3 URNAL OF
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`T, E AMERiCAN
`
`VOLUME 96
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`av MBER 16, 2000 I
`
`1 OF 2 PARTS
`
`800:};E‘TY OF
`MATOLOGY ;
`
`
`
`~ ~
`
`ematology
`I ~
`~
`
`ty-second
`~ 1 ~
`
`al meeting
`4 I
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`~
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`ber1-5, 2000 V
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`Francisgb,
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`DR. REDDY’S LABS., INC. EX. 1047 PAGE 1
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`DR. REDDY’S LABS., INC. EX. 1047 PAGE 1
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`168a
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`MYELOMA/CLL - NOVEL APPROACHES INCLUDING BIOLOGICAL AGENTS, IMMUNE THERAPY, AND THALIDC)MIDE
`
`Witzig.'Hematology,
`
`py
`
`I
`
`h
`
`722-I
`Poster Board ¹-Session:
`722
`Abstract¹
`THALIDOMIDE PLUS DEXAMETHASONE (THAL/DEX) AND
`THALIDOMIDE ALONE (THAL) AS FIRST LINE THERAPY FOR
`NEWLY DIAGNOSED MYELOMA (MM). S.V. Rajkumar,'.
`Hayman,'. Fonseca,'. Dispenzieri,'.Q. Lacy,'. Geyer"','.
`Wellik4,( J.A. Lust,'.A. Kyle,'R. Greipp,( M.A. Gertz,'E.
`Mayo Clinic, Rochester, MN, USA.
`V~k'ldph
`dThl
`fThVfy*
`lll
`l
`fl
`hl
`1
`conelative
`studies
`(mtenm analysis).
`m new untreated MM with laboiatory
`Methods: Patients
`(pts) with active MM werc treated with the Thai/Dex combmation.
`or mdolent MM (SMM/IMM) were treated with Thai alone Thai
`Pts with smoldenng
`was given orally at a dose of 200 mg/day
`for 2 weeks, and then increased as tolerated by
`every 2 weeks to a maximum dose of 800 mg/day. Dex was given orally at a
`200 mg/day
`days 1-4
`orally on days 1-4, 9-12, 17-20 (odd cycles) and 40 mg/day
`dose of 40 mg/day
`(even cycles) repeated monthly. Response was defined as a decrease in serum and urine
`(M) protein by 50% or greater. Bone marrow (BM) microvessel
`monoclonal
`density
`for CD34 was estimated by determming
`(MVD) using immunostainmg
`the average number
`of vessels in 3 hot spots at 400x magnification. BM angiogenesis was also visually graded
`as Iow, intermediate
`and high.
`Results: 42 pts (26 with active MM and 16 with smoldering/mdolent
`MM) were
`arm, 2 pts had grade 3-4 skin toxicity among the first 7 pts
`In the Thai/Dex
`studied
`at Thai dose of 400mg. The Thai/Dex
`to stop dose
`then amended
`treated,
`arm was
`and keep Thai dose constant at 200mg. An objective response was seen in 20
`escalation,
`'I'he iesponse rate was 86% with Thai
`pts (77%) with active MM treated with Thai/Dex.
`dose escalation {6of 7 pts), and 74% with Thai dose constant
`at 200mg (14 of 19 pts),
`Ma)or grade 3-4 toxicities were rash in 3 pts, and sedation, constipation
`and myalgias
`in
`I pt each. In the SMM/IMM arm, 6 pts (38%) achieved a response with Thai alone
`Median pre-treatment MVD was 27 in the active MM arm, and 7 m the SMM/IMM arm
`grade was high in 64% of active MM and 8% of SMM/IMM,
`(p&0.001). Angiogenesis
`(p&0.001) The proportion of pts with a high(&1) PCLI was 67%, 9%, 0% for high,
`(p&0.001). No significant
`and low grade angiogenesis
`intermediate,
`changes
`respectively
`were observed m MVD following treatment; pre-treatment MVD and angiogenesis
`grade
`did not appear
`to be associated with response to therapy.
`Conclusions: Thai/Dex is strikingly
`effective as first
`(and an oral
`line therapy
`to mfusional VAD) for new, active MM. SMM/IMM pts also appear
`to
`alternative
`responses with Thai alone, However,
`achieve significant
`these results are preltmina(y
`and
`in the final
`are still being evaluated
`responses/toxicities
`confirmation
`and need further
`analysis of this trial.
`
`Poster Board ¹-Session: 723-1
`Abstract¹ 723
`A PHASE II TRIAL OF THALIDOMIDE IN THE TREATMENT OF
`RELAPSED MULTIPLE MYELOMA (MM) WITH LABORATORY
`CORRELATIVE STUDIES. S.V.Rajkumar,'. Fonseca,'. Dispenzieri,'.Q.
`
`Lacy '.Geyer* '.Wellik*,'. Hayman,'.A. Lust,'.A. Kyle,'.R.
`
`Greipp,'.A. Gertz,'.E. Witzig.'Hematology, Mayo Clinic, Rochester,
`MN, USA.
`Aim: A phase II trial of thalidomide
`correlative
`in relapsed MM with laboratory
`studies examimng bone marrow (BM) angiogenesis
`and plasma cell proliferation.
`Methods: 32 patients
`(pts), 22 male and 10 female, with relapsed MM were tteated
`between April 1999 and July 2000. Thalidomide was given orally at a dose of 200 mg/day
`then increased as tolerated by 200 mg/day
`for 2 weeks,
`every 2 weeks, up to a maximum
`daily dose of 800 mg/day. Response was defined as a decrease in serum and urine monoclonal
`(M) protein by 50% or greater, and confirmed by repeat measurements
`at leas( 2 weeks
`apart. BM angiogenesis was studied in a bhnded manner using immunohistocheinical
`in 27 pts (84%). Microvessel density (MVD)
`staming for CD34 to identify riucrovessels
`the ave(age number of vessels
`in 3 hot spots examined
`was estima(ed by deternuning
`at
`400x magmfication. Angiogenesis was also visually graded as low,
`intermediate
`and high
`Plasma cell (PC) proliferation was studied using a slide based immunofluorescent
`assay (plasma cell labeling uidex, PCLI).
`bromodeoxyuridine mcoiporation
`(range, 36-78) All pts had failed poor
`Results: The median
`age was 67 years
`and 5 (16%) had failed stem cell transplantation.
`Response is still bemg
`chemotherapy
`two cycles of data are evaluable
`and currently 26 patients with at least
`for
`evaluated,
`rate of 38%. No complete
`response. 10 responses were confirmed,
`a response
`yieldmg
`responses were seen. Ma)or grade 3 toxicities were sedation (10%) and neuropathy
`(10%). One pt each had grade 3 constipation,
`rash and vertigo. Pre-treatment MVD
`ranged 5-47 per 400x field (median 20) Angiogenesis grade was high in 52%, intermediate
`in 30%, and low in 18% No sigiuficant changes were observed in MVD followmg treatment
`on whom at least 2 BM samples were available
`in 4 responders
`for study Pre-treatment
`MVD and angiogenesis
`grade did not appear
`to be associated with response
`(o therapy
`in pts with a high PCLI (&I) compared to those
`Response rates were significantly
`higher
`with a low PCLI, 57% versus 21%, respectively,
`(p=0.02)
`is effective in the treatment of relapsed MM with a
`Conclusions: Thahdomide
`response rate of 38% ui this study. Its mechanism of action remains unclear. These results
`that a high PCLI is a potential predictor of iesponse to therapy.
`suggest
`
`Poster Board ¹-Session.
`724
`Abstract¹
`72(I I
`ANGIOGENESIS FACTORS AND SENSITIVITY TO THALIDOMIDE
`IN PREVIOUSI Y UNTREATED MULTIPLE MYELOMA (MM). D.IVI
`Weber, K. Rankin", M. Gav(no4, K. Delasalle*, A. Aguayo*, M. Albitar
`of Texas M.D. Anderson Cancer Cen(e,.
`R Alexanian
`University
`Hoes(on, TX.
`Between 5/99 — I/00 plasma levels of multiple
`factors (VEGF, bFGF
`angiogenesis
`(11.-6, IL-8, EGF, IL-lb) were assessed ni 19
`HGF, TNF-a, angiogemn)
`and cytokines
`patients with asymptomatic MM. The median level of VEGF
`untreated
`previously
`(100 8 pg/mL) was 3.8 tunes higher
`than that of 11 control pts. with solid tumors
`(26 7
`than pnor median levels measured for all categories of leukem,c
`(p& 05), and higher
`pg/mL)
`disordeis Values of bFGF, HGF, and angiogenin were approximately
`double
`that pf
`in leukemia. Only minunal
`controls and similai
`to those observed previously
`elevatipii pf
`density was increased (median 14.5 blppd
`cytokmcs was noted. Marrow miciovascular
`field) m 8 untreated pts with available samples compared to control pts. Because
`vessels/
`effect of thalidomide,
`of (he pos(ula(ed antiangiogenic
`an agent effective in resistant
`myeloma, we treated 26 previously
`pts. with thalidomide
`untreated
`asymptomatic
`in
`doses of 200 mg p o q. h s, increasing to a maximum of 600 mg. Partial response, defined
`protein and/or & 75% reduction of Bence Jones
`by & 50% reduction of serum myeloma
`protein, was aclneved in 9 pts. (35%). Onset of response was rapid (median 1.5 months),
`and the piojected mean remission duration was 14 months. Median VEGF of responding
`patients was 4 times that of nonresponding
`pts. (p.06); response was observed in I of 10
`pts with VEGF & 100, and in 3 of 8 pts with VEGF & 100 (p.16). Microvascular
`density
`was available m only one respondmg pt., and the level of 23 vessels/field was the highest
`occurred with high dose
`specimens. Subsequent
`noted among 8 available
`remissions
`ui 2 of 5 pts. with disease resistant
`to thalidomide. These observations
`dexamethasone
`Justify fu(ther correlations of angiogenesis markers with thalidomide
`trials, extend tbe
`spectrum of thahdomide
`to previously
`untreated disease, and support
`ant(myeloma
`further
`trials in combination with other active agents.
`
`Kienast,'Department
`
`Poster Board ¹-Session:
`Abstract¹ 725
`725-I
`HYPKRFRACTIONATED CYCLOPHOSPHAMIDE IN COMBINATION
`WITH PUI (sED DEXAMKTHASONE AND THALIDOMIDE (HYPER-CDT)
`IN PRIMARY REFRACTORY OR RELAPSED MULTIPLE MYELOMA,
`Martin H. Kropff*,'eorg Innig"','anfred Mitterer",'hristian
`Strakaa,4
`Helmut Ostermann,'laf M. Koch,'olfgang E.Berdel,'oachim
`of Internal Med(cine, Hematology/Oncology,
`University of
`of Internal Medicine,
`'Department
`Muens(er, Muenster, Germany;
`'Abteitung fur Hamatologie
`Paracelsuskl(n(k, Osnabrueck, Germany;
`und
`Italy&; Medical Clinic, Kh'nikum
`KMT, Reg(onalkrankenhaus,
`IIozen,
`Innenstad( of Ludwig -Maxi ini lian s- Uni vers i(y, Munich, Germany; Medical
`Clinic Ill, Klinikuni Graf)hadern, Mumch, Germany.
`is active in = 30 % of patients with advanced multiple myeloma
`Thalidonude
`(MM)
`has been reported to restore the sensitivity of myeloma
`Moreover,
`thahdonude
`cells to
`(DEX) The present phase II trial was intitiated to study the combination
`dexamethasone
`of thalidomide with pulsed DEX and hyperfracuonated
`cyclophosphainide
`(HyperC).
`at the schedule employed in this study and combined with VAD has
`HyperC administered
`been shown to mduce 40 % iesponses
`in VAD-resistant MM. 20 patients
`previously
`courses of HyperC (300 mg/ni
`with advanced (VIM were treated with 2 to 6 monthly
`IV
`ovei 3 h q 12 h x 6 doses, days 1 — 3, total dose 1800 mg/m')
`combined with pulsed DEX
`PO, days 1 —4, 9 - 12, 17 - 20) and once daily thalidomide
`(20 mg/m'/d
`at individually
`escalating doses (100 to 400 mg/d)
`care included G-CSF, ciprofloxacin and
`Supportive
`non-absorbable
`agents. Responding patients were maintained on daily thalidomide
`annfungal
`and monthly DEX pulses. 6 patients had primary
`refractory disease on VAD or ID. 14
`Patient characteristics
`had relapsed aftei high-dose melphalan
`patients
`included median
`age 63 years, B2M & 2,5 mg/L, 25 %; CRP & 4,0 mg/L, 10 %; and poor standard therapy
`& 12 mo, 80 % Among 14 evaluable patients, 12 (86 %) achieved a partial
`remission (PR);
`(2 - 14), all 12 PR
`as yet, no complete (emission. After a median follow-up of 7 months
`are ahve and free of disease progression,
`experienced grade 4
`10/20 patients
`pa(ients
`during ai least one cycle; no grade 4 thrombocytopenia.
`neutropenia
`There were two grade
`3/4 infections, one patient died dunng neutropenic
`another patient developed
`pneumonia;
`colitis but recovered Other side effects included grade 2 constipation (35 %),
`neutropenic
`grade 2/3 skm reactions (15 %), and 1 deep venous
`thrombosis.
`In 3 patients
`thalidomide
`(2) or stun reaction (1), and treatment was continued
`was stopped due to neurotoxicity
`requued a dose linutation of thalidomide
`to 300 mg
`In addition, 5 patients
`with HypeiCD.
`(1), 200 mg (1), oi 100 mg (3) due to neurotoxicity. HyperCDT appears
`to be a highly
`active and ieasonably well
`tolerated regimen in advanced MM
`
`Poster Board ¹-Session: 726-I
`Abstract¹ 726
`ENDURABLE RESPONSE TO THALIDOMIDE IN RELAPSED/
`REFRACTORY MULTIPLE MYELOMA (MM). Syed N. Raza~,'uliya
`Veksler*,'ariq Sabir','ujun Li','orraine Anderson4,'undar
`Jagannath.'S(. Vincentr Comprehensive Cancer Center, New York Medical
`College, New York, NY, USA.
`Recently Thalidomide
`anti-cancer
`as a promising
`has re-emerged
`agent
`in many
`(via b-FGF) and on
`due to its mhibitory
`effects on angiogenegis
`refractory mahgnancies
`TNF-(( Last year we repoi ted the impressive eflicscy of Thalidomide
`in re) apsedhefractor)'M
`An update with more patients
`(pts) and longer
`follow-up
`is presented here'e
`(F/U)
`have treated 35 pts with ielapsed/refractory MM from March 1998 to July 2000
`with a median F/U ot'2 montlis
`(mo) {(ange 6-28+) Median age was 58yrs (range 33-77)
`Median number of piro( cheniotheiapies was 3 (range 1-8). 12 pts had one and 3 pts had
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