`
`original paper
`
`
`Low-dose thalidomide plus
`dexamethasoneis an effective
`Salvage therapy for advanced
`myeloma
`
`
`ANTonto PALuMBo, Luisa GIACCONE, ALESSANDRA BERTOLA,
`PATRIZIA PREGNO*, SARA BRINGHEN, CECILIA Rus, SABRINA
`TRIOLO, EUGENIO GaLLo,* ALESSANDRO Piteri, Marto
`Boccaboro
`Divisione di Ematologia dell'Universita di Torino, *Divisione di
`Ematologia Ospedaliera, Azienda Ospedaliera S. Giovanni
`Battista, Torino, Italy
`
`Background and Objectives. The immunomodulatory drug
`thalidomide caninhibit 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 mgwith significanttoxicity. No data are available
`on the impactof low-dosethalidomide plus dexametha-
`sone as salvage therapyfor relapsedpatients.
`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 monthsoftreatment, 14
`patients (18%) showed a myelomaprotein 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 survival 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% ofpatients.
`
`interpretation and Conclusions, The associationof low-
`dose thalidomide plus dexamethasoneis 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
`
`haematologica 2001: 86:399-403
`http://www.haematologica.it/2001_04/0399.htm
`
`
`
`Correspondence: Mario Boccadoro, M.D., Divisione di Ematologia dell'U-
`niversita di Torino, Azienda Ospedaliera S. Giovanni Battista, Via Genova
`3, 10126Torino,Italy. Phone: international + 39-011-6635814 _ Fax:
`international +39-011-6963737 - E-mail: mario.boccadoroe@unito.it
`
`Aresresisincreased inmultiplemyelomaand
`
`has a prognostic value in the disease.12 The
`antiangiogenic properties of thalidomide? provide
`the rationale for studying the effect of this drug in
`myeloma. Thalidomide may directly inhibit the growth
`and survival of myelomacells;4 its efficacy may also be
`linked to modulation of growth-related genes, such as
`c-myc.> The interleukin-6 (IL-6) receptor gene is also
`dramatically downregulated!
`For more than 30 years theinitial therapy of multiple
`myelomahasconsisted of melphalan and prednisone.¢*
`A therapeutic strategy to improveclinical outcomeis
`high-dose chemotherapyfollowed by autologous stem
`cell transplantation.2"° Relapses, however, constantly
`occur and cure is rarely achieved."
`To improve treatment outcome andintroduce the pos-
`sibility of curative therapy,it is necessary to search for
`new drugs or new uses of old drugs. One such com-
`poundis thalidomide. This drug was foundto beeffec-
`tive in refractory and recurrent myelomas producing an
`Overall response rate of 32%.'2 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 managementof patients with advanced myelo-
`ma.'*"'5 In vitro, thalidomide enhanced the anti-myelo-
`ma activity of dexamethasone which, conversely, was
`inhibited by IL-6."
`Based on these pieces of evidence, we evaluated the
`toxicity and clinical efficacy of low-dose thalidomide
`combined with corticosteroids on 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.
`
`renee
`haematologica vol. 86(4):April 2001
`
`ALVOGEN, Exh. 1015, p. 0001
`
`ALVOGEN, Exh. 1015, p. 0001
`
`
`
`400
`
`A. Palumboet al.
`
`
`
`No.ofpatients
`Median age (y)
`
`Stage at diagnosis
`IIA
`{IB
`illA
`IIIB
`B2-microglobulin < 3 mg/mL
`B2-microglobulin > 3 mg/mL
`
`M-protein class
`IgG
`IgA
`IgM
`BenceJonesprotein
`
`Bone marrow plasmacells > 30%
`
`71
`65
`
`30
`4
`40
`3
`34
`43
`
`% of patients
`
`60
`27
`1
`12
`
`64
`
`13
`WHOperformancestatus >3
`
`
`Table 2. Response.
`
`
`"
`
`Design and Methods
`Patients
`Between June 1999 and August 2000, 77 consecutive
`patients with refractory or relapsed myelomaentered the
`protocol. The SWOG''8 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/m?as previously described),!? and
`40 were treated with conventional chemotherapy (32
`received oral melphalan and prednisone, 8 dexametha-
`sone-doxorubicin-vincristine). These regimens werealso
`used as salvage therapy. Thalidomide plus dexametha-
`sone was administered a median of 46 monthsafter 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 oneline of therapy, 21 after two and 30 after
`three. Among those receiving high-dose chemotherapy,
`17 werein first untested relapse, 18 in second untested
`relapse and 2 werein resistantrelapse. Of those treated
`with conventional chemotherapy, 4 had primary resis-
`tance, 19 werein resistant relapse and 17 in untested
`relapse. No patients were excluded on the basis of car-
`M-protein reduction No. ofpatients—%of total
`
`diac, renal, pulmonaryorliver function.All patients were
`
`treated in two hematologic centers. Written informed
`75%-100%
`14
`18
`consent was obtained from all patients.
`50%-75%
`18
`23
`Treatment
`25%-50%
`19
`25
`Thalidomide was supplied in 100 mg capsules by
`Grunenthal GmbH, 52222 Stolberg, Germany. Thalido-
`
`26No response* 34
`
`mide was administered at the dose of 100 mg at bedtime
`*Disease progressionorstable disease or <25% M-protein reduction.
`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 Jonesproteinuria >0.5
`g/24h. Pre-treatment evaluation included complete
`blood count, renal andliver function tests, serum and
`urine myelomaprotein and serum Bo-microglobulin eval-
`uation. Patients were evaluated for neurological abnor-
`malities and electromyography wasperformedif clinical
`signs of neuropathy were detected. Patients were eval-
`uated monthly and physical examination and bloodtest
`were routinely performed. The patient’s characteristics
`are listed in Table 1.
`
`was >90%, and >50%, respectively. All other results
`were recorded as failures. Progression was defined by
`increases in serum or urine myelomaprotein >25%. The
`curve was plotted according to the method of Kaplan
`and Meier from the beginning of the treatment with
`thalidomide.2°
`
` Table 1. Patients’ characteristics.
`
`Results
`
`Responserate
`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 suspendedafter a median
`of 3 months (range 1-11). The monthly dose of dexa-
`methasone wasstopped in 1% ofpatients. All patients
`were considered in the evaluation:
`41% showed a
`myelomaprotein 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-
`sion.
`The median time required to obtain the maximum
`response to thalidomide plus dexamethasone was 4.2
`months (range 0.6-10.2): 33% of maximum responses
`were apparentafter 2 months, 15% after 3 months and
`17% after 4 months; however, 35% became apparent
`
`Responsecriteria and statistics
`Complete remission required disappearance of serum
`or urine myeloma protein analyzed by standard elec-
`trophoresis and marrow plasmacytosis <1% forat 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 ofurine myeloma pro-
`tein was recorded asa Clinical response of 75%-100%.
`Clinical
`responses 50%-75%, and 25%-50% were
`defined when the reduction of urine myeloma protein
`ee
`haematologica vol. 86(4):April 2001
`
`ALVOGEN, Exh. 1015, p. 0002
`
`ALVOGEN, Exh. 1015, p. 0002
`
`
`
`Thalidomide for advanced myeloma
`
`401
`
`
`
`PROGRESSION-FREESURVIVAL
`
`
`
`10
`
`MONTHS
`
`12
`
`14
`
`16
`
`18
`
`
`
`
` Figure 1. Progression-free survival of myelomapatients treated with thalidomide plus dexamethasone.
`
`between 4 and 6 months. Improvementof 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 werealive.
`
`Toxicity
`Most adverse effects were recorded as grade | 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, changesin 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% ofpatients, but main-
`ly in elderly subjects. Tingling and numbness were
`observed in an unexpected 14% of patients as grade|,
`in 3% as grade Il. 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 presentin 3% ofpatients and were generally mild.
`Dizziness wasa 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 oralantibiotics. In another patient,
`a severe necrotic ulcer of the skull was observed. Two
`patients had evidence of hypothyroidism. Blood counts
`generally improved whendisease response wasachieved,
`Two patients showed anincrease in creatininelevels. 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 wasdelivered in these subjects. Pre-
`viously reported episodes of deep vein thrombosis were
`not observed (Table 3).2!
`
`Discussion
`The association of low-dose thalidomide plus dexam-
`ethasonewashighly 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
`ee
`haematologica vol. 86(4):April 2001
`
`ALVOGEN, Exh. 1015, p. 0003
`
`ALVOGEN, Exh. 1015, p. 0003
`
`
`
`402
`
`A. Palumboetal.
`
`Table 3. Toxicity.
`
`
`
`
`No.ofpatients % of total
`=
`3
`9
`6
`5
`3
`3
`
`Tingling and numbness
`Constipation
`Weaknessand fatigue
`Sedation
`Changesin work habit
`Mood changesand depression
`Tremor
`Dizziness
`Erysipela
`Hypothyroidism
`Renaltoxicity
`=i a
`Toxicity that required discontinuation of treatment
`
`
`aoRm
`
`WWWWoB&Oco
`
`
`
`but 12 days each month."3 Whenthalidomide was admin-
`istered alone at doses ranging from 200 mg to 800 mg
`partial responses were achieved in 25% of cases in one
`report’? and 40% in another.23
`In conclusion this study confirms previous findings
`showing that thalidomide is a new compoundfor the
`management of myeloma and is the first demonstra-
`tion that low-dose thalidomide plus dexamethasoneis
`an effective treatment for myeloma patients. The low-
`dose thalidomide schedule is very well tolerated and
`highly effective. Whetherthis efficacy is due to an addi-
`tive or synergistic effect with dexamethasoneis not
`Clear.
`
`Contributions and Acknowledgments
`AnPconception, design, interpretation of data, draft-
`ing the article; LG, AB, PP SB, CRSTanalysis, interpreta-
`tion of data, critical revision; EG, AP critical revision,
`importantintellectual suggestions, final approvalof the
`version to be submitted. MB conception, design, drafting
`the article,final approvalof the version to be submitted
`Funding
`This work was supported in part by AssociazioneIta-
`liana Ricerca Cancro (AIRC), AssociazioneItaliana Leu-
`cemie (AIL), and Ministero Universita e Ricerca Scien-
`tifica e Tecnologica (MURST).
`Disclosures
`Conflictof interest: none.
`Redundantpublications: no substantial overlapping
`with previous papers.
`Manuscript processing
`This manuscript was peer-reviewed by two external
`referees and by Prof. Jesus F. San Miguel, who actedas an
`Associate Editor. The final decision to acceptthis paper
`was takenjointly by Prof. San Miguel and the Editors.
`Manuscript received January 5, 2001; accepted March
`8, 2001.
`
`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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`
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`