research paper
A phase 2 study of two doses of bortezomib in relapsed or
refractory myeloma
S. Jagannath,1 B. Barlogie,2 J. Berenson,3
Summary
D. Siegel,4 D. Irwin,5 P. G. Richardson,6
R. Niesvizky,7 R. Alexanian,8
In a phase 2 open-label study of the novel proteasome inhibitor bortezomib, 54
S. A. Limentani,9 M. Alsina,10 J. Adams,11
patients with multiple myeloma who had relapsed after or were refractory to
M. Kauffman,12 D.-L. Esseltine,13
frontline therapy were randomized to receive intravenous 1Æ0or1Æ3 mg/m2
D. P. Schenkein13 and K. C. Anderson6
bortezomib twice weekly for 2 weeks, every 3 weeks for a maximum of eight
1St. Vincent's Catholic Medical Center, New York,
cycles. Dexamethasone was permitted in patients with progressive or stable
NY, 2University of Arkansas, Little Rock, AR,
disease after two or four cycles respectively. Responses were determined using
3Institute for Myeloma and Bone Cancer Research,
modified European Group for Blood and Marrow Transplantation criteria. The
West Hollywood, CA, 4Hackensack University
complete response (CR) + partial response (PR) rate for bortezomib alone was
Medical Center, Hackensack, NJ, 5Alta Bates
30% [90% confidence interval (CI), 15Æ7­47Æ1] and 38% (90% CI, 22Æ6­56Æ4) in
Comprehensive Cancer Center, Berkeley, CA,
the 1Æ0 mg/m2 (8 of 27 patients) and 1Æ3 mg/m2 (10 of 26 patients) groups
6Dana-Farber Cancer Institute, Boston, MA,
respectively. The CR + PR rate for patients who received bortezomib alone
7New York Presbyterian Hospital Weill Medical
or in combination with dexamethasone was 37% and 50% for the 1Æ0 and
College, Cornell University, New York, NY, 8M.D.
1Æ3 mg/m2 cohorts respectively. The most common grade 3 adverse events were
Anderson Cancer Center, Houston, TX,
9Carolinas Hematology-Oncology Associates,
thrombocytopenia (24%), neutropenia (17%), lymphopenia (11%) and
Charlotte, NC, 10H. Lee Moffitt Cancer Center,
peripheral neuropathy (9%). Grade 4 events were observed in 9% (five of
Tampa, FL, 11Infinity Pharmaceuticals, Inc.,
54 patients). Bortezomib alone or in combination with dexamethasone
Cambridge, MA, 12Predix Pharmaceuticals, Inc.,
demonstrated therapeutic activity in patients with multiple myeloma who
Woburn, MA, and 13Millennium
relapsed after frontline therapy.
Pharmaceuticals, Inc., Cambridge, MA, USA
Keywords: bortezomib, myeloma, relapsed, refractory, dexamethasone.
Received 22 June 2004; accepted for publication
10 August 2004
Correspondence: Sundar Jagannath, Chief of
Blood Stem Cell and Bone Marrow
Transplantation, St. Vincent's Comprehensive
Cancer Center, 325 W. 15th Street, New York,
NY 10011-8202, USA.
E-mail: sjaganna@salick.com
Multiple myeloma is an incurable haematological malignancy
(Desterro et al, 2000) and angiogenesis (Dulic et al, 1994).
of B-cell origin. The median duration of survival among
Bortezomib reversibly inhibits proteasome function by target-
patients with multiple myeloma is 3 years with standard
ing the chymotryptic-like site (Ki ¼ 0Æ6 nmol/l) of the
therapy, and approximately 25% of patients survive 5 years or
proteasome, with little affinity for other proteases, such as
longer; fewer than 5% are alive at 10 years (Alexanian &
chymotrypsin
(Ki ¼ 320 nmol/l)
and
thrombin
Dimopoulos, 1994; Rajkumar et al, 2002). Although patients
(Ki ¼ 13 000 nmol/l) (Adams et al, 1998).
generally respond to front-line chemotherapy, most either
Preclinical studies suggested that bortezomib could be
relapse or become refractory to these therapies.
effective in patients with multiple myeloma (Hideshima et al,
Proteasome inhibition is an attractive approach to cancer
2001; LeBlanc et al, 2002). Application of bortezomib to either
therapy because it can potentially target multiple signalling
myeloma cell lines or cells freshly isolated from myeloma
pathways that are critical for tumour cell growth and survival,
patients directly inhibited proliferation and induced apoptosis,
including cell cycle regulation (King et al, 1996), apoptosis
regardless of p21, p27 or p53 expression (Hideshima et al,
(Orlowski, 1999), cell adhesion (Read et al, 1995), transcription
2001). In xenograft mouse models, bortezomib significantly
ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 127, 165­172
doi:10.1111/j.1365-2141.2004.05188.x

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S. Jagannath et al
inhibited myeloma tumour growth, including complete
receive 20 mg oral dexamethasone on the day of and the day
tumour regression, and prolonged overall survival compared
following each bortezomib dose. The overall dexamethasone
with controls (LeBlanc et al, 2002). Taken together, these
dose of 160 mg over a 3-week cycle was similar to the amount
results provide strong evidence supporting the use of bortez-
received with standard monthly high-dose treatment, such as
omib as a therapy for multiple myeloma.
40 mg/d for 4 d every 4 weeks. Treatment was withheld from
In a phase 1 analysis of patients with refractory haemato-
patients with drug-related grade 3 non-haematological or
logical malignancies, activity was reported in nine of nine fully
grade 4 haematological toxicity and then resumed at a 25%
assessable patients with heavily pretreated plasma cell dyscra-
dose reduction upon resolution of the toxicity to grade 1 or
sias (Orlowski et al, 2002). Based on an evaluation of two
better. Reduction to 0Æ7 mg/m2 was allowed, but lower doses
phase 1 studies (Aghajanian et al, 2002; Orlowski et al, 2002),
were not permitted. Continuation of therapy in a separate
the dose and schedule selected for bortezomib administration
extension study was available if, in the investigator's opinion,
for the phase 2 SUMMIT trial was 1Æ3 mg/m2 given twice
the patient might benefit or continue to benefit from treatment
weekly for 2 weeks every 21 d (Richardson et al, 2003).
or re-treatment.
In the exploratory phase 2 study reported here (CREST),
Investigators and representatives from Millennium Pharma-
the safety and efficacy of two doses of bortezomib (1Æ0 and
ceuticals, Inc. designed the study. Medical and statistical
1Æ3 mg/m2) were evaluated in patients with relapsed or
representatives from Millennium collected and analysed data
refractory multiple myeloma who had received only front-line
in conjunction with the investigators. All investigators had
therapy. In order to be sure that the activity of the two dose
access to the primary data and authored this report. All
levels was studied in similar patient populations, a centre-
participating institutions received clinical grant support for the
specific randomization was used, based on disease stage and
conduct of the study.
previous chemotherapy. As preclinical studies reported additive
activity with bortezomib in combination with dexamethasone
Assessment of efficacy
(Hideshima et al, 2001), patients with a suboptimal response to
bortezomib alone were allowed to receive dexamethasone.
The primary end-point was overall response rate (ORR) [the
sum of complete response (CR), partial response (PR) and
minimal response (MR)] to bortezomib alone. Time to
Methods
progression on bortezomib alone or in combination with
dexamethasone, survival, safety and response rate to bortezomib
Patients
in combination with dexamethasone were also assessed. Eval-
Patients were at least 18 years of age and had either relapsed
uation of response was performed between days 11­18 of cycles
following or were refractory to front-line chemotherapy, which
2, 4 and 6, and following cycle 8. Responses were assessed using
was defined as their first regimen for the treatment of myeloma
the European Group for Blood and Marrow Transplantation
(e.g. high-dose therapy with stem cell support). Other require-
(EBMT) response criteria (Blade´ et al, 1998) by an independent
ments were measurable disease, a Karnofsky performance status
review committee (IRC) consisting of three independent
60%, a life expectancy >3 months, aspartate aminotransferase
myeloma experts not otherwise involved in the trial. As per the
or alanine aminotransferase £3· upper limit of normal, total
EBMT criteria, CR required a negative immunofixation test
bilirubin £2· upper limit of normal, creatinine clearance
result for myeloma protein in serum and urine, disappearance of
30 ml/min (exceptions were allowed for creatinine clearance
soft-tissue plasmacytomas, normal serum calcium, stable skel-
10 and <30 ml/min), platelet count 30 · 109/l, haemoglobin
etal disease and <5% plasma cells in the marrow with
8 g/dl and absolute neutrophil count 0Æ5 · 109/l. Patients
confirmation of response by all of these criteria 6 weeks later.
agreed to use contraception, and women were required to have
An additional category of near CR was defined as the absence of
a confirmed negative pregnancy test result before enrolment.
M protein by electrophoresis but with positive immunofixation,
All patients provided signed informed consent before study
plus stable bone disease and normal serum calcium. Patients
entry. The study was performed in accordance with the
with insufficient data to assess efficacy were considered
Declaration of Helsinki, with prior approval of the institutional
treatment failures (not evaluable) by the IRC and considered
review board at each of the participating centres.
non-responders in the analyses.
Time-to-event analyses were performed using the Kaplan­
Meier method, and results are reported as of 11 May 2004. The
Study design and treatment
time to first response was from the date of the first
Patients were randomized to receive bortezomib (VELCADEÒ
administration of bortezomib to the first evidence of a
for Injection, Millennium Pharmaceuticals, Inc., Cambridge,
confirmed response. The duration of response was the time
MA, USA) 1Æ0or 1Æ3 mg/m2 as a 3­5-s intravenous bolus twice
from achievement of response to progression. The time to
weekly for 2 weeks (days 1, 4, 8 and 11) of a 21-d cycle for up
disease progression for patients receiving bortezomib alone or
to eight cycles. Patients with progressive disease after two
in combination with dexamethasone was the interval from the
cycles or stable disease after the first four cycles were eligible to
initial administration of bortezomib to disease progression
166
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Bortezomib for Relapsed or Refractory Multiple Myeloma
(without censoring for the addition of either dexamethasone
with 53 patients evaluable for response by the IRC (one patient
or additional bortezomib in the extension study). For the
with non-secretory myeloma was excluded as preplanned). The
bortezomib-alone analysis, patients who received dexametha-
median age was 63 years (range, 30­84 years) (Table I).
sone in combination with bortezomib or alternate therapy, and
Twenty-eight patients received 1Æ0 mg/m2 and 26 patients
patients who died without a reported date of progression, were
received 1Æ3 mg/m2. The two dose groups were balanced with
censored at the last evaluation before starting additional
respect to most demographics and baseline characteristics,
therapy or before death. Patients who were characterized as
with some exceptions. There were more women and more
refractory to dexamethasone were those who had received
patients identified with IgG myeloma in the higher dose group.
dexamethasone alone or in combination as prior therapy and
A higher proportion of patients in the 1Æ0 mg/m2 group had a
had disease progression within 30 days of receiving steroid-
platelet count <75 · 109/l at baseline, whereas a higher
containing therapy.
percentage in the 1Æ3 mg/m2 group had abnormal cytogenetics
in a bone marrow sample. The median duration of time from
the diagnosis of multiple myeloma to the first dose of
Assessment of safety and other secondary end points
bortezomib was 2Æ0 years for both dose groups, and 56 and
Adverse events were assessed at each visit and graded according
62% of patients in the 1Æ0 and 1Æ3 mg/m2 dose groups,
to the National Cancer Institute Common Toxicity Criteria,
respectively, were Durie-Salmon stage III disease at diagnosis.
version 2.0, from the first dose until 20 d after the last dose of
Table II details prior therapy in the two groups and shows that
bortezomib. Patients completed the Functional Assessment of
the majority of patients had previously received corticoster-
Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity
oids.
(FACT/GOG-NTX) questionnaire to evaluate peripheral neu-
At baseline, the majority of patients in each dose group (21
rological symptoms at the screening visit and on day 1 of cycles
of 25 and 15 of 23 patients in the 1Æ0 and 1Æ3 mg/m2 dose
3, 5 and 7 and at the end of study. A neurologist performed a
groups, respectively) reported symptoms of peripheral neur-
complete neurological evaluation during the initial screening,
opathy, as assessed by the FACT/GOG-NTX questionnaire.
during treatment if needed and at the end of the study.
Neurological examination detected sensory and/or motor
Electromyelography and testing for amyloidosis were not
symptoms in 34 of 51 patients (67%) and functional impair-
required.
ment in 16 of 51 patients (31%) prior to bortezomib therapy.
Randomization procedures and statistical analysis
Dose intensity and duration of treatment and follow-up
Patients who met all eligibility criteria at cycle 1, day 1, were
Twenty-four patients (86%) in the 1Æ0 mg/m2 dose group and
eligible for randomization, at which point the next available
19 patients (73%) in the 1Æ3 mg/m2 dose group completed four
randomization envelope was selected, based on the patient's
or more cycles of treatment, and 61% of the 1Æ0 mg/m2
Durie-Salmon disease stage (I/II or III) and front-line chemo-
patients and 27% of the 1Æ3 mg/m2 patients completed all eight
therapeutic regimen (conventional standard-dose therapy or
high-dose therapy/stem cell transplantation). The goal of the
Table I. Demographics and baseline characteristics (all treated
randomization schema was to achieve balance of treatment
patients, n ¼ 54).
group assignment (bortezomib 1Æ0or 1Æ3 mg/m2) within each
Bortezomib dose group
stratum by utilizing a centre-specific strategy that would
prevent early closure or delayed enrolment of any stratum.
1.0 mg/m2
1.3 mg/m2
The study was prospectively designed to determine whether
Characteristic
(n ¼ 28)
(n ¼ 26)
the rate of response to bortezomib alone was at least 20%
Age [years, Mean (range)]
64 (39­82)
60 (30­84)
(a ¼ 0Æ05), with at least 80% power to conclude a response
Males [n (%)]
14 (50)
9 (35)
rate of 40% or more. This study was planned to enrol 64
Type of myeloma [n (%)]
patients (32 patients in each dose group); no formal statistical
IgG/IgA/other*
15 (54)/8 (29)/
17 (65)/6 (23)/
comparisons of bortezomib between the two dose groups were
5 (18)
3 (12)
planned or conducted in this exploratory study. All descriptive
Karnofsky performance
3 (11)
4 (15)
statistical analyses were performed using SAS statistical soft-
status £70 [n (%)]
ware (version 8.2).
b2-microglobulin 4 mg/l
14/24 (58)
11/23 (48)
[n/N (%)]
Platelet count <75 · 109/l
5/26 (19)
0/25 (0)
Results
[n/N (%)]
Abnormal cytogenetics
7/24 (29)
11/23 (48)
Patient characteristics
[n/N (%)]
Fifty-four patients were accrued onto this multi-institutional
*Includes L-chain myeloma and one patient with non-secretory
study between May 2001 and January 2002 from 10 centres,
myeloma.
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167

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S. Jagannath et al
1Æ0 mg/m2 and 794 d (26Æ1 months) for the group receiving
Table II. Prior therapy for all treated patients (n ¼ 54).
1Æ3 mg/m2.
Dose reduction was necessary in a higher proportion of
Bortezomib dose group
patients in the 1Æ3 mg/m2 dose group because of an adverse
1Æ0 mg/m2
1Æ3 mg/m2
event (nine of 26 patients, 35%), compared with the lower-
Prior therapy
(n ¼ 28)
(n ¼ 26)
dose group (three of 28 patients, 11%). The maximum
percentage of patients who required a dose reduction for any
Steroids, e.g. dexamethasone,
27 (96)
26 (100)
cycle on study was 11%, occurring in both cycles 7 and 8 in the
VAD [n (%)]
lower-dose group, and 19% at cycle 3 for the higher-dose
Alkylating agents, e.g. MP,
21 (75)
18 (69)
group. Seventeen of 54 patients (31%) continued onto the
VBMCP [n (%)]
Anthracyclines, e.g. VAD,
12 (43)
17 (65)
extension study. Early discontinuation occurred in 12 of 54
mitoxantrone [n (%)]
patients (22%) because of adverse events, in 11 (20%) because
Thalidomide therapy [n (%)]
9 (32)
7 (27)
of lack of efficacy and in two patients (4%) by their request.
Stem cell transplantation or other
15 (54)
11 (42)
high-dose therapy [n (%)]
Response to bortezomib treatment
Radiation therapy [n (%)]
10 (36)
8 (31)
Number of prior regimens of
3 (1­7)
3 (1­7)
Response rates to bortezomib monotherapy and the combi-
treatment* [Median (range)]
nation of bortezomib and dexamethasone are listed in
Table III. Of the 27 patients in the 1Æ0 mg/m2 dose group
*A regimen was defined as a single drug or combination therapy.
Front-line therapy could be composed of more than one regimen. The
with measurable disease and the 26 from the 1Æ3 mg/m2 dose
intent of this protocol was to enroll patients for second-line therapy.
group, the ORR (CR + PR + MR) to bortezomib alone was
VAD, vincristine, adriamycin, dexamethasone; MP, melphalan, pred-
33% (nine of 27 patients) in the 1Æ0 mg/m2 dose group and
nisone; VBMCP, vincristine, carmustine, melphalan, cyclophospha-
50% in the 1Æ3 mg/m2 dose group (13 of 26 patients). One
mide, prednisone.
patient in each dose group experienced CR using the EBMT
criteria (immunofixation negative), and in addition, two
cycles of therapy. The mean duration of treatment was 142Æ6d
patients from the 1Æ0 mg/m2 dose group achieved near CR.
in the 1Æ0 mg/m2 group (range, 1­228 d) and 115Æ9 d (range,
An additional seven patients (26%) in the 1Æ0 mg/m2 cohort
12­172 d) in the 1Æ3 mg/m2 group. Dexamethasone was added
and five patients (19%) in the 1Æ3 mg/m2 cohort had evidence
to the bortezomib treatment regimen for 16 patients (57%) in
of stable disease in response to bortezomib alone.
the 1Æ0 mg/m2 dose group and 12 patients (46%) in the
The ORR for patients who received bortezomib alone or in
1Æ3 mg/m2 dose group. One patient began dexamethasone
combination with dexamethasone was 44% in the 1Æ0 mg/m2
therapy in cycle 2, seven in cycle 3, one in cycle 4, 10 in cycle 5
dose group and 62% in the 1Æ3 mg/m2 dose group. In the
and the remaining nine in later cycles. The median duration of
1Æ0 mg/m2 dose group, there were two patients with CR and
follow-up was 796 d (26Æ2 months) for the group receiving
three with near CR. In the 1Æ3 mg/m2 dose group, one patient
Table III. Summary of responses to bortezomib (IRC-evaluated population, n ¼ 53).
Bortezomib dose group
1Æ0 mg/m2 (n ¼ 27)*
1Æ3 mg/m2 (n ¼ 26)
Bortezomib alone (%)
Bortezomib ± Dex. (%)
Bortezomib alone %
Bortezomib ± Dex. %
Confirmed response combined
(90% CI)
(90% CI)
(90% CI)
(90% CI)
Overall response (CR + PR + MR)
33 (18Æ6­50Æ9)
44 (28Æ0­61Æ8)
50 (32Æ7­67Æ3)
62 (43Æ6­77Æ4)
CR + PR
30 (15Æ7­47Æ1)
37 (21Æ7­54Æ7)
38 (22Æ6­56Æ4)
50 (32Æ7­67Æ3)
Confirmed response by category
CR + near CR
11 (3Æ1­26Æ3)
19 (7Æ6­35Æ1)
4 (0Æ2­17Æ0)
4 (0Æ2­17Æ0)
PR
19 (7Æ6­35Æ1)
19 (7Æ6­35Æ1)
35 (19Æ4­52Æ6)
46 (29Æ2­63Æ8)
MR
4 (0Æ2­16Æ4)
7 (1Æ3­21Æ5)
12 (3Æ2­27Æ2)
12 (3Æ2­27Æ2)
NC
26
19
19
12
PD/NE (non-responders)
41
37
31
27
*One patient with non-secretory myeloma was not evaluable.
Confidence intervals not calculated.
Dex., dexamethasone; CI, confidence interval; CR, complete response; MR, minimal response; NC, no change; NE, not evaluable; PD, progressive
disease; PR, partial response.
168
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Bortezomib for Relapsed or Refractory Multiple Myeloma
achieved CR. Of nine patients who were previously determined
diarrhoea (44%), pyrexia (41%), constipation (37%), periph-
to have steroid-refractory disease (progression within 30 d of
eral neuropathy (41%), arthralgia (35%), insomnia (35%),
steroid-containing therapy), two (22%) achieved improved
headache (31%), limb pain (31%), thrombocytopenia (30%)
response after the addition of dexamethasone.
and upper respiratory tract infection (30%). The most
common grade 3 and 4 adverse events in each dose group
are shown in Table IV. Grade 4 events were observed in five
Time to response
subjects. Three patients had grade 4 events unrelated to
The median time to first response (CR, PR or MR) for treatment
bortezomib therapy (incidental finding of aortic aneurysm,
with bortezomib alone was similar in both treatment groups:
hypercalcaemia with progressive disease and perforation of the
1Æ3 months (39 d) in the 1Æ0 mg/m2 dose group and 1Æ5 months
large intestine). Two grade 4 adverse events were considered
(45 d) in the 1Æ3 mg/m2 dose group. The first measurement of
probably (peripheral neuropathy) or possibly (thrombocy-
response as specified by the protocol was after two cycles.
topenia) related to the study drug. The patient with grade 4
peripheral neuropathy had symptoms at baseline consistent
with grade 3 neuropathy and developed grade 4 neuropathy on
Duration of response and time to progression
the 1 mg/m2 dose. For the patient with grade 4 thrombocy-
The median duration of response (CR, PR and MR) for
topenia, this event was recorded at cycle 1 day 5, after two
treatment with bortezomib alone or in combination with
doses of bortezomib.
dexamethasone was 9Æ5 months (288 d) and 13Æ7 months
Figure 2 displays the events that occurred at a 20% greater
(417 d) in the 1Æ0 mg/m2 (n ¼ 12) and 1Æ3 mg/m2 groups
rate in the 1Æ3 mg/m2 dose group compared with patients
(n ¼ 16) respectively. The median time to progression for
treated at the 1Æ0 mg/m2 dose. Comparing these adverse events
patients who received bortezomib alone or in combination
by grade suggests that the divergence between the two dose
with dexamethasone was 7Æ0 months (212 d) and 11Æ0 months
groups occurs primarily in the grade 1 and grade 2 events. In
(333 d) in the 1Æ0 mg/m2 and 1Æ3 mg/m2 groups respectively
contrast, arthralgia and peripheral oedema occurred with a
(Fig. 1).
20% higher incidence in the 1Æ0 mg/m2 dose group versus the
1Æ3 mg/m2 group.
Figure 3 displays the mean platelet count over the time course
Overall survival
of bortezomib administration by dose group (1Æ0 and
The median survival for all patients in both dose groups
1Æ3 mg/m2) and illustrates the dose-related decrease in platelet
combined has not been reached. Median duration of follow-up
counts with recovery observed during the rest period within each
was approximately 26 months (796 d for the 1Æ0 mg/m2 dose
cycle.
group, and 794 d for the 1Æ3 mg/m2 dose group). The median
Peripheral neuropathy was reported in at least one patient in
survival for the patients in the 1Æ0 mg/m2 group was
every cycle. In the group receiving 1Æ3 mg/m2, its incidence
26Æ7 months (813 d) but has not been reached in the
peaked at cycle 6. Symptoms of peripheral neuropathy were
1Æ3 mg/m2 group.
recorded on the baseline FACT/GOG-NTX questionnaire in
71% of patients (20 of 28) who later developed worsening of
peripheral neuropathy or any potential symptoms of periph-
Adverse events
eral neuropathy, and the remaining 28% (8 of 28) reported
Overall, the most commonly reported adverse events of any
grade in this study were fatigue (70%), nausea (54%),
Table IV. Treatment-emergent grade 3 and 4 adverse events reported
by 10% of patients.
Bortezomib dose group
1Æ0 mg/m2
1Æ3 mg/m2
(n ¼ 28)
(n ¼ 26)
Grade 3
Grade 4
Grade 3
Grade 4
Adverse event
[n (%)]
[n (%)]
[n (%)]
[n (%)]
Peripheral neuropathy
1 (4)
1 (4)
4 (15)
0 (0)
Pain in limb
3 (11)
0 (0)
2 (8)
0 (0)
Thrombocytopenia
8 (29)
0 (0)
5 (19)
1 (4)
Weakness
1 (4)
0 (0)
3 (12)
0 (0)
Neutropenia
3 (11)
0 (0)
6 (23)
0 (0)
Fig 1. Kaplan­Meier curve for time to progression for 28 patients in
Lymphopenia
3 (11)
0 (0)
3 (12)
0 (0)
the 1Æ0 mg/m2 and 26 patients in the 1Æ3 mg/m2 bortezomib cohorts.
Pneumonia NOS
0 (0)
0 (0)
4 (15)
0 (0)
Censoring for the addition of dexamethasone or additional bortezomib
Hyponatraemia
3 (11)
0 (0)
2 (8)
0 (0)
was not performed. Results are reported as of 11 May 2004.
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169

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S. Jagannath et al
Fig 2. Incidence of overall adverse events that
occurred at a 20% greater rate in the
1.3 mg/m2 dose group relative to the 1.0 dose
group by CTC grade.
Fig 3. Mean platelet count by dose of bortez-
omib over the time course of treatment for all
patients
(1.0 mg/m2:
n ¼ 28;
1.3 mg/m2:
n ¼ 26).
new-onset symptoms. Among the patients without treatment-
group during the study. An additional seven patients died in
emergent peripheral neuropathy, 80% had baseline symptoms.
the poststudy period: six patients from progressive myeloma
The dose of bortezomib was reduced at least once in six
and one patient from multi-organ failure at 84 d after the last
patients, held at least once in two patients, and permanently
dose.
discontinued in five patients because of peripheral neuropathy.
At the end of the study, symptoms of peripheral neuropathy
Discussion
had resolved in three patients and were ongoing in 19 patients.
A rash was reported in an approximately equal proportion of
Bortezomib is the first of a novel class of anti-cancer agents
patients in each dose group: 21% of patients in the 1Æ0 mg/m2
that functions by inhibiting proteasome activity. Based in part
and 19% of patients in the 1Æ3 mg/m2 dose group. No apparent
on data from the SUMMIT and CREST studies, single-agent
trend was observed with regard to the cycle at which a rash
bortezomib was approved at 1Æ3 mg/m2 twice weekly every
appeared, and no rash was graded >2.
3 weeks for the treatment of patients with relapsed and
Twelve patients discontinued because of adverse events, of
refractory myeloma. This study (CREST) is the first prospect-
which eight were considered possibly or probably attributed to
ive multicentre study to report the activity of bortezomib at
bortezomib. Five patients discontinued because of peripheral
1Æ0 mg/m2 in a patient group. Although the study was not
neuropathy, and one patient each discontinued because of
designed to be comparative with 1Æ3 mg/m2, the patient groups
limb pain, cardiac arrhythmia and myelosuppression (anaemia
were comparable by individual centre randomization. An ORR
and thrombocytopenia).
(CR + PR + MR) of 33% was observed for patients treated
One patient from the 1Æ3 mg/m2 dose group died of
with bortezomib monotherapy in the 1Æ0 mg/m2 dose group
pneumonia within 20 d after the last administration of
and an ORR of 50% was observed in the 1Æ3 mg/m2 dose
bortezomib. No deaths were reported for the 1Æ0 mg/m2 dose
group. This trial provides valuable information to the treating
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Bortezomib for Relapsed or Refractory Multiple Myeloma
physician who needs to reduce the bortezomib dose for
neurologist's assessment. It is noteworthy that one patient with
toxicity, because it demonstrated meaningful benefit at the
significant neuropathy at baseline developed grade 4 neurop-
1Æ0 mg/m2 dose.
athy while on the lower dose. A phase 3 trial is being
The results of this phase 2 study in patients with relapsed or
conducted in which the management of peripheral neuropa-
refractory multiple myeloma after front-line therapy suggest
thies and effectiveness of dose reduction will be evaluated in an
that bortezomib in combination with dexamethasone is active
exploratory analysis.
at both doses evaluated. Dexamethasone was added to the
The intent of this protocol was to treat patients after
regimens of patients who were not adequately responding to
front-line therapy. Although patients in first relapse are
bortezomib therapy alone. With the addition of dexametha-
treated with chemotherapeutic regimens, such as VAD
sone, the ORR was 44% in the 1Æ0 mg/m2 dose group and 62%
(vincristine, adriamycin, dexamethasone) (Rajkumar et al,
in the 1Æ3 mg/m2 dose group.
2002), thalidomide has recently emerged as a potential
The results from this trial compare favourably with those
single-agent salvage therapy in myeloma patients who have
published by Richardson et al (2003), who treated a more
relapsed or become refractory to standard therapies (Rajku-
advanced relapsed and refractory myeloma population. The
mar et al, 2002; Strasser & Ludwig, 2002). Singhal et al
patients in their study were at a median of 4 years since
(1999) demonstrated an ORR (defined as a decrease in M
diagnosis and had had a median of 6 prior lines of therapy. In
protein levels by 25% or more) of 32%, and 2% of patients
the trial reported here, the median duration of disease since
in that study achieved CR (100% decrease in M protein
diagnosis was 2 years for both groups, and the patients were
levels by standard electrophoresis).
treated after front-line therapy (a median of three regimens).
The findings in this study demonstrate that bortezomib has
At 1Æ3 mg/m2, Richardson et al (2003) demonstrated an ORR
substantial therapeutic activity in patients with relapsed or
of 35%; the higher response rate at 1Æ3 mg/m2 in this current
refractory multiple myeloma after front-line therapy at two
study suggests that enhanced efficacy may be observed in an
different dose levels. Some additional response effect occurred
earlier patient population.
after the addition of dexamethasone in patients that had a less
In the current study, toxicities were manageable and consis-
than optimal response to bortezomib alone and is suggestive of
tent with those observed in phase 1 and other phase 2 clinical
possible synergy. The efficacy results described herein are also
trials (Orlowski et al, 2002; Richardson et al, 2003). Overall, the
favourable relative to other standard cytotoxic therapies used
most commonly reported adverse events in this study were
for salvage therapy after front-line treatment.
fatigue, nausea, diarrhoea, pyrexia, constipation, peripheral
The observation of activity at lower doses supports the fea-
neuropathy, arthralgia, insomnia, headache, limb pain, thromb-
sibility of a dose reduction strategy to manage certain
ocytopenia and upper respiratory tract infection. Adverse events
toxicities, such as those observed less frequently in the
that were reported more frequently in the 1Æ3 mg/m2 compared
1Æ0 mg/m2 dose group, and will potentially enhance the safety
with the 1Æ0 mg/m2 dose group with a 20% difference in
profile of bortezomib. By assuring activity at lower doses, this
incidence rates included diarrhoea, peripheral neuropathy,
observation also facilitates the clinical testing of the preclinical
vomiting, anxiety, myalgia, night sweats, dyspepsia and blurred
synergy noted with the combination of bortezomib and other
vision, indicating a possible dose effect. Fatigue, constipation
active agents in this disease, and also in other cancers. Ongoing
and thrombocytopenia occurred at a similar rate in both dose
and future clinical studies include examining bortezomib as a
groups. Interestingly, arthralgia and peripheral oedema were
single agent or in combination therapy as initial therapy in
more common in the lower-dose group.
multiple myeloma and in non-Hodgkin's lymphoma, other
As has been observed in previous phase 1 trials (Aghajanian
haematological diseases and solid tumours.
et al, 2002; Orlowski et al, 2002), the occurrence of thromb-
ocytopenia with bortezomib is transient, with recovery within
Acknowledgements
the rest period suggesting a possible different pathogenesis
than that seen with conventional chemotherapeutic agents. In
This study was supported by Millennium Pharmaceuticals, Inc.
addition, a trend towards overall improvement of the baseline
was also noted and possibly relates to improvement in the
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