoposide, and cisplatin (DCEF‘Y'l or glu-
`cocorricoids. ‘4
`
`Unfortunately, once disease progression occurred, es-
`pecially within the first year after single or
`tandem
`autotransplants, few treatment options were available. In
`search of an antiangiogenic agent to target the increased
`microvessel density noted in the bone marrow of patients
`with active MM,29-3’ thalidomide was evaluated because
`of
`its multiple,
`including anriangiogenic, antitumor
`mechanismsmt“
`
`250
`
`Seminar: in Hematology; V0138, Na 3 (filly), 2001: pp 250-259
`
`Dr. Reddy’s Laboratories, Inc. v. Oeigene Corp.
`IPR2018-01509
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`

`
`
`Thalidomide in Mye/ama 251
`
`Table 1. Phase II Study of Thalidomide
`
` Regimen Parameter 96
`
`
`200 mg
`1
`400 mg
`1
`600 mg
`1,
`800 mg
`
`Every 2 weeks
`
`Age > 60 yr
`#2M > 6 mg/L
`Abnormal cytogcnetlcs
`Deletion 13
`Prior therapy > 60 mo
`Prior high-dose therapy
`>1 cycle
`
`44
`2
`67
`37
`20
`76
`53
`
`The Arkansas Experience
`
`Single-Agent Thalidomide in Post-
`tranSplant Refractory Myeloma7vls
`Between December 1997 and December 1998, 169
`consecutive eligible patients with extensively pretreated
`and progressive MM were enrolled in a phase II trial that
`called for a dose-escalating schedule of thalidomide of 200
`mg daily with ZOO-mg increments every 2 weeks to a
`maximum of 800 mg, according to tolerance. Study
`endpoints included paraprotein reduction (PPR) in serum
`or urine of at least 25%, 50%. 75%. or 90%; CR was
`defined by the absence of monoclonal protein on immuno—
`fixation analysis. Patients who achieved a PPR less than
`25% or who discontinued treatment before response
`could be assessed (minimum of 4 weeks of therapy) were
`considered treatment failures. All results are presented on
`an intent-to-treat basis; relapse criteria have been previ-
`ously reported.
`Table 1 summarizes patient characteristics. Impor-
`tantly, 67% had cytogenetic abnormalities,
`including
`57% who presented with chromosome 13 deletion. More
`than two thirds had at least one and more than 50% had
`
`two or more cycles of prior high-dose therapy with
`autologous stem cell support. Dose escalation of thalido-
`mide to 400 mg was possible in almost 90% and to 800
`mg in more than 50% of patients. Treatment-related
`
`Table 2. Responses to Phase II Study of Thalidomide
`
`“0590"“
`0R
`290% PPR
`27596 PRR
`250% PPR
`iii-1% PPR
`
`9‘
`2
`12
`6
`1°
`3;
`
`WW“! 2 0'8“ 3
`Treatment—related mortality
`Sedation
`Constipation
`Neuropathy
`Deep “In thrombosis
`
`96
`0
`25
`16
`9
`2
`
`mortality was not observed. Grade 2 3 toxicities in-
`cluded sedation/somnolence in 25%, constipation in
`l6%. and mainly sensory neuropathy in 9% (Table 2).
`These toxicities were related to both intensity and cumu-
`lative dose of
`thalidomide administered. Deep vein
`thrombosis (DVT) or cytopenia was encountered in fewer
`than 5% of patients.
`PPR Z 25% was observed in 57%; 30% achieved
`PPR Z 50%; and CR or near-CR (>90% PPR) was
`obtained in 14% (Table 2). Response kinetics were such
`that 90% had achieved PPR Z 25% within 4.5 months.
`PPR 2 25% was more common when cytogenetics were
`normal (52% r‘ 28%, P = .003) and when the plasma cell
`labeling index (PCLI) was less than the median of S
`0.5% (44% v 10%, P < .001). Responses were associated
`with significant reductions in marrow plasmacytosis and
`[32-microglobulin (32M), as well as improvement
`in
`hemoglobin and levels of IgM as an indicator of recovery
`of normal B-cell function (Table 3).
`With a median follow—up of 22 months among 84
`alive and refractory patients, 2-year EFS and OS estimates
`are, respectively, 20% I 6% and 48% I 6% (Fig 1). On
`multivariate analysis, EFS and 05 were longer in the
`presence of normal cytogenctics, low PCLI, and low [32M
`(53 mg/L), so that four distinct risk groups could be
`identified (Fig 2). As cytogenetic and cytokinetic data are
`not commonly available. the analysis was performed in
`the absence of these two variables and demonstrated that
`
`three risk groups could be readily discerned on the basis
`of 32M and C-reactive protein (CRP) levels (Fig 2).
`Prognosis was not superior
`in patients who had not
`received prior high-dose therapy or in those with a longer
`time lapse since the last transplant.
`As this phase II study was not designed to determine
`whether a dose-response effect existed, a 3-month land-
`mark analysis wzu performed to determine whether pa-
`tients tolerating dose escalation had better disease con-
`trol. Indeed, 54% of those receiving greater than 42 g of
`thalidomide over a period of 3 months (median cumula-
`tive dose) responded (PPR 2 25%), compared to 21% in
`the lower-dose group (P < .001). Similarly, the 2-year
`survival estimate was higher in the high-dose group (63%
`r
`t
`.
`'
`/
`i- 896 L 45% 1- 13%, P < '001) (1:13 3)‘ Table. “
`examines whether such dose escalation benefited a partic-
`ular subgroup defined on the basis of cytogenetics, 32M,
`and PCLI; 2-year survival
`rates were superior among
`high-risk patients receiving the higher thalidomide dose.
`
`
`Table 3. Myeloma Protein Response and Associated Laboratory Changes
`Ill-Protein Response
`
`Parameter
`
`Bone marrow
`plasma cells
`32M
`IgM
`Hemoglobin
`
`' Median 96 change.
`T lnterquartlle range.
`
`N
`
`2 5096
`
`N
`
`< 50%
`
`P
`
`41
`42
`29
`44
`
`<.0001
`+13 (183)
`78
`—20* (75)?
`<.0001
`+22 (55)
`86
`-7 (35)
`.002
`- 9 (48)
`56
`+ 58 (107)
`
`+9 (15) .003 89 O (24)
`
`
`
`Dr. Reddy's Laboratories, Inc. v. Celgene Corp.
`IPR2018-01509
`Exhibit 2032, Page 2
`
`

`

`252
`
`Bm-logie er 4/
`
`Proportion
`
`
`
`Months
`
`Figure 1. EFS and 05 survival after
`single-agent thalldomlde for 169 pa-
`tients with advanced and refractory
`myelome.
`
`Combination Trials
`
`Clinical trials in progress will
`Post-transplant relapse.
`determine the role of thalidomide in the management of
`both refractory and newly diagnosed patients in combi-
`nation with glucocorticoids and. because of its virtual
`lack of myelosuppression, cytotoxic chemotherapy (Table
`5). At our center, post—transplant relapses are categorized
`in terms of cytogenetics and PCLI.
`
`Patients with low tumor burden or at
`
`low risk of
`
`relapse post—transplantation ate randomized to dexameth-
`asone with or without thalidomide. To date, 25 patients
`have been enrolled and their characteristics are listed in
`
`Table 6. Responses graded by tumor cytoreduction and
`survival are depicted in Fig 4. With a median follow-up
`of 23 months, 2-year EFS and OS rates {or the entire
`population are 40% and 80%. respectively. The incidence
`
`EVENT-FREE
`
`ALIVE
`
`1.0
`
`(32M >3 mg/L, LI >0.5%, and Abnormal Cytogenetics)
`
`Proportion
`
`1.0
`(l 8
`'
`0-5
`0.4
`02
`
`0
`
`5
`
`12
`
`1e
`
`s
`0
`so
`24
`Months from Enrollment
`
`12
`
`1a
`
`24
`
`30
`
`> 42 9/3 mo
`(n-83)
`
`5 4312;536:10
`
`p=0.009
`
`0 4
`
`0.2
`
`2 25% Response
`> 42 g
`54
`p < .001
`42
`5—921‘
`
`0
`
`5
`
`15
`10
`Months From 90 Day Landmark
`
`25
`
`3o
`
`Flame 3. Higher response rate and
`{E'mdi‘f'v'va' w'"‘ “'9’” “5" "W
`
`Dr. Reddy’s Laboratories, Inc. v. Oelgene Corp.
`IPR2018-01509
`Exh bit 2032, Page 3
`
`EFS (left) and 05 (right)
`Figure 2.
`according to the number of unfavor-
`able prognostic factors present prior
`to thalidomide. Top: Risk discrimina—
`tion on the basis of abnormal oytogi.L
`netlcs (EFS HR 2.15, P < .001; 05 HR
`2.53, P = .002), PCU > 0.5% (EFS HR
`1.86, P = .002: 05 HR 1.82, P =
`.009) and 82M > 3 mg/L (EFS HR
`
`Number of risk factors represented by
`solid lines 0. dashed 1. dotted 2.
`dash-dotted 3. Bottom: Risk discrimi-
`nation on the basls of standard vari—
`abls 32M > 3 mg/L (EFS HR 1.61.
`P = .009. 05 HR 3.33, P > .001) and
`CRP > 7 mg/L(EFS HR 1.37, P = .08:
`05 HR 1.92, P = .005). Number of
`risk factors represented by solid lines
`0, dashed 1, dotted 2.
`
`1.0
`
`0.8
`
`:
`
`1.54, P = .016; 05 HR .99, P < .001).
`
`
`t I
`
`O 3
`
`E
`
`

`

`
`
`Tlm/ir/wnit/e in MJ‘e/OII/a 253M
`
`Table 4. Higher Thalidomide Dose Benefits High-Risk Disease
`95 Aim
`Thalidomide Dose >
`Response
`No. of Risk
`
`
`
`42 ya mo N z 25% P at 2 yrFactors‘ Pa
`
`
`51
`Yes
`45
`74
`55
`NS
`'01
`No
`36
`19
`66
`.01
`02
`Yes
`28
`43
`42
`>1
`
`30 13 'No 20m
`
`
`* [32M > 3 mg/L: PCLi > 0.5%; abnormal cytogenetics.
`Abbreviation: NS. not significant.
`
`
`
`
`
`of 250% PPR was 57% among 14 patients on dexameth—
`asone plus thalidomide versus 27% on dexamethasone
`alone; 29% on the combination but none of 11 patients
`on dexamethasone alone achieved CR (P = .04).
`DCEP plus thalidomide was offered to patients relaps-
`ing with high tumor burden, high proliferative disease,
`or high-risk cytogenetics (Table 7). With a median
`
`follow—up of 17 months, response could be assessed in
`80 patients. After
`three cycles (intent-io-treat), 27%
`achieved 250% myeloma protein reduction including
`18% with CR or near-CR. Added thalidomide doubled
`
`||
`I"
`III
`
`169
`25
`80
`
`Table 5. Thalidomide Alone and In Combination
`for Multiple Myeloma (as of April 1, 2001)
`
`PM
`N
`Eil
`5
`iii
`may
`59
`an iv
`Thalidomide
`Advanced. refractory
`Dex I Thalidomide
`”51+qu relapse,
`'°“’""‘
`DCEP :Thaildomlde
`Post-HOT relapse.
`high risk
`Prior therapy
`229
`III
`DT PACE
`
`
`
`III 309Total Therapy II UntreatedE
`
`the response rate (56% l' 18%), including 290% PPR in
`25% versus 10% (P
`.07). At 2 years, 58% are
`event-free and 48% are alive; no difference is yet apparent
`between the two treatment arms (data not shown).
`The
`DT PACE snimge Ibempy without prior transplant.
`combination DT PACE regimen consists of dcxarnerha—
`some,
`thalidomide, and 4-day continuous infusions of
`.
`.
`.,
`.
`.
`a
`Cisplatin 40 mg/m‘, doxorubicm 40 mg/m", cyclophos-
`phamide 1,600 mg/m2, and etoposide 160 mg/mz. A
`previous pilot
`trial
`in 12 high-risk patients with high
`1
`dhd
`-(LDH1 i‘d i‘i’"
`“lame
`'3 Y ”36‘1““
`)
`"C S
`‘m P” ‘ ““1“
`disease demonstrated a first—cycle CR rate of greater than
`50%.“ Hence, patients not qualifying for Total Therapy II
`(those with more than one cycle of prior therapy) are
`eligible for two induction cycles with PBSC collection.
`Responders (250% PPR) with a CD34 yield large
`enough for two autortansplants (>12 X 106 CD34/kg)
`are randomized to continuation of DT PACE versus the
`standard melphalan (200 mg/m")-based tandem trans-
`’
`.
`.
`.
`_
`plant program. For maintenance, patients are again ran
`domized to dexamethasone plus thalidomide at 200
`versus 50 mg daily. Another question examines the CD34
`‘4
`57
`36
`Age > 60 y'
`d
`d
`’
`' r
`d v'th the
`cond trans l
`t
`nd its
`1'0
`64
`73
`male
`‘ ose a minis ere
`\ i
`se
`1;: an
`a
`10
`43
`45
`32M > 2.5 mg/L
`impact on the subsequent development of MDS/AML.
`.7
`43
`27
`cRp > 4.0 mg/L
`As of March 1, 2001, 229 patients have been enrolled.
`1.0
`43
`45
`igG
`Patient characteristics are depicted in Table 8, and the
`2
`36
`9
`[EA
`V
`y
`-
`h
`’
`-
`F.
`Th
`Cl-
`1.0
`14
`18
`-13/13q—
`
`Prior HOT e me ian 82 93 .6 fio“ through the program is s can in ig 6.
`
`
`
`
`
`
`Abbreviations: Dex. dexamethasone; DCEP, dexamethasone, cyclo-
`phosphamide. etoposide. cisplatin; HDT, high-dose therapy.
`
`Table 6. Patient Characteristics for
`Dexamethasone 1- Thalidomide Study
`
`Dex Alone (n
`Dex — Thai
`
`Fame",
`_ 11).“.
`(n = 14).”
`P
`
`
`
`
`
`gas
`g
`19a 0.4
`a
`
`L-
`
`Event-Free
`L-"
`'Ih
`
`o 2
`
`Median Follow-up: 23 months
`
`30
`
`6 M
`
`12
`18
`24
`onths From Enrollment
`
`a
`
`
`
`% Responding After 3" Cycle
`Thalidomide
`
`
`CR"
`0
`7
`> 90%,.
`
`_
`z 75%
`14
`1s
`
`
`
`
`
`
`a 50%
`
`*p=0.04
`
`randomized
`Figure 4. Results of
`trial of dexamethasone 1' thalidomide
`for post-transplant relapse (low risk).
`Significantly higher response rate with
`dexamethasone + thalidomide. No
`apparent diflerence in EFS or 05 yet
`(data shown for combined groups).
`
`Dr. Reddy's Laboratories, Inc. v. Ceigene Corp.
`IPR2018—01509
`Exhibit 2032, Page 4
`
`

`

`Bar/ogre et a!
`254
`_—_—_______————————————
`
`Table 7. Patlent Characterlstios for
`DCEP 1 Thalidomide Study
`DC? Alone
`DC? + ‘nial
`Parameter
`(n - 42). 96
`(n - 38), 96
`P
`
`
`1.0
`39
`38
`Age > 60 yr
`.2
`55
`71
`Male
`1.0
`74
`71
`{32M > 2.5 mg/L
`.1
`75
`55
`CRP > 4.0 mg/L
`.4
`47
`60
`IgG
`.8
`24
`19
`IgA
`.2
`32
`45
`-13/1.3q—-
`
`
`
`Prior HOT .2 98 89
`
`Table 8. Patient Characterlstics (N = 229)
`for DT PACE Study
` Parameter SS
`
`
`Age > 60 yr
`Male
`32M > 6 mg/L
`CRP > 4 mg/L
`Deletion 13
`Months of prlor therapy
`75
`:12
`15
`12-24
`
`>24 12
`
`53
`64
`25
`1,3
`21
`
`age is 60 years with an upper age of 89 years. Twenty-
`seven percent had greater
`than 12 months of prior
`therapy, and 20% had chromosome 13 abnormalities. A
`Full-dose first cycle was given to 73% of the patients.
`Among the 179 enrolled at
`least 15 weeks prior to
`analysis, and hence reaching the first randomization stage,
`only 45% rather than the expected 80% were random-
`ized, mainly due to a lower than expected response rate to
`the induction regimen. Thus, only 26% achieved 275%
`tumor mass reduction,
`indicating that only a small
`percentage indeed of cases is exquisitely sensitive to DT
`PACE. Among the first 80 patients randomized and
`actually treated according to the randomization arm, 26
`of 39 on the tandem tran5planr arm and only 11 of41 on
`the DT PACE continuation arm achieved CR (P =
`
`.0005). In addition, by protocol design, 40% of patients
`on the DT PACE arm crossed over
`to the tandem
`
`transplant arm because of failure to show ongoing re-
`sponse and especially to acheive CR. lmportantly, how-
`ever,
`the 2—year EFS of 73% I 20% was identical
`between the two arms. In addition, 33 patients failing
`two cycles of DT PACE received tandem transplant as a
`rescue regimen with a 2—year EFS rate of 70% t 27%
`(Fig 7). A multivariate prognostic factor analysis was
`performed to determine features associated with at least a
`partial response (PR) (PPR Z 75%) after two induction
`cycles. Higher PR rates were noted with the application
`of full doses of DT PACE (odds ratio [OR], 19.4; P =
`.005) and, surprisingly,
`in the presence of cytogenetic
`
`abnormalities, including those involving chromosome 13
`(OR, 2.9; P = .05), whereas a level of marrow plasma—
`cytosis greater than 30% was an unfavorable feature (OR,
`0.2; P = .002). Thus, for the first time, we have identified
`an active regimen for high—risk chromosome 13 disease, as
`observed in the initial pilot trial.
`the trial has been
`On the basis of these results,
`modified to call for one cycle of DT PACE with PBSC
`collection and immediate randomization to tandem trans-
`
`the use of a
`plants with melphalan 200 mg/mz, or
`recently developed hybrid regimen employing DT PACE
`(with whole doses given in 48 rather than 96 hours)
`combined with melphalan 100 mg/m2 and PBSC support.
`The latter regimen, when tested in the third and fourth
`transplant salvage setting, had a high incidence of CR and
`considerably less stomatitis than standard melphalan 200
`mg/mz. Three hundred patients will be enrolled to
`determine whether EFS increases from 25% to 35% at the
`end of 5 years.
`Total Therapy 1! asfront-li‘ne tberapyfir newly diagnosed
`patients (51 cycle prior standard therapy).
`The trial
`design (Fig 8) consists of four phases:
`(1)
`induction
`chemotherapy with VAD, DCEP, and cyclophosphamide,
`doxorubicin, and dexamethasone (CAD) with subsequent
`PBSC collection followed by a further cycle of DCEP; (2)
`tandem autotranSplanrs with two cycles of melphalan 200
`mg/mz;
`(3) consolidation chemotherapy with either
`DCEP every 3 months for four cycles or DCEP alternating
`with CAD every 6 weeks for 1 year; and (4) interferon
`
`
`
`% Responding After 3" Cycle
`
`
`
`Thalidomide
`
`
`
`5
`8
`CR *
`5
`17
`3 90% *
`
`
`a 75%
`3
`o
`
`E. 50%
`
`36
`* p=0.07
`
`1
`
`0.8
`
`g 0.6
`g
`E 0-4
`
`0.2
`
`o
`
`
`
`
`18
`24
`30
`°
`6 Months From Enrollment
`
`Event-Free
`
`
`.1-—
`
`Median Follow-up: 17 months
`
`38
`
`randomlzed
`Flame 5. Results of
`trlal of combinatlon chemotherapy
`wlth DCEP : thalldomlda: no appar-
`ent dlfference yet in EFS or 05 (data
`shown for comblned groups).
`
`Dr. Reddy’s Laborataios Inc. v. Oelgene Corp.
`IPR2018—01509
`Exh bit 2032, Page 5
`
`

`

`
`
`Thalidomide in Myeloma 255
`
`DTPACExZ
`
`(w/ PBSC
`collection
`after 1sl cycle)
`
`Transplant
`
`“9’2””N i:
`
`Random,“
`patients w/
`response
`
`°
`
`No PR
`or
`
`Relapse
`
`I
`
`Immunological
`R Manipulation phase II
`
`DT PACE
`
`Patientsw/
`no response
`°’%’#iii§i’°"
`
`UARK
`97-014
`
`No CRTransplant
`DT pACEMe]200X 2
`CR
`
`trials
`
`Figure 6. OT PACE schema.
`
`maintenance. All patients are initially randomized to
`receive or not receive thalidomide at a starting dose of
`400 mg with reduction to 200 mg during consolidation
`and 100 mg for maintenance.
`As of April 2001, 50‘) patients have been enrolled
`(Table 10). Among the first 135 patients eligible for
`second transplant, the incidence of CR/near-CR increased
`from 44% at the end of induction to 61% after the first
`
`transplant and to 69% after the second transplant, with
`an additional 9% achieving 275% PPR,
`including
`normalization of the bone marrow. The 2-year EFS and
`OS rates are 88% and 92%, respectively, with a median
`follow-up of 13 months (Fig 9). These results are reflec-
`tive of the overall population because of blinding with
`respect to thalidomide randomization
`With an expected accrual of 660 patients, extensive
`laboratory research will help identify the molecular and
`biological mechanisms associated with response and sus-
`
`tained CR duration, as well as to determine the role of
`thalidomide in the up-front management of newly diag-
`nosed patients with MM. Research will include cytogc-
`netics, interphase fluorescent in situ hybridimtion (FISH),
`S-bromodeoxyuridine (BUDR) labeling index, myeloma
`telomere length, and telomerase activity; gene expression
`profiling to be performed at baseline and serially during
`the trial has recently been added.
`Available toxicity data. in the thalidomide arm showed
`a significantly higher incidence of deep venous thrombo-
`sis
`(DVT)
`(28%)
`than in controls (6%)
`(Fig 10)."3
`Prophylactic low-dose warfarin sodium 1 mg/d has there-
`fore been instituted, resulting in a reduction of DVT
`complications to a level seen without thalidomide. Un-
`explained is the dampening of CD34 procurement after
`CAD on the thalidomide arm (Fig 11)." Subsequent
`patients randomized to thalidomide discontinued the
`
`drug after completion of CAD on day S and resumed
`
`
`
`I. . .-.... . .........
`
`P= .08
`
`0.8
`
`IE 0.0
`i
`e
`“-
`
`%EVEN1-FREE
`
`0.4 ’m—i—“Iw
`uel zoo TX
`35 —A— 86(6)
`mm
`
`41 d- 51(6)
`73(27)
`DTPaee
`
`Salvage TX
`33 ul- 85(9)
`7mm
`
`
`
`0
`6
`12
`18
`24
`30
`Months from DTPace1
`
`02
`
`0
`
`Flame 1. Equlvalent EFS or patlents
`with previously treated myeloma re-
`calving DT PACE randomized to con-
`tinuation of DT PACE or melphalan
`200 myrtle-based autotransplant fol-
`lowing lnltlal response to D'l’ PACE x
`2 years. Higher relapse rate among 01’
`PAGE nonresponders receiving sai-
`vage therapy (P = .08).
`
`
`Table 9. DTPACE—MEL 100 Hybrid
`
`Prlnr Therapy
`Prior
`Pal-therapy
`9; Response
`
`Patient No.
`06
`(mo)
`Response
`Therapy
`DCEP N0.
`Thal (mo)
`DTPACE—MEI.
`
`>50
`0
`2
`2
`1° UNR
`14
`-13
`1
`>90
`8
`3
`1
`1° UNR
`54
`ABN
`2
`>50
`12
`5
`1
`RR
`88
`-13
`3
`>50
`30
`O
`2
`RR
`1.12
`ABN
`4
`nCR
`0
`0
`1
`RR
`60
`—13
`6
`
`6 Stable -13 4 RR 1 2 2
`
`
`
`
`
`
`
`Abbreviations: CG, —: ABN. —; 1° UNR. —: RR, —; nCR, —.
`
`Dr. Reddy's Labomtories, Inc. v. Celgene Corp.
`IPR2018—01509
`Exhibit 2032, Page 6
`
`

`

`
`
` 256 Bar/ogie et 41
`
`Induction
`
`—> Transplant —> Consolidation —> Maintenance
`
`r—>DCEP
`
`Thalidomide—> Mel 200 x2 Randomizatrblnterferon
`
`i
`Randomization
`
`EDCEP/CAD
`
`Figure 8. Total Therapy ll schema.
`
`i
`N°
`Thalidomide
`
`,——>DCEP
`—> Mel zoo x2
`Randomization
`l——> DC EPICAD
`
`Interferon
`
`First 133 Patients Eligible for Tx-2
`
`309 Patients Enrolled as of Apr. 2001
`
`Ind. Tx-1 Tx-2
`
`Response
`
`%
`
`%
`
`%
`
`Pa
`
`0-2
`
`Probability
`
`Median Survival: 13 months
`Pa O
`
`6
`24
`1B
`12
`Months From Enrollment
`
`30
`
`Figure 9. Response, EFS. and 05
`after Total Therapy ll. After 2 cycles of
`melphalan 200 mg/m2 (Tx—2). 69% of
`patients achieved CR or near-CR (in-
`tent-to-tteat). Approximately 90% are
`projected event-free and alive 24
`months after start of therapy.
`
`therapy upon completion of PBSC collection. As with
`previous interferon trials, subclinical hypothyroidism was
`observed with greater frequency among patients random-
`ized to thalidomide}
`
`Global Experience With
`Thalidomide Alone and in
`Combination for Multiple
`Myeloma
`
`Table 11 summarizes available data pertaining to trials
`With at
`least 20 patients. Seven single-agent
`trials in
`refractory disease showed an overall response rate (PPR 2
`50%) of 36% among 352 patients with available infor«
`mation. The addition of dexamethasone increases the
`
`10
`
`
`
`
`3"”
`.L_0 50
`3
`u, 40
`
`Sx
`
`30
`3 20D
`0 10
`O
`
`A
`A
`
`‘
`
`A
`
`6
`
`0 Thalidomide
`A NoThalidomlde
`p=0.06
`
`10
`
`12
`
`ii
`
`38
`
`O
`9
`°
`
`
`
`
`Days of Collection
`
`Figure 11. CD34 collection after CAD in Total Therapy ll.
`
`Dr. Reddy’s Laboratories, Inc. v. Oelgene Corp.
`IPR2018-01509
`Exh hit 2032, Page 7
`
`8323
`Percent a
`
`
`
`‘DVTfToIal N
`Thalidomide Arm
`(N=50)
`
`Control Arm
`(N=50)
`
`Figure 10. DVT in Total Therapy II.
`
`Table 10. Patient Characteristics for Total Therapy ll Study
`96
`Parameter
`
`Age > 60 yr
`Male
`[32M > 2.5 mg/L
`CRP > 4.0 mg/L
`Dude-Salmon stage 2 2
`lgG
`lgA
`PCLI > 1%
`Abnormal karyotype
`13/13::
`
`

`

`
`
`Tba/inlmflde in Myeloma 257”R
`
`Table 11. Thalidomide in Multiple Myeloma
`
`Prior Tx
`
`2 7596
`
`Response Rate by PPR Lew!
`2 50%
`
`z 2596
`
`10
`53 (17 Tx x 2)
`
`'
`
`N/A
`13
`13 (9 Tx x 2)
`N/A
`
`123 (so Tx x 2)
`
`N/A
`13%
`
`12%
`N/A
`N/A
`N/A
`
`43%
`47%
`
`46%
`N/A
`25%
`30%
`
`N/A
`56%
`
`69%
`75%
`45%
`N/A
`
`20%
`17%
`(43/273)
`
`30%
`36%
`(127/352)
`
`37%
`52%
`(178/346)
`
`0
`
`12
`
`N/A
`
`14
`
`N/A
`
`0
`
`24%
`
`N/A
`
`N/A
`
`51%
`
`52%
`
`52%
`
`52%
`(63/122)
`
`N/A
`
`35% (of 14
`evaluable)
`
`7% (ca)
`
`44%
`(OR. 27%)
`
`73%
`
`54%
`
`73%
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`WA
`
`35%
`(62/177)
`
`62%
`(113/191)
`
`Thalidomide—untreated myoloma
`Symptomatic disease
`Thai 200 mg —» 800 mg. Dex
`40 mg ((1 1-4, 9-12, 17-20,
`every 36 d)
`Smolderlng disease
`16
`Thai 200 - 800 mg
`38%
`26
`Thai 200 —) 600 mg
`35%
`68
`Summary oi above studies
`51%
`(35/68)E—
`
`Rajkumar”
`
`26
`
`Rajkumar“
`Weber“
`
`0
`
`0
`0
`
`77%
`
`N/A
`
`N/A
`N/A
`
`N/A
`
`N/A
`N/A
`
`Abbreviations: N/A. not available; CTX, cyclopnosphamlde; Thai, thalidomide: Dex. dexamethasone; VP16. eioposide: DDP. clsplatin; TX. therapy.
`
`response rate beyond 50%. The inclusion of cytotoxic
`chemotherapy raises the average response rate to about
`60%.
`
`In untreated MM, single-agent thalidomide effected a
`PPR Z 50% in 36% of 42 patients with smoldering
`disease. Added dexamethasone for 26 patients with symp-
`tomatic MM resulted in a higher response rate of 77%
`(PPR Z 50%), although CR5 were not recorded by the
`end of four cycles. These data suggest that thalidomide
`plus dexamethasone is a synergistic oral regimen provid-
`ing similar antitumor activity to that of primary VAD.3
`
`An Eastern Cooperative Oncology Group randomized
`trial is Currently evaluating dexamerhasone pulsing versus
`dexamethasone plus thalidomide 200 mg.
`
`Discussion
`
`The data presented support the idea that thalidomide has
`major acrivity in patients with advanced and refractory
`MM. Hence, after almost four decades of clinical trial
`research,
`thalidomide represents only the third non—
`
`Dr. Reddy’s Laboratories, Inc. v. Ceigene Corp.
`IPR2018-01509
`Exhibit 2032, Page 8
`
` m T
`
`Treatment Regimen
`
`First Aulhor
`
`halidomide alone—refractory disease
`Thal 200 mg —> 800 mg
`Median Thai 400 mg (range. 50-
`800 mg)
`Thai 200 mg —> 800 mg
`Thai 200 mg
`Thai 100 mg —. 800 mg
`Thai 200 mg —> 800 mg (12
`wk); Thai + IFN (>12 wk)
`Thai 200 mg —» 800 mg
`Summary of above studies
`
`Juliusson"
`Yakoub-Agha"
`
`Razaa‘
`Rodriguez”
`Tosl"
`Prince“
`
`Barioglem
`
`Thalidomide + dexamethasone—«efraotory disease
`Thai 100 mg, Dex 40 mg X 4 d.
`Palumbou
`every 28 d
`Thai 200 mg —> 400 mg. Dex 40
`mg X 4 d (d 1-4. 9-12, 17-
`20. every 35 (1)
`Thai 200 mg —v 800 mg. Dex 20
`mg/m2 (d 1-5, 8-15 In
`month 1. d 1-5 In following
`months)
`Summary oi above studies
`
`Weber“
`
`Dlmopouiosm
`
`N
`
`20
`83
`
`26
`40
`27
`27
`
`169
`392
`
`37
`
`38
`
`47
`
`122
`
`Thalidomide + dexamethasone + chemotherapy—refractory disease
`Thal 100 mg —> 400 mg. Dex 20
`Krop1'ii“B
`20
`mg/m’. :1 1-4, 9-12. 17-20,
`CTX 1.8 g/rn’
`TcED: Dex 40 mg. OTX 400 mg/
`m”. VP16 40 mg/m2 (x4
`d) and Thai 400 mg (daily)
`“DT PACE”: Dex 40 mg. DDP 10
`mg/m’, doxorubioln 10
`mg/m’. CTX 400 mg/m‘,
`VP16 40 mym2 (x4 d)
`and Thai 400 mg (daily) X
`2 cycles
`Summary of above studies
`
`Moehler"
`
`Barlogle
`(unpublished)
`
`42
`
`135
`
`19']
`
`

`

`
`
`258 Barlogie et al
`
`cross-resisrant active antimyeloma agent. Some patients
`attain their best response with thalidomide after having
`received high-dose glucocorticoids and melphalan.
`Much is yet to be learned about dose— and schedule-
`dependent antirumor effecrs and toxicities. A plethora
`of potential antimyeloma mechanisms has been in-
`voked,
`including but not
`limited to ditecr
`tumor
`apOptosis,52 suppression of antiapoptotic cytokines
`elaborated by the bone marrow microenvironment,”
`disruption of tumor—stromal cell adhesion,” antian-
`giogenesis," and immunomodularion.21 Although
`prognostically relevant at baseline, bone marrow mi-
`crnvessel density is not consistently altered in patients
`responding to thalidomide.“l Others have reported on
`thalidomide-induced elevations of B-fibroblast growth
`factor in re5pondersfi°
`Studies in the SCID-hu mouse model revealed that
`
`thalidomide's activity depended on coimplantation of
`human liver,
`indicating the need for
`its metabolic
`activation. Significantly, both increased rates of DVT
`and interference with CD34 mobilization may hold
`important clues to its mechanism of action and inter—
`action with other agents, such as dexamethasone.
`Important clinical questions regarding thalidomide’s role
`in myeloma management should address the following:
`
`0 Dose-dependent role during induction with dexameth-
`asone or VAD (O, 100 mg, 400 mg).
`0 Continuation of thalidomide at 50 to 100 mg versus
`no drug peritransplant and, in the setting of tandem
`transPIants, between cycles, in an effort to dampen
`the cytokine storm associated with hematopoietic
`recovery, which may contribute to disease persis-
`tence and relapse by providing critical survival/
`proliferative signals to residual myeloma cells.
`0 Maintenance treatment with dexamethasone alone or
`combined with different dose levels of thalidomide (50
`
`mg, 200 mg) with similar considerations for interferon
`combinations.
`
`Such randomized clinical trials should include laboratory
`research addressing thalidomide pharmacokinetics and
`antiangiogenic and immunomodulatory effects.
`As data about thalidomide’s contribution to the front-
`
`line management of myeloma with standard— or high-dose
`therapies emerge, phase II studies of use of the thalido-
`mide derivative immunomodulatory drug (IMiD) at a
`dose level of 50 mg daily in advanced disease show
`promising antitumor activity (Barlogie, unpublished
`data).
`The therapeutic armamentarium for the management
`of MM has been markedly expanded. Now, larger num-
`bers of patients can be expected to respond more mark-
`edly for sustained periods of time, and perhaps with less
`drug toxicity.
`On the basis of preliminary data revealing thalidomide
`responses in MDS,” an important secondary aspect of
`Total Therapy 11 will be the analysis of secondary
`leukemia according to thalidomide randomization. With
`this in mind, serial cytogenetic, FISH, telomere/telomer-
`
`ase, and in vitro hematopoietic progenitor assays are
`being performed.
`
`Acknowledgment
`This contribution is dedicated to the memory of the late Ira
`Wolmer, MD. who was the first patient in the Arkansas program
`to receive thalidomide and, sadly, died in his early 405 after
`having endured four autologous transplants and finally thalido-
`mide to control his high-risk chromosome 13 deletion disease.
`
`.L\
`
`!"
`
`References
`l. Attal M, HarousseauJ: Randomized trial experience of the
`IFM. Semin Hematol 38:226—230. 2001
`Attal M, Harousseau J, Stoppa A. et al: A prospective,
`randomized trial of autologous bone marrow transplantation
`and chemotherapy in multiple myeloma. N Engl J Med
`335:91-97, 1996
`3. Badros A, Barlogie B, Siegel E, ct at High dose therapy and
`autolngous stem cell support in multiple myeloma patients
`over age 70: A single center experience. Br J Hematol (in
`press)
`. Badros A, Siege] E, Tricot G, er al: Melphalan-based high
`dose therapy (HDT) with peripheral blood stem cell (PBSC)
`support is safe and effective in multiple myeloma (MM)
`with renal failure. Blood 96:16583, 2000 (suppl 1, abstr)
`5. Badros A, Zangari M, Bodenner D, et al: Hypothyroidism
`in patients with multiple myeloma (MM) receiving thalid-
`omide. Blood 9624973a, 2000 (suppl 1, abstr)
`6. Barlogie B, Alexanian R, Dicke KA, Zagars G, Spitzer G,
`Jaganneth S, Horowitz L: High-dose chemoradiotherap