Monoclonal Gammopathies
`
`original paper
`
`Low-dose thalidomide plus
`dexamethasone is an effective
`salvage therapy for advanced
`myeloma
`
`ANTONIO PALUMBO, LUISA GIACCONE, ALESSANDRA BERTOLA,
`PATRIZIA PREGNO*, SARA BRINGHEN, CECILIA RUS, SABRINA
`TRIOLO, EUGENIO GALLO,* ALESSANDRO PILERI, MARIO
`BOCCADORO
`Divisione di Ematologia dell'Università di Torino,*Divisione di
`Ematologia Ospedaliera, Azienda Ospedaliera S. Giovanni
`Battista, Torino, Italy
`
`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 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% 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
`
`haematologica 2001; 86:399-403
`http://www.haematologica.it/2001_04/0399.htm
`
`Correspondence: Mario Boccadoro, M.D., Divisione di Ematologia dell'U-
`niversità di Torino, Azienda Ospedaliera S. Giovanni Battista, Via Genova
`3, 10126 Torino, Italy. Phone: international + 39-011-6635814 – Fax:
`international +39-011-6963737 - E-mail: mario.boccadoro@unito.it
`
`Angiogenesis is increased in multiple myeloma and
`
`has a prognostic value in the disease.1,2 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 (IL-6) receptor gene is also
`dramatically downregulated.5
`For more than 30 years the initial therapy of multiple
`myeloma has consisted of melphalan and prednisone.6–8
`A therapeutic strategy to improve clinical outcome is
`high-dose chemotherapy followed by autologous stem
`cell transplantation.9,10 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 IL-6.16
`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.
`
`haematologica vol. 86(4):April 2001
`
`DR. REDDY’S LABS., INC. EX. 1053 PAGE 1
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`

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`400
`
`A. Palumbo et al.
`
`Table 1. Patients’ characteristics.
`
`No. of patients
`Median age (y)
`
`Stage at diagnosis
`IIA
`IIB
`IIIA
`IIIB
`β2-microglobulin < 3 mg/mL
`β2-microglobulin > 3 mg/mL
`
`M-protein class
`IgG
`IgA
`IgM
`Bence Jones protein
`
`Bone marrow plasma cells > 30%
`
`WHO performance status >3
`
`Table 2. Response.
`
`77
`65
`
`30
`4
`40
`3
`34
`43
`
`% of patients
`
`60
`27
`1
`12
`
`64
`
`13
`
`M-protein reduction
`
`No. of patients
`
`% of total
`
`41
`
`
`
`
`
`18
`
`23
`
`25
`
`34
`
`14
`
`18
`
`19
`
`26
`
`75%-100%
`
`50%-75%
`
`25%-50%
`
`No response*
`
`*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-
`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 apparent after 2 months, 15% after 3 months and
`17% after 4 months; however, 35% became apparent
`
`Design and Methods
`Patients
`Between June 1999 and August 2000, 77 consecutive
`patients with refractory or relapsed myeloma entered the
`protocol. The SWOG17,18 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 of 100 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 >0.5
`g/24h. Pre-treatment evaluation included complete
`blood count, renal and liver function tests, serum and
`urine myeloma protein and serum β2-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
`
`haematologica vol. 86(4):April 2001
`
`DR. REDDY’S LABS., INC. EX. 1053 PAGE 2
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`

`

`Thalidomide for advanced myeloma
`
`401
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`14
`
`16
`
`18
`
`MONTHS
`
`1
`
`0,9
`
`0,8
`
`0,7
`
`0,6
`
`0,5
`
`0,4
`
`0,3
`
`0,2
`
`0,1
`
`PROGRESSION-FREE SURVIVAL
`
`0
`
`0
`
`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
`Most 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
`
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`

`402
`
`Table 3. Toxicity.
`
`A. Palumbo et al.
`
`No. of patients
`
`% of total
`
`Tingling and numbness
`Constipation
`Weakness and fatigue
`Sedation
`Changes in work habit
`Mood changes and depression
`Tremor
`Dizziness
`Erysipela
`Hypothyroidism
`Renal toxicity
`Toxicity that required discontinuation of treatment
`
`13
`9
`6
`5
`3
`3
`2
`2
`2
`2
`2
`8
`
`17
`12
`8
`6
`4
`4
`3
`3
`3
`3
`3
`10
`
`low-dose thalidomide and dexamethasone have a true
`anti-tumor effect and that this is superior to that
`achieved by oral melphalan and prednisone.
`Recent data suggest that thalidomide alone is active
`in 30-60% of patients with refractory/relapsed myelo-
`ma.12,16,21,23,24 With doses ranging from 200 mg to 800
`mg/day, side-effects were encountered in 10-50%.12 In
`our study, adverse effects were recorded in 5-15%. In
`the escalating dose studies already performed, no rela-
`tion between dose and response has been demonstrat-
`ed.12,21 In preliminary reports, a dose as low as 50 mg/day
`was claimed to be effective in myeloma patients.25,26 In
`our series, median time to response was 4.2 months.
`This was longer than previously reported times, perhaps
`due to the lower dose of thalidomide.
`The importance of glucocorticoids has been demon-
`strated by evaluating melphalan and prednisone admin-
`istration in the primary management of myeloma. Sur-
`vival time was found to correlate with the dose of pred-
`In refractory
`nisone and not with that of melphalan.27
`patients high doses of prednisone or dexamethasone may
`induce remission in a significant proportion of cases.13,14
`Thalidomide and dexamethasone are a logical combi-
`nation since they may differ in their action against
`myeloma. Thalidomide acts via adhesion molecule alter-
`ation, anti-angiogenesis and modulation of T-lympho-
`cytes, whereas dexamethasone exerts its effect by
`inhibiting IL-6 production. In vitro, the addition of dex-
`amethasone increased the inhibition of proliferation
`induced by thalidomide on myeloma cell lines by about
`35%. Thalidomide induced apoptosis in cells resistant to
`dexamethasone, suggesting the potential utility of the
`combination of these two drugs.16
`Here, we demonstrate that the combination of
`thalidomide at 100 mg/day plus dexamethasone at only
`40 mg, 4 days each month, is an effective treatment
`against myeloma. At this dose dexamethasone alone
`cannot induce partial response in 40% of refractory
`patients. For these patients, 30% partial responses were
`recorded when dexamethasone was delivered at 40 mg
`
`haematologica vol. 86(4):April 2001
`
`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 SB, CR, ST analysis, interpreta-
`tion of data, critical revision; EG, AP critical revision,
`important intellectual suggestions, final approval of the
`version to be submitted. MB 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 Italiana Leu-
`cemie (AIL), and Ministero Università e Ricerca Scien-
`tifica e Tecnologica (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. Jesús 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, 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.
`
`References
`
`1. Ribatti D, Vacca A, Nico B, et al. Bone marrow angio-
`genesis and mast cell density increase simultaneously
`with progression of human multiple myeloma. Br J Can-
`cer 1999; 79:451-5.
`2. Vacca A, Ribatti D, Presta M, et al. Bone marrow neo-
`vascularization, plasma cell angiogenic potential, and
`matrix metalloproteinase-2 secretion parallel progres-
`sion of human multiple myeloma. Blood 1999; 93:3064-
`73.
`3. D'Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalido-
`mide is an inhibitor of angiogenesis. Proc Natl Acad Sci
`
`DR. REDDY’S LABS., INC. EX. 1053 PAGE 4
`
`

`

`Thalidomide for advanced myeloma
`
`403
`
`USA 1994; 91:4082-5.
`4. Parman T, Wiley MJ, Wells PG. Free radical-mediated
`oxidative DNA damage in the mechanism of thalidomide
`teratogenicity. Nat Med 1999; 5:582-5.
`5. Shaughnessy J, Zhan F, Tian E, et al. Global gene expres-
`sion analysis shows loss of c-myc and IL-6 receptor gene
`mRNA after exposure of myeloma to thalidomide and
`IMiD. Blood 2000; 96:579a.
`6. San Miguel JF, Bladé Creixenti J, Garcia-Sanz R. Treat-
`ment of multiple myeloma. Haematologica 1999; 84:36-
`58.
`7. Alexanian R, Dimopoulos M. The treatment of multiple
`myeloma. New Engl J Med 1994; 330:484-9.
`8. Bataille R, Harousseau JL. Multiple myeloma. N Engl J
`Med 1997; 336:1657-64.
`9. Attal M, Harousseau JL, Stoppa AM, et al. A prospective,
`randomized trial of autologous bone marrow transplan-
`tation and chemotherapy in multiple myeloma. Inter-
`groupe Français du Myelome. N Engl J Med 1996; 335:
`91-7.
`10. Barlogie B, Jagannath S, Desikan KR, et al. Total therapy
`with tandem transplants for newly diagnosed multiple
`myeloma. Blood 1999; 93:55-65.
`11. Desikan R, Barlogie B, Sawyer J, et al. Results of high-
`dose therapy for 1000 patients with multiple myeloma:
`durable complete remissions and superior survival in the
`absence of chromosome 13 abnormalities. Blood 2000;
`95:4008-10.
`12. Singhal S, Metha J, Desikan R, et al. Antitumor activity
`of thalidomide in refractory multiple myeloma. N Engl J
`Med 1999; 341:1565-71.
`13. Alexanian R, Barlogie B, Dixon D. High-dose glucocorti-
`coid treatment of resistant myeloma. Ann Intern Med
`1986; 105:8-11.
`14. Alexanian R, Yap BS, Bodey GP. Prednisone pulse thera-
`py for refractory myeloma. Blood 1983; 62:572-7.
`15. Alexanian R, Dimopoulos MA, Delasalle K, Barlogie B. Pri-
`mary dexamethasone treatment of multiple myeloma.
`Blood 1992; 80:887-90.
`16. Hideshima 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.
`17. Durie BG, Salmon SE. A clinical staging system for mul-
`tiple myeloma. Correlation of measured myeloma cell
`mass with presenting clinical features, response to treat-
`ment, and survival. Cancer 1975; 36:842-54.
`18. Durie BGM, Salmon SE. Multiple myeloma, macroglobu-
`linemia and monoclonal gammopathies. In: Hoffbrand
`AV, Brown MC Hirsch J, eds. Recent Advances in Haema-
`tology. Edinburgh: Churchill Livingstone, 1977:243-61.
`19. Palumbo A, Triolo S, Argentino C, et al. Dose-intensive
`melphalan with stem cell support (MEL100) is superior to
`standard treatment in elderly myeloma patients. Blood
`1999; 94:1248-53.
`20. Kaplan EL, Meier P. Nonparametric estimation from
`incomplete observations. J Am Stat Assoc 1958; 53:457-
`81.
`21. Kneller A, Raanani P, Hardan I, et al. Therapy with
`thalidomide in refractory multiple myeloma patients: the
`revival of an old drug. Br J Haematol 2000; 108:391-3.
`22. Buzaid AC, Durie BG. Management of refractory myelo-
`ma: a review. J Clin Oncol 1988; 6:889-905.
`23. Juliusson G, Celsing F, Turesson I, Lenhoff S, Adriansson
`M, Malm C. Frequent good partial remissions from
`thalidomide including best response ever in patients with
`advanced refractory and relapsed myeloma. Br J Haema-
`tol 2000; 109:89-96.
`24. Yakoub-Agha I, Moreau P, Leyvraz S, et al. Thalidomide
`in patients with advanced multiple myeloma. Hematol J
`2000; 1:186-9.
`25. Pini M, Baraldi A, Pietrasanta D, et al. Low-dose of
`thalidomide in the treatment of refractory myeloma.
`Haematologica 2000; 85:1111-2.
`26. Leleu X, Cornillon J, Magro L, et al. Is thalidomide 50
`mg/d as a minimal first dose effective in advanced myelo-
`ma? Blood 2000; 96:290b.
`27. Palmer M, Belch A, Hanson J, Brox L. Dose intensity
`analysis of melphalan and prednisone in multiple myelo-
`ma. J Natl Cancer Inst 1988; 80:414-8.
`
`haematologica vol. 86(4):April 2001
`
`DR. REDDY’S LABS., INC. EX. 1053 PAGE 5
`
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