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`www.bloodjournal.orgFrom
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`Brief report
`
`Extended survival in advanced and refractory multiple myeloma after single-agent
`thalidomide: identification of prognostic factors in a phase 2 study of 169 patients
`
`Bart Barlogie, Raman Desikan, Paul Eddlemon, Trey Spencer, Jerome Zeldis, Nikhil Munshi, Ashrof Badros, Maurizio Zangari,
`Elias Anaissie, Joshua Epstein, John Shaughnessy, Dan Ayers, Dan Spoon, and Guido Tricot
`
`This report of a phase 2 trial of thalido-
`mide (THAL) (200 mg/d; 200 mg incre-
`ment every 2 weeks to 800 mg) for 169
`patients with advanced myeloma (MM)
`(abnormal cytogenetics (CG), 67%; prior
`autotransplant, 76%) extends earlier re-
`sults in 84 patients. A 25% myeloma pro-
`tein reduction was obtained in 37% of
`patients (50% reduction in 30% of pa-
`Introduction
`
`tients; near-complete or complete remis-
`sion in 14%) and was more frequent with
`low plasma cell labeling index (PCLI) (be-
`low 0.5%) and normal CG. Two-year event-
`free and overall survival rates were
`20% 6 6% and 48% 6 6%, respectively,
`and these were superior with normal CG,
`PCLI of less than 0.5%, and b2-micro-
`globulin of 3 mg/L. Response rates were
`
`higher and survival was longer especially
`in high-risk patients given more than 42 g
`THAL in 3 months (median cumulative
`dose) (landmark analysis); this supports
`a THAL dose-response effect in advanced
`MM. (Blood. 2001;98:492-494)
`
`© 2001 by The American Society of Hematology
`
`Thalidomide (THAL) represents the first new class of active agents in
`the treatment of multiple myeloma (MM) since the introduction of
`melphalan and glucocorticoids more than 3 decades ago.1 Its possible
`antitumor mechanisms in MM include a direct effect on MM and/or
`bone marrow stromal cells,2 modulation of MM stromal cell adhesion,3
`suppression of MM cell–sustaining cytokines,4 antiangiogenic effects
`by repression of vascular endothelial growth factor and basic fibroblast
`growth factor pathways,5 and immunomodulation such as induction of
`TH1 T-cell response with secretion of interferon-g and interleukin-2.6
`More recently, synergistic apoptotic signaling of THAL and dexametha-
`sone has also been observed.7
`We now report on the follow-up of all 169 patients enrolled in a
`phase 2 trial for advanced and refractory MM.
`
`defined by absence of monoclonal protein on immunofixation analysis.1
`Patients with a PPR less than 25% and those discontinuing treatment before
`response could be assessed (minimum of 4 weeks of therapy) were
`considered to have failed treatment; all results were evaluated on an
`intent-to-treat basis. Relapse criteria have been previously reported.1
`Survival distributions (Kaplan-Meier) were compared by means of the
`log-rank test.8,9 Multivariate modeling of bivariate responses was performed by
`means of logistic regression and stepwise selection methods. Similarly, multivar-
`iate modeling of event-free (EFS) and overall survival (OS) employed stepwise
`selection and proportional hazard regression models.10 The percentage of change
`in laboratory measures was calculated from baseline to 90 days post–THAL
`administration. Wilcoxon rank sum tests were used to compare the percentage-
`change distributions of patients with 50% or greater reduction in paraprotein
`levels and of patients with less than 50% reduction.
`
`Study design
`
`Between December 1997 and December 1998, 169 consecutive eligible patients
`with extensively pretreated and progressive MM were enrolled in a phase 2 trial.
`THAL (50-mg capsules) (Celgene, Warren, NJ) was started at a daily dose of 200
`mg and escalated by 200 mg every 2 weeks to 800 mg according to tolerance.
`Patients with cardiopulmonary or renal dysfunction were not excluded; liver
`function tests could not exceed twice the upper limit of normal. All patients were
`enrolled at a single institution and provided written informed consent in keeping
`with institutional and Food and Drug Administration guidelines.
`Baseline and follow-up laboratory tests were performed as previously
`outlined.1 Patients kept a diary to document the occurrence and severity of
`toxicities. Follow-up visits were scheduled every 3 months, and more than
`90% of patients adhered to this.
`Study endpoints included paraprotein responses (PPRs) in serum and/or
`urine of at least 25%, 50%, 75%, or 90%; complete remission (CR) was
`
`Results and discussion
`
`Patient characteristics and percentages consisted of the following:
`age older than 60 years in 40% of patients, b2-microglobulin
`(B2M) greater than 3 mg/L in 50%, abnormal cytogenetics (CG) in
`67% (deletion 13 in 37%), longer than 5 years of prior therapy in
`20%, and longer 2 years of prior therapy in 72%. Seventy-six
`percent had received at least 1 and 53% had received 2 or more
`cycles of prior high-dose therapy with stem cell support. THAL
`could be escalated to 400 mg, 600 mg, and 800 mg in 87%, 68%,
`and 56% of patients, respectively. No treatment-related deaths were
`observed; 58% developed toxicities greater than grade 2 which
`affected the central nervous system in 25% (mainly sedation and
`somnolence; confusion; depression; tremor), gastrointestinal tract
`in 16% (mainly constipation; infrequently nausea or vomiting), and
`peripheral nerves (sensory neuropathy) in 9%. These toxicities
`
`From the Myeloma and Transplantation Research Center, University of
`Arkansas for Medical Sciences, Little Rock, AR; and Celgene Co, Warren, NJ.
`
`Reprints: Bart Barlogie, Director, ACRC, University of Arkansas for Medical
`Sciences, 4301 West Markham, Slot 623, Little Rock, AR 72205.
`
`Submitted November 17, 2000; accepted March 23, 2001.
`
`Supported in part by grant CA55819 from the National Cancer Institute in
`Bethesda, MD.
`
`The publication costs of this article were defrayed in part by page charge
`payment. Therefore, and solely to indicate this fact, this article is hereby
`marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
`
`© 2001 by The American Society of Hematology
`
`492
`
`BLOOD, 15 JULY 2001 z VOLUME 98, NUMBER 2
`
`ALVOGEN, Exh. 1053, p. 0001
`
`

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`by guest
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`www.bloodjournal.orgFrom
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`
`BLOOD, 15 JULY 2001 z VOLUME 98, NUMBER 2
`
`THALIDOMIDE IN ADVANCED MYELOMA
`
`493
`
`were related to both intensity and cumulative dose of THAL
`administered (data not shown). Fewer than 2% of patients devel-
`oped deep venous thrombosis (Doppler) or cytopenia.
`A PPR of 25% was observed in 37% of patients; a PPR of 50%
`in 30%; and a PPR of 90% in 14% (Figure 1). Of patients exhibiting
`25% PPR, 70% achieved that response within 2 months and 90%
`within 4.5 months. PPRs of 25% were more frequent with normal
`CG (52% vs 28%; P 5 .003) and with low PCLI (44% vs 10%;
`P , .001). Importantly, 14% of patients experienced their best
`response ever on THAL. THAL-induced PPRs were associated
`with significant reductions in bone marrow plasmacytosis and B2M
`as well as improvement in hemoglobin and uninvolved immuno-
`globulin M levels (data not shown).
`Twenty-four patients remain on study. Reasons for study
`removal were disease progression in 105 patients, toxicity in 28,
`and other reasons in 12. With a median follow-up of 22 months
`among 84 alive patients, 2-year EFS and OS rates are 20% 6 6%
`and 48% 6 6%, respectively (Figure 1).
`On multivariate analysis, EFS and OS were superior with normal
`CG, PCLI lower than or equal to 0.5%, and B2M lower than or equal to
`3 mg/L, permitting distinction of 4 risk groups (see Figure 1). When
`results were re-examined without CG and PCLI, which are usually not
`available in the standard practice setting, B2M greater than 3 mg/L and
`C-reactive protein (CRP) greater than 7 mg/L emerged as key adverse
`variables for OS and EFS. Better prognosis was not associated with no
`prior transplant or longer time lapse since transplant.
`To evaluate a possible dose effect of THAL on clinical
`outcome, a 3-month landmark analysis was performed. Patients
`given more than 42 g THAL in 3 months (median cumulative dose)
`had a higher response rate (25% PPR) (54% vs 21%; P , .001) and
`superior 2-year survival (63% 6 8% vs 45% 6 13%; P , .001);
`this was especially the case among patients with at least 1 of 3
`adverse prognostic features present (Table 1; Figure 1). Responders
`(25%, 3-month landmark) had superior 2-year EFS and OS rates
`(34% and 69%, respectively) compared with nonresponders (20%
`and 47%, respectively; P , .001 and P 5 .01, respectively).
`These data extend, in twice as many patients with longer follow-up,
`our earlier observations in 84 patients.1 Considering the high-risk study
`cohort, the EFS and OS rates of 26% and 48%, respectively, 2 years after
`initiation of treatment are impressive. In fact, 38% of patients had
`received salvage treatment with dexamethasone (32 patients) or combi-
`nation chemotherapy (dexamethasone and 4-day continuous infusions
`of cyclophosphamide, etoposide, and cisplatin [DCEP],11 33 patients)
`and progressed when THAL was initiated.
`Results similar to ours have since been reported with THAL alone
`and in combination with dexamethasone.12-17 Anticipating a THAL
`
`Table 1. Higher thalidomide dose benefits patients with high-risk disease
`
`No. risk
`factors*
`
`# 1
`
`$ 1
`
`Thalidomide
`dose of more
`than 42 g/3 mo
`
`No.
`patients
`
`PPR by at
`least 25%
`
`yes
`no
`yes
`no
`
`55
`36
`28
`30
`
`45
`19
`43
`13
`
`P
`
`.01
`
`.02
`
`% alive
`at 2 y
`
`74
`66
`42
`20
`
`P
`
`NS
`
`.01
`
`*Risk factors are b2-microglobulin . 3 mg/L, plasma cell labeling index . 0.5%,
`and abnormal cytogenetics.
`dose-response effect in a patient population with such advanced MM,
`our study called for dose escalation according to tolerance. Indeed, a
`dose-response effect was apparent in the high-risk subgroup defined by
`abnormal CG, B2M, and PCLI. However, prospective investigations are
`needed to determine, separately in early and advanced MM, the optimal
`THAL dose and schedule.
`We had previously not observed a consistent antiangiogenic effect of
`THAL using serial microvessel density measurements of anti-CD34
`monoclonal antibody–stained bone marrow biopsies.1 This may not be
`surprising since the major effect of an antiangiogenesis agent should be
`prevention of new microvessel formation rather than destruction of
`existing blood vessels. Many of the multiple mechanisms already
`demonstrated in vitro may be operative in different patient subsets or
`even in MM subpopulations in the same patient.7 Gene array technology
`is uniquely suited to unravel the mechanisms of action of THAL and its
`congeners in vivo.18
`The virtual lack of myelosuppression makes THAL an ideal drug for
`combination with cytotoxic agents earlier in the disease. Such trials are
`currently in progress. Deep venous thrombosis,19 hypothyroidism, and
`bradycardia were more frequent in patients randomized to THAL.20
`In conclusion, THAL has definite activity in refractory MM. Its role
`in the up-front management of newly diagnosed MM and as mainte-
`nance therapy is under investigation. Issues of pharmacokinetics, dose
`intensity and scheduling, mechanism of action, and drug combinations
`need to be addressed.21 Since THAL’s activity in MM may involve,
`among other things, an antiangiogenic mechanism, this malignancy
`lends itself well to investigation of strictly antiangiogenic agents such as
`angiostatin and endostatin, shown to possess remarkable antitumor
`activity in the human severe combined immunodeficiency disease
`model of MM (J. Epstein, personal communication, May 2000).
`
`Acknowledgments
`
`Drs D. Siegel, S. Lim, S. Singhal, and J. Mehta are acknowledged
`for having contributed patients to this study.
`
`Figure 1. Response, toxicity, and survival. (A) Response rates
`and grade 3 toxicities; (B) EFS and OS. (C) EFS and (D) OS
`according to the number of unfavorable prognostic factors present
`prior to thalidomide. Risk discrimination on the basis of abnormal
`CG (EFS hazard ratio [HR] 2.15, P, .001; OS HR 2.53, P5 .002);
`plasma cell labeling index (PCLI) greater than 0.5% (EFS HR
`1.86, P5 .002; OS HR 1.82, P5 .009); and B2M greater than 3
`mg/L (EFS HR 1.54, P5 .016; OS HR 2.99, P, .001). Solid lines
`indicate no risk factors; dashed line, 1; dotted line, 2; and
`dash-dotted line, 3 risk factors. Additional unfavorable variables
`that are only univariately significant included the following for
`EFS: albumin level less than 3.5 g/dL, P5 .003; and BM plasmacyto-
`sis greater than 30%, P5 .001. Additional unfavorable variables
`that are only univariately significant included the following for OS:
`less than 3.5 g/dL, P, .001; BM plasmacytosis
`albumin level
`greater than 30%, P5 .05; hemoglobin level less than 10 g/dL,
`P, .001; creatinine greater than 1.5 mg/dL, P, .001; and
`platelet count fewer than 100 000 mL, P5 .007. TRM indicates
`treatment-related mortality; DVT, deep veinous thrombosis.
`
`ALVOGEN, Exh. 1053, p. 0002
`
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`www.bloodjournal.orgFrom
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`For personal use only.on November 22, 2017.
`
`494
`
`BARLOGIE et al
`
`References
`
`BLOOD, 15 JULY 2001 z VOLUME 98, NUMBER 2
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`
`ALVOGEN, Exh. 1053, p. 0003
`
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`www.bloodjournal.orgFrom
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`For personal use only.on November 22, 2017.
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`2001 98: 492-494
`doi:10.1182/blood.V98.2.492
`
`Extended survival in advanced and refractory multiple myeloma after
`single-agent thalidomide: identification of prognostic factors in a phase 2
`study of 169 patients
`
`Bart Barlogie, Raman Desikan, Paul Eddlemon, Trey Spencer, Jerome Zeldis, Nikhil Munshi, Ashrof Badros,
`Maurizio Zangari, Elias Anaissie, Joshua Epstein, John Shaughnessy, Dan Ayers, Dan Spoon and Guido
`Tricot
`
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`ALVOGEN, Exh. 1053, p. 0004
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