in the Management of Multiple Myeloma
`Thalidomide
`Burt Burlogie, Mmrizio Zangari, Twy Spencer, Athdnusios Fusses, Elias Anaissie,
`Ashaf Badros, JeuBa Cram, and Gzlido Tricot
`
`A
`
`(MM).
`in refractory multiple myeloma
`activity
`to have significant
`been shown
`has recently
`Thalidomide
`shows P-year survival of 60%; patients
`phase
`II trial, expanded
`to 169 patients,
`of the original
`follow-up
`242 g over 3 months had a higher
`response
`rate and superior
`survival
`than
`those
`receiving
`lower
`receiving
`doses. The addition
`of thalidomide
`to dexamethasone
`and chemotherapy
`for
`the management
`of post-
`transplant
`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
`(CR) and near-CR
`rate of 69% after two
`melphalan-based
`transplants
`(whether
`or not
`receiving
`thalidomide).
`In addition,
`available
`clinical
`trial
`Information
`involving
`at
`least 20 patients
`confirms
`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
`SO% paraprotein
`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.
`Semin Hematol38:250-259.
`Copyright
`0 2001 by W.B. Saunders Company.
`
`as
`
`A DVANCES
`
`of multiple
`management
`THE
`IN
`two
`seminal
`to
`be
`traced
`can
`(MM)
`myeloma
`of glucocor-
`dose
`intensity
`First,
`increasing
`observations.
`pulsing
`of dexamethasone
`in
`the
`form
`ticoids,
`mainly
`doxorubicin,
`and dexametha-
`vincristine,
`realized
`in
`the
`sone
`(VAD)
`regimen,
`was shown
`to overcome
`resistance
`to
`standard
`alkylating
`agent-prednisone
`combinations
`and
`when
`applied
`in
`the
`setting
`of primary
`unresponsive
`key
`the
`resistant
`relapse.l*
`Similarly,
`dose escalation
`of
`alkylating
`agent
`melphalan
`to myeloablative
`intensity,
`facilitated
`by autologous
`hematopoietic
`stem
`cell support,
`to
`was
`shown
`to overcome
`resistance
`both
`alkylating
`agents
`in standard
`doses
`and
`high-dose
`glucocorticoid-
`and
`containing
`regimens.
`G,9~26 Historically
`controlled
`high-
`subsequently
`randomized
`trials
`demonstrated
`that
`periph-
`dose melphalan-based
`regimens,
`especially
`with
`in
`the
`eral blood
`stem
`cell
`(PBSC)
`support,
`when
`applied
`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).lJJo,ll
`This progress
`is closely
`linked
`to
`the
`recognition
`that mobilized
`PBSC,
`with
`the use of either
`stem
`cell-sparing
`chemotherapy
`(such
`as cyclophospha-
`
`Research
`and Transplantation
`the Myeioma
`From
`of Arkansas
`for Medical
`Rock, AR.
`Sciences,
`Little
`by Grant
`No. CA55819
`Supported
`in part
`MD.
`Cancer
`Znstitate,
`Beth&
`to Burt
`Address
`reprint
`requests
`Little
`Markham,
`Mail
`Slot 623,
`Copyright
`0 2001
`by W.B.
`0037-1963/01/3803-0011$35.00/O
`doi:10.1053/shem.2001.26014
`
`MD,
`Barlogie,
`72205.
`Rock,
`AR
`Saunders
`Company
`
`Center,
`
`University
`
`fvom the National
`
`PhD,
`
`4301
`
`W
`
`facilitated
`alone,
`factors
`growth
`or hematopoietic
`mide)
`neutro-
`earlier
`with
`engraftment
`hematopoietic
`brisker
`case with
`the
`had been
`recovery
`than
`platelet
`and
`phi1
`at
`risk,
`bone marrow.
`45 Thus,
`the
`duration
`autologous
`reduced
`be
`in elderly
`and
`frail
`patients,
`could
`especially
`treatment-
`from
`3 weeks
`to 7 days with
`a decrease
`in
`consider-
`related
`mortality
`to 1%
`to 2%.
`An
`important
`recognition
`ation
`for successful
`high-dose
`therapy
`was
`the
`that
`stem
`cell-toxic
`agents
`such
`as melphalan,
`nitro-
`soureas,
`and
`ionizing
`radiation
`to marrow-containing
`obtain
`bone
`sites
`needed
`be avoided
`in
`order
`to
`to
`hematopoietic
`stem
`cells of sufficient
`quantity
`and quality
`to
`facilitate
`rapid
`engraftment17x44
`and
`avoid
`secondary
`acute
`myelodysplasia
`syndrome
`(MDS)/acute
`myeloge-
`nous
`leukemia
`(AML).“*
`Single-agent
`melphalan,
`usually
`at 200 mglm’,
`as conditioning
`results
`in superior
`out-
`come with
`less
`toxicity
`than
`regimens
`containing
`total-
`body
`irradiation
`.lJ9 With
`appropriate
`dose modifications
`to
`of melphalan,
`such autotransplants
`can also be applied
`of
`the elderly
`(>65
`and >70
`years)3,40
`and
`in
`the setting
`had
`renal
`failure.4*43
`Post-transplantation
`management
`on
`relied
`mainly
`interferon33
`recent
`years
`on
`in
`and
`consolidation
`chemotherapy
`dexamethasone,
`cyclo-
`with
`phosphamide,
`etoposide,
`cisplatin
`(DCEP)l*
`or glu-
`cocorticoids.14
`progression
`disease
`once
`Unfortunately,
`after
`single
`the
`first
`year
`pecially
`within
`options
`were
`few
`treatment
`autotransplants,
`agent
`to
`target
`search
`of an antiangiogenic
`the bone marrow
`in
`microvessel
`density
`noted
`with
`active MM,Z9,35
`thalidomide
`was evaluated
`of
`its multiple,
`including
`antiangiogenic,
`mechanisms.1G,41
`
`es-
`occurred,
`or
`tandem
`available.
`In
`the
`increased
`of patients
`because
`antitumor
`
`and
`
`250
`
`Seminars
`
`in Hematology,
`
`Vol 38, No 3
`
`(July),
`
`2001:
`
`pp 250-259
`
`DR. REDDY’S LABS., INC. EX. 1051 PAGE 1
`
`

`

`Tbalidomi&
`
`in Myelomd
`
`251
`
`Table 1. Phase
`
`II Study
`
`of Thalidomide
`
`Regimen
`
`200 mg
`1
`400 mg
`L
`600 mg
`1
`800 mg
`
`Every 2 weeks
`
`Parameter
`
`Age > 60 yr
`P2M
`> 6 mg/L
`Abnormal
`cytogenetics
`Deletion
`13
`Prior
`therapy
`Prior
`high-dose
`>I
`cycle
`
`> 60 mo
`therapy
`
`%
`
`44
`22
`67
`37
`20
`76
`53
`
`The Arkansas Experience
`Single-Agent Thalidomide in Post-
`transplant Refractory Myeloma7J3
`169
`1998,
`Between
`December
`1997
`and
`December
`pretreated
`consecutive
`eligible
`patients
`with
`extensively
`trial
`that
`II
`and progressive
`MM
`were
`enrolled
`in a phase
`of 200
`called
`for a dose-escalating
`schedule
`of thalidomide
`to a
`mg
`daily
`with
`200-mg
`increments
`every
`2 weeks
`Study
`maximum
`of
`800 mg,
`according
`to
`tolerance.
`in serum
`endpoints
`included
`paraprotein
`reduction
`(PPR)
`CR was
`or urine
`of at
`least
`25%,
`50%,
`75%,
`or 90%;
`immuno-
`defined
`by
`the absence
`of monoclonal
`protein
`on
`less
`than
`fixation
`analysis.
`Patients
`who
`achieved
`a PPR
`response
`25%
`or who
`discontinued
`treatment
`before
`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.
`Impor-
`characteristics.
`patient
`Table
`1 summarizes
`including
`abnormalities,
`tantly,
`67%
`had
`cytogenetic
`37%
`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
`
`Response
`
`CR
`290%
`~75%
`~50%
`225%
`Total
`
`PPR
`PRR
`PPR
`PPR
`
`96
`
`2
`12
`6
`10
`7
`37
`
`Toxicity 2 Grade 3
`
`mortality
`
`Treatment-related
`Sedation
`Constipation
`Neuropathy
`Deep
`vein
`
`thrombosis
`
`%
`
`0
`25
`16
`9
`2
`
`2
`
`in-
`toxicities
`3
`Grade
`in
`constipation
`in
`25%,
`2).
`in 9%
`(Table
`neuropathy
`intensity
`and cumu-
`to both
`administered.
`Deep
`vein
`was encountered
`in
`fewer
`
`observed.
`not
`was
`mortality
`sedation/somnolence
`cluded
`and mainly
`sensory
`16%,
`toxicities
`were
`related
`These
`of
`dose
`thalidomide
`lative
`(DVT)
`thrombosis
`or cytopenia
`than
`5% of patients.
`achieved
`in 37%;
`PPR
`2
`25%
`was observed
`PPR)
`was
`PPR
`2
`50%;
`and CR
`or near-CR
`(>90%
`were
`such
`obtained
`in 14%
`(Table
`2). Response
`kinetics
`4.5 months.
`that
`90%
`had achieved
`PPR
`1 25%
`within
`PPR
`2 25%
`was more
`common
`when
`cytogenetics
`were
`normal
`(52%
`~28%,
`P =
`,003)
`and when
`the plasma
`cell
`labeling
`index
`(PCLI)
`was
`less
`than
`the median
`of 5
`0.5%
`(44%
`v IO%,
`P <
`.OOl).
`Responses
`were
`associated
`with
`significant
`reductions
`in marrow
`plasmacytosis
`and
`&microglobulin
`(P2M),
`as well
`improvement
`in
`as
`and
`hemoglobin
`levels
`of
`IgM
`as an
`indicator
`of recovery
`B-cell
`of normal
`function
`(Table
`3).
`a median
`84
`among
`With
`follow-up
`of 22 months
`refractory
`alive
`and
`patients,
`2-year
`EFS and OS estimates
`are,
`respectively,
`20%
`t
`6% and 48%
`? 6%
`(Fig
`1). On
`multivariate
`analysis,
`EFS
`and OS were
`longer
`in
`the
`presence
`of normal
`cytogenetics,
`low PCLI,
`and
`low P2M
`(53
`mg/L),
`so
`that
`four
`distinct
`risk
`groups
`could
`be
`(Fig
`identified
`2). As cytogenetic
`and cytokinetic
`data are
`not
`commonly
`available,
`the
`analysis
`was performed
`in
`the absence
`these
`two
`variables
`and demonstrated
`that
`of
`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.
`to determine
`As
`this phase
`II study
`was not designed
`whether
`a dose-response
`effect
`existed,
`a 3-month
`land-
`mark
`analysis
`was performed
`to determine
`whether
`pa-
`tients
`tolerating
`dose
`escalation
`had
`better
`disease
`con-
`54%
`trol.
`Indeed,
`of
`those
`receiving
`greater
`than
`42 g of
`over
`thalidomide
`a period
`of 3 months
`(median
`cumula-
`in
`responded
`tive
`dose)
`(PPR
`2 25%),
`compared
`to 21%
`the
`lower-dose
`group
`(P <
`.OOl).
`Similarly,
`the
`2-year
`survival
`estimate
`was higher
`in
`the high-dose
`group
`(63%
`?
`8%
`ZJ 45%
`i
`13%;
`P <
`,001)
`(Fig
`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.
`
`30%
`
`4
`
`Table
`
`3. Myeloma
`
`Protein
`
`Response
`
`and Associated
`
`Laboratory
`
`Changes
`
`M-Protein
`
`Response
`
`Parameter
`
`Bone marrow
`plasma
`cells
`P2M
`EM
`Hemoglobin
`
`9/o change.
`* Median
`t
`Interquartile
`range.
`
`N
`
`41
`42
`29
`44
`
`t 50%
`
`-2o*
`-7
`f58
`+9
`
`(75)T
`(35)
`(107)
`(15)
`
`N
`
`78
`86
`56
`89
`
`< 50%
`
`(183)
`+13
`(55)
`f22
`(48)
`-9
`0 (24)
`
`P
`
`<.OOOl
`<.OOOl
`,002
`,003
`
`DR. REDDY’S LABS., INC. EX. 1051 PAGE 2
`
`

`

`Barlogie et al
`
`0.8
`
`Y",T
`
`Alive
`
`Event-free
`
`0
`
`I
`3
`
`I
`6
`
`I
`9
`
`I
`15
`
`I
`12
`Months
`
`I
`18
`
`I
`21
`
`I
`24
`
`7
`
`1.
`Figure
`slngle-agent
`tients
`with
`myeloma.
`
`EFS and OS survival
`thalidomide
`for 169
`advanced
`refractory
`
`and
`
`after
`pa-
`
`Combination Trials
`Post-transplant
`relapse.
`Clinical
`determine
`the
`role
`of
`thalidomide
`both
`refractory
`and
`newly
`diagnosed
`nation
`with
`glucocorticoids
`and,
`lack of myelosuppression,
`cytotoxic
`5). At our
`center,
`post-transplant
`in
`terms
`of cytogenetics
`and PCLI.
`
`will
`of
`
`in progress
`trials
`in
`the management
`patients
`in combi-
`because
`of
`its virtual
`chemotherapy
`(Table
`relapses
`are categorized
`
`of
`
`tumor
`
`risk
`low
`or at
`burden
`low
`with
`Patients
`randomized
`to dexameth-
`are
`relapse
`post-transplantation
`To date,
`25 patients
`thalidomide.
`asone with
`or without
`in
`their
`characteristics
`are
`listed
`and
`have
`been
`enrolled
`and
`graded
`by
`tumor
`cytoreduction
`Table
`6. Responses
`in Fig
`4. With
`a median
`follow-up
`survival
`are depicted
`EFS and OS
`rates
`for
`the
`entire
`of 23 months,
`2-year
`population
`are 40%
`and 80%,
`respectively.
`The
`incidence
`
`2.
`
`(right)
`and OS
`(left)
`EFS
`Figure
`to
`the number
`of unfavor-
`according
`able
`prognostic
`factors
`present
`prior
`to
`thalidomide.
`Top: Risk
`discrimina-
`tion on
`the basis
`of abnormal
`cytoge
`netics
`(EFS HR 2.15,
`P <
`.001; OS HR
`2.53, P = .002),
`PCLI > 0.5%
`(EFS HR
`1.86,
`P =
`.002;
`OS HR 1.82,
`P =
`.009)
`and
`92M
`> 3 mg/L
`(EFS HR
`1.54, P = ils;
`OS HR
`.99, P < .OOl).
`Number
`of risk
`factors
`represented
`by
`solid
`lines
`0, dashed
`1, dotted
`2,
`dash-dotted
`3. Bottom:
`Risk
`discrimi-
`nation
`on
`the
`basis
`of standard
`vari-
`abls
`62M
`> 3 mg/L
`(EFS HR 1.61,
`P =
`.009, OS HR 3.33,
`P >
`.OOl) and
`CRP > 7 mg/L
`(EFS HR 1.37, P = .Os;
`OS HR 1.92,
`P =
`.005).
`Number
`of
`risk
`factors
`represented
`by solid
`lines
`0, dashed
`I, dotted
`
`2.
`
`EVENT-FREE
`
`(B2M ~3 mg/L, LI *OS%, and Abnormal
`
`Cytogenetics)
`
`. . . .
`
`. . .
`
`. rz:.:.:l..
`
`12
`
`18
`
`24
`
`30
`
`0
`
`6
`
`12
`
`18
`
`24
`
`30
`
`0
`
`LO
`0.
`
`.
`0.8
`0.6
`0.4
`0.2
`
`0
`
`6
`
`12
`
`18
`
`12
`
`18
`
`24
`
`30
`
`Minths3;rom
`
`Eonrollrient
`
`1.0
`
`0.8-
`
`2 25% Response
`> 42 g
`54
`*, p<
`
`s42g
`
`.OOl
`
`> 42 g/3 mo
`
`5 42 913 mo
`(n=86)
`
`p=o.o09
`
`0
`
`5
`
`10
`Months
`
`20
`15
`From 90 Day Landmark
`
`25
`
`30
`
`Higher
`3.
`survival
`with
`
`response
`higher
`
`rate and
`dose
`tha-
`
`Figure
`longer
`lidomide.
`
`DR. REDDY’S LABS., INC. EX. 1051 PAGE 3
`
`

`

`Tbalidomid
`
`in Myeloma
`
`No. of Risk
`Factors*
`
`51
`
`>I
`
`Table
`
`4. Higher
`
`Thalidomide
`
`Dose Benefits
`
`High-Risk
`
`Disease
`
`Dose >
`Thalidomide
`42 g/3 mo
`
`Yes
`NO
`
`Yes
`No
`
`N
`
`55
`36
`
`28
`30
`
`Response
`2 25%
`
`45
`19
`
`43
`13
`
`P
`
`.Ol
`
`.02
`
`% Alive
`at 2 yr
`
`74
`66
`
`42
`20
`
`253
`
`P
`
`NS
`
`.Ol
`
`PCLI > 0.5%;
`> 3 m&‘L;
`* P2M
`Abbreviation:
`NS, not significant.
`
`abnormal
`
`cytogenetics.
`
`on dexameth-
`14 patients
`among
`PPR was 57%
`of 250%
`27%
`on dexamethasone
`versus
`thalidomide
`asone
`plus
`but
`none
`of 11 patients
`on
`the
`combination
`alone;
`29%
`CR
`(P =
`.04).
`on dexamethasone
`alone
`achieved
`DCEP
`plus
`thalidomide
`was offered
`to patients
`ing with
`high
`tumor
`burden,
`high
`proliferative
`or
`high-risk
`cytogenetics
`(Table
`7). With
`
`relaps-
`disease,
`a median
`
`5. Thalidomide
`Table
`for Multiple
`Myeloma
`
`in Combination
`and
`Alone
`(as of April
`1, 2001)
`
`Study
`
`Phase
`
`Thalidomide
`Dex ? Thalidomide
`
`DCEP
`
`f Thalidomide
`
`DT PACE
`Total Therapy
`
`II
`
`II
`Ill
`
`III
`
`Ill
`Ill
`
`N
`
`169
`25
`
`80
`
`229
`309
`
`Eligibility
`
`refractory
`relapse,
`
`Advanced,
`Post-HDT
`low
`risk
`relapse,
`Post-HDT
`risk
`high
`Prior
`therapy
`Untreated
`
`Abbreviations:
`phosphamide,
`
`Dex, dexamethasone;
`etoposide,
`cisplatin;
`
`dexamethasone,
`DCEP,
`HDT, high-dose
`therapy.
`
`cyclo-
`
`6. Patient
`Table
`Dexamethasone
`
`Characteristics
`-f Thalidomide
`
`for
`Study
`
`Parameter
`
`Age > 60 yr
`Male
`> 2.5 mg/L
`/32M
`CRP > 4.0 mg/L
`I%G
`W
`- 13/13q
`Prior HDT
`
`-
`
`(n
`Dex Alone
`= II), %
`
`Dex + Thai
`(tl = 14), %
`
`36
`73
`45
`27
`45
`9
`18
`82
`
`57
`64
`43
`43
`43
`36
`14
`93
`
`P
`
`.4
`1.0
`1.0
`.7
`1.0
`.2
`1.0
`.6
`
`of
`
`in
`be assessed
`could
`response
`of 17 months,
`follow-up
`(intent-to-treat),
`27%
`cycles
`After
`three
`80
`patients.
`reduction
`including
`protein
`achieved
`250%
`myeloma
`thalidomide
`doubled
`Added
`18%
`with
`CR
`or near-CR.
`in
`the
`response
`rate
`(36%
`0 lS%),
`including
`290%
`PPR
`are
`25%
`versus
`10%
`(P
`=
`.07).
`At
`2
`years,
`38%
`event-free
`and 48%
`are alive;
`no difference
`is yet apparent
`between
`the
`two
`treatment
`arms
`(data
`shown).
`not
`DT PACE salvage therapy without prior
`transplant.
`The
`combination
`DT PACE
`regimen
`consists
`of dexametha-
`sane,
`thalidomide,
`and
`4-day
`continuous
`infusions
`cisplatin
`40 mgima,
`doxorubicin
`40 mg/m*,
`cyclophos-
`A
`phamide
`1,600
`mgima,
`and
`etoposide
`160 mg/m*.
`high
`previous
`pilot
`trial
`in 12 high-risk
`patients
`with
`lactate
`dehydrogenase
`(LDH)
`levels
`and
`proliferative
`disease
`demonstrated
`a first-cycle
`CR
`rate of greater
`than
`50%.8
`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
`autotransplants
`(>12
`X
`lo6 CD34ikg)
`the
`are
`randomized
`to continuation
`of DT PACE
`versus
`standard
`melphalan
`(200
`mg/ma)-based
`tandem
`trans-
`plant
`program.
`For maintenance,
`patients
`are again
`ran-
`domized
`to
`dexamethasone
`thalidomide
`at
`200
`versus
`50 mg daily.
`Another
`examines
`the CD34
`dose
`administered
`with
`transplant
`and
`its
`impact
`on
`the
`subsequent
`of MDS/AML..
`As of March
`1, 2001,
`have been enrolled.
`Patient
`characteristics
`in Table
`8, and
`the
`flow
`through
`the program
`in Fig 6. The median
`
`plus
`question
`second
`the
`development
`229 patients
`are depicted
`is shown
`
`% Responding
`
`CR*
`2 go%*
`
`Total
`*p=o.o4
`
`After 3rd Cycle
`Thalidomide
`+
`
`-
`
`29
`7
`
`14
`
`0
`0
`
`18
`
`57
`
`27
`
`I
`
`randomized
`of
`Results
`4.
`Figure
`thalidomide
`2
`trial of dexamethasone
`(low
`risk).
`relapse
`for post-transplant
`rate with
`response
`Significantly
`higher
`No
`thalidomide.
`dexamethasone
`in EFS or OS yet
`apparent
`difference
`(data
`shown
`for combined
`groups).
`
`+
`
`e 0.4
`P
`
`.
`
`Median
`
`Follow-up:
`
`“:/
`
`”
`
`0
`
`6
`Months
`
`12
`From
`
`23 months
`
`18
`Enrollment
`
`24
`
`30
`
`DR. REDDY’S LABS., INC. EX. 1051 PAGE 4
`
`

`

`254
`
`Barlogie et al
`
`Characteristics
`7. Patient
`Table
`DCEP 5 Thalidomide
`Study
`
`for
`
`Table
`
`Characteristics
`8. Patient
`for DT PACE Study
`
`(N = 229)
`
`Parameter
`
`Age > 60 yr
`Male
`> 2.5 mg/L
`P2M
`CRP > 4.0 mg/L
`EG
`w
`-13/13q-
`Prior HDT
`
`DCEP Alone
`(II = 42), %
`
`DCEP + Thai
`(n = 38), 56
`
`38
`71
`71
`55
`60
`19
`45
`98
`
`39
`55
`74
`75
`47
`24
`32
`89
`
`P
`
`1.0
`.2
`1.0
`.l
`.4
`.8
`.2
`.2
`
`Parameter
`
`Age > 60 yr
`Male
`> 6 mg/L
`P2M
`CRP > 4 mUL
`Deletion
`13
`Months
`of prior
`32
`12-24
`>24
`
`therapy
`
`%
`
`53
`64
`25
`13
`21
`
`75
`15
`12
`
`to
`
`Twenty-
`age of 89 years.
`an upper
`is 60 years with
`age
`of prior
`than
`12 months
`greater
`seven
`percent
`had
`had
`chromosome
`13 abnormalities.
`A
`therapy,
`and
`20%
`full-dose
`first
`cycle was
`given
`to 73%
`of
`the
`patients.
`to
`Among
`the
`179
`enrolled
`at
`least
`15 weeks
`prior
`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
`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
`26
`arm,
`of 39 on
`the
`tandem
`transplant
`arm and only
`11 of 41 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
`of
`transplant
`arm
`because
`failure
`to
`show
`ongoing
`re-
`sponse
`and especially
`to acheive
`CR.
`Importantly,
`how-
`ever,
`the
`a-year
`EFS
`of
`73%
`?
`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%
`5
`27%
`(Fig
`7). A multivariate
`prognostic
`factor
`analysis
`was
`performed
`to determine
`features
`associated
`with
`at
`least a
`partial
`response
`(PR)
`(PPR
`2
`75%)
`after
`two
`induction
`cycles. Higher
`PR
`rates were
`noted
`with
`the application
`of
`full
`doses of DT PACE
`(odds
`ratio
`{ORI,
`19.4;
`P =
`,005)
`and,
`surprisingly,
`the
`presence
`of cytogenetic
`
`in
`
`four
`for
`
`as
`
`a
`
`13
`chromosome
`involving
`those
`including
`abnormalities,
`2.9; P =
`of marrow
`plasma-
`a level
`.05), whereas
`(OR,
`than
`30% was an unfavorable
`feature
`(OR,
`cytosis
`greater
`0.2; P =
`Thus,
`for
`the
`first
`time, we have
`identified
`.002).
`for high-risk
`chromosome
`13 disease,
`an active
`regimen
`initial
`pilot
`trial.
`observed
`in
`the
`been
`has
`trial
`the
`On
`the
`basis
`of
`these
`results,
`PBSC
`with
`modified
`to call
`for one
`cycle
`of DT PACE
`trans-
`tandem
`collection
`and
`immediate
`randomization
`to
`of
`the
`use
`plants
`with
`melphalan
`200
`mg/m’,
`or
`DT PACE
`recently
`developed
`hybrid
`regimen
`employing
`96 hours)
`(with
`whole
`doses
`given
`in 48
`rather
`than
`support.
`combined
`with melphalan
`100 mgima
`and PBSC
`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/m’.
`Three
`hundred
`patients
`will
`be
`enrolled
`to
`determine
`whether
`EFS
`increases
`from
`25%
`to 35%
`at the
`end of 5 years.
`therapy for newly diagnosed
`Total Therapy II aspont-line
`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
`(2)
`PBSC
`collection
`followed
`by a further
`cycle of DCEP;
`200
`tandem
`autotransplants
`with
`two
`cycles of melphalan
`either
`mg/m2;
`(3)
`consolidation
`chemotherapy
`with
`DCEP
`every
`3 months
`for
`cycles or DCEP
`alternating
`with
`CAD
`every
`6 weeks
`1 year;
`and
`(4)
`interferon
`
`% Responding
`
`After 3rd Cycle
`
`1
`
`Thalidomide
`+
`
`-
`
`8
`17
`
`3
`
`8
`
`36
`
`5
`5
`
`0
`
`8
`
`18
`
`2 0.6
`z
`4
`g 0.4
`
`0.2
`
`”
`
`0
`
`CR*
`2 90% *
`
`~75%
`
`2 50%
`
`Total
`
`* p=o.o7
`
`Median
`
`Follow-up:
`
`17 months
`
`6
`
`12
`
`18
`
`24
`
`30
`
`36
`
`Months
`
`From Enrollment
`
`randomized
`of
`Results
`5.
`Figure
`chemotherapy
`combination
`of
`trial
`no appar-
`with DCEP
`i
`thalidomide;
`ent difference
`yet
`in EFS or OS (data
`shown
`for combined
`groups).
`
`DR. REDDY’S LABS., INC. EX. 1051 PAGE 5
`
`

`

`TbaLidomi&
`
`in Myelom
`
`255
`
`-,-I.
`D
`I rACEx2
`(WI PBSC
`collection
`after
`1 syycle)
`
`Patients
`no resm
`or pro&ession
`off study
`
`DT PACE
`X4
`
`UARK
`97-014
`
`CR
`
`CR
`
`DT PACE
`x4
`
`_ Transplant
`
`Figure
`
`6.
`
`DT PACE
`
`schema.
`
`No PR
`
`se
`
`Phase
`trials
`
`II
`
`to
`of
`
`the
`to
`
`randomized
`initially
`are
`patients
`All
`maintenance.
`at a starting
`dose
`receive
`thalidomide
`receive
`or not
`reduction
`to 200 mg during
`consolidation
`400 mg with
`for maintenance.
`and
`100 mg
`enrolled
`been
`have
`patients
`As of April
`2001,
`309
`eligible
`for
`patients
`(Table
`10).
`Among
`the
`first
`133
`increased
`the
`second
`transplant,
`incidence
`of CR/near-CR
`the
`first
`after
`from
`44%
`at
`the end of
`induction
`to 61%
`with
`transplant
`and
`to 69%
`after
`the
`second
`transplant,
`an
`additional
`9%
`achieving
`275%
`PPR,
`including
`The
`normalization
`of
`the bone marrow.
`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
`overall
`population
`because
`of blinding
`with
`respect
`thalidomide
`randomization.
`With
`an expected
`accrual
`of 660
`laboratory
`research
`help
`identify
`biological
`mechanisms
`associated
`with
`
`will
`
`extensive
`patients,
`the molecular
`and
`response
`and
`sus-
`
`of
`role
`the
`as ro determine
`as well
`duration,
`CR
`tained
`diag-
`of newly
`management
`in
`the up-front
`thalidomide
`cytoge-
`include
`Research
`will
`with MM.
`nosed
`patients
`(FISH),
`in situ hybridization
`fluorescent
`netics,
`interphase
`myeloma
`labeling
`index,
`(BUDR)
`5-bromodeoxyuridine
`expression
`activity;
`gene
`telomerase
`and
`telomere
`length,
`profiling
`to be performed
`at baseline
`and
`serially
`during
`the
`trial
`has recently
`been
`added.
`showed
`arm
`thalidomide
`Available
`toxicity
`data
`in
`the
`thrombo-
`of deep
`venous
`a significantly
`higher
`incidence
`(Fig
`lO).*a
`controls
`(6%)
`sis
`(DVT)
`(28%)
`than
`in
`has
`there-
`sodium
`1 mgid
`Prophylactic
`low-dose
`warfarin
`of DVT
`in a
`reduction
`fore
`been
`instituted,
`resulting
`Un-
`complications
`to a
`level
`seen without
`thalidomide.
`after
`explained
`is the dampening
`of CD34
`procurement
`CAD
`on
`the
`thalidomide
`arm
`(Fig
`11).2s
`Subsequent
`patients
`randomized
`to
`thalidomide
`discontinued
`the
`drug
`completion
`of CAD
`on day
`5 and
`resumed
`
`after
`
`1
`
`Mel 200 TX
`DTPace
`Salvage
`
`TX
`
`N
`
`39
`41
`33
`
`6
`
`P=
`
`.08
`
`%EVENT-FREE
`I-YRISE)
`Z-YRISE)
`
`66(6)
`+
`91(6)
`d-
`mm’. 95(9)
`
`73(17)
`73(27)
`70(27)
`
`12
`Months
`
`18
`from DTPacel
`
`24
`
`30
`
`Table
`
`9. DTPACE-MEL
`
`100
`
`Hybrid
`
`EFS of patients
`Equivalent
`7.
`Figure
`re-
`myeloma
`previously
`treated
`with
`DT PACE
`randomized
`to con-
`ceiving
`of DT PACE
`or melphalan
`tinuation
`fol-
`200 mum*-based
`autotransplant
`lowing
`initial
`response
`to DT PACE X
`2 years. Higher
`relapse
`rate among
`DT
`PACE
`nonresponders
`receiving
`sal-
`vage
`therapy
`(P =
`
`.06).
`
`Patient No.
`
`1
`2
`3
`4
`5
`6
`
`CG
`
`-13
`ABN
`-13
`ABN
`-13
`-13
`
`Prior Therapy
`imo)
`
`14
`54
`88
`112
`60
`4
`
`Flesoonse
`
`1” UNR
`1” UNR
`RR
`RR
`RR
`RR
`
`Prior
`Therapv
`
`Post-therapy
`
`DCEP No.
`
`Thai
`
`(mo)
`
`% Response
`DTPACE-MEL
`
`2
`1
`1
`2
`1
`1
`
`2
`3
`5
`0
`0
`2
`
`0
`8
`12
`30
`0
`2
`
`>50
`290
`>50
`>50
`nCR
`Stable
`
`Abbreviations:
`
`CG, -; ABN,
`
`-; 1” UNR,
`
`-; RR,
`
`-; nCR,
`
`-.
`
`DR. REDDY’S LABS., INC. EX. 1051 PAGE 6
`
`

`

`256
`
`Barlogie et al
`
`Induction
`
`-+ Transplant
`
`-+ Consolidation + Maintenance
`
`Thalidomide*
`t
`Randomization
`f
`No
`Thalidomide
`
`I’
`Mel 200 x2
`-
`
`DCEP
`Randomization
`DCEPlCAD
`
`7,
`+ Mel 200 x2
`k
`
`DCEP
`Randomization
`
`Interferon
`
`Interferon
`
`Ftgure
`
`8.
`
`Total Therapy
`
`II schema.
`
`First 133 Patients Eligible
`
`for TX-~
`
`309 Patients Enrolled
`
`as of Apr. 2001
`
`Response
`
`jr-& TX-I TX-~
`--
`%
`%
`%
`
`CR
`2 90%
`
`175%
`
`150%
`
`Total
`
`24
`20
`
`13
`
`27
`
`64
`
`41
`20
`
`14
`
`9
`
`64
`
`43
`26
`
`9
`
`2
`
`80
`
`.c 0.6
`.a
`4
`2 0.4
`
`t
`
`
`
`:‘/ Median Su,.,,iva,: .,3 ,““‘“.
`
`,
`
`0
`
`6
`Months
`
`16
`12
`From Enrollment
`
`24
`
`30
`
`
`
`Figure ‘- Response: EFS7 andf
`
`of
`2 cycles
`II. After
`after Total Therapy
`melphalan
`200 mg/m
`(TX-~), 69/o of
`patients
`achieved
`CR or near-CR
`(in-
`tent-to-treat).
`Approximately
`90%
`are
`projected
`event-free
`and
`alive
`24
`months
`after
`start
`therapy.
`
`of
`
`therapy
`previous
`observed
`ized
`to
`
`collection.
`of PBSC
`completion
`upon
`hypothyroidism
`subclinical
`interferon
`trials,
`with
`greater
`frequency
`among
`patients
`thalidomide.5
`
`As with
`was
`random-
`
`26
`
`0
`
`Thalidomide
`(N=50)
`
`Arm
`
`Control
`(N=50)
`
`Arm
`
`Figure
`
`10.
`
`DVT in Total Therapy
`
`IL
`
`Table
`
`10. Patient
`
`Characteristics
`
`for Total
`
`Therapy
`
`II Study
`
`Parameter
`
`Age > 60 yr
`Male
`/32M > 2.5 mg/L
`CRP > 4.0 mg/L
`DurieSalmon
`stage
`W
`Ign
`PCLI > 1%
`Abnormal
`13/13q
`
`karyotype
`
`2 2
`
`%
`
`36
`64
`43
`46
`78
`53
`20
`6
`30
`15
`
`Global Experience With
`Thalidomide
`Alone and in
`Combination
`for Multiple
`Myeloma
`
`pertaining
`data
`available
`11 summarizes
`Table
`at
`least
`20 patients.
`Seven
`single-agent
`with
`rate
`refractory
`disease
`showed
`an overall
`response
`SO%)
`of 36%
`among
`352
`patients
`with
`available
`mation.
`The
`addition
`of
`dexamethasone
`increases
`
`trials
`to
`trials
`in
`(PPR
`2
`infor-
`the
`
`A
`
`A
`
`‘*A
`
`0 Thalidomide
`
`A No Thalidomide
`
`p= 0.06
`
`70..
`
`0-160.
`E
`4 60s
`
`40.
`
`g
`"0
`r; 30.
`
`g 20.
`
`8
`
`IO.
`
`0
`
`0.
`
`0
`
`,
`2
`
`n
`4
`Days
`
`6
`of Collection
`
`6
`
`10
`
`I
`12
`
`Figure
`
`11.
`
`CD34
`
`collection
`
`after CAD
`
`in Total Therapy
`
`II.
`
`DR. REDDY’S LABS., INC. EX. 1051 PAGE 7
`
`

`

`ThaUmzi&
`
`in Mydomu
`
`257
`
`Table
`
`11. Thalidomide
`
`in Multiple
`
`Myeloma
`
`Treatment Regimen
`
`First Author
`
`Thalidomide
`Thal200
`Median
`
`alone-refractory
`mg --f 800 mg
`Thai 400 mg (range,
`800 mg)
`mg + 800 mg
`Thal200
`Thal 200 mg
`Thal 100 mg --) 800 mg
`Thal200
`mg + 800 mg (I.2
`wk); Thal
`+
`IFN (>I2
`mg --f 800 mg
`of above
`studies
`
`Thal200
`Summary
`
`disease
`
`50.
`
`wk)
`
`Thal200
`
`+ dexamethasone-refractory
`Thalidomide
`Thal 100 mg, Dex 40 mg X 4 d,
`every
`28 d
`mg + 400 mg, Dex 40
`mg X 4 d (d
`l-4,9-12,17-
`20, every
`35 d)
`Thal 200 mg + 800 mg, Dex 20
`mg/m*
`(d 1-5, 8-15
`in
`1, d
`month
`l-5
`in
`following
`months)
`Summary
`of above
`
`studies
`
`luliusson24
`Yakoub-Agha47
`
`Razaes
`Rodriguez39
`Toe?*
`Princes4
`
`8arlogie13
`
`disease
`Palumbo31
`
`Dimopoulo@
`
`Webe@
`
`N
`
`20
`83
`
`26
`40
`27
`27
`
`169
`392
`
`37
`
`38
`
`47
`
`Il.22
`
`Prior TX
`
`2 75%
`
`2 50%
`
`Z 25%
`
`Response
`
`Rate by PPR Level
`
`10
`(17 TX X 2)
`
`58
`
`WA
`18
`(9 TX X 2)
`WA
`
`I3
`
`128
`
`(90 TX X 2)
`
`0
`
`I2
`
`WA
`13%
`
`12%
`WA
`WA
`N/A
`
`20%
`17%
`(48/278)
`
`24%
`
`N/A
`
`WA
`
`WA
`66%
`
`69%
`75%
`45%
`N/A
`
`37%
`52%
`(178/345)
`
`N/A
`
`WA
`
`43%
`47%
`
`46%
`WA
`25%
`30%
`
`30%
`36%
`(l27/352)
`
`51%
`
`52%
`
`52%
`(63/122)
`
`+ chemotherapy-refractory
`+ dexamethasone
`Thalidomide
`Thai 100 mg + 400 mg, Dex 20
`Kropffs”
`mum’,
`d 14,
`g-12,
`17-20,
`CTX 1.8 g/m*
`TCED: Dex 40 mg, CTX 400 mg/
`m*, VP18
`40 mg/ms
`(X4
`d) and Thal 400 mg (daily)
`“DT PACE”: Dex 40 mg, DDP 10
`mg/m2,
`doxorubicin
`10
`mg/m2,
`CTX 400 mg/mo,
`VP16
`40 mgIm*
`(X4
`d)
`and Thal 400 mg (daily)
`2 cycles
`Summary
`of above
`
`X
`
`studies
`
`Moehlerz7
`
`Barlogie
`(unpublished)
`
`myeloma
`
`Thalidomide-untreated
`disease
`Symptomatic
`Thal 200 mg + 800 mg, Dex
`40 mg (d 14,
`9-12,
`17-20,
`every
`35 d)
`Smoldering
`disease
`Thal200
`--) 800 mg
`Thal200
`--f 600 mg
`Summary
`of above
`studies
`
`Rajkumar’s
`
`Rajkumar3e
`Webep
`
`disease
`
`20
`
`42
`
`I35
`
`197
`
`26
`
`16
`26
`68
`
`14
`
`WA
`
`0
`
`0
`
`0
`0
`
`WA
`
`7%
`
`(CR)
`
`44%
`(CR, 27%)
`
`(of 14
`86%
`evaluable)
`
`78%
`
`54%
`
`35%
`(62/177)
`
`62%
`(118/191)
`
`WA
`
`77%
`
`WA
`WA
`
`38%
`35%
`51%
`(35/W
`
`WA
`
`WA
`
`N/A
`
`WA
`
`WA
`WA
`
`Abbreviations:
`
`N/A, not available;
`
`CTX, cyclophosphamide;
`
`Thal,
`
`thalidomide;
`
`Dex, dexamethasone;
`
`VP16,
`
`etoposide;
`
`DDP, cisplatin;
`
`TX, therapy.
`
`beyond
`raises
`
`The
`50%.
`the
`average
`
`inclusion
`response
`
`of cytotoxic
`rate
`to about
`
`rate
`response
`chemotherapy
`60%.
`effected
`thalidomide
`single-agent
`MM,
`In untreated
`smoldering
`of 42 patients
`with
`in 36%
`PPR
`2
`50%
`with
`symp-
`dexamethasone
`for 26 patients
`disease. Added
`rate
`of 77%
`resulted
`in a higher
`response
`tomatic
`MM
`although
`CRs were
`not
`recorded
`by
`the
`(PPR
`50%),
`2
`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
`
`a
`
`Eastern
`An
`is currently
`trial
`dexamethasone
`
`Group
`Oncology
`Cooperative
`dexamethasone
`evaluating
`plus
`thalidomide
`200 mg.
`
`randomized
`pulsing
`versus
`
`Discussion
`
`the
`support
`The data presented
`with
`major
`activity
`in patients
`four
`MM.
`Hence,
`after
`almost
`research,
`thalidomide
`represents
`
`that
`idea
`advanced
`decades
`only
`
`has
`thalidomide
`and
`refractory
`of clinical
`trial
`the
`third
`non-
`
`DR. REDDY’S LABS., INC. EX. 1051 PAGE 8
`
`

`

`258
`
`Barlogie et al
`
`antimyeloma
`active
`cross-resistant
`best
`response
`with
`attain
`their
`received
`high-dose
`glucocorticoids
`Much
`is yet
`to be
`learned
`dependent
`antitumor
`effects
`of potential
`antimyeloma
`voked,
`including
`but
`of
`apoptosis,3a
`suppression
`elaborated
`the
`bone marrow
`cell
`disruption
`tumor-stromal
`giogenesis,15
`and
`immunomodulation.21
`prognostically
`relevant
`at baseline,
`density
`crovessel
`is not
`consistently
`to
`responding
`thalidomide.*’
`Others
`thalidomide-induced
`elevations
`of
`factor
`in
`responders.3O
`revealed
`mouse model
`Studies
`in
`the SCID-hu
`thalidomide’s
`activity
`depended
`on coimplantation
`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-
`with
`action
`other
`agents,
`such
`as dexamethasone.
`Important
`clinical
`questions
`regarding
`thalidomide’s
`in myeloma
`management
`should
`address
`the
`following:
`
`antian-
`Although
`mi-
`bone marrow
`altered
`in patients
`have
`reported
`/3-fibroblast
`growth
`
`on
`
`patients
`having
`
`Some
`agent.
`after
`thalidomide
`and melphalan.
`dose-
`and