Updated survival analyses after prolonged follow-up of the phase 2, Download full-text
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
• Bortezomib (VELCADE®) is approved for the
treatment of multiple myeloma (MM) patients who
have received at least one prior therapy.1
– Accelerated approval in the United States was
based on the results of the phase 2 SUMMIT2,3
– Final approval was based on the results of the
phase 3 APEX trial.5,6
• CREST is the only phase 2 study of two doses of
bortezomib as second-line therapy, and it
established the activity of bortezomib 1.0 mg/m2
and 1.3 mg/m2in comparable patient populations.4
– Here, we present updated data from the CREST
study after prolonged follow-up (median 5 years).
• To evaluate overall survival (OS) in the CREST4
phase 2 trial of bortezomib ± dexamethasone after
prolonged follow-up (median >5 years) in patients
– Bortezomib 1.0 mg/m2
– Bortezomib 1.3 mg/m2.
• Patients were enrolled to receive bortezomib as
• Patients had relapsed following chemotherapy or
were refractory to front-line chemotherapy.
– Front-line therapy could be composed of more
than one regimen, defined as a single drug or
• Patients were randomized to receive bortezomib
1.0 mg/m2or 1.3 mg/m2on days 1, 4, 8, and 11 of
a 21-day cycle for up to 8 cycles.
– To ensure that the two dose levels were studied
in similar patient populations, a center-specific
randomization was used, based on disease stage
and previous chemotherapy.
• Patients with suboptimal response to bortezomib
alone (progressive disease after 2 cycles or stable
disease after 4 cycles) were eligible to add
• 54 patients were enrolled:
– 28 received bortezomib 1.0 mg/m2
– 26 received bortezomib 1.3 mg/m2.
• Patient demographics and baseline characteristics
are shown in Table 1.
– Patients were balanced with respect to
demographics and prior therapies across the two
• Exposure to treatment in CREST and the extension
study for each dose group are summarized in Table 2.
• Of the 54 patients enrolled, 53 were evaluable
– One patient with non-secretory myeloma was
Kane RC, et al. Clin Cancer Res 2006;12:2955–60.
Richardson PG, et al. N Engl J Med 2003;348:2609–17.
Richardson PG, et al. Cancer 2006;106:1316–9.
Jagannath S, et al. Br J Haematol 2004;127:165–72.
Richardson PG, et al. N Engl J Med 2005;352:2487–98.
Richardon PG, et al. Blood 2007;110:3557–60.
Millennium Pharmaceuticals, Inc. VELCADE®(bortezomib) for injection. Prescribing Information.
Rev 7. October 2007.
Berenson JR, et al. Cancer 2005;104:2141–8.
Bladé J, et al. Br J Haematol 1998;102:1115–23.
10. Conner TM, et al. Blood 2006;108:1007a (abstract 3531).
11. Sood R, et al. Ann Oncol 2006;17:ix205-6 (abstract 679P).
12. Wolf JL, et al. Blood 2006;108:1008a (abstract 3532).
The authors thank Steve Hill, Sarah Maloney, and Jane Saunders for their assistance in drafting the
poster. Steve Hill and Sarah Maloney are Medical Writers, and Jane Saunders is a Medical Editor with
• Employment: Millennium Pharmaceuticals (DLE)
• Consultancy: Millennium Pharmaceuticals (JB, RN, KA), Celgene (RN, KA), Novartis (KA)
•Ownership interest: Millennium Pharmaceuticals (DLE)
• Research funding: Millennium Pharmaceuticals (JB, RN, KA), Celgene (RN, KA), Novartis (KA)
• Honoraria: Millennium Pharmaceuticals (SJ, BB, RA, PR, RN, KA), Celgene (BB, PR, RN, KA),
Novartis (KA), Johnson & Johnson (PR)
• Membership: Millennium (SJ, BB, JB, DS, PR), Celgene (SJ, BB, PR), Johnson & Johnson (PR)
Presented at the 2007 ASH Annual Meeting, Atlanta, GA, USA, December 8–11, 2007.
dexamethasone 20 mg on the day of and day after
each bortezomib dose.
• Patients who, in the investigator’s opinion, could
benefit or continue to benefit from treatment or
retreatment could continue receiving bortezomib
in an extension study.8
• Response and progression were assessed
according to the European Group for Blood and
Marrow Transplantation (EBMT) criteria.9
– Also included near CR (nCR) – 100% M-protein
reduction but with positive immunofixation.
• Secondary efficacy endpoints assessed included
time to progression (TTP), duration of response,
– Time-to-event analyses were performed using
the Kaplan-Meier method.
• Adverse events (AEs) were assessed at each visit
and graded according to the National Cancer
Institute Common Toxicity Criteria version 2.
– Bortezomib dose reductions were required for
drug-related grade ≥3 non-hematologic and
grade 4 hematologic toxicities.
• The study was prospectively designed to
determine whether the rate of response to
bortezomib alone was at least 20% (α=0.05),
with at least 80% power to conclude a
response rate of 40% or more.
• The study objective was met. In the 1.0 mg/m2 dose
group, 30% of the patients achieved CR+PR and
33% achieved CR+PR+MR.
• Both the 1.0 mg/m2and 1.3 mg/m2doses were
active and induced durable responses, as shown in
• Median treatment duration in the 1.3 mg/m2group is
similar to that in the APEX phase 3 trial of
bortezomib 1.3 mg/m2.
• Median follow-up was:
– 61 (59–65) months in the 1.0 mg/m2dose group
– 65 (55–71) months in the 1.3 mg/m2dose group.
• OS at the 5-year mark was 32% and 45% for the
1.0 mg/m2and 1.3 mg/m2, respectively.
• Kaplan-Meier distributions of OS in the two dose
groups are shown in Figure 1.
– Survival rates are summarized in Table 4.
• Toxicities were manageable.
• AEs reported at ≥20% greater rate with the 1.3 mg/m2
dose compared with the 1.0 mg/m2dose included:
– Diarrhea, vomiting, anxiety, peripheral neuropathy,
night sweats, myalgia, blurred vision, and dyspnea.
• A higher proportion of patients at the 1.3 mg/m2dose
level required dose reductions due to AEs compared
with the 1.0 mg/m2dose level (35% vs 11%).
– Patients’ final bortezomib dose was the same as
their starting dose in 82% of patients in the
1.0 mg/m2dose level and 65% in the 1.3 mg/m2
– The median dose intensity (% of dose expected)
was 95% and 86.9% for the 1.0 mg/m2dose
level and 1.3 mg/m2dose level, respectively.
• Thirteen patients (23%) discontinued due to AEs,
including three (11%) at the 1.0 mg/m2dose level
and ten (38%) at the 1.3 mg/m2dose level.
– Of these AEs resulting in discontinuation, two and
six, respectively, were considered related to
• Comprehensive data on subsequent therapies
received for MM is not available.
• Some patients received retreatment with
bortezomib-based therapy, which has been shown
to be active in patients with relapsed MM.10–12
• Some patients received treatment with other novel
therapies, including thalidomide and lenalidomide.
• Subsequent therapy with bortezomib and other
novel agents may have contributed to the prolonged
survival reported here.
Bortezomib dose group
Mean age, years (range) 64 (39–82)60 (30–84)
Male, n (%)14 (50)9 (35)
IgG/IgA/other MM, % 54/29/1865/23/12
Karnofsky Performance Status ≤70, n (%) 3 (11) 4 (15)
β2-microglobulin ≥4 mg/L, n/N (%) 14/24 (58)11/23 (48)
Platelets <75 x 109/L, n/N (%) 5/26 (19)0/25 (0)
Abnormal cytogenetics, n/N (%)7/24 (29)11/23 (48)
Durie-Salmon Stage III, n/N (%)15/27 (56)16/26 (62)
Median time since diagnosis, years 2.02.0
Median no. of prior regimens, n (range)3 (1–7) 3 (1–7)
Prior ASCT/other high-dose therapy, n (%) 15 (54)11 (42)
Table 1. Patient demographics and baseline characteristics
Bortezomib dose group
Median duration of treatment in CREST,
Patients completing ≥4 cycles, n (%) 24 (86) 19 (73)
Patients completing 8 cycles, n (%) 17 (61)7 (27)
Median number of cycles86
Patients requiring dose reductions due
to AEs, n (%)
3 (11)9 (35)
Patients receiving added dexamethasone,
16 (57)12 (46)
Patients continuing in extension study, n (%) 12 (43)5 (19)
Table 2. Exposure to treatment with bortezomib ±
dexamethasone in CREST and the extension study
Bortezomib dose group
Overall response rate (CR+PR+MR), n (%)
To bortezomib alone9 (33) 13 (50)
To bortezomib ± dexamethasone 12 (44)16 (62)
CR+PR rate, n (%)
To bortezomib alone 8 (30)10 (38)
To bortezomib ± dexamethasone10 (37) 13 (50)
Median time to first response, months 1.3 1.5
Median duration of response (CR/PR/MR), months9.5 13.7
Median TTP, months7.011.0
Table 3. Response rates and TTP by bortezomib dose group
Bortezomib dose group
1-year survival rate, %82 81
2-year survival rate, %54 69
3-year survival rate, % 43 58
4-year survival rate, %36 54
5-year survival rate, %3245
Number of patients who have died, n (%) 21 (75) 14 (54)
Median follow-up, months 6165
Table 4. Survival rates by bortezomib dose group
Survival distribution function
1.0 mg/m2 (n=28)
1.3 mg/m2 (n=26)
Figure 1. Kaplan-Meier analyses of OS in patients who received
bortezomib 1.0 mg/m2or 1.3 mg/m2± dexamethasone
• Long-term follow-up confirms the survival benefit
conferred by bortezomib ± dexamethasone after a
– 1.3 mg/m2: 3-year survival rate is 58%
– 1.0 mg/m2: 3-year survival rate is 43%.
• Bortezomib demonstrated substantial activity at
both dose levels:
– 1.3 mg/m2: CR+PR = 38%
– 1.0 mg/m2: CR+PR = 30%.
• The 1.0 mg/m2dose is associated with better
tolerance compared with the 1.3 mg/m2dose:
– 1.3 mg/m2: 27% of patients completed eight
cycles; 35% had dose reductions and 35%
discontinued due to AEs
– 1.0 mg/m2: >60% of patients completed eight
cycles; 11% had dose reductions and 11%
discontinued due to AEs.
• A starting dose of 1.3 mg/m2is the preferred dose
for bortezomib;7patients should be closely
monitored for AEs, especially neuropathy. In cases
of toxicity, bortezomib dose can be reduced to
1 mg/m2and retain acceptable efficacy.
• A starting dose of 1.0 mg/m2is acceptable in
special circumstances where patients may not be
able to tolerate the higher dose.
JX603431 Jagannath Poster4.qxd 4/12/07 16:54 Page 1