JeffreyA. Zonder,1John Crowley,2MohamadA. Hussein,3Vanessa Bolejack,2Dennis F. Moore Sr,4Brock F. Whittenberger,5
Muneer H.Abidi,1Brian G. M. Durie,6and Bart Barlogie7
1Karmanos Cancer Institute, Wayne State University, Detroit, MI;2Southwest Oncology Group Statistical Center, Seattle, WA;3Cleveland Clinic Foundation,
Cleveland, OH;4Wichita Community Clinical Oncology Program, Wichita, KS;5Montana Community Clinical Oncology Program, Billings, MT;6Cedars Sinai
Outpatient Clinical Cancer Center at the Samuel Oschin Comprehensive Cancer Institute, LosAngeles, CA; and7University ofArkansas for Medical Sciences,
The Southwest Oncology Group con-
lidomide (LEN) plus dexamethasone
(DEX; n ? 97) to placebo (PLC) plus DEX
(n ? 95) in newly diagnosed myeloma.
Three 35-day induction cycles applied
DEX 40 mg/day on days 1 to 4, 9 to 12, and
17 to 20 together with LEN 25 mg/day for
28 days or PLC. Monthly maintenance
used DEX 40 mg/day on days 1 to 4 and
15 to 18 along with LEN 25 mg/day for
21 days or PLC. Crossover from PLC-DEX
to LEN-DEX was encouraged on progres-
sion. One-year progression-free survival,
overall response rate, and very good par-
DEX (78% vs 52%, P ? .002; 78% vs 48%,
P < .001; 63% vs 16%, P < .001), whereas
1-year overall survival was similar (94%
vs 88%; P ? .25). Toxicities were more
pronounced with LEN-DEX (neutropenia
grade 3 or 4: 21% vs 5%, P < .001; throm-
boembolic events despite aspirin prophy-
laxis: 23.5% [initial LEN-DEX or cross-
over] vs 5%; P < .001). This trial was
registered at www.clinicaltrials.gov as
#NCT00064038. (Blood. 2010;116(26):
The immunomodulatory agent lenalidomide (LEN) was approved
by the U.S. Food and Drug Administration for use in combination
with dexamethasone (DEX) for previously treated myeloma. LEN
directly induces myeloma cell apoptosis and exerts indirect effects
via modulation of the bone marrow microenvironment and immune
system.1,2Results of a multicenter randomized placebo-controlled
trial S0232 by the Southwest Oncology Group (SWOG) demon-
strated superiority of LEN-DEX over placebo (PLC)–DEX as
first-line therapy for multiple myeloma patients.
Untreated myeloma patients were randomized to either LEN-DEX or
PLC-DEX, using a dynamic balancing algorithm to assign treatment.3
Initial randomization was stratified by International Staging System
stage4(1 vs 2 vs 3) and Zubrod performance status (0 or 1 vs 2 or 3).
Transplantation-ineligible or -denying patients had to have symptomatic
disease with a measurable M-protein, be at least 18 years old, and have a
performance status less than 3 (unless resulting from myeloma).
Induction therapy consisted of 3 35-day cycles of DEX 40 mg/day on
days 1 to 4, 9 to 12, and 17 to 20 plus LEN at 25 mg/day for 28 days or
PLC. Maintenance therapy consisted of DEX 40 mg/day on days 1 to 4
and 15 to 18 plus LEN 25 mg/day for 21 days or PLC in repeating
28-day cycles. Both treatment arms were continued until disease
progression or unacceptable toxicity. After a high incidence of thrombo-
embolic events (TEEs) in the first 21 patients, all subsequent patients
were required to take aspirin 325 mg/day, unless already on anticoagula-
tion therapy for other reasons. On disease progression, patients on
PLC-DEX could cross over to open-label LEN-DEX. Participants with
progressive disease after therapy with LEN-DEX (initially or after
crossover) were removed from the protocol.
The primary objective was to compare progression-free survival (PFS),
defined as the time from registration until either progressive disease or
death from any cause, between the 2 treatment groups. Other objectives
included comparisons of overall response rate5,6overall survival (OS), and
toxicity.The original study design called for accrual of 500 patients, to have
83% power to detect a 33% improvement in PFS on the experimental arm.
PFS and OS were estimated by the Kaplan-Meier method7and compared on
an intent-to-treat basis using the log-rank test. Response rates according to
both SWOG and IMWG criteria were compared using ?2tests. Patients who
did not progress or died were censored at the date of last contact for this
Results and discussion
Between October 15, 2004 and April 2, 2007, 198 patients were
enrolled. Based on inferior efficacy of PLC-DEX8and concern for
the relative safety of combining LEN with DEX in excess of 40 mg
weekly,9the Data and Safety Monitoring Committee recommended
early study closure. Original treatment allocation was unblinded,
open-label LEN-DEX was made available to all patients, and dose
Submitted August 25, 2010; accepted September 15, 2010. Prepublished
online as Blood First Edition paper, September 27, 2010; DOI 10.1182/blood-
The online version of this article contains a data supplement.
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.
© 2010 by TheAmerican Society of Hematology
5838BLOOD, 23 DECEMBER 2010?VOLUME 116, NUMBER 26
For personal use only.on October 22, 2015. by guest
reduction of DEX to 40 mg weekly was recommended. The flow of
all registered patients is summarized in Figure 1.
Baseline characteristics were well matched between arms (supple-
tal Materials link at the top of the online article). Cytogenetic
abnormalities (CAs) were present in 29 of 128 patients. As of July
16, 2010, the median follow-up of live patients was 47.2 months.
The 1-year PFS with LEN-DEX was superior at 78% compared
with 52% for the control arm (Figure 2A, P ? .002). At 3 years,
PFS remained superior for LEN-DEX: 52% vs 32%. Regardless of
randomization, PFS was significantly shorter in patients with than
without CAs (both P ? .05), supporting Mayo Clinic data.10
Overall response (partial response or better) was higher with
LEN-DEX (78% vs 48%; P ? .0001) as was the very good partial
response rate (63% vs 16%; P ? .001; supplemental Table 2). The
superior response rate of LEN-DEX compared with DEX is
consistent with data from other studies in the frontline11-13and
relapsed/refractory settings.14,15In addition, although the overall
response rate achieved in S0232 is similar to that reported with
thalidomide plus dexamethasone (THAL-DEX) in 2 large trials,8,16
the superior very good partial response rate and PFS achieved with
LEN-DEX underscore its greater efficacy compared with THAL-
DEX as initial therapy of multiple myeloma.11,17
OS was not different between arms in S0232 (1-, 2-, and 3-year
OS values for LEN-DEX were 94%, 87%, 79% vs 88%, 78%, 73%,
respectively, for PLC-DEX; P ? .28; Figure 2B). This can be
explained by the crossover design, the availability of other salvage
therapies, and the impact early study closure had on statistical
power. Early deaths (defined as death before the first response
assessment at 6 weeks) occurred in 1% of patients on LEN-DEX
and 3% of those on PLC-DEX. The presence of CAs imparted
shorter OS in both study arms (Figure 2C).
Efficacy of crossover therapy
Of 40 eligible patients crossing over from PLC-DEX to
LEN-DEX before study closure and unblinding of original
treatment allocation, all were assessable for toxicity and 31 were
evaluable for response. The median PFS from the time of
Figure 1. Trial design and patient flow. PD/D indicates progressive disease or death; andAE/W, adverse event or withdrawal.
LEN/DEX IN NEWLY DIAGNOSED MYELOMA5839 BLOOD, 23 DECEMBER 2010?VOLUME 116, NUMBER 26
For personal use only.on October 22, 2015. by guest
crossover was 19 months, and the median OS was approxi-
mately 43 months (Figure 2D), consistent with experience in
Myelosuppression was more frequent with LEN-DEX (grades 3 or
4: 21% vs 5%; P ? .0009; supplemental Table 3A), possibly
explaining the higher rate of infection (supplemental Table 3B).
The frequency of adverse events after crossover from PLC-DEX to
LEN-DEX was similar to that seen in patients initially randomized
to LEN-DEX induction (supplemental Table 3C). The types of
adverse events experienced by patients treated with LEN-DEX in
our study were similar to those reported previously.14,15,18Consis-
tent with previous reports, TEE occurred more often with LEN-
DEX.19-21Before instituting aspirin thromboprophylaxis, TEE
occurred in 8 of the first 12 patients randomized to LEN-DEX
versus none in the control arm (P ? .0019). Our previous findings
of TEE reduction by aspirin prophylaxis22were not confirmed as a
TEE excess with LEN-DEX persisted after amendment (19% vs
6%; P ? .0095). Therefore, other thromboprophylaxis strategies,
such as low molecular weight heparin, should be considered,
particularly if any other risk factors are present or DEX dosing
exceeds 40 mg/week.23
In conclusion, S0232 confirms the superiority LEN-DEX
over PLC-DEX alone as first-line therapy in terms of response
rates and PFS. The higher incidence of TEE despite aspirin
325 mg prophylaxis calls attention to the need for more effective
thromboprophylaxis. SWOG is currently leading a US Inter-
group trial S0777 comparing LEN-DEX versus LEN-DEX plus
bortezomib as initial myeloma treatment, using lower DEX
dosing (40 mg/week) to minimize glucocorticoid-associated
The authors thank Marjorie A. Godfrey, Dana Sparks, and Harry
Erba (SWOG), and Robert Knight and Jerome Zeldis (Celgene
This work was supported in part by the National Cancer
Service Cooperative Agreement grants CA32102, CA38926,
CA04919, CA35431, CA14028, CA67575, CA35090, CA58861,
CA20319, CA35178, CA76429, CA35176, CA68183, CA95860,
CA27057, CA35119, CA35281, CA45808, CA37981, CA16385,
CA76448, CA63848, CA12644, CA86780, CA46282, CA58658,
CA11083, CA58882, and CA58416) and by Celgene Corporation.
Contribution: B.B., J.C., B.G.M.D., M.A.H., and J.A.Z. con-
ceived and designed the study; B.B., V.B., J.C., B.G.M.D., and
J.A.Z. analyzed and interpreted data; V.B. collected and as-
sembled data; J.A.Z. and B.B. wrote the manuscript; M.H.A.
provided administrative support (responded to study inquiries in
the absence of the study coordinator); M.H.A., B.B., V.B.,
B.G.M.D., J.C., M.A.H., D.F.M., B.F.W., and J.A.Z. reviewed
and approved the manuscript; and B.B., M.A.H., D.F.M.,
B.F.W., and J.A.Z. provided study materials/patients.
Conflict-of-interest disclosure: B.B. received research fund-
ing and was on the speaker’s bureau for Celgene and Millen-
nium and received honoraria from Celgene. B.G.M.D. received
research funding and honoraria from Celgene. M.A.H. is
presently employed by Celgene, but was not at the time the
Figure 2. PFS and OS from the times of randomization and crossover with attention to the effects of cytogenetic abnormalities. (A) PFS: Estimated 1-year PFS rate
was 78% with LEN ? DEX and 52% with DEX (P ? .0003). (B) OS: No difference is apparent between arms. (C) OS according to the presence or absence of CAs: patients
without CAs had superior OS, regardless of treatment arm. No statistically significant OS differences between LEN-DEX and DEX could be demonstrated within the CAand no
CAgroups. Testing CAversus No CAwithin treatment groups: LEN-DEX, P ? .09; DEX, P ? .03.Testing LEN-DEX versus DEX within CAgroups: CA, P ? .42; No CA, P ? .7.
(D) PFS and OS after crossover from DEX to LEN-DEX.
5840 ZONDER et al BLOOD, 23 DECEMBER 2010?VOLUME 116, NUMBER 26
For personal use only. on October 22, 2015. by guest
study was conducted. J.A.Z. received research funding and was
on the speaker’s bureau (continuing medical education only; no
promotional speaking) for Celgene and Millennium. The remain-
ing authors declare no competing financial interests.
Correspondence: Jeffrey A. Zonder, Wayne State University,
Karmanos Cancer Institute, Division of Hematology/Oncology,
4 HWCRC, 4100 John Rd, Detroit, MI 48201; e-mail:
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LEN/DEX IN NEWLY DIAGNOSED MYELOMA5841 BLOOD, 23 DECEMBER 2010?VOLUME 116, NUMBER 26
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online September 27, 2010
2010 116: 5838-5841
Brock F. Whittenberger, Muneer H. Abidi, Brian G. M. Durie and Bart Barlogie
Jeffrey A. Zonder, John Crowley, Mohamad A. Hussein, Vanessa Bolejack, Dennis F. Moore, Sr,
Southwest Oncology Group trial (S0232)
dexamethasone as initial therapy for multiple myeloma: a randomized
Lenalidomide and high-dose dexamethasone compared with
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