`
`original paper
`
`
`
`Low-dose thalidomide plus
`dexamethasone is an effective
`salvage therapy for advanced
`myeloma
`
`ANrONIo PALUMBO, LUISA GIAcc0NE, ALESSANDRA BERTOLA,
`PATRIZIA PREGNO*, SARA BRINGHEN, CECllJA Rus, SABRINA
`TRIOLo, EUGENIO GALLo,* ALESSANDRo PlLERl, MARIO
`BOCCADORO
`
`Divisione di Ematologia dell'Universita di Torino,*Divisione di
`Ematologla Ospedaliera, Azienda Ospedaliera 3. Giovanni
`Battista, Torino, ltaly
`
`Background and Objectives. The immunomodulatory drug
`thalidomide can inhibit angiogenesis and induce apop-
`tosis in experimental models. It can also induce marked
`and durable response in advanced myeloma patients.
`Thalidomide has been used at doses ranging from 200
`to 800 mg with significant toxicity. No data are available
`on the impact of low-dose thalidomide plus dexametha-
`sone as salvage therapy for relapsed patients.
`
`Design and Methods. To address this issue, myeloma
`patients were treated with 100 mg/day thalidomide con-
`tinuously and dexamethasone 40 mg, days 1-4, every
`month. Between June 1999 and August 2000, 77
`patients (median age 65 years) who had relapsed or
`were refractory to chemotherapy were treated with
`thalidomide plus dexamethasone.
`
`Results. After a minimum of 3 months of treatment, 14
`patients (18%) showed a myeloma protein reduction of
`75%-100%, 18 patients (23%) showed a response of
`50-75%, 19 patients (25%) a response of 25-50% and
`26 patients (34%) a response of <25% or disease pro-
`gression. After a median follow-up of 8 months, median
`progression-free sun/ival was 12 months. Thalidomide
`was well tolerated. Constipation (12%) and sedation
`(6%) were mild. Tingling or numbness were present in
`17% of patients, discontinuation of treatment was
`required in 10% of patients.
`
`interpretation and Conclusions. The association of low-
`dose thalidomide plus dexamethasone is active against
`advanced myeloma. A significant proportion of patients
`benefit from this treatment as a salvage therapy post-
`poning the delivery of chemotherapy.
`©2001, Ferrata Storti Foundation
`
`
`Key words: myeloma, thalidomide, dexamethasone,
`salvage therapy
`
`baematologica 2001; 86:399-403
`http://www.haematologicait/ZOO1_04/0399.htm
`
`
`
`Correspondence: Mario Boccadoro, M.D., Divisione di Ematologia dell'U-
`niversita di Torino, Azienda Ospedaliera S. Giovanni Battista, Via Genova
`3, 10126 Torino, ltaly. Phone: international + 39-011-6635814 — Fax:
`international +39-011-o963737 - Email: mario.boccadoro@unito.it
`
`Angiogenesis is increased in multiple myeloma and
`
`has a prognostic value in the disease?2 The
`antiangiogenic properties of thalidomide3 provide
`the rationale for studying the effect of this drug in
`myeloma. Thalidomide may directly inhibit the growth
`and survival of myeloma cells;4 its efficacy may also be
`linked to modulation of growth—related genes, such as
`c-myc.5 The interleukin-6 (lL-é) receptor gene is also
`dramatically downregulated.5
`For more than 30 years the initial therapy of multiple
`myeloma has consisted of melphalan and prednisonefia8
`A therapeutic strategy to improve clinical outcome is
`high-dose chemotherapy followed by autologous stem
`cell transplantation.“10 Relapses, however, constantly
`occur and cure is rarely achieved.11
`To improve treatment outcome and introduce the pos-
`sibility of curative therapy, it is necessary to search for
`new drugs or new uses of old drugs. One such com—
`pound is thalidomide. This drug was found to be effec-
`tive in refractory and recurrent myelomas producing an
`overall response rate of 32%.12 The study design called
`for a gradual increase in the dose, but only 55% of the
`patients received the intended maximal daily dose of
`800 mg. Most patients received 400 mg of thalidomide
`daily. Glucocorticoids are effective and extensively used
`in the management of patients with advanced myelo—
`ma.13—15 In vitro, thalidomide enhanced the anti-myelo-
`ma activity of dexamethasone which, conversely, was
`inhibited by lL-é.16
`Based on these pieces of evidence, we evaluated the
`toxicity and clinical efficacy of low-dose thalidomide
`combined with corticosteroids 0n the assumption that
`lower thalidomide doses are better tolerated and the
`association with corticosteroids may exert a synergistic
`effect. Refractory/relapsed myeloma patients were
`treated with this schedule. Low-dose thalidomide plus
`dexamethasone was shown to be extremely well toler—
`ated and highly effective.
`
`
`
`baernatologica vol. 86(4):April 2001
`
`ALVOGEN, Exh. 1015, p. 0001
`
`ALVOGEN, Exh. 1015, p. 0001
`
`
`
`400
`
`A. Palumbo et al.
`
`Design and Methods
`Patients
`
`Table 1. Patients' characteristics.
`
`
`Between June 1999 and August 2000, 77 consecutive
`patients with refractory or relapsed myeloma entered the
`protocol. The SWOGW-18 and Durie and Salmon staging
`systems were used. At diagnosis, 37 patients were treat—
`ed with high—dose chemotherapy (two or three courses of
`melphalan at 100 mg/m2 as previously described),19 and
`40 were treated with conventional chemotherapy (32
`received oral melphalan and prednisone, 8 dexametha-
`sone-doxorubicin-vincristine) These regimens were also
`used as salvage therapy. Thalidomide plus dexametha—
`sone was administered a median of 46 months after diag-
`nosis. Four patients had primary resistance to induction
`treatment, 21 were in resistant relapse and 52 were in
`untested relapse. Twenty-six patients received thalido-
`mide after one line of therapy, 21 after two and 30 after
`three. Among those receiving high-dose chemotherapy,
`17 were in first untested relapse, 18 in second untested
`relapse and 2 were in resistant relapse. Of those treated
`with conventional chemotherapy, 4 had primary resis-
`tance, 19 were in resistant relapse and 17 in untested
`relapse. No patients were excluded on the basis of car-
`diac, renal, pulmonary or liver function. All patients were
`treated in two hematologic centers, Written informed
`consent was obtained from all patients.
`Treatment
`
`Thalidomide was supplied in 100 mg capsules by
`Grunenthal GmbH, 52222 Stolberg, Germany. Thalido—
`mide was administered at the dose of1OO mg at bedtime
`and associated with dexamethasone administered oral-
`ly at the dose of 40 mg on days 1, 2, 3, and 4 every
`month. Data were analyzed when the duration of
`thalidomide treatment ranged from 3 to 16 months
`(median 6.9). At the time of treatment, all patients had
`progressive disease with a >50% increase in myeloma
`protein or reappearance of Bence Jones proteinuria >05
`g/24h. Pre-treatment evaluation included complete
`blood count, renal and liver function tests, serum and
`urine myeloma protein and serum B2-microglobulin eval—
`uation. Patients were evaluated for neurological abnor-
`malities and electromyography was performed if clinical
`signs of neuropathy were detected. Patients were eval-
`uated monthly and physical examination and blood test
`were routinely performed. The patient's characteristics
`are listed in Table 1.
`
`Response criteria and statistics
`Complete remission required disappearance of serum
`or urine myeloma protein analyzed by standard elec-
`trophoresis and marrow plasmacytosis <1 % for at least
`2 months. Clinical responses were defined according to
`the reduction of serum myeloma protein: 75%-100%,
`50%-75%, 25%-50%, and <25%, respectively. In Bence
`Jones myeloma, disappearance of urine myeloma pro-
`tein was recorded as a clinical response of 75%—100%.
`Clinical
`responses 50%-75%, and 25%-50% were
`defined when the reduction of urine myeloma protein
`
`
`baamatologica vol. 86(4):April 2001
`
`
`
`N0. of patients
`Median age (y)
`
`Stage at diagnosis
`”A
`MB
`IIIA
`MB
`pZ-microglobulin < 3 mg/mL
`BZ-microglobulin > 3 mg/mL
`
`M-protein class
`lgG
`19A
`lgM
`Renee Jones protein
`
`Bone marrow plasma cells > 30%
`
`77
`65
`
`30
`4
`40
`3
`34
`43
`
`% of patients
`
`60
`27
`1
`12
`
`64
`
`13
`WHO performance status >3
`
`
`Table 2. Response.
`
`
`% of total
`No. ofpatients
`M—protein reduction
`
`75%-100%
`14
`18
`50%-75%
`18
`23
`} 41
`25%-50%
`19
`25
`
`26No response* 34
`
`*Disease progression or stable disease or <25% M—protein reduction.
`
`was >90%, and >50%, respectively. All other results
`were recorded as failures. Progression was defined by
`increases in serum or urine myeloma protein >25%. The
`curve was plotted according to the method of Kaplan
`and Meier from the beginning of the treatment with
`thalidomide.20
`
`Results
`
`Response rate
`The daily dose of thalidomide was reduced from 100
`mg to 50 mg in 4% of patients and in 10% the admin—
`istration of thalidomide was suspended after a median
`of 3 months (range 1-11) The monthly dose of dexa-
`methasone was stopped in 1% of patients. All patients
`were considered in the evaluation:
`41% showed a
`myeloma protein decline >50%: in 18% the decline was
`75-100%, in 23% it was 50-75%, and in 25% it was 25-
`.50% (Table 2). Three percent showed complete remis-
`sron.
`
`The median time required to obtain the maximum
`response to thalidomide plus dexamethasone was 4.2
`months (range 06-102): 33% of maximum responses
`were apparent after 2 months, 15% after 3 months and
`17% after 4 months; however, 35% became apparent
`
`ALVOGEN, Exh. 1015, p. 0002
`
`ALVOGEN, Exh. 1015, p. 0002
`
`
`
`Thalidomlde for advanced myeloma
`
`401
`
`
`
`
`0,2 ,-
`
`0,1 7*
`
`
`
`PROGRESSION-FREESURVIVAL
`
`
`l
`7
`,
`7
`77
`7
`77 77777
`2
`4
`8
`1o
`12
`
`0
`
`0
`
`6
`
`MONTHS
`
`7 i + ext“.
`14
`16
`18
`
`
`Figure 1. Progression-free survival of myeloma patients treated with thalidomide plus dexamethasone.
`
`between 4 and 6 months. Improvement of performance
`status, skeletal pain, blood count, anemia and transfu-
`sion requirements were slower and related to the degree
`of response. After a response of 50-100%, the median
`levels of hemoglobin increased from 11 g/dL to 13 g/dL,
`Clinical outcome
`Among the 51 patients with a >25% decline in the
`myeloma protein, 10 showed disease recurrence. After
`a median follow—up of 8 months (range 3 to 16), the
`median time to progression was 12 months (Figure 1).
`The median overall survival was not reached and 91%
`of patients were alive.
`
`Toxicity
`l\/lost adverse effects were recorded as grade i accord-
`ing to the World Health Organization toxicity classification.
`Thalidomide had to be discontinued because of toxicity in
`only 8 patients. Constipation was relatively frequent but
`well controlled with appropriate medication. Sedation
`was recorded in 6% of patients, changes in full—time or
`part—time working habits were required in 4% only.
`Weakness and fatigue were experienced in 8% of
`patients. These symptoms were drastically reduced when
`patients took thalidomide at dinnertime. Mood changes
`or depression were present in 4% of patients, but main-
`ly in elderly subjects. Tingling and numbness were
`observed in an unexpected 14% of patients as grade I,
`in 3% as grade II. These symptoms developed after a
`median time of 3 months. Tingling required thalidomide
`
`
`
`discontinuation in 5% of patients, but 3% then experi—
`enced an improvement. Tremors and inco—ordination
`were present in 3% of patients and were generally mild.
`Dizziness was a late adverse effect (3%), and was main—
`ly a clinical progression of foot numbness. One patient
`developed a severe skin rash on her face followed by
`vesicles and bullae: erysipelas was diagnosed and suc-
`cessfully treated with oral antibiotics. In another patient,
`a severe necrotic ulcer of the skull was observed, Two
`patients had evidence of hypothyroidism. Blood counts
`generally improved when disease response was achieved.
`Two patients showed an increase in creatinine levels. in
`one patient disease progression occurred with a slight
`increase in Bence Jones proteinuria accompanied by
`acute renal failure requiring dialysis. No concomitant
`nephrotoxic therapy was delivered in these subjects. Pre—
`viously reported episodes of deep vein thrombosis were
`not observed (Table 3).21
`
`Discussion
`
`The association of low—dose thalidomide plus dexam-
`ethasone was highly effective in patients with relapsed
`or refractory myeloma: 41% showed a >50% decrease
`in myeloma protein.
`in most patients, the serological
`response was accompanied by a significant improve-
`ment of asthenia and bone pain, and a marked increase
`in hemoglobin levels. Oral melphalan and prednisone
`induced a tumor mass reduction >50% in only 20% of
`resistant/relapsing patients.22 Our data clearly show that
`
`
`haematologica vol. 86(4):April 2001
`
`ALVOGEN, Exh. 1015, p. 0003
`
`ALVOGEN, Exh. 1015, p. 0003
`
`
`
`402
`
`A. Palumbo et al.
`
`but 12 days each month.13 When thalidomide was admin—
`istered alone at doses ranging from 200 mg to 800 mg
`partial responses were achieved in 25% of cases in one
`report12 and 40% in another.23
`In conclusion this study confirms previous findings
`showing that thalidomide is a new compound for the
`management of myeloma and is the first demonstra-
`tion that low-dose thalidomide plus dexamethasone is
`an effective treatment for myeloma patients. The low-
`dose thalidomide schedule is very well tolerated and
`highly effective. Whether this efficacy is due to an addi-
`tive or synergistic effect with dexamethasone is not
`clear.
`
`
`
`Contributions and Acknowledgments
`AnP conception, design, interpretation of data, draft-
`ing the article; LG, AB, PP 58, CR, STana/ysis, in terpreta-
`tion of data, critical revision; EG, AP critical revision,
`important intellectual suggestions, final approval of the
`version to be submitted ll/IB conception, design, drafting
`the article, final approval of the version to be submitted
`
`Funding
`This work was supported in part by Associazione Ita—
`liana Ricerca Cancro (AIRC), Associazione Ital/aha Leu-
`cemie (AIL), and Ministero Universita e Ricerca Scien—
`tifica e Tecno/ogica (MURST).
`Disclosures
`Conflict of interest: none.
`Redundant publications: no substantial overlapping
`with previous papers.
`
`Manuscript processing
`This manuscript was peer—reviewed by two external
`referees and by Prof. Jesds F. San Miguel, who acted as an
`Associate Editor. The final decision to accept this paper
`was taken jointly by Prof. San Miguel and the Editors.
`Manuscript received January 5, 2001; accepted March
`8, 2007.
`
`Potential implications for clinical practice
`
`Low—dose thalidomide is well tolerated and highly
`effective on refractory myeloma. A significant pro—
`portion these patients benefit from this treatment as
`a salvage therapy postponing the delivery of chemo—
`therapy.
`
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`No. ofpatients % of total
`
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`anti—tumor effect and that this is superior to that
`achieved by oral melphalan and prednisone.
`Recent data suggest that thalidomide alone is active
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`patients. For these patients, 30% partial responses were
`recorded when dexamethasone was delivered at 40 mg
`
`
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`baematologica vol. 86(4):Aprii 2001
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`ALVOGEN, Exh. 1015, p. 0005
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`