DURIE B.G.M. and STEPAN D.E.
`
`Electronic Journal of Oncology, 2000, 1, 1-8
`
`Efficacy of Low Dose Thalidomide in Multiple Myeloma
`
`Brian G. M. DURIE 1 and Daniel E. STEPAN 2
`
`Abstract
`Purpose
`During 1998 evidence became
`available that thalidomide is an active anti
`myeloma agent.1· 2 The initial study was a
`rapid (Q 2 week) dose escalation protocol
`using 200 - 1200 mg of thalidomide daily.
`Since initial response occurred early and
`dose escalation significantly
`increased
`toxicity it was decided to evaluate the
`efficacy of
`less
`toxic
`lower doses
`·
`i.e. thalidomide 50-400 mg daily.
`
`Patients and Methods
`or
`relapsing
`Patients with
`progressive multiple myeloma following
`either standard chemotherapy and/or high
`dose chemotherapy with
`transplantation
`were treated with thalidomide. Doses
`between 50 mg and 400 mg/day were
`utilized with dose escalation based upon
`lack of response. An adequate trial was 8
`weeks
`with
`myeloma M-protein
`monitoring every 14-28 days.
`
`Results
`1998,
`in October
`Starting
`36 patients were accrued, and evaluated
`for both response and
`toxicity. Nine
`patients (25o/o) achieved partial (PR: 50%
`partial
`(PR: >50%
`regression)
`or
`
`to
`(CR: ~75%) according
`complete
`(SWOG)
`Southwest Oncology Group
`criteria. Of note 2 patients achieved
`excellent
`remission with
`thalidomide
`50mg/day and an additional 3 patients
`with 100 or 200 mg/day. An additional 7
`patients (19%) had lesser response or
`disease stabilization and 11 patients (31%)
`had progressive disease despite dose
`escalation to 400 mg/day. Nine patients
`(25%) were unable to tolerate thalidomide
`and/or discontinued medication prior to 8
`weeks because of progressive disease.
`
`Conclusion
`Low dose thalidomide is generally
`well tolerated and can induce excellent
`rem1ss1on
`in 25% of
`relapsing or
`refractory myeloma patients. Response is
`more likely with kappa subtype disease
`(81 % versus 27%) and may be enhanced
`by co-administration of glucocorticords
`such as dexamethasone. Further studies
`are warranted to more fully assess the
`efficacy and tolerance of thalidomide used
`alone and in combination.
`
`Correspondence to: Brian G. M. DURIE
`Cedars-Sinai Comprehensive Cancer Center,
`8700 Beverly Blvd.,
`Los ANGELES, CA 90048 (USA)
`e-mail: sgoodvin@csccc.com
`
`1 CEDARS-SINAI Comprehensive Cancer Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA
`2 Oregon Health Sciences University
`
`ALVOGEN, Exh. 1007, p. 0001
`
`

`

`Low dose Thalidomide in multiple myeloma - DURIE B.G.M. and STEPAN D.E.
`
`Introduction
`. There .are .a limited number of agents
`which are active m the treatment of multiple
`myeloma. 3
`Preliminary
`evidence
`of
`thalidomide efficacy was
`therefore very
`12 B
`e!1c~uragmg. '
`ecause of
`reports of
`•
`sigmficant (>50% of ~ Grade 1) toxicity
`with thalidomide at doses >400mg/day as
`~el.I ~s compassionate use experience
`mdicatmg
`excellent
`responses
`with
`thal~domide at doses ~00 mg/day, it was
`decided to evaluate low doses of thalidomide
`in multiple myeloma patients relapsing/
`refractory after standard or high dose
`therapy. It was noted that in patients with
`leprosy, thalidomide at doses <100 mg/day
`induced 83% complete responses versus
`68.4% at 100-200 mg/day, 67.8% at >200-
`and
`50%
`at >300 mg-
`300 mg/day
`400. mg/day. 4 This obviously implies almost
`an mverse dose relationship in this setting.
`The study
`in myeloma was
`therefore
`designed to evaluate thalidomide at doses
`between 50 mg and 400 mg/day with dose
`escalation based only upon lack of response.
`
`Patients and treatment
`
`Patients were eligible for thalidomide
`treatment if they had documented relapsing
`or refractory myeloma and an M-component
`marker to allow quantitation of response.
`Baseline restaging was a prerequisite for
`study entry and included skeletal radiographs
`and/or whole body scans, bone marrow
`aspiration/biopsy, complete blood counts
`panel, serum and urine M~
`chemistry
`comp~nent quantitation, serum ~2 micro(cid:173)
`6
`glo~ulm and serum creatinine protein. 5
`•
`Patients had to be at least 3 weeks past their
`last radiotherapy and/or chemotherapy or 6
`weeks from
`their last treatment with a
`nitrosourea.
`Patients were treated with
`thalidomide at doses between 50 mg and 400
`mg/day with testing every 14-28 days and
`dose escalation (50 mg, 100 mg, 200 mg,
`300 mg, 400 mg) only in the absence of
`response.
`All patients wer~ .tr~ated with signed
`.
`mformed consent utihzmg Thalomid®
`provided as 50 mg capsules through th~
`S.T.E.P.S. program
`from
`the Celgene
`Corporation.2
`Limiting
`toxicities were
`
`defmed as grade 2 peripheral neuropathy,
`grade 3 sedation, fatigue, dizziness or related
`neurologic
`difficulties
`and
`grade
`4
`hematologic toxicity. An adequate trial was
`8
`_we~ks with myeloma M-protein
`momtonng every 14-28 days. All patients
`were seen and examined at least every 28
`days with assessment of toxicity and
`monitoring of complete blood counts and
`chemistry panel in addition to myeloma
`specific marker studies. Because of concerns
`a~out achieving rapid response in patients
`with aggressive disease the starting dose in
`these
`instances was 200 mg/day. All
`responses of ~ 50% regression had to be
`sustained for >8 weeks to be considered a
`«respondern.
`The Southwest Oncology
`Group (SWOG) criteria were utilized to
`classify patients into: (I) Responders: Partial
`Response (PR) ~ 50% regression; Complete
`response (CR) ~ 75% regression: (ii) Stable
`disease or response < PR; (iii) Progressive
`6 The point of maximum regression
`disease. 5
`'
`was typically further documented by follow(cid:173)
`up bone marrow, biopsy, whole body
`imaging, and/or other testing.
`In an effort to reduce the sedation
`side effects the full dose of thalidomide was
`administered as a single dose in the evening.
`In an effort to reduce constipation, proactive
`measures were
`taken
`to prophylactically
`manage bowel function.
`The study was planned such that if a
`minimum of 2 patients of the first 15 patients
`achieved an objective response, an additional
`20 patients would be accrued for a total of
`35 patients. Since 5 of the first 15 patients
`responded,
`the
`study
`proceeded
`and
`36 patients were included. The trial design
`was such there was an 84% power to detect a
`response rate of 30%.
`
`In addition to routine staging and
`monitoring, patients had serial testing with
`whole body FDG/PET
`imaging.
`This
`scanning which detects F18 glucose (FDG)
`uptake
`is a very accurate method for
`detection of any active myeloma either in the
`b.~me marrow and/or any extra medullary
`sites throughout the body. 7 Since several
`patients had extra medullary disease, this
`a~lowed documentation of response at these
`sites.
`
`2
`
`ALVOGEN, Exh. 1007, p. 0002
`
`

`

`DURIE B.G.M. and STEPAN D.E. - Low dose Thalidomide in multiple myeloma
`
`Results
`
`A total of 36 patients were accrued to
`this study. The basic characteristics of the
`patients are summarized in Table 1. There
`were 24 men and 12 women. The median
`age was 56 years with a range of 36-77
`years. All patients had received prior therapy
`of some sort. 29 patients (81 % ) had received
`3 or more types of prior chemotherapy
`regimens and 9 patients (25%) had received
`prior stem cell transplant, usually in addition
`to extensive prior chemotherapy.
`(> 8 weeks) objective
`Sustained
`response
`occurred
`in 9 patients
`as
`summarized in Table 1 and detailed
`in
`Table 2, which provides more information
`responding patients. Of the
`about
`the
`(> 75%
`«CR>>
`9 patients, 6
`achieved
`regression) and 3 achieved «PR>> 1~ 50;
`:5 75%) according to SWOG criteria. As
`can be seen in the comments section of
`Table 2, the thalidomide, at doses between
`50 mg-400 mg/day, was well tolerated.
`Patient 1 had significant sedation
`with thalidomide 50 mg daily and herself
`reduced her dosage to 50 mg every other
`day. At this dosage she has had no major
`side effects/difficulties and has achieved an
`excellent sustained remission. The
`time
`in
`serum
`course of changes
`IgGx:
`M-co1q:>0nent and hemoglobin levels
`in
`response to thalidomide are summarized in
`Figure 1. These changes are contrasted with
`similar changes in Patient 7 who achieved an
`excellent remission with thalidomide 300 mg
`daily. In this instance response was after
`
`Examples of Response
`
`Figure 1: Examples of hemoglobin and monoclonal
`component variations in two responding patients
`
`3
`
`Table 1. Patient Characteristics
`
`Total Patients
`Sex
`
`36
`
`12
`24
`
`Female
`Male
`Age (years)
`56
`Median
`36-77
`Range
`Prior Chemotherapy
`(No. ofregimens)
`Chemotherapy
`
`0-------- 0
`1 ------- 2
`2 ------- 5
`~3 ----- 29 (81%)
`0------ 27
`1 ------ 8 "-..
`25%
`2------ I /
`Response (SWOG Criteria)*
`CR(> 75% regression------ 6 "--.
`25%
`PR(~ 50 - 75%)
`-------- 3 /
`< PR or «stable»
`------- 7
`Progressive disease -------- 16
`Not evaluable I resp.•••--- 4
`
`Transplant
`
`~.,
`
`/
`
`70
`
`19"/o
`
`* SWOG criteria: see reference 6
`** 5 of the 16 patients had progressive disease, plus
`toxicity which resulted
`in discontinuance of
`thalidomide prior to 8 weeks. 3 had lambda BJ
`myeloma with increasing serum creatinine (see text).
`
`to 8 weeks
`thalidomide prior
`*** Discontinued
`(adequate trial) in absence of clearly progressive
`disease.
`
`relapse following extensive prior therapy
`including stem cell
`transplant. In both
`instances the drop in serum M-component
`and
`improvement
`in hemoglobin
`levels
`parallel each other. Interestingly although
`patient 7 has now slowly relapsed after
`1 year, patient 1 continues
`to
`further
`improve.
`Of note patient 2, also receiving very
`low dose thalidomide, (50 mg/day), is also
`demonstrating continued improvement after
`9 months of treatment. Other side effects
`besides sedation, which has been a WHO
`grade 1 toxicity at most, have included
`transient mild rash in patient 2 and 4, mild
`peripheral neuropathy in patients 3 and 8,
`plus constipation which required specific
`management
`in
`patient
`3
`and
`the
`development of a rather unusual palmar
`erythema
`in patient 7. The
`erythema
`disappeared with temporary discontinuation
`of thalidomide.
`
`ALVOGEN, Exh. 1007, p. 0003
`
`

`

`Low dose Thalidomide in multiple myeloma - DURIE B.G.M. and STEPAN D.E.
`
`Table 2. Patient Outcome: Responders
`
`Ptt
`
`Thalidomide
`dose I day
`
`Age
`
`Sex M-Component Prior***
`type
`Therapy
`
`o/o
`Regression
`
`Follow-up
`(months)
`
`Comments
`
`SO mg
`
`SO mg
`
`100-200mg
`
`200mg
`
`200-300mg
`
`300mg
`
`300mg
`
`400mg
`
`400mg
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`77
`
`53
`
`55
`
`47
`
`36
`
`52
`
`40
`
`51
`
`66
`
`F
`
`lgGc
`
`lgAK
`
`lgGc
`
`JgGc
`
`lgAK
`
`lgAK
`
`IgGc
`
`lgOc
`
`K(BJ)
`
`M
`
`M
`
`M
`
`M
`
`M
`
`M
`
`F
`
`c,
`
`c,
`T,C,
`
`c,
`T,C,
`
`T,C,
`
`T,C,
`
`T2C.
`c,
`
`81%
`
`70%
`
`81%
`
`53%
`
`75%
`
`77%
`
`86%
`
`10
`
`9
`
`13
`
`10
`
`12
`
`Dose decreased to Q.O.D.
`with sustained remission
`Rash; resolved
`
`Mild Neuropathy;
`constipation
`
`Rash; resolved
`
`Best response to any R,
`
`8**
`Extra medullary relapse
`12 .. Developed palmar erythema
`Relapse after I yr.
`
`75%
`
`98%*
`
`13
`
`9
`
`Mild neuropathy
`
`Blood counts improved only
`with addition of steroids
`(Pulse dexamethasone 40 mg
`QDx4 twice/month
`
`• Kappa BJ protein decreased from 24 grams/24 hours to 0.2 grams/24 hours.
`::. Both relapsed; some restabili~ation with dose increase and addition of steroids.
`C and T refer to number of prior chemotherapy (C) regimens or transplants (T) previously.
`
`The benefit of thalidomide was
`particularly evident in patients who had
`I!reviousl}'." received stem cell transplanta(cid:173)
`tion. Patients 3, 5, 7 and 8 have achieved
`remissions which are better
`that
`those
`obtained with stem cell transplantation. The
`M-component levels are lower and blood
`count lev~ls, particularly hemoglobin, are
`b~tter. Pa!ient ~has been in remission longer
`with thahdormde than with prior stem cell
`transplantation. 1:ive of the responders had
`req1:1rred
`erythropoietin
`by
`pr~vu;msly
`1IlJect1on to sustam an adequate hemoglobin
`level, but have now discontinued
`this
`treatment.
`Other aspects of note include the
`ex~ medullary relapse which occurred in
`patient 6. Retroperitoneal plasmacytoma
`evident on whole body FDG/PET, obstructed
`both ureters. Stents were placed and further
`response has been achieved with the addition
`of pulse dexamethasone as was also true for
`patient 7. Patient 9 with kappa BJ only
`myeloma had a dramatic reduction in urine
`~J protein with thalidomide which was
`this
`mcreased to 400 mg/day to achieve
`result. The BJ protein level dropped from 24
`grams/24 hrs to 0.2 grams/24 hrs. Despite
`that,
`severe _anemia
`(7-8 gm/%)
`and
`thrombocytopema (< 50,000/cumm.) persis(cid:173)
`ted. It was elected to add pulse dexa-
`
`methasone ( 40 mg daily for 4 days twice a
`month) to the thalidomide. Over 2 'months
`the hemoglobin and platelet counts improved
`steadily and now at over 8 months later the
`blood counts are normal. With a current
`follow up of over 1 year, 2 responders have
`relapsed at 8 mo~ths and 1 ye~, both having
`ha~ refractory disease followmg extensive
`pnor chemotherapy and
`trans-plantation.
`Remission. duration
`for
`the
`responders
`(Table 2) is currently 8-13+ months with a
`~edian of 9 months. No responders have
`died.
`. The 7 patients (19%) who failed to
`achieve a PR{< 50% regression) as noted in
`Tabl~ 1, repr~s.ented a mixed group. Table 4
`pro_v1des addit10na_l follow up details. One
`patient had a bnef 30% regression then
`relapsed and died after 4 months. However
`4 patients have been stable or slowly
`responding over 4 - 9 months. One of these 4
`has had improvement in skin amyloidosis of
`the face, but otherwise stable disease with no
`reduction in serum lgGK M-component nor
`improvement in blood count values. Two of
`the 4 have been slowly improving over 4-
`6 i;r10nths on 50 mg and 100 mg thalidomide
`daily. The other patient in this group has
`been completely stable for 9 months on
`400 i;rig
`thalidomide
`daily. The
`final
`2 patten~ out of the 7 «mixed response»
`group failed to respond with thalidomide at
`
`4
`
`ALVOGEN, Exh. 1007, p. 0004
`
`

`

`DURIE B.G.M. and STEPAN D.E. -Low dose Thalidomide in multiple myeloma
`
`Table 3. Light Chain Subtype and Thalidomide Response
`
`Lambda(l.)
`N° of patients
`
`Kappa(K) % Ka a
`N° of patients
`pp
`
`Pvalue
`
`Responders
`• CR(;;::75%)
`•
`PR (;;::SQO/o)
`•
`Stable/Mixed
`
`Progressive Disease
`
`0
`0
`3
`8*
`
`7
`2
`4
`3
`
`81% .............
`/
`27%/
`
`0.001
`
`*Patients with progressive disease and adequate trial.
`
`400 mg/daily, but have since responded with
`the addition of pulse dexamethasone added
`as for patient 9, Table 2.
`A total of 20 patients had progressive
`disease on thalidomide and/or were non
`tolerant of the drug. Of these 20, 11 (55%)
`patients had progressive disease despite an
`adequate
`trial and ability
`to
`tolerate
`thalidomide. Six of these 11 patients have
`since died with progressive disease. Five
`patients had progressive disease and non
`tolerance which led to discontinuation of
`thalidomide prior to 8 weeks. Three of these
`5 had lambda (A.) BJ myeloma and had a
`progressive increase in serum creatinine (1.7
`to 4.3 mg%; 3.6 to 4.3 mg%; and 1.0 to
`2.3 mg%)
`associated with
`concomitant
`disease
`progression which
`required
`discontinuation of thalidomide. One of these
`patients subsequently developed renal failure
`and died.
`
`Four patients were unable to tolerate
`thalidomide even at low doses (50 mg,
`50 mg, 50 mg, and 100 mg/day). One patient
`(man, aged 66 years) had extreme dizziness
`and almost had a fatal fall in the shower. The
`3 others all had neurologic toxicity which
`was limiting including sedation, dizziness,
`tremor, incoordination and confusion. Of
`note one patient intolerant with 50 mg
`thalidomide daily has been rechallenged with
`10 mg thalidomide daily which she can
`tolerate and with which she is manifesting
`early evidence of response (serum IgGte
`M-component reduced from 6 G/DL to
`4.5 G/DL).
`The different response categories
`(CR, PR, Mixed, PD) were evaluated with
`respect to predictors of response. Since
`advanced, chemotherapy resistance did not
`preclude response (Table 2) other types of
`
`Table 4. Patient Outcome: Stable Disease and Relapse Patients
`
`Patient Category
`
`Patient
`Numbers
`
`Outcome
`
`Further Response
`
`(1) Stable/<PR*
`Transient Response
`Stable/mixed
`Non response
`
`(2) Relapse Patients**
`Patient 6
`
`Patient 7
`
`* See materials and methods.
`**See Table 2.
`
`1
`4
`2
`
`Relapse
`Continued stable
`Pulse dexamethasone added
`(see Table 2)
`
`Subsequently died
`Stable at 4, 6, 6, 9 months
`Now both responders with >50%
`regression at 2 and 3 months
`
`response: now on
`Pulse dexamethasone added Transient
`alternate treatment
`Pulse dexamethasone added Ongoing response.
`
`5
`
`ALVOGEN, Exh. 1007, p. 0005
`
`

`

`Low dose Thalidomide in multiple myeloma - DURIE B.G.M. and STEPAN D.E.
`
`parameters were assessed. The only apparent
`predictor proved to be light chain sub type as
`summarized in Table 3. Responders were
`much more likely to have kappa (K) sub type
`disease (81% versus 27%; P< .001). All the
`excellent responders had K sub type disease,
`although obviously K sub type patients also
`fell into the PD and intolerant categories.
`Initial evidence of response occurred with 4-
`6 weeks, but maximum response was
`frequently delayed beyond 6 months.
`Responding patients
`typically developed
`some reduction in total white count. Of
`interest, 2 responders who had persistent
`chronic hepatitis C had substantial reduction
`in PCR titers concomitant with response to
`thalidomide.
`
`Discussion
`is an effective anti(cid:173)
`Thalidomide
`myeloma drug in 25% of patients with
`relapsed/refractory myeloma even with doses
`as low as 50 mg/day. In the dose range of 50
`mg-400 mg/day thalidomide is well tolerated
`with grade 0-1
`(WHO)
`toxicity, most
`commonly sedation, consti-pation and/or
`mild peripheral neuropathy. Our data support
`the further evaluation of thalidomide in this
`dose range.
`In responding patients the magnitude
`(% regression) and duration of response do
`not appear to be influenced by the dose. For
`example, as shown in Table 2 and Figure 1,
`response at 50 mg/day is 81% for over
`9 months with ongoing evidence of further
`regression. Although
`the anti-angiogenic
`effects
`of
`thalidomide
`have
`been
`10
`highlighted, 8
`9
`11
`the benefit with
`low
`•
`•
`•
`dosages is most consistent with responses
`noted in inflammatory diseases such as
`lepromatous
`leprosy ( erythema nodosum
`
`leprosum [ENL] 12), Behcet's syndrome 13
`,
`ulcers14
`oral
`aphthous
`tuberculous
`,
`meningitis15
`and
`systemic
`lupus
`In these settings 50 mg-
`erythematosus 16.
`100 mg/day dosages have been effective
`without clear added benefit using higher
`dosages. For example, in the randomized,
`double-blind placebo-controlled
`trial
`in
`Behcet's syndrome 13
`, 100 mg/day was as
`effective as 300 mg/day.
`The plasma concentrations achieva(cid:173)
`ble with low doses of thalidomide ,e.g. 50
`1 These
`mg-150 mg doses) are 1-4 µg/ml. 17
`•
`
`concentrations of 1-4 LLg/ml are sufficient to
`18 and interleukin-12
`modulate TNF-a17
`•
`(IL-12) production19 which are the likely
`of
`thalidomide
`efficacy
`in
`targets
`inflammatory diseases. It is important to note
`that partial inhibition of TNF-a and IL-12
`production by low doses of thalidomide is
`preferable to total inhibition, in that TNF-a
`role
`in host
`resis(cid:173)
`plays a }iositive
`tance 17•18·10 1 and IL-12 is required for viral
`specific, NK. cell mediated immunity. 22 This
`explains the paradoxical effects in HIV
`patients in whom thalidomide can directly
`replication of HIV, 23 but also
`inhibit
`suppress
`the
`required
`IL-12 mediated
`immune response to HN. 14
`19 The higher
`•
`plasma concentrations of thalidomide (e.g.
`~ 10 µg/ml) attempted in an effort to inhibit
`the disadvantage of
`angiogenesis have
`suppressing Il-12 and the NK. mediated anti
`19
`viral response. 10
`4
`• 1
`•
`Cytokine abnormalities have been
`strongly implicated in the pathogenesis of
`myeloma. 24 Although much attention has
`focused on interleukin-6 (IL-6), TNF-a is
`involved. TNF-a
`also very much
`is
`implicated in the pathogenesis of both the
`anemia25 and bone disease.26 Of note,
`dramatic improvement in hemoglobin was
`noted in our responding patients (Table 2;
`Figure 1 ). Even more interesting is the
`marked benefit in myeloma patients with
`kappa sub type disease (Table 3). TNF-a
`triggers activation of NF-KP which is a
`critical enhancer of kar.pa immunoglobulin
`2
`transcription. 28
`chain
`.JO This
`selective
`•
`mechanism may explain
`the
`apparent
`preferential benefit of thalidomide in kappa
`sub type disease. This also fits with other
`data imnlicating NF-KP in myeloma bone
`disease. ~ 1' 32 Recent studies have shown that
`deletion of NF-KP produces osteopetrosis in
`mice. 33, 34, 35, 36
`
`It is also important to note that TNF-a
`has been more broadly
`implicated
`in
`carcinogenesis and disease susceptibili~ in
`8 39
`ways which are relevant in myeloma.37
`•
`•
`40 Most
`impressive are data
`indicating
`TNF-a deficiency can induce resistance to
`carcinogenesis.37 In addition polymorphisms
`the TNF-a promoter
`in
`significantly
`influence transcriptorial activation. 38 Such
`polymorphisms are linked to predisposition
`to both systemic lupus erythematosis39 and
`viral infection. 40
`
`6
`
`ALVOGEN, Exh. 1007, p. 0006
`
`

`

`DURIE B.G.M. and STEPAN D.E. - Low dose Thalidomide in multiple myeloma
`
`In
`of
`use
`the
`study,
`our
`dexamethasone enhanced the efficacy of
`thalidomide both for patient 9 (Table 2)
`who's blood counts improved only with the
`addition of steroids and 2 stable disease
`patients who became responders with the
`addition of steroids
`(Table 4). This
`additional benefit has also been noted by
`others.41 Although many mechanisms can be
`proposed for this synergism, the synergistic
`inhibition of TNF-a by thalidomide plus
`dexamethasone is important. 17
`18 Since other
`•
`drugs such as pentoxifylline are also
`synergistic
`in
`this fashion, a range of
`possible combination strategies could be
`available.
`the
`raise
`therefore
`data
`Our
`possibility that a focus on the cytokine and
`immunomodulatory effects of thalidomide
`may be more appropriate than considering
`thalidomide as purely an anti-angiogenic
`agent. From a clinical standpoint thalidomide
`is an important new agent with efficacy at
`low, well tolerated dosages and deserves
`detailed evaluation both as a single agent and
`combined with any agents which prove to be
`additive or synergistic.
`
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`
`