Original a r t ic le - - - - - - - - - - - - - - - - -
`
`Annals of Oncology 12: 991-995. 2001
`© 2001 Kl11ll'er Academic Pubhshers. Primed in the Netherlands.
`
`Thalidomide and dexamethasone combination for refractory
`multiple myeloma
`
`M.A. Dimopoulos, 1 K. Zervas,3 G. Kouvatseas, 1 E. Galani, 1 V. Grigoraki,4 Ch. Kiamouris, 1
`· E. Vervessou, 2 E. Samantas, 5 Ch. Papadimitriou, 1 0. Economou, 1 D. Gika, 1 P. Panayiotidis, 2
`I. Christakis 3 & N. Anagnostopoulos4
`Departments of 1Clinical Therapeutics. 2 Intemal Medicine. University of Athens School of Medicine. Athens: 3 Department of Hemmology.
`Theagenion Cancer Center. Thessalomk1: 4 Depart me/I/ of Hematology. General Hospital of Athens. 5 Department of Oncology. Agti Anargiri
`Hospital. Athens. Greece
`
`Summary
`
`Background: Thalidomide is effective in approximately 30% of
`patients with refractory multiple myeloma. Dexamethasone is
`active in 25'!/o of patients with disease resistant to alkylating
`agents. We investigated the combination of thalidomide with
`dexameth,rso·neas-~lvage treatment for heavily pretreated
`patients with multiple myeloma, in order to assess its efficacy
`and toxicity.
`Patients 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 intermittently 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
`standard chemotherapy, 77% were resistant to dexamethasone(cid:173)
`based regimens and 32% had previously received high-dose
`therapy.
`
`Results: On an intention-to-treat basis twenty-four patients
`(55%) achieved a partial response with a median time to
`response of 1.3 months. The thalidomide and dexamethasone
`combination was equally effective in patients with or without
`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 constipation,
`morning somnolence, tremor, xerostomia and peripheral neuro(cid:173)
`pathy. The median time to progression for responding patients
`is expected to exceed 10 months and the median survival for all
`patients is 12.6 months.
`Co11clusion: The combination of thalidomide with dexa(cid:173)
`methasone 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: dexamethasone. multiple myeloma. thalidomide
`
`Introduction
`
`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 (YAO), or
`pulse dexamethasone alone, with a subsequent median
`survival for all patients of approximately three years [l].
`Over the last decade it has been demonstrated that
`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'Yo of patients with multiple myeloma because of
`restrictions of age, performance status and other organ
`functions. Furthermore, most of the transplanted pa(cid:173)
`tients 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]. This 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 II multicenter study.
`
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`

`

`992
`
`1i1h/e I Patient charactenstics.
`
`fob/e 3 Response to treatment.
`
`Percent of patients(%)
`
`Number of patients(%)
`
`95°/., Cl
`
`73
`21
`
`57
`26
`12
`5
`
`Partial response
`> 75°/., 1 m-peak
`> 50% 1 m-peak
`Minor response
`Stable disease
`Progressive disease
`
`24 (55)
`13 (30)
`11 (25)
`I (2)
`8 (18)
`11 (25)
`
`Abbreviation. Cl - confidence mterval.
`
`39-69
`17-45
`13-40
`0-12
`8-33
`13-40
`
`Male sex
`Age > 70 years
`Myeloma type
`IgG
`IgA
`Light chain only
`Non secretory
`Light cham
`k
`
`None
`Performance status :,, 2
`Hemoglob111 < 8.5 g/dl
`Platelets < I 00 x I 06/dl
`Serum calcium > 11.5 g/dl
`Serum creatinine > 1.5 mg/di
`Serum LOH > 220 I U/1
`Serum ~2-microglobulm > 6 mg/I
`Bone marrow plasma cells > 50%
`
`59
`36
`5
`30
`23
`23
`12
`14
`28
`29
`42
`
`tests and serum and urine electrophoretic studies. Thereafter these
`tests were repeated on a monthly basis. Bone marrow reassessment
`was performed when patients' monoclonal prote111 reached maximum
`reduction.
`The initial dose of thalidomide was 200 mg p.o. daily at bedtime,
`with dose escalation to 400 mg after 14 days in absence of severe side
`effects. Dexamethasone was administered intermittently at a dose of
`20 mg/m 2 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
`graded according to the classification system of the Word Health
`Organization (WHO) [4] Patients who d1scont111ued treatment before
`a response could be assessed were considered to have had no response
`to treatment. Thus. the results were evaluated on an intention-to-treat
`basis.
`Complete response was defined as disappearance of the monoclo(cid:173)
`nal protein by serum and/or unne immunofixation and less than 5%
`bone marrow plasma cells. Partial response was defined as a greater
`than 50% reduction of serum myeloma protein and/or greater than
`75% reduction of Bence Jones protein, with > 50'X, reduction of bone
`marrow plasma cells For the purpose ofth1s study mmor response was
`defined as at least 25% reduction of serum monoclonal protein, and
`the disease was considered stable when the serum monoclonal protein
`changes were < 25% without additional complications of the myelo(cid:173)
`ma. Patients were considered in progression when they did not meet
`critena for response or stable disease. Relapse was defined by at least a
`25% increase of monoclonal protein from the lowest value, mcreasing
`bone lesions or bone marrow plasmacytosis.
`The time to response was defined as the interval between the start
`of therapy and the first confirmation of partial response The time to
`progression was defined as the time from the start of therapy to disease
`progression. Overall survival was calculated from the start of therapy
`to death from any cause or the last follow-up visit, whichever occurred
`first. Several clinical and laboratory variables were assessed for their
`Between July 1999 and November 2000. 44 patients were treated with
`the combination of thalidomide and dexamethasone (TD) after in-
`possible association with response to and with overall survival. Those
`vanables which were found statistically significant in the univariate
`formed consent was obtained from each patient. Patient characteristics
`h
`· T bl
`I Th
`d'
`analysis of overall survival were subsequently included 111 a Cox
`(
`38 t 87
`67
`0
`ares ow_n tn a. e
`·
`e me tan age was
`years rang~
`regression analysis [5]. In order to assess the 1n1pact of response to
`-
`d cl
`years), 1unc-pat1ents were older than 70 years and 32 were male.
`h
`.
`.
`h
`·
`,
`·
`d
`k
`1
`1
`--
`-
`-
`-
`.
`-
`--.---t ahdom1de an
`examet asone on patients surv1va . a an mar
`f
`Features of advanced disease such as severe anemia, thrombocytopema,
`]
`d [
`6
`1
`extensive bone marrow plasmacytosis, hypercalcemia, markedly ele-
`ana ysis was per orme
`·
`vated serum ~2-microglobulin and high levels of serum LOH were
`often present (Table I). Thirty-four percent of patients had not re-
`sponded to any previous regimen (primary refractory) and 66% of
`patients were relapsing despite chemotherapy (resistant relapse). Three
`or more treatment regimens were administered to 66% of patients and
`77% were resistant to an immediate prior regimen which contained
`high dose dcxamethasone. One-third of patients had also received
`high-dose therapy (Table 2). The median lime from 1111tial treatment to
`inclusion in thts study was 23.3 months (range: 2.7 to 134.4 months).
`All patients had baseline evaluations that 111cludcd physical exami(cid:173)
`nation, blood counts. hepatic and renal function tests, bone marrow
`aspirate and/or biopsy. serum and urine protein electrophoreses.
`quant1tat1011 of serum immunoglobulins. serum LOH and ~2-micro(cid:173)
`globulin. Chest X-ray and a limited bone survey were also performed.
`For the first two months of treatment patients were followed up with
`biweekly physical examinations. blood counts. renal and liver function
`
`foble 2 Disease status and pnor treatment.
`
`Percent of
`patients(%)
`
`Disease status
`Primary refractory
`Resistant relapse
`Number of prior regimens
`I
`2
`3
`4
`:,, 5
`Pnor resistance to dexamethasone-based regiment
`Pnor treatment with high dose chemotherapy
`
`34
`66
`
`II
`23
`34
`25
`7
`77
`32
`
`Patients and methods
`
`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(cid:173)
`more, one patient achieved minor 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 status and of
`
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`

`

`Table 4. Parameters associated with response to TD.
`
`1 0
`
`Parameter percent
`
`Response
`
`P-value
`
`Performance status
`0
`;;, I
`Light chain type
`k
`
`"
`
`83
`37
`
`73
`25
`
`0.002
`
`0.004
`
`Table 5. Toxicity (WHO scale)
`
`Adverse effect
`
`Percent of patients(%)
`
`f 05 I a.
`
`00
`
`Constipation
`Somnolence and/or fatigue
`Mood changes
`Xerostomia
`Tremor
`Peripheral neuropathy
`Skin rash
`Headache
`Edema
`Vein thrombosis
`
`75
`57
`33
`34
`30
`23
`21
`21
`17
`7
`
`Table 6. Parameters associated with survival after TD.
`
`Parameter
`
`Median survival (months)
`
`P-value
`
`Gender
`Female
`Male
`Disease status
`Primary refractory
`Refractory relapse
`Hemoglobin
`;;, 8.5 g/dl
`< 8.5 g/dl
`Performance stat us
`0
`;;, I
`Light chain type
`k
`
`"
`
`Serum LOH
`,;;;220 lU/1
`>220 IU/1
`
`Not reached
`12.6
`
`Not reached
`9.6
`
`13.0
`4.8
`
`13.0
`6.6
`
`Not reached
`6.6
`
`13.0
`6.6
`
`0.05
`
`0 06
`
`0.0004
`
`0.002
`
`0.004
`
`0.009
`
`anemia, and a decrease of previously elevated serum ~2-
`microglobulin and LOH levels.
`Several variables such as gender, age, myeloma heavy
`and light chain type, hemoglobin, platelet count, serum
`LOH and ~2-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 40'1., 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
`
`993
`
`12
`
`18
`
`Months
`
`,.
`
`Fig11re /. Overall survival after treatment with thalidomide and dexa(cid:173)
`methasone.
`
`combination induced responses in 5TYc, of patients who
`had previously received high dose therapy with stem cell
`support. The TD regimen was equally effective in pa(cid:173)
`tients with either primary resistant myeloma or with
`disease in resistant relapse; partial responses occurred
`in 60% and 52°/., 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 TD (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 IO 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 attributed 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 status retained significance (P < 0.0001,
`P < 0.002 and P = 0.001, respectively). A landmark
`analysis at 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 ofnonresponding patients was 13 months (P = 0.01).
`
`Discussion
`
`Singha( et al. first 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 myeloma 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 CDS+ T cells [10]. Furthermore, there
`is recent evidence that thalidomide and its analogues act
`directly, by inducing apoptosis or GI 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 multicenter phase II
`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°1<, 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 ~2-microglobulin levels. All
`
`responding patients showed evidence of anti tumor 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 [I I]. 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 thalidomide 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 TD regimen was also effective in patients
`with high tumor burden, as indicated by markedly
`elevated serum levels of ~2-microglobulin, 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 TD.
`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.
`
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`

`

`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 TD regimen is also being evaluated as
`primary treatment for patients with active myeloma and
`the preliminary results are very promising [13].
`
`References
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`3. Weber DM. Gavino M, Delasalle K et al. Thalidomide alone or
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`Juliusson G. Cels111g F. Tureson I et al Frequent good partial
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`9. Yakoub-Agha I. Moreau P. Leyvraz Set al Thalidomide in patients
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`10. Raje N. Anderson K. Thalidomide-A revival 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 myeloma
`cells to conventional therapy. Blood 2000: 96: 2943-50.
`12. Weber DM. Rankin K. Gav1110 Met al. Thalidomide with dexa(cid:173)
`methasone for resistant multiple myeloma Blood 2000: 96 (Suppl
`I): 167a (Abstr 719).
`13. Rajkumar SY. Hayman S. Fonseca R et al. Thalidomide plus dexa(cid:173)
`methasone and thalidomide alone as first line therapy for newly
`diagnosed myeloma. Blood 2000: 96 (Suppl I): 168a (Abstr 722).
`
`Received 18 December 2001: accepted II April 2001.
`
`Correspondence to.
`M.A. Dimopoulos, MD
`227 Kifiss1as Avenue
`K1fissia. Athens 14561
`Greece
`E-mail: mdimop@cc.uoa.gr
`
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