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`For personal use only.
`
`CLINICAL TRIALS AND OBSERVATIONS
`
`Lenalidomide plus dexamethasone versus thalidomide plus dexamethasone in
`newly diagnosed multiple myeloma: a comparative analysis of 411 patients
`Francesca Gay,1 Suzanne R. Hayman,1 Martha Q. Lacy,1 Francis Buadi,1 Morie A. Gertz,1 Shaji Kumar,1 Angela Dispenzieri,1
`Joseph R. Mikhael,2 P. Leif Bergsagel,2 David Dingli,1 Craig B. Reeder,2 John A. Lust,1 Stephen J. Russell,1 Vivek Roy,3
`Steven R. Zeldenrust,1 Thomas E. Witzig,1 Rafael Fonseca,2 Robert A. Kyle,1 Philip R. Greipp,1 A. Keith Stewart,2 and
`S. Vincent Rajkumar1
`
`1Department of Internal Medicine, Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN; 2Division of Hematology/Oncology, Mayo Clinic
`College of Medicine, Scottsdale, AZ; and 3Division of Hematology/Oncology, Mayo Clinic College of Medicine, Jacksonville, FL
`
`The objective of this case-control study
`was to compare the efficacy and toxicity
`of lenalidomide plus dexamethasone (len/
`dex) versus thalidomide plus dexametha-
`sone (thal/dex) as initial therapy for newly
`diagnosed myeloma. We retrospectively
`studied 411 newly diagnosed patients
`treated with len/dex (228) or thal/dex (183)
`at the Mayo Clinic. The differences were
`similar in a matched-pair analysis that
`adjusted for age, sex, transplantation sta-
`tus, and dexamethasone dose. The pro-
`portions of patients achieving at least a
`Introduction
`
`partial response to len/dex and thal/dex
`were 80.3% versus 61.2%, respectively
`(P < .001); very good partial response
`rates were 34.2% and 12.0%, respectively
`(P < .001). Patients receiving len/dex had
`longer time to progression (median, 27.4
`vs 17.2 months; P ⴝ .019), progression-
`free survival (median, 26.7 vs 17.1 months;
`P ⴝ .036), and overall survival (median
`not reached vs 57.2 months; P ⴝ .018).
`A similar proportion of patients in the
`2 groups experienced at least one grade 3
`or 4 adverse event
`(57.5% vs 54.6%,
`
`P ⴝ .568). Main grade 3 or 4 toxicities of
`len/dex were hematologic, mainly neutro-
`penia (14.6% vs 0.6%, P < .001); the most
`common toxicities in thal/dex were ve-
`nous thromboembolism (15.3% vs 9.2%,
`P ⴝ .058) and peripheral neuropathy
`(10.4% vs 0.9%, P < .001). Len/dex ap-
`pears well-tolerated and more effective
`than thal/dex. Randomized trials are
`needed to confirm these results. (Blood.
`2010;115:1343-1350)
`
`Multiple myeloma (MM) is a malignant plasma cell proliferative
`disorder that accounts for more than 11 000 deaths each year in the
`United States.1,2 For more than 40 years, melphalan and prednisone
`(MP) remained the standard of care for elderly patients. For more
`than a decade, a combination of vincristine, doxorubicin, and
`dexamethasone (VAD) was used as pretransplantation induction
`therapy for patients eligible for stem cell transplantation (SCT).2-4
`The combination of thalidomide plus dexamethasone (thal/dex) has
`shown significant activity in newly diagnosed MM. Indeed,
`2 randomized phase 3 trials compared thal/dex with high-dose
`dexamethasone alone and reported higher response rates and
`prolonged time to progression (TTP) in patients receiving thal/dex,
`even though this did not
`translate into overall survival (OS)
`improvement, albeit with relatively short follow-up.5,6 The main
`toxicities related to thalidomide therapy were deep vein thrombosis
`(DVT; 13%-19%) and peripheral neuropathy (3%-7%).5-7 A random-
`ized study that compared MP with the thal/dex combination in
`patients not eligible for SCT found that thal/dex resulted in a higher
`proportion of very good partial response (VGPR) rate and partial
`response (PR), but TTP, progression-free survival (PFS), and OS
`were better for MP because of the toxicity of high-dose dexametha-
`sone, especially in patients older than 75 years.7 A prospective
`randomized trial comparing thal/dex with standard VAD as pretrans-
`plantation induction regimen showed a higher response rate after
`induction in patients treated with thal/dex, although the benefit was
`
`not sustained 6 months after SCT because VGPR rates were almost
`identical after the high-dose melphalan.8
`Lenalidomide (CC-5013), an analog of thalidomide, is more
`potent in preclinical assays than thalidomide9,10 and has fewer
`nonhematologic side effects compared with the parent drug.11,12 In
`newly diagnosed patients, lenalidomide plus high-dose dexametha-
`sone was compared with high-dose dexamethasone alone in a
`double-blinded, placebo-controlled trial and was demonstrably
`superior to high-dose dexamethasone in terms of both response
`rates and 1-year PFS, but no differences in OS have been reported
`to date.13 Another recent phase 3 study compared the combination
`of lenalidomide plus low-dose dexamethasone with the lenalido-
`mide plus high-dose dexamethasone regimen: major grade 3 or
`higher toxic effects,
`including thrombosis (25% vs 9%) and
`infections (16% vs 6%), were significantly higher in the lenalido-
`mide plus high-dose dexamethasone group, and 1-year OS was
`significantly better with the association of lenalidomide plus
`low-dose dexamethasone. The differences were confirmed in both
`younger and elderly patients.14
`No randomized trial of thal/dex versus lenalidomide plus
`dexamethasone (len/dex) has been reported so far, and unfortu-
`nately none is ongoing or planned. Thalidomide has significant
`nonhematologic toxicity,
`including a high risk of peripheral
`neuropathy. On the other hand, lenalidomide has more hematologic
`toxicity than thalidomide, and is not widely available in many
`
`Submitted August 17, 2009; accepted November 15, 2009. Prepublished
`online as Blood First Edition paper, December 11, 2009; DOI 10.1182/blood-
`2009-08-239046.
`
`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 USC section 1734.
`
`The online version of this article contains a data supplement.
`
`© 2010 by The American Society of Hematology
`
`BLOOD, 18 FEBRUARY 2010 䡠 VOLUME 115, NUMBER 7
`
`1343
`
`ALVOGEN, Exh. 1039, p. 0001
`
`

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`
`1344
`
`GAY et al
`
`Table 1. Patient characteristics
`
`BLOOD, 18 FEBRUARY 2010 䡠 VOLUME 115, NUMBER 7
`
`All patients
`
`High-dose dexamethasone patients
`
`Characteristic
`
`thal/dex (n ⴝ 183), n (%)
`
`len/dex (n ⴝ 228), n (%)
`
`Median age, y (range)
`Less than 65 y
`Male sex
`International Staging System
`I/II*
`III*
`Missing
`Type of M protein
`IgG
`IgA
`No serum M protein
`Biclonal
`Light-chain only
`Missing
`Cytogenetic
`High-risk*
`Data missing
`Treatment
`High-dose dexamethasone
`Transplantation
`
`60.2 (22.2-79.5)
`125 (68.3)
`109 (59.6)
`
`62.9 (29.0-92.9)
`127 (55.7)
`142 (62.3)
`
`95 (75.4)
`31 (24.6)
`57 (31.2)
`
`105 (57.4)
`34 (18.6)
`2 (1.1)
`3 (1.6)
`19 (10.4)
`20 (10.9)
`
`17 (37.8)
`138 (75.4)
`
`135 (73.7)
`110 (60.1)
`
`151 (77.4)
`44 (22.6)
`33 (14.5)
`
`136 (59.6)
`43 (18.9)
`4 (1.8)
`5 (2.2)
`35 (15.4)
`5 (2.2)
`
`25 (32.9)
`152 (66.7)
`
`72 (31.6)
`111 (48.7)
`
`P
`
`.061
`.009
`.574
`
`.673
`.673
`—
`
`.642
`.942
`.696
`.737
`.138
`—
`
`.586
`—
`
`⬍ .001
`.021
`
`thal/dex (n ⴝ 72)
`
`len/dex (n ⴝ 72)
`
`P
`
`63.3 (36.6-78.7)
`40 (55.6)
`44 (61.1)
`
`63.5 (29.0-78.4)
`40 (55.6)
`43 (59.7)
`
`41 (71.9)
`16 (28.1)
`15 (20.8)
`
`45 (62.5)
`18 (25.0)
`0 (0)
`0 (0)
`5 (6.9)
`4 (5.6)
`
`4 (40.0)
`62 (86.1)
`
`72 (100)
`37 (51.4)
`
`53 (81.5)
`12 (18.5)
`7 (9.7)
`
`40 (55.6)
`17 (23.6)
`1 (1.4)
`2 (2.8)
`9 (12.5)
`3 (4.2)
`
`9 (33.3)
`45 (62.5)
`
`72 (100)
`37 (51.4)
`
`.952
`⬎ .999
`.865
`
`.208
`.208
`—
`
`.397
`.846
`⬎ .999
`.497
`.400
`—
`
`.715
`—
`
`⬎ .999
`⬎ .999
`
`Percentages may not total 100 because of rounding.
`— indicates not applicable.
`*Percentage calculated on number of patients for whom data were available.
`
`countries. The goal of this case-control study was to compare the
`efficacy and the toxicity of thal/dex versus len/dex as primary
`therapy for newly diagnosed MM patients.
`
`Methods
`
`Patients and treatment schedule
`
`After approval from the Mayo Clinic Institutional Review Board, data from
`411 consecutive patients with newly diagnosed symptomatic MM seen
`at the Mayo Clinic and treated with thal/dex (183 patients) or len/dex
`(228 patients) were obtained by review of medical records and our existing
`database. We included all patients started on these agents, regardless of
`whether or not the treatment was administered as part of a trial to avoid bias
`in patient selection. Patients in the thal/dex group were treated from January
`2000 through March 2008, whereas patients in the len/dex group were
`treated from March 2004 through December 2008. Thalidomide was given
`at a dose ranging from 100 mg/day to 400 mg/day continuously; lenalido-
`mide dose was 25 mg/day, days 1 to 21 on a 28-day cycle. All patients
`received dexamethasone, either at high dose (40 mg orally on days 1-4,
`9-12, and 17-20) or at low dose (40 mg orally on days 1, 8, 15, and 22); each
`cycle was repeated every 4 weeks. Patients were risk-stratified into 2 groups
`according to genetic abnormalities. The high-risk group was defined by the
`presence of at least one of the following abnormalities: deletion of p53
`(locus 17p13), translocation t(4;14) or t(14;16) by fluorescent in situ
`hybridization, or loss of chromosome 13 or its long arm or hypodiploidy by
`metaphase cytogenetics.15 The standard-risk group included patients with-
`out any of these abnormalities. In addition to studying all patients, we also
`identified for accurate outcome comparison an equal number of pair mates
`among patients who received high-dose dexamethasone in the thal/dex and
`len/dex groups. Case matching was performed with respect to age, sex, and
`SCT status (patients treated with len/dex who received SCT were matched
`with patients treated with thal/dex who received SCT; patients treated with
`len/dex who did not receive SCT were matched with patients treated with
`thal/dex who did not received SCT).
`
`Assessment of efficacy and safety
`
`The response criteria used were standard International Myeloma Working
`Group Uniform Response Criteria.16 Briefly, a PR was defined as a 50% or
`
`higher decrease in the serum monoclonal protein (M-protein) levels from
`baseline and a greater than 90% reduction in 24-hour urine M-protein
`excretion or less than 200 mg/24 hours (if M-protein was immeasurable, a
`50% or higher decrease in the difference between involved and uninvolved
`free light chain or a 50% or higher reduction in bone marrow plasma cells);
`for patients with soft-tissue plasmacytomas, a 50% size reduction was
`required. A VGPR required a 90% or greater reduction in serum M-protein
`and urinary M-protein less than 100 mg/24 hours or M-protein detectable
`by immunofixation but not on electrophoresis. A complete response (CR)
`was defined as negative serum and urine immunofixation, disappearance of
`any soft tissue plasmacytoma, and less than 5% plasma cells on bone
`marrow examination. Disease that did not satisfy the criteria for PR, VGPR,
`CR, or progressive disease was classified as stable disease. Disease
`progression required any of the following: 25% or greater increase in serum
`M-protein (absolute ⱖ 0.5 g/dL) or urine M-protein (absolute ⱖ 200 mg/
`dL) or, in case of immeasurable M-protein, in the difference between
`involved and uninvolved free light chain (absolute ⬎ 10 mg/dL) or
`25% increase in bone marrow plasma cell percentage; development of new
`bone lesions, or plasmacytomas; and disease-related hypercalcemia. All
`responses needed to be confirmed in at least 2 consecutive assessments.
`TTP was calculated from the start of therapy until progression, relapse, or
`last known remission (death from causes other than progression were
`censored); PFS was calculated from the start of therapy until the date of
`progression, relapse, death from any cause, or known remission; OS was
`calculated from the start of therapy until the date of death or the date the
`patient was last known to be alive. All adverse events (AEs) were graded
`according to the National Cancer Institute Common Terminology Criteria
`(Version 3.0).17
`
`Statistical analysis
`
`The endpoint of this study was to compare the efficacy (response rate, PFS,
`TTP, and OS) and the toxicity profile (rate of grade 3 or 4 AEs) of these
`2 regimens. Outcomes were analyzed on an intention-to-treat basis. The ␹2
`test or 2-sided Fisher exact test was used to compare differences in nominal
`variables, and the rank-sum test was used for continuous variables.
`Time-to-event analysis was performed using the Kaplan-Meier method.18
`All comparisons were determined by the log-rank test and by the Cox
`proportional hazards model to estimate crude hazard ratios (HRs) and 95%
`confidence intervals (95% CIs). Analyses were performed using SAS
`software, Version 9.1. Times of observation were censored on May 5, 2009.
`
`ALVOGEN, Exh. 1039, p. 0002
`
`

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`by guest
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`www.bloodjournal.orgFrom
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`on July 29, 2016.
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`BLOOD, 18 FEBRUARY 2010 䡠 VOLUME 115, NUMBER 7
`
`LENALIDOMIDE VS THALIDOMIDE INDUCTION IN MYELOMA
`
`1345
`
`thal/dex (n ⴝ 139), n (%)
`
`len/dex (n ⴝ 97), n (%)
`
`14 (10.1)
`21 (15.1)
`34 (24.5)
`0 (0)
`23 (16.6)
`47 (33.8)
`
`18 (18.6)
`28 (28.9)
`22 (22.7)
`4 (4.1)
`10 (10.3)
`15 (15.5)
`
`P
`
`.061
`.014
`.752
`.028
`.174
`.002
`
`Table 2. Second-line salvage regimens
`Regimen
`
`Transplantation
`Bortezomib-based regimen
`Lenalidomide-based regimen
`Lenalidomide-bortezomib based regimen
`Thalidomide-based regimen
`Others
`
`Results
`
`Patient characteristics
`
`Patient characteristics are listed in Table 1. Median age was similar
`in the 2 groups, although in the thal/dex group 68.3% of patients
`were younger than 65 years compared with 55.7% in the len/dex
`group (P ⫽ .009). A similar proportion of len/dex and thal/dex
`patients presented with International Staging System (ISS) stage
`I/II at diagnosis (77.4% vs 75.4%, P ⫽ .673). Cytogenetic data
`were available in only 33.3% of patients who received len/dex and
`24.6% of patients treated with thal/dex. The proportions of
`evaluable patients presenting with high-risk cytogenetic in both
`groups were similar (32.9% vs 37.8%, respectively, in len/dex and
`thal/dex groups, P ⫽ .586). The majority of patients received
`thalidomide and lenalidomide not as part of a clinical trial. Only
`64 of 183 (35.0%) patients and 96 of 228 (42.1%) were treated as
`part of a clinical trial in the thal/dex and len/dex groups, respec-
`tively. A high proportion of patients in the thal/dex group received
`high-dose dexamethasone compared with patients in the len/dex
`group (73.7% vs 31.6%, P ⬍ .001), reflecting changing in clinical
`practice. Patients were allowed to proceed to SCT if they wished
`and were deemed eligible for such therapy: 39.9% versus 47.5% of
`patients, respectively (P ⫽ .121),
`in the len/dex and thal/dex
`groups received SCT as front-line therapy within 9 months after
`initial diagnosis. Overall, 48.7% versus 60.1% of patients, respec-
`tively (P ⫽ .021), received transplantation at some point during
`their clinical course. A significantly higher proportion of patients
`treated with len/dex received salvage therapy (as second-line only)
`with bortezomib-based regimens (bortezomib-based regimens:
`28.9% vs 15.1%, respectively, with len/dex and thal/dex, P ⫽ .014;
`lenalidomide plus bortezomib-based regimens: 4.1% vs 0%, respec-
`tively, with len/dex and thal/dex, P ⫽ .028; Table 2). Patient
`characteristics in the subgroup of matched patients receiving
`high-dose dexamethasone were similar to those of the whole
`population.
`
`Response to therapy
`
`Based on standard International Myeloma Working Group criteria,
`the response rate was significantly higher in len/dex patients
`compared with thal/dex patients (Table 3). On intention-to-treat
`analysis, considering all 411 patients, a significantly higher propor-
`tion of patients achieved at least a PR with len/dex compared with
`thal/dex (80.3% vs 61.2%, respectively, P ⬍ .001). A significant
`difference between the 2 groups was also found in terms of both
`VGPR or better (34.2% vs 12.0%, P ⬍ .001) and CR rate (13.6%
`vs 3.3%, P ⬍ .001), respectively. These differences remained
`significant when the analysis was restricted to 144 patients who
`received high-dose dexamethasone; len/dex (n ⫽ 72) patients ob-
`tained a significantly higher proportion of PR or better (90.3% vs
`61.1%, P ⬍ .001), VGPR or better (50.0% vs 9.7%, P ⬍ .001), and
`CR (22.2% vs 2.8%, P ⬍ .001).
`
`Survival
`
`The median duration of follow-up for survivors from diagnosis was
`20.9 months in the len/dex group and 46.5 months in the thal/dex
`group. Duration of therapy was significantly longer in the len/dex
`patients compared with the thal/dex patients: 36.7% vs 12.6% of
`patients who did not stop treatment to receive SCT were still
`receiving immunomodulatory drugs at 1 year (P ⬍ .001). A
`significantly higher proportion of patients in the len/dex group was
`still receiving therapy at the time of analysis compared with
`patients in the thal/dex group (18.4% vs 7.1%, respectively,
`P ⫽ .001). In the following analyses, patients who received SCT
`and patients who switched to another chemotherapy regimen before
`progression were censored at the date of transplantation/chemotherapy.
`Among all patients, TTP was significantly better in the len/dex
`group (median, 27.4 months) than in patients receiving thal/dex
`(median, 17.2 months, HR ⫽ 0.64; 95% CI, 0.44-0.93; P ⫽ .019;
`Figure 1A). This was also confirmed in the subgroup of pair mates
`receiving high-dose dexamethasone (median TTP, 33.0 months vs
`15.3 months, HR ⫽ 0.52; 95% CI, 0.28-0.94; P ⫽ .030; Figure
`1B). Similarly, PFS was significantly higher in len/dex patients,
`
`Table 3. Best responses to treatment
`
`All patients
`
`Response
`
`thal/dex (n ⴝ 183), n (%)
`
`len/dex (n ⴝ 228), n (%)
`
`CR or VGPR
`PR or better
`CR
`VGPR
`PR
`SD
`PD
`NA
`
`22 (12.0)
`112 (61.2)
`6 (3.3)
`16 (8.7)
`90 (49.2)
`42 (22.9)
`1 (0.6)
`28 (15.3)
`
`78 (34.2)
`183 (80.3)
`31 (13.6)
`47 (20.6)
`105 (46.1)
`26 (11.4)
`5 (2.2)
`14 (6.1)
`
`P
`
`⬍ .001
`⬍ .001
`⬍ .001
`⬍ .001
`.528
`.002
`.232
`—
`
`High-dose dexamethasone patients
`
`thal/dex (n ⴝ 72), n (%)
`
`len/dex (n ⴝ 72), n (%)
`
`7 (9.7)
`44 (61.1)
`2 (2.8)
`5 (6.9)
`37 (51.4)
`21 (29.2)
`1 (1.4)
`6 (8.3)
`
`36 (50.0)
`65 (90.3)
`16 (22.2)
`20 (27.8)
`29 (40.3)
`3 (4.2)
`1 (1.4)
`3 (4.2)
`
`P
`
`⬍ .001
`⬍ .001
`⬍ .001
`.001
`.181
`⬍ .001
`⬎ .999
`—
`
`Percentages may not total 100 because of rounding.
`SD indicates stable disease; PD, progressive disease; NA, not available; and —, not applicable.
`
`ALVOGEN, Exh. 1039, p. 0003
`
`

`

`by guest
`
`
`
`www.bloodjournal.orgFrom
`
`on July 29, 2016.
`
`For personal use only.
`
`1346
`
`GAY et al
`
`BLOOD, 18 FEBRUARY 2010 䡠 VOLUME 115, NUMBER 7
`
`1. 00
`
`0. 75
`
`0. 50
`
`0. 25
`
`0. 00
`
`% of patients
`
`A
`
`len/dex
`
`thal/dex
`
`len/dex: 27.4 m (60 events)
`thal/dex: 17.2 m (55 events)
`HR 0.64; 95% CI 0.44-0.93; P = .019
`
`0
`
`20
`
`40
`
`1. 00
`
`0. 75
`
`0. 50
`
`0. 25
`
`0. 00
`
`%ofpatients
`
`A
`
`Number at risk
`len/dex
`thal/dex
`B
`
`1. 00
`
` 228
` 183
`
`months
`
` 39
` 19
`
`14
`8
`
`len/dex
`
`thal/dex
`
`len/dex: 26.7 m (68 events)
`thal/dex: 17.1 m (59 events)
`HR 0.69; 95% CI 0.48-0.98; P = .036
`
`0
`
`20
`
`40
`
`Number at risk
`len/dex 228
`thal/dex 183
`B
`
`1. 00
`
`months
`
` 40
` 19
`
`14
`8
`
`6
`
`
`
`len/dex
`
`thal/dex
`
`len/dex: 33.0 m (27 events)
`thal/dex: 11.8 m (27 events)
`HR 0.50; 95% CI 0.29-0.89; P = .017
`
`0. 75
`
`0. 50
`
`0. 25
`
`0. 00
`
`% of patients
`
`0
`
`10
`
`20
`
`30
`months
`
`40
`
`50
`
`Number at risk
`len/dex 72
`thal/dex 72
`
` 17
` 7
`
`12
`3
`
`Figure 2. PFS in the intention-to-treat population of patients treated with
`len/dex and thal/dex. (A) PFS in all patients, regardless of dexamethasone dose.
`(B) PFS in pair mates who received high-dose dexamethasone. Median PFS is
`provided in the figure. m indicates months.
`
`Given the longer duration of therapy in patients treated with
`len/dex, probably in part related to a higher treatment discontinua-
`tion rate because of AEs in thal/dex group (“Toxicity and deaths”),
`survival analyses were repeated excluding patients who stopped
`treatment for toxicity in both groups: again, TTP, PFS, and OS were
`significantly longer for patients who received lenalidomide.
`
`Subgroup analyses
`
`We studied the effect of therapy by ISS stage. In patients who
`presented with ISS stage I or II at diagnosis, OS was better in
`patients treated with len/dex compared with thal/dex, both consid-
`ering all patients (HR ⫽ 0.57; 95% CI, 0.32-1.00; P ⫽ .052) and
`high-dose pair mates only (HR ⫽ 0.20; 95% CI, 0.08-0.50;
`P ⬍ .001). In contrast, in patients with stage III ISS, no survival
`differences were found between patients receiving lenalidomide
`and patients treated with thalidomide, but this may be a function of
`small sample size.
`There were no significant differences in OS of patients present-
`ing with high-risk cytogenetics and treated with len/dex compared
`with patients treated with thal/dex (HR ⫽ 0.76; 95% CI, 0.23-2.51;
`
`len/dex
`
`thal/dex
`
`len/dex: 33.0 m (25 events)
`thal/dex: 15.3 m (23 events)
`HR 0.52; 95% CI 0.28-0.94; P = .030
`
`0. 75
`
`0. 50
`
`0. 25
`
`0. 00
`
`%ofpatients
`
`0
`
`10
`
`20
`
`30
`months
`
`40
`
`50
`
`Number at risk
`len/dex 72
`thal/dex 72
`
` 17
` 7
`
`12
`3
`
`
`
`Figure 1. TTP in the intention-to-treat population of patients treated with
`len/dex and thal/dex. (A) TTP in all patients, regardless of dexamethasone dose.
`(B) TTP in pair mates who received high-dose dexamethasone. Median TTP is
`provided in the figure. m indicates months.
`
`both considering all patients (median, 26.7 months vs 17.1 months,
`HR ⫽ 0.69; 95% CI, 0.48-0.98; P ⫽ .036; Figure 2A) and pair
`mates receiving high-dose dexamethasone only (33.0 months vs
`11.8 months, HR ⫽ 0.50; 95% CI, 0.29-0.89; P ⫽ .017; Figure
`2B). These analyses were then repeated without censoring at the
`date of therapy patients who received SCT or switched to another
`chemotherapy regimen. Both TTP and PFS, for all patients and for
`high-dose dexamethasone pair mates only, remained significantly
`better with len/dex (survival curves are provided in the supplemen-
`tal data, available on the Blood website; see the Supplemental
`Materials link at the top of the online article).
`OS was significantly higher among len/dex patients, both
`considering all patients (median not reached vs 57.2 months,
`HR ⫽ 0.60; 95% CI, 0.40-0.92; P ⫽ .018; Figure 3A) and matched
`patients receiving high-dose dexamethasone only (median not
`reached vs 50.0 months, HR ⫽ 0.35; 95% CI, 0.18-0.68; P ⫽ .002;
`Figure 3B). Early deaths (during the first 4 months of therapy) were
`reported in 6 of 228 (2.6%) patients receiving lenalidomide and
`4 of 183 (2.2%) patients treated with thalidomide in the 2 groups
`(P ⬎ .999).
`
`ALVOGEN, Exh. 1039, p. 0004
`
`

`

`by guest
`
`
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`
`on July 29, 2016.
`
`For personal use only.
`
`BLOOD, 18 FEBRUARY 2010 䡠 VOLUME 115, NUMBER 7
`
`LENALIDOMIDE VS THALIDOMIDE INDUCTION IN MYELOMA
`
`1347
`
`A
`
`1. 00
`
`0. 75
`
`0. 50
`
`0. 25
`
`0. 00
`
`% of patients
`
`A
`
`1. 00
`
`len/dex
`
`len/dex
`
`thal/dex
`
`0. 75
`
`0. 50
`
`0. 25
`
`% of patients
`
`thal/dex
`
`len/dex: 71.3% at 51.5 m (33 events)
`thal/dex: 57.2 m (81 events)
`HR 0.60; 95% CI 0.40-0.92; P = .018
`
`0
`
`20
`
`months
`Number at risk
` 115
` 228
`len/dex
`thal/dex 183 138
`B
`
`1. 00
`
`40
`
`49
`95
`
`6
`
`0. 00
`
`len/dex: 80.8% at 47.1 m (11 events)
`thal/dex: 80.6 m (47 events)
`HR 0.54; 95% CI 0.28-1.06; P = .075
`
`0
`
`20
`
`40
`
`Number at risk
`len/dex 111 69
`thal/dex
` 110 102
`
`months
`
`30
`74
`
`len/dex
`
`B
`
`1. 00
`
`% of patients
`
`thal/dex
`
`len/dex: 78.9% at 51.5 m (12 events)
`thal/dex: 50.0 m (40 events)
`HR 0.35; 95% CI 0.18-0.68; P = .002
`
`0. 75
`
`0. 50
`
`0. 25
`
`0. 00
`
`% of patients
`
`0
`
`20
`
`months
`
`Number at risk
`len/dex 72
`thal/dex 72
`
` 54
` 53
`
`40
`
`37
`37
`
`Figure 3. OS in the intention-to-treat population of patients treated with len/dex
`and thal/dex. (A) OS in all patients, regardless of dexamethasone dose. (B) OS in
`pair mates who received high-dose dexamethasone. Median OS is provided in the
`figure. m indicates months.
`
`P ⫽ .652), nor
`for patients with standard-risk cytogenetics
`(HR ⫽ 0.87; 95% CI, 0.31-2.43; P ⫽ .795), which again is prob-
`ably the result of small sample size.
`In the subgroup of patients who underwent SCT, there was a
`trend toward better OS in the len/dex group compared with thal/dex
`treated patients (median not reached vs 80.6 months, HR ⫽ 0.54;
`95% CI, 0.28-1.06; P ⫽ .075; Figure 4A). In the subgroup of
`patients who did not receive SCT, OS was significantly longer with
`len/dex (median not reached vs 42.4 months, HR ⫽ 0.53; 95% CI,
`0.31-0.92; P ⫽ .023; Figure 4B). In this subgroup of patients,
`response rate and TTP were significantly better with len/dex, too.
`Considering only patients who stopped treatment to pursue SCT
`(similar treatment duration in the 2 groups), OS was significantly
`longer in len/dex patients compared with thal/dex (median not
`reached vs 54.4 months, respectively, in len/dex and thal/dex,
`HR ⫽ 0.38; 95% CI, 0.15-0.96; P ⫽ .040).
`To evaluate whether the availability of better rescue therapies
`introduced after 2004 influenced survival, we compared len/dex
`
`0. 75
`
`0. 50
`
`0. 25
`
`0. 00
`
`len/dex
`
`thal/dex
`
`len/dex: 59.1% at 51.5 m (22 events)
`thal/dex: 42.4 m (34 events)
`HR 0.53; 95% CI 0.31-0.92; P = .023
`
`0
`
`20
`
`40
`
`6
`
`Number at risk
` 46
`len/dex 117
`thal/dex 73 36
`
`months
`
`19
`21
`
`Figure 4. Subgroup analysis of OS in the intention-to-treat population of
`patients treated with len/dex and thal/dex according to transplantation status.
`(A) OS in patients who received transplantation. (B) OS in patients in patients who did
`not receive transplantation. Median OS is provided in the figure. m indicates months.
`
`patients and thal/dex patients treated after March 2004: OS was
`significantly longer in the 228 patients treated with len/dex
`compared with 108 patients treated with thal/dex (median not
`reached for len/dex vs 54.4 months for thal/dex, HR ⫽ 0.60; 95%
`CI, 0.37-0.96; P ⫽ .033). In addition, subgroup analysis of OS of
`thal/dex patients only, treated before March 2004 and after March
`2004, showed no differences between the 2 groups (HR ⫽ 1.07;
`95% CI, 0.67-1.73; P ⫽ .767).
`
`Toxicity and deaths
`
`Major grade 3 or 4 toxicities observed with len/dex and thal/dex are
`listed in Table 4. A total of 131 (57.5%) patients receiving len/dex
`and 100 (54.6%) patients receiving thal/dex experienced at least
`one grade 3 or higher toxicity (P ⫽ .568). Toxicities were different
`in the 2 groups. The main toxicities of len/dex were hematologic, in
`
`ALVOGEN, Exh. 1039, p. 0005
`
`

`

`by guest
`
`
`
`www.bloodjournal.orgFrom
`
`on July 29, 2016.
`
`For personal use only.
`
`1348
`
`GAY et al
`
`BLOOD, 18 FEBRUARY 2010 䡠 VOLUME 115, NUMBER 7
`
`Table 4. Grade 3 or 4 adverse events
`
`All patients
`
`High-dose dexamethasone patients
`
`thal/dex (n ⴝ 183), n (%)
`
`len/dex (n ⴝ 228), n (%)
`
`P
`
`thal/dex (n ⴝ 72), n (%)
`
`len/dex (n ⴝ 72), n (%)
`
`P
`
`Treatment-related deaths
`At least one grade 3 or 4 adverse event
`Hematologic
`Anemia
`Thrombocytopenia
`Neutropenia
`Extrahematologic
`Peripheral neuropathy
`Fatigue
`Gastrointestinal toxicity
`Constipation
`Diarrhea
`Venous thromboembolism
`DVT
`Pulmonary embolism
`Dermatologic
`Infections
`Pneumonia
`Sepsis
`Cardiovascular
`Transaminase increase
`Myopathy
`
`1 (0.5)
`100 (54.6)
`
`0 (0)
`0 (0)
`1 (0.6)
`
`19 (10.4)
`13 (7.1)
`12 (6.6)
`9 (4.9)
`0 (0)
`28 (15.3)
`21* (11.5)
`7 (3.8)
`12 (6.6)†
`15 (8.2)
`5 (2.7)
`2 (1.1)
`10 (5.5)
`0 (0)
`4 (2.2)
`
`3 (1.3)
`131 (57.5)
`
`10 (4.4)
`11 (4.8)
`32 (14.0)
`
`2 (0.9)
`23 (10.1)
`14 (6.1)
`0 (0)
`8 (3.5)
`21 (9.2)
`16 (7.0)
`5 (2.2)
`21 (9.7)‡
`30 (13.1)
`16 (7.0)
`4 (1.8)
`10 (4.4)
`7 (3.1)
`1 (0.4)
`
`.632
`.568
`
`.003
`.002
`⬍ .001
`
`⬍ .001
`.288
`.863
`.001
`.01
`.058
`.117
`.385
`.258
`.109
`.070
`.696
`.614
`.019
`.177
`
`1 (1.4)
`44 (61.1)
`
`0 (0)
`0 (0)
`0 (0)
`
`3 (4.2)
`5 (6.9)
`5 (6.9)
`4 (5.6)
`0 (0)
`14 (19.4)
`9* (12.5)
`5 (6.9)
`6 (8.3)
`6 (8.3)
`1 (1.4)
`1 (1.4)
`5 (6.9)
`0 (0)
`2 (2.8)
`
`2 (2.8)
`51 (70.8)
`
`3 (4.2)
`3 (4.2)
`10 (13.9)
`
`0 (0)
`10 (13.9)
`7 (9.7)
`0 (0)
`3 (4.2)
`8 (11.1)
`6 (8.3)
`2 (2.8)
`5 (6.9)‡
`10 (13.8)
`8 (11.1)
`0 (0)
`5 (6.9)
`4 (5.6)
`1 (1.4)
`
`⬎ .999
`.218
`
`.245
`.245
`.001
`
`.245
`.275
`.764
`.120
`.245
`.165
`.413
`.441
`⬎ .999
`.289
`.033
`⬎ .999
`⬎ .999
`.120
`⬎ .999
`
`*One plus hemorrhage.
`†One Steven-Johnson syndrome and 1 toxic epidermal necrolysis.
`‡One Stevens-Johnson syndrome.
`
`particular neutropenia, reported in 14.0% patients in the len/dex
`group compared with 0.6% in the thal/dex group (P ⬍ .001).
`The most common toxicity in patients treated with thal/dex was
`peripheral neuropathy: 28 (15.3%) patients compared with
`8 (3.5%) patients treated with len/dex (P ⬍ .001) developed a
`grade 2 to 4 peripheral neuropathy (grade 3 or 4, 10.4% vs 0.9%,
`P ⬍ .001). Thrombotic events were more frequent in the thal/dex
`group, but the difference was not significant (15.3% vs 9.2%,
`P ⫽ .058). Similar rates of infections (13.1% vs 8.2%, P ⫽ .109),
`fatigue (10.1% vs 7.1%, P ⫽ .288), dermatologic toxicity (9.7% vs
`6.6%, P ⫽ .258), and cardiovascular events (4.4% vs 5.5%,
`P ⫽ .614) were reported in patients who received len/dex and
`thal/dex, respectively. The incidence of gastrointestinal events was
`not significantly different
`in the 2 groups (6.1% and 6.6%,
`respectively, in len/dex and thal/dex groups, P ⫽ .863), but toxici-
`ties were different: mainly diarrhea in patients who received
`lenalidomide and constipation in patients treated with thalidomide.
`When the analysis was restricted to pair mates who received
`high-dose dexamethasone, most of the data were confirmed.
`Incidence of peripheral neuropathy in the thal/dex group was lower
`if compared with the whole cohort of thal/dex patients, and the
`difference between thal/dex and len/dex patients was no more
`significant; however, even in this subgroup, patients who received
`thalidomide had a higher rate of neuropathy than patients treated
`with lenalidomide (grade 2-4, 8.3% vs 2.8%, respectively, P ⫽ .275;
`grade 3 or 4, 4.2% vs 0%, respectively, P ⫽ .245). Incidence of
`venous thromboembolism was slightly higher in both len/dex
`and thal/dex patients treated with high-dose dexamethasone
`compared with the all cohort of len/dex and thal/dex patients, as
`was the incidence of pneumonia in len/dex high-dose dexameth-
`asone patients. Twenty-two (9.7%) patients treated with len/dex
`discontinued treatment for AEs (main reason was dermatologic
`toxicity in 27.3%) compared with 33 (18.0%) patients receiving
`thal/dex (P ⬍ .013; main reason for thalidomide discontinuation
`was peripheral neuropathy in 30.3%). There was 1 toxic death in
`
`the thal/dex group (resulting from pulmonary embolism) and 3
`in the len/dex patients (1 sepsis, 1 pneumonia, and 1 gastrointes-
`tinal perforation).
`
`Discussion
`
`In newly diagnosed MM patients, 2 randomized studies have
`shown that the thal/dex regimen is better than high-dose dexameth-
`asone alone: in the first study, the response rate was significantly
`higher with thal/dex than with dexamethasone alone (63% vs 41%,
`P ⬍ .002)5; the second study showed that TTP was also improved
`in the thal/dex group (P ⬍ .001).6 No differences in survival were
`reported, but
`the trials were not powered to detect survival
`differences and follow-up was relatively short. The increased
`response rates and TTP with thal/dex needed to be balanced against
`the increased toxicity. In the thal/dex group compared with the
`dexamethasone group, the rates of any grade 3 or 4 toxic effects in
`the first 4 months were significantly higher (45% vs 21%, P ⫽ .001)
`as were DVT (17% vs 3%) and grade 3 or 4 peripheral neuropathy
`(7% vs 4%).5
`A prospective randomized study confirmed the efficacy of the
`thal/dex regimen also in comparison with the standard VAD
`regimen. The frequency of at least a VGPR was 25% after thal/dex
`induction compared with 7% after VAD (P ⬍ .003). However, the
`benefit was not sustained at 6 months after SCT (VGPR rates, 44%
`vs 42%, P ⫽ .87). DVT was higher in the thal/dex group (23% vs
`8%, P ⫽ .004).8 In elderly patients not eligible for SCT, thal/dex
`resulted in a higher proportion of VGPR rate (26% vs 13%,
`P ⫽ .006) and PR rate (68% vs 50%, P ⫽ .002) than did standard
`MP, but OS was inferior with thal/dex resulting from the increase in
`toxicity seen with thal/dex, particularly in patients older than
`75 years.7
`Although thal/dex has emerged as an efficacious oral induction
`regimen for myeloma, more effective and safer regimens are
`
`ALVOGEN, Exh. 1039, p. 0006
`
`

`

`by guest
`
`
`
`www.bloodjournal.orgFrom
`
`on July 29, 2016.
`
`For personal use only.
`
`BLOOD, 18 FEBRUARY 2010 䡠 VOLUME 115, NUMBER 7
`
`LENALIDOMIDE VS THALIDOMIDE INDUCTION IN MYELOMA
`
`1349
`
`lenalidomide, an analog of
`needed. Recent studies show that
`thalidomide, is also highly active and, wit