JX603431 Jagannath Poster4.qxd
4/12/07
16:54
Page 1
Updated survival analyses after prolonged follow-up of the phase 2,
multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma
Sundar Jagannath,1 Bart Barlogie,2 James R. Berenson,3 David S. Siegel,4 David Irwin,5 Paul G. Richardson,6 Ruben Niesvizky,7 Raymond Alexanian,8 Steven A. Limentani,9 Melissa Alsina,10 Dixie-Lee Esseltine,11 Kenneth C. Anderson6
1St. Vincent's Comprehensive Cancer Center, New York, NY; 2Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR; 3Oncotherapeutics, West Hollywood, CA; 4Hackensack University Medical Center, Hackensack, NJ; 5Alta Bates Cancer Center, Berkeley, CA; 6Dana-Farber Cancer Institute, Boston, MA;
7Weill-Cornell Medical College of Cornell University, New York Presbyterian Hospital, NY; 8University of Texas M. D. Anderson Cancer Center, Houston, TX; 9Carolinas Hematology/Oncology Associates, Charlotte, NC; 10H. Lee Moffitt Cancer Center Research Institute, Tampa, FL; 11Millennium Pharmaceuticals, Inc., Cambridge, MA
Table 1. Patient demographics and baseline characteristics
Table 3. Response rates and TTP by bortezomib dose group
Figure 1. Kaplan-Meier analyses of OS in patients who received
BACKGROUND
dexamethasone 20 mg on the day of and day after
each bortezomib dose.
bortezomib 1.0 mg/m2 or 1.3 mg/m2 ± dexamethasone
CONCLUSIONS
Bortezomib dose group
Bortezomib dose group
· Bortezomib (VELCADE®) is approved for the
· Patients who, in the investigator's opinion, could
· Long-term follow-up confirms the survival benefit
1.0 mg/m2
1.3 mg/m2
1.0 mg/m2
1.3 mg/m2
1.0 mg/m2 (n=28)
treatment of multiple myeloma (MM) patients who
benefit or continue to benefit from treatment or
(n=28)
(n=26)
(n=27)
(n=26)
1.0
1.3 mg/m2 (n=26)
conferred by bortezomib ± dexamethasone after a
have received at least one prior therapy.1
retreatment could continue receiving bortezomib
0.9
first relapse:
in an extension study.8
Mean age, years (range)
64 (39­82)
60 (30­84)
Overall response rate (CR+PR+MR), n (%)
0.8
­ Accelerated approval in the United States was
­ 1.3 mg/m2: 3-year survival rate is 58%
function 0.7
based on the results of the phase 2 SUMMIT2,3
Male, n (%)
14 (50)
9 (35)
0.6
­ 1.0 mg/m2: 3-year survival rate is 43%.
Assessments
To bortezomib alone
9 (33)
13 (50)
0.5
and CREST4 trials.
· Response and progression were assessed
IgG/IgA/other MM, %
54/29/18
65/23/12
0.4
· Bortezomib demonstrated substantial activity at
To bortezomib ± dexamethasone
12 (44)
16 (62)
distribution 0.3
­ Final approval was based on the results of the
according to the European Group for Blood and
both dose levels:
Karnofsky Performance Status 70, n (%)
3 (11)
4 (15)
0.2
phase 3 APEX trial.5,6
Marrow Transplantation (EBMT) criteria.9
CR+PR rate, n (%)
Survival 0.1
­ 1.3 mg/m2: CR+PR = 38%
2-microglobulin 4 mg/L, n/N (%)
14/24 (58)
11/23 (48)
0
· CREST is the only phase 2 study of two doses of
­ Also included near CR (nCR) ­ 100% M-protein
0
12
24
36
48
60
72
­ 1.0 mg/m2: CR+PR = 30%.
To bortezomib alone
8 (30)
10 (38)
Time (months)
bortezomib as second-line therapy, and it
reduction but with positive immunofixation.
Platelets <75 x 109/L, n/N (%)
5/26 (19)
0/25 (0)
· The 1.0 mg/m2 dose is associated with better
established the activity of bortezomib 1.0 mg/m2
· Secondary efficacy endpoints assessed included
To bortezomib ± dexamethasone
10 (37)
13 (50)
Abnormal cytogenetics, n/N (%)
7/24 (29)
11/23 (48)
tolerance compared with the 1.3 mg/m2 dose:
and 1.3 mg/m2 in comparable patient populations.4
Safety8
time to progression (TTP), duration of response,
­ 1.3 mg/m2: 27% of patients completed eight
Durie-Salmon Stage III, n/N (%)
15/27 (56)
16/26 (62)
Median time to first response, months
1.3
1.5
­ Here, we present updated data from the CREST
and OS.
· Toxicities were manageable.
cycles; 35% had dose reductions and 35%
study after prolonged follow-up (median 5 years).
­ Time-to-event analyses were performed using
Median time since diagnosis, years
2.0
2.0
Median duration of response (CR/PR/MR), months
9.5
13.7
· AEs reported at 20% greater rate with the 1.3 mg/m2
discontinued due to AEs
the Kaplan-Meier method.
dose compared with the 1.0 mg/m2 dose included:
­ 1.0 mg/m2: >60% of patients completed eight
Median no. of prior regimens, n (range)
3 (1­7)
3 (1­7)
(n=28)
(n=26)
OBJECTIVE
cycles; 11% had dose reductions and 11%
· Adverse events (AEs) were assessed at each visit
­ Diarrhea, vomiting, anxiety, peripheral neuropathy,
discontinued due to AEs.
and graded according to the National Cancer
Prior ASCT/other high-dose therapy, n (%)
15 (54)
11 (42)
Median TTP, months
7.0
11.0
night sweats, myalgia, blurred vision, and dyspnea.
· To evaluate overall survival (OS) in the CREST4
Institute Common Toxicity Criteria version 2.
· A higher proportion of patients at the 1.3 mg/m2 dose
· A starting dose of 1.3 mg/m2 is the preferred dose
phase 2 trial of bortezomib ± dexamethasone after
­ Bortezomib dose reductions were required for
level required dose reductions due to AEs compared
Table 2. Exposure to treatment with bortezomib ±
for bortezomib;7 patients should be closely
prolonged follow-up (median >5 years) in patients
drug-related grade 3 non-hematologic and
dexamethasone in CREST and the extension study
· Median follow-up was:
with the 1.0 mg/m2 dose level (35% vs 11%).
monitored for AEs, especially neuropathy. In cases
who received:
grade 4 hematologic toxicities.
of toxicity, bortezomib dose can be reduced to
­ 61 (59­65) months in the 1.0 mg/m2 dose group
­ Patients' final bortezomib dose was the same as
Bortezomib dose group
1 mg/m2 and retain acceptable efficacy.
­ Bortezomib 1.0 mg/m2
their starting dose in 82% of patients in the
· The study was prospectively designed to
­ 65 (55­71) months in the 1.3 mg/m2 dose group.
1.0 mg/m2
1.3 mg/m2
1.0 mg/m2 dose level and 65% in the 1.3 mg/m2
· A starting dose of 1.0 mg/m2 is acceptable in
­ Bortezomib 1.3 mg/m2.
determine whether the rate of response to
(n=28)
(n=26)
dose level.
bortezomib alone was at least 20% (=0.05),
· OS at the 5-year mark was 32% and 45% for the
special circumstances where patients may not be
with at least 80% power to conclude a
Median duration of treatment in CREST,
4.7
3.9
1.0 mg/m2 and 1.3 mg/m2, respectively.
­ The median dose intensity (% of dose expected)
able to tolerate the higher dose.
METHODS
response rate of 40% or more.
months (range)
(0.03­7.6)
(0.4­5.7)
was 95% and 86.9% for the 1.0 mg/m2 dose
· Kaplan-Meier distributions of OS in the two dose
level and 1.3 mg/m2 dose level, respectively.
Patients completing 4 cycles, n (%)
24 (86)
19 (73)
Study design
groups are shown in Figure 1.
REFERENCES
RESULTS
· Thirteen patients (23%) discontinued due to AEs,
Patients completing 8 cycles, n (%)
17 (61)
7 (27)
· Patients were enrolled to receive bortezomib as
­ Survival rates are summarized in Table 4.
including three (11%) at the 1.0 mg/m2 dose level
second-line therapy.
1.
Kane RC, et al. Clin Cancer Res 2006;12:2955­60.
· 54 patients were enrolled:
Median number of cycles
8
6
and ten (38%) at the 1.3 mg/m2 dose level.
2.
Richardson PG, et al. N Engl J Med 2003;348:2609­17.
Table 4. Survival rates by bortezomib dose group
3.
Richardson PG, et al. Cancer 2006;106:1316­9.
· Patients had relapsed following chemotherapy or
­ 28 received bortezomib 1.0 mg/m2
Patients requiring dose reductions due
3 (11)
9 (35)
­ Of these AEs resulting in discontinuation, two and
4.
Jagannath S, et al. Br J Haematol 2004;127:165­72.
to AEs, n (%)
5.
Richardson PG, et al. N Engl J Med 2005;352:2487­98.
were refractory to front-line chemotherapy.
­ 26 received bortezomib 1.3 mg/m
Bortezomib dose group
six, respectively, were considered related to
2.
6.
Richardon PG, et al. Blood 2007;110:3557­60.
1.0 mg/m2
1.3 mg/m2
bortezomib.
7.
Millennium Pharmaceuticals, Inc. VELCADE® (bortezomib) for injection. Prescribing Information.
­ Front-line therapy could be composed of more
Patients receiving added dexamethasone,
16 (57)
12 (46)
· Patient demographics and baseline characteristics
Rev 7. October 2007.
n (%)
(n=28)
(n=26)
8.
Berenson JR, et al. Cancer 2005;104:2141­8.
than one regimen, defined as a single drug or
are shown in Table 1.
9.
Bladé J, et al. Br J Haematol 1998;102:1115­23.
Subsequent therapy
combination therapy.
10. Conner TM, et al. Blood 2006;108:1007a (abstract 3531).
Patients continuing in extension study, n (%)
12 (43)
5 (19)
1-year survival rate, %
82
81
­ Patients were balanced with respect to
11. Sood R, et al. Ann Oncol 2006;17:ix205-6 (abstract 679P).
· Comprehensive data on subsequent therapies
12. Wolf JL, et al. Blood 2006;108:1008a (abstract 3532).
· Patients were randomized to receive bortezomib
demographics and prior therapies across the two
2-year survival rate, %
54
69
received for MM is not available.
1.0 mg/m2 or 1.3 mg/m2 on days 1, 4, 8, and 11 of
arms.
ACKNOWLEDGMENTS
· The study objective was met. In the 1.0 mg/m2 dose
a 21-day cycle for up to 8 cycles.
The authors thank Steve Hill, Sarah Maloney, and Jane Saunders for their assistance in drafting the
· Some patients received retreatment with
3-year survival rate, %
43
58
· Exposure to treatment in CREST and the extension
poster. Steve Hill and Sarah Maloney are Medical Writers, and Jane Saunders is a Medical Editor with
group, 30% of the patients achieved CR+PR and
bortezomib-based therapy, which has been shown
Gardiner-Caldwell London.
­ To ensure that the two dose levels were studied
study for each dose group are summarized in Table 2.
33% achieved CR+PR+MR.
4-year survival rate, %
36
54
to be active in patients with relapsed MM.10­12
DISCLOSURES
in similar patient populations, a center-specific
· Both the 1.0 mg/m2 and 1.3 mg/m2 doses were
·
Employment: Millennium Pharmaceuticals (DLE)
randomization was used, based on disease stage
5-year survival rate, %
32
45
· Some patients received treatment with other novel
Efficacy
·
Consultancy: Millennium Pharmaceuticals (JB, RN, KA), Celgene (RN, KA), Novartis (KA)
active and induced durable responses, as shown in
and previous chemotherapy.
·
Ownership interest: Millennium Pharmaceuticals (DLE)
therapies, including thalidomide and lenalidomide.
· Of the 54 patients enrolled, 53 were evaluable
Table 3.
·
Research funding: Millennium Pharmaceuticals (JB, RN, KA), Celgene (RN, KA), Novartis (KA)
Number of patients who have died, n (%)
21 (75)
14 (54)
· Patients with suboptimal response to bortezomib
·
Honoraria: Millennium Pharmaceuticals (SJ, BB, RA, PR, RN, KA), Celgene (BB, PR, RN, KA),
for response.
· Median treatment duration in the 1.3 mg/m2 group is
· Subsequent therapy with bortezomib and other
Novartis (KA), Johnson & Johnson (PR)
alone (progressive disease after 2 cycles or stable
Median follow-up, months
61
65
·
Membership: Millennium (SJ, BB, JB, DS, PR), Celgene (SJ, BB, PR), Johnson & Johnson (PR)
­ One patient with non-secretory myeloma was
similar to that in the APEX phase 3 trial of
novel agents may have contributed to the prolonged
disease after 4 cycles) were eligible to add
not evaluable.
bortezomib 1.3 mg/m2.
survival reported here.
Presented at the 2007 ASH Annual Meeting, Atlanta, GA, USA, December 8­11, 2007.

---