Original article
`
`A1111als of011rology 12; 991-995. 2001
`© 200 I Kl1111•,•r Arademic P11Mshers. Primed i11 the Ne1herl111ul.l'.
`
`Thalidomide and dexamethasone combination for refractory
`multiple myeloma
`
`M.A. Dimopoulos,1 K . Zervas,3 G. Kouvatseas,1 E. Galani, 1 Y. G rigoraki,4 Ch. Kiamouris, 1
`· E.Vervessou,2 E. Samantas,5 Ch. Papadimitriou,' 0. Economou,' D. Gika,1 P. Panayiotidis,2
`I. Christakis3 & N. Anagnostopoulos 4
`Departme111., of 1Cli11ical Thcrapeut,cs. ~ /11/emal Med1ci11e. University of Athe11s Sdwul of Medicim•. Athe11s; 3 Depart me/II of He1111110/ogy.
`Theage11io11 Cancer Cemer. Thessa/0111k1: • Departme111 of Hematology. General Hospital of Athens. s Depar1111e111 of 011cology. Ag1i A1111rgiri
`Ho.ipital. Athe11s. Greece
`
`Summary
`
`Backgrou11d: Thalidomide is effective in approximately 30% of
`patients with refractory multiple myeloma. Dexamethasone is
`active in 25% of patients with disease resistant to alkylating
`agents. We investigated the combination of thalidomide with
`dexarnethaToneanalvage treatment for heavily pretreated
`patients with multiple myeloma, in order to assess its efficacy
`and toxicity.
`f(l(ients and methods: Forty-four patients with refractory
`myeloma were treated with thalidomide, 200 mg p.o. daily at
`bedtime, with dose escalation to 400 mg after 14 days, and
`dexamethasone, which was administered interminently at a
`dose of 20 mg/m2 p.o. daily for four days on day 1-4, 9-12,
`17-20, followed by monthly dexamethasone for four days.
`Patients' median age was 67 years. All patients were resistant to
`stand.ird chemotherapy, 77% were resistant to dexamethasone(cid:173)
`based regimens and 32% had previously received high-dose
`therapy.
`
`Resul!s: On an intention-to-treat basis twenty-four patients
`(55%) achieved a partial response with a medi.111 time to
`response of 1.3 months. The thalidomide and dexametlrnsonc
`combination was equally effective in patients with or wi1hout
`prior resistance to dexamethasone-based regimens and in
`patients with or without prior high-dose therapy. Toxicities
`were mild or moderate and consisted primarily of constipalion.
`morning somnolence, tremor, xerostomia and peripheral neuro(cid:173)
`pathy. The median time to progression for responding patients
`is expected 10 exceed 10 months and the median survival for all
`patients is 12.6 months.
`Co11c/11sio11: The combination of thalidomide with dexa(cid:173)
`methasonc appears active in patients with refractory multiple
`myeloma. If this activity is confirmed. further studies of this
`combination as second-line treatment for patients resistant to
`conventional chemotherapy. and as primary treatment for
`patients with active myeloma. should be considered.
`
`Key words: dexi1rne1hasone. multiple myeloma. thalidomide
`
`I ntroduction
`
`Approximately one half of patients with previously un(cid:173)
`treated multiple myeloma respond to several conventional
`therapies including melphalan and prednisone, vincris(cid:173)
`tine, doxorubicin and pulse dexamethasone (VAD), or
`pulse dexamethasone alone, with a subsequent median
`survival for all patients of approximately three years [I].
`Over the last decade it has been demonstrated th at
`melphalan-based high-dose chemotherapy with stem
`cell support increases the response rate and prolongs
`the overall survival. This modality can be applied to less
`than 50% of patients with multiple myeloma because of
`restrictions of age, performance status and other organ
`functions. Furthermore, most of the transplanted pa(cid:173)
`t ients still relapse. For these patients, as well as for those
`who are not eligible for high dose therapy, options for
`salvage therapy are limited.
`Recently, thalidomide, an oral agent with immuno-
`
`modulatory and antiangiogenetic properties, has shown
`activity in approximately 30% of patients with refractory
`multiple myeloma [2]. T his agent is usually not associated
`with myelosuppression but can cause side effects such as
`constipation, somnolence, fatigue, mood changes. skin
`rash and peripheral neuropathy. The incidence and
`severity of these adverse effects are usually dose-related
`and drug intolerance may be more pronounced in older
`patients. In order to enhance the therapeutic index of
`thalidomide, ongoing studies combine this agent to other
`active agents against myeloma. Preliminary evidence from
`the M. D. Anderson Cancer Center has shown that four
`of six patients with resistance to dexamethasone-based
`regimens and without prior thalidomide, responded to a
`combination of thalidomide and dexamethasone. indi(cid:173)
`cating improved results with the combination of these
`two agents [3]. In order to clearly define the activity of
`this combination in the treatment of refractory myeloma
`we performed a large phase I I multicenter study.
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`992
`
`Tc,hf,, f Pa1ient charnc1eris1ics.
`
`Table 3 Response 10 1rea1men1.
`
`Percent of patients('¼,)
`
`Number of pauen1s (%)
`
`95%CI
`
`Male sex
`Age > 70 ye:1rs
`Myeloma 1ypc
`lgG
`lgA
`Light drnin only
`Non sccrc1ory
`Light cham
`k
`),
`None
`Performance srn1us :;;, 2
`Hemoglobm < 8.5 g/dl
`Pla1elc1s < 100 x 10''/d l
`Scrum c<1icium > 11.5 g/dl
`Scrum crcalininc > 1.5 mg/di
`Scrum LDH > 220 IU/1
`Scrum ~ 2-microglobulm > 6 mg/I
`Bone m.irrow plasma cells > 50%
`
`73
`21
`
`57
`26
`12
`5
`
`59
`36
`5
`JO
`23
`23
`12
`14
`28
`29
`42
`
`7/,ble l Disease status ant.! pnor 1rca1men1.
`
`Disease status
`Primary refractory
`Rcsist,1111 relapse
`Number of prior regimens
`I
`2
`J
`4
`
`Prior res1s1anee 10 dc~a mc1hasonc-based regiment
`Prior 1rca1mcn1 with high dose chemo1herapy
`
`Percen1 of
`pa1ien1s (%)
`
`)4
`66
`
`11
`23
`34
`25
`7
`77
`32
`
`Patients and methods
`
`Between July 1999 and November 2000, 44 patients were treaied with
`the combination of thalidomide and dexamelhasone (T D) after in-
`formed conscnl was obtained from each p.llienl. Patient characteristics
`arc shown in Table I. The median age w~s 67 years (range: 38 10 87
`years). ninc-p.llients were older than 70 years and 32 ~e malC:-
`.
`-
`·
`·
`·
`-
`-.- -
`--
`-
`Features of ,1dvanced disease such as severe anemia, 1hrombocytope111a.
`e.~1cns1ve bone marrow plasmacytosis, hypercalcemia. ma rkedly elc-
`vatcd scrum P2-mi.roglobulin and high levels of serum LDH were
`often present (1i1blc I). Thirty-four pcrccnl of patients had not re-
`sponded 10 any previous regimen (prim~ry refractory) and 66% of
`pa11en1s were relapsing despite chemotherapy (resistant relapse). Three
`or more 1rea1men1 regimens were adminis1cred 10 66% of pa11cn1s and
`77'Y:, were rcsisrnm 10 iin immediate prior regimen which contained
`high dose dc.«1me1hasone. One-third of patients had also received
`high-dose 1hcrdpy (Table 2). The median 11me from mnial 1reatmen1 10
`inclusion in 1h1s study was 23.3 months (range: 2.7 10 134.4 months).
`A U palicnts h1.1d baseline eva luations that included physica l exam i(cid:173)
`nation. blood counts. hepatic and renal function 1es1s. bone marrow
`aspirate and/or biopsy. serum and urine protein clcc1rophorescs.
`quan111a11on of serum immunoglobulins. serum LDH and P2-m1cro(cid:173)
`globulin. Chest X-ray and a limited bone survey were also performed,
`For the first two months of treatmcn1 patients were followed up wnh
`biweekly physical examina11ons. blood counts. ren.il and liver function
`
`Partial response
`> 75% J m-peak
`> 50% l m-pcak
`Minor response
`S1able disease
`Progressive disease
`
`24 (55)
`13 (30)
`11 (25)
`I (2)
`8 (18)
`11 (25)
`
`Abbrevia tion. Cl - confidence 1111erval.
`
`39-69
`17-45
`13-40
`0- 12
`8-33
`13-40
`
`1es1s and serum and urine clcc1rophore1ic studies. Thereafter these
`1cs1s were repeated on a monthly basis. Bone ma rrow reassessment
`was performed when patiems' monoclonal protein reached 1m1ximum
`reduction.
`The ini1i:tl dose of thalidomide was 200 mg p.o. daily !II bedtime.
`wi1h dose escala1ion 10 400 mg after 14 days in absence of severe side
`ctfccts. Dexamcthasone was administered imenmllenlly al a dose of
`20 mg/ m2 p.o. q.d. for four days on days 1-4. 9- 12. 17-20, followed by
`monthly dexamethasone for four days.
`All patients who received the TD combination for at least one day
`were eligible for assessment of toxicity and response Toxicity was
`grndcd according 10 1he classification system of the Word Hc:tll h
`Organization (WHO) [4] Pa11en1s who d1scon1mucd treatment before
`a response could be assessed were considered 10 have had no response
`10 1rca1men1. Thus. the rcsulls were evaluaicd on an in1e111ion-10-1rea1
`basis.
`Complete response was defined as disappearance of 1hc monoclo(cid:173)
`nal protein by serum and/or urine immunofixation and less than 5%
`bone marrow plasma cells. Pama! response was defined as a greater
`than 50o/o rcdu!;;t1on of ~ rum rnyclom,l protein and/ or grcu tcr than
`75% reduction of Bence Jones protein, with > 50% reduction of bone
`marrow plasma cells For the purpose ofth1s study minor response was
`defined as al least 25% reduc11on of scrum monoclonal protein, and
`the disease was considered stable when the serum monoclonal pro1cin
`changes were < 25% w11hou1 addition.ii complic.11ions of the myelo(cid:173)
`ma. Patients were considered in progression when they did 1101 meet
`criteria for response or stable disease. Relapse was defined by al least a
`25% increase of monoclonal protein from the lowest value, 111creasing
`bone lesions or bone marrow plasmacytosis.
`The time 10 response was defined as the interval between the s1ar1
`of therapy and the first confirmation of panial response The lime 10
`prog ression was defi ned as the time from the star\ of therapy 10 disease
`progression. Overall survival was calculated from the Siar! of therapy
`10 dc:11 h from any cause or the last follow-up vis11. whichever occurred
`firs1. Severn! cl111ical and laboratory variables were assessed for their
`possible associa11on with response 10 and w11h overall survival. Those
`variables which were found s1atis11eally significant in the univariate
`analysis of overall survival were subsequently included m a Co,
`regr~ssio1.1 analysis (5). In order 10 asse~ the_ impact of response to
`1hahdom1de and dexa111e1hasone on patients survival. a landmar~
`d 161
`~
`1
`ana ysis was per orme
`·
`
`Results
`
`Twenty-four of 44 patients (55%) achieved a partial
`response including 13 patients with at least 75% reduc(cid:173)
`tion of serum monoclonal protein (Table 3). Further-
`mo re, o ne patient achieved m inor response to treatment.
`Complete responses were not noted. The median inter(cid:173)
`val between the start of treatment and a decrease in the
`paraprotein level of at least 50% was 1.3 months (range
`0.75 to 3.6 months). Responding patients demonstrated
`an improvement of their performance sta tus and of
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`Tttble 4. Parameters associated with response 10 TD.
`
`Pammeter percent
`
`Response
`
`P-valuc
`
`Performance status
`0
`;;, I
`Light chain type
`k
`J..
`
`83
`37
`
`73
`25
`
`0.002
`
`0.004
`
`Table 5. Toxicity (WHO scale)
`
`Adverse effect
`
`Percent of patients(¾)
`
`t .,
`
`1
`
`00
`
`993
`
`12
`
`..
`
`, .
`
`Constipation
`Somnolence and/or fatigue
`Mood changes
`Xcrostomia
`Tremor
`Peripheral neuropathy
`Skin msh
`Headache
`Edema
`Vein thrombosis
`
`75
`57
`33
`34
`30
`23
`21
`21
`17
`7
`
`7c,hle 6. Parameters associated with survival afier TD.
`
`P,1n,mctcr
`
`Median survival (months)
`
`P-valuc
`
`Gender
`Female
`Male
`Disease stat us
`Primary refractory
`Refractory relapse
`Hemoglobin
`;;, 8.5 g/dl
`< 8.5 g/dl
`Performance stat us
`0
`;;, I
`Ltgh1 chain type
`k
`)..
`Serum LDH
`,,; 220 IU/1
`>220 IU/ 1
`
`Nol reached
`12.6
`
`Not re11chec.l
`9.6
`
`13.0
`4.8
`
`13.0
`b.6
`
`Not rc.1chcd
`6.6
`
`13.0
`6.6
`
`0.05
`
`006
`
`0.0004
`
`0.002
`
`0.004
`
`0.009
`
`anemia, and a decrease of previously elevated serum P2-
`microglobulin and LOH levels.
`Several variables such as gender, age. myeloma heavy
`and light chain type, hemoglobin, platelet count, serum
`LOH and P2-microglobulin, performance status, bone
`marrow plasmacytosis, disease status, prior high dose
`therapy and resistance to dexamethasone, were evaluated
`for their possible correlation with response to TD. Our
`combination induced responses in 40%, of patients with
`thrombocytopenia (platelet count < 100 x 106/dl) and in
`59% of patients without thrombocytopenia (P = 0.47).
`The TD regimen was active in 56% of patients whose
`disease was resistant to an immediate prior treatment
`which contained high dose dexamethasone. Also, our
`
`Figure I. Overall survival after treatment with thalidomide and dcxa(cid:173)
`mcthasone.
`
`combination induced responses in 57% of patients who
`had previously received high dose therapy with stem cell
`support. The TD regimen was equally eftective in pa(cid:173)
`tients with either primary resistant myeloma or with
`disease in resistant relapse; partial responses occurred
`in 60% and 52°A, of patients respectively. Among all the
`variables tested for their possible association with re(cid:173)
`sponse, light chain of lambda type and impaired perfor(cid:173)
`mance status were associated with a lower probability of
`response to T D (Table 4).
`Furthermore, the TD regimen was administered to
`eight patients with primary refractory myeloma who were
`eligible for high-dose therapy with autologous stem cell
`support, but this procedure could not be performed due
`to extensive tumor load with heavily infiltrated bone
`marrow, thrombocytopenia and/or significantly impaired
`performance status. Four of such patients responded,
`blood stem cells were collected and subsequently the
`patients received high dose melphalan with autologous
`blood stem cells as a consolidation treatment.
`Side effects after treatment with TD are shown in
`Table 5. Most adverse effects were due to thalidomide
`and were mild or moderate (grade I or 2 on the WHO
`scale). The more common adverse effects were constipa(cid:173)
`tion, somnolence and fatigue. Approximately one-third
`of patients developed mood changes, xerostomia or
`tremor. Some degree of peripheral neuropathy occurred
`in 10 patients and this side effect necessitated interrup(cid:173)
`tion of thalidomide in three patients. Maculopapular
`skin rash was not uncommon but it usually subsided
`with reduction of the dose of thalidomide. Deep vein
`thrombosis occurred in three patients. Grade I or 2
`leukopenia occurred in 4 patients. Thrombocytopenia
`or anemia that could be anributed to the treatment were
`not seen. The dose of thalidomide was escalated to the
`scheduled dose of 400 mg p.o. daily in 36 patients (82%).
`The average daily dose of thalidomide was 400 mg in 32
`patients, 300 mg in 3 patients and 200 mg in 9 patients.
`The median time to progression for all patients was
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`994
`
`4.2 months, whereas the median time to progression
`for patients achieving a partial response has not been
`reached as yet and it is projected to exceed 10 months.
`The median overall survival is 12.6 months (Figure I).
`Multiple parameters were assessed for their possible
`association with survival after treatment with thalido(cid:173)
`mide and dexamethasone. Variables such as age, serum
`b2-microglobulin. bone marrow plasmacytosis, prior
`treatment with high dose therapy and prior resistance
`to dexamethasone-based regimens were not predictive
`of survival. However, female gender, primary refractory
`disease, absence of severe anemia, very good performance
`status, kappa light chain and normal levels of serum
`LOH were associated with longer survival after treatment
`(Table 6). A Cox regression analysis was also performed
`which indicated that only performance status, gender
`and disease stallls retained significance (P < 0.0001,
`P < 0.002 and P = 0.00 I, respectively). A landmark
`analysis ,ll 4 months was performed and showed that
`the median survival of patients who responded to thali(cid:173)
`domide and dexamethesone has not been reached and
`that of non responding patients was 13 months (P = 0.01).
`
`Discussion
`
`Singha) et al. fi rst demonstrated that thalidomide has
`significant activity in one-third of patients with refractory
`myeloma [2]. This activity was subsequently confirmed
`by several independent studies (7- 9). Thus, besides alky(cid:173)
`lating agents and corticosteroids, thalidomide now rep(cid:173)
`resents the third distinct class of agents with activity in
`patients with multiple myeloma. The antitumor mecha(cid:173)
`nisms of thalidomide in multiple myelorna are probably
`complex and not clearly defined. Possible mechanisms
`of action include inhibition of angiogenesis, modulation
`of adhesion molecules involved in the interaction of
`myeloma cells and bone marrow stroma, modulation of
`several cytokines that may affect the survival of myelo(cid:173)
`ma cells and increased secretion of interferon-y and
`interleukin-2 by COS+ T cells [JO]. Furthermore, there
`is recent evidence that thalidomide and its analogues act
`directly, by inducing apoptosis or G l growth arrest, in
`myeloma cell lines and in patient myeloma cells that are
`resistant to melphalan, doxorubicin and dexamethasone
`[11).
`Preliminary data have suggested that some pa(cid:173)
`tients with resistance to dexamethasone-based regimens
`achieved a response after treatment with a combination
`of thalidomide and dexamethasone (3). Based on this
`encouraging result we performed a mul ticenter phase 11
`study in order to evaluate the efficacy and toxicity of TD
`combination in patients with refractory multiple mye(cid:173)
`loma. We found that this combination was active in 55%
`of patients with multiple myeloma, including 30% pa(cid:173)
`tients who achieved > 75%, reduction of myeloma pro(cid:173)
`tein. Responses were associated with an improvement of
`performance status, an increase in hemoglobin levels
`and decrease of elevated P2-microglobulin levels. All
`
`responding patients showed evidence of antitumor effect
`within two months, so that trials longer than three
`months may not be necessary to assess whether this
`regimen is active in patients with resistant multiple
`myeloma.
`The activity of our TD regimen appeared higher than
`that observed with single agent thalidomide (7-9)). Our
`regimen was equally effective in patients with or without
`prior resistance to dexamethasone-based regimens.
`Weber et al. recently reported that the combination of
`thalidomide and dexamethasone was active in 46% of
`patients who were resistant to prior treatment with high
`dose dexamethasone and subsequent thalidomide alone
`[12]. Furthermore, Hideshima et al. recently showed
`that thalidomide enhances the antimyeloma activity of
`dexamethasone in vitro [11]. All these observations in(cid:173)
`dicate that there is a synergistic effect between thalido(cid:173)
`mide and dexamethasone. However, a prospective
`randomized comparison of thalidomide vs. thalidomide
`and dexamethasone is needed in order to define whether
`the combination is more active than t halidomide alone
`in patients with refractory multiple myeloma. Our
`combination was equally active in patients with either
`primary refractory disease or with disease in resistant
`relapse. The TO regimen was also effective in patients
`with high tumor burden, as indicated by markedly
`elevated serum levels of P2-microglobul in, and in patients
`with aggressive myeloma as indicated by high serum
`LOH. Patients with very good performance status, and
`with monoclonal kappa light chain had a higher probality
`of response to TO.
`The median time to progression for responding pa(cid:173)
`tients is expected to exceed 10 months and the median
`survival of this group of patients with advanced myeloma
`was 12.6 months. A Cox regression analysis indicated that
`female gender, good performance status and primary
`refractory disease, were independent factors associated
`with an improved survival after treatment with thalido(cid:173)
`mide and dexamethasone. Thus, treatment with TD
`provided an opportunity for symptomatic improvement
`and prolonged survival in patients with myeloma who
`had failed not only conventional chemotherapy but also
`had developed resistance after high dose chemotherapy.
`Furthermore, the administration of TD provided the
`opportunity for high dose therapy in 4 of 8 patients who
`could not previously undergo the procedure because
`of poor performance status, thrombocytopenia and/or
`heavily infiltrated bone marrow.
`The side effects of the combination were primarily
`attributed to thalidomide and were generally manageable
`and reversible with appropriate dose reduction. They
`consisted primarily of constipation, morning somnolence,
`mood changes. xerostomia, tremor and peripheral neuro(cid:173)
`pathy. The latter adverse effect may be dose-limiting and
`its appearance necessitated dose reduction or even inter(cid:173)
`ruption of thalidomide. The lack of myelosuppression
`makes the TD combination a pertinent treatment for
`patients with heavily infiltrated bone marrow or with
`hypoplastic marrow due to prior high-dose therapy.
`
`Dr. Reddy’s Laboratories, Inc. v. Celgene Corp.
`IPR2018-01504
`Exhibit 2024, Page 4
`
`

`

`We conclude that the combination of thalidomide and
`dexamethasone represents an active salvage regimen for
`patients with refractory myeloma. If its activity is con(cid:173)
`firmed from randomized studies, it should be used as
`soon as resistance to high-dose dexamethasone-based
`regimens is observed. This combination may also be
`used for the in vivo ' purging' of patients with primary
`refractory myeloma who are otherwise eligible for high
`dose therapy. The T D regimen is also being evaluated as
`primary treatment for patients with active myeloma and
`the preliminary results are very promising (13].
`
`References
`
`I. Alexanian R, D,mopoulos M. The treatment of multiple myeloma.
`N Engl J Med 1994; 330: 484-9.
`2. Singha) S. Mehta J. Dcsikan R el al. Antilumor activity of
`thalidomide in refractory mulu ple myeloma. N Engl J Med 1999:
`341: 1565- 71.
`3. Weber DM. Gavino M, Dclasalle K cl al. Thalidomide alone or
`with dexamethasone for muhiple myeloma. Blood 1999:94 (Suppl
`I): 604a (Abslr 2686}.
`4. Miller AB. Hoogstralen B, Staquet M. Winkler A. Reporling
`results of cancer treatment. Cancer 1981: 47: 207-14.
`5. Cox D. Regression models and l,fc tables. J R Stal Soc Bull 1972:
`34: 187-220.
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`6. Anderson JR. Ca111 KC. Gelber RD. Analysis of survival by
`tumor response. J Clin Oncol 1983: I: 710- 9.
`7. Alcxaman R. Weber D. Tlmlidomide for resistan1 and relapsing
`myeloma. Semm Hema10I 2000: 37 (Suppl 3): 22-5.
`8 Juliusson G. Cels1ng F. Tureson I ct al Frequent good panial
`remissions from 1halidomide includmg best response ever in
`patients wi1h advanced refractory and relapsed myelom,1. Br J
`Haem,110I 2000: 109: 89-96.
`9. Yakoub-Agha I. Moreau P. Leyvraz S el al Thalidomide in pa1ien1s
`with advanced multiple myeloma. Hematology J 2000: I: 186-9.
`10. Raje N. Anderson K. Thalidomide-A rcviv:11 story. N Engl J Med
`1999; 341: 1606-9.
`11. H1desh1ma T. Chauhan D. Shima Y et al. Thalidomide and its
`analogs overcome drug resistance of human multiple mycloma
`cells lo conventional therapy. Blood 2000: 96: 2943-50.
`12. Weber DM. Rankin K. Gav,no M ct al. Thalidomide with dexa(cid:173)
`methasone for resistant muhiple myeloma Blood 2000: 96 (Suppl
`I): 167a (Abslr 719}.
`13. Rajkumar SV. Hayman S. Fonseca Rel al. Thnlidomidc plus dexa(cid:173)
`methasone and thalidomide alone as first line therapy for newly
`diagnosed myeloma. Blood 2000: 96 (Suppl I): 168.i (Abslr 722).
`
`Received 18 December 200 I: accepted 11 April 200 I.
`
`Corre.<11rmtfe11ce to.
`M. A. Dimopoulos. MD
`227 Kifiss,as Avenue
`K,fissia. Athens 14561
`Greece
`E-mail: mdimop@cc.uoa.gr
`
`Dr. Reddy’s Laboratories, Inc. v. Celgene Corp.
`IPR2018-01504
`Exhibit 2024, Page 5
`
`