Bortezomib as First-Line Therapy in
Patients With Multiple Myeloma
A Multicenter Phase 2 Clinical Trial
S. Jagannath,1 B.G.M. Durie,1 J. Wolf,1 A. Berliner,1 E. Camacho,1
E. Gabayan,1 D. Irwin,1 J. Lutzky,1 M. McKinley,1 P. Potts,1
S. Noble-Kempin,1 B. Davis,1 A. Mazumder,1 J. Jacobson,2
D. Schenkein3, J. Crowley2
1Salick Health Care Research Network, Los Angeles, CA; 2Center for Research
& Biostatistics, Seattle, WA; 3Millennium Pharmaceuticals, Inc., Cambridge, MA
Rationale
· Bortezomib was effective in relapsed and in refractory
myeloma - SUMMIT1 and CREST2 phase 2 studies
· Complete responses and durable responses were noted
in phase 2 trials
· Dexamethasone could be safely combined with
bortezomib for additive antitumor effect
· This phase 2 study was conceived as a pilot to
investigate safety and efficacy of bortezomib in newly
diagnosed MM
1Richardson et al. N Engl J Med. 2003;348:2609.
2Jagannath et al. Br J Haematol. 2004;127:165.
Objectives
Primary Objectives
· Determine response rate by EBMT1 criteria to
bortezomib alone or in combination with Dex
in newly diagnosed MM patients
· Assess tolerability and toxicity of bortezomib alone and
in combination with Dex
Ancillary Objectives
· Assess ability to harvest stem cells after bortezomib
with G-CSF alone
1Blade et al. Br.J.Haematol., 102, 1115.
Patient Eligibility
· Patients with newly diagnosed MM requiring treatment
· Inclusion criteria
­ No previous chemotherapy; KPS 50%
­ Measurable disease
­ Age >18 years
­ Creatinine clearance > 20 mL/min
· Exclusion criteria
­ HIV
­ Hemodialysis
­ Plasma cell leukemia
Treatment Plan
· Bortezomib 1.3 mg/m2 twice weekly for 2 weeks, every
3 weeks for a maximum of 6 cycles
· Patients received bortezomib alone for the first 2
cycles
· Dex 40 mg on the day of and day after each
bortezomib dose was added if
­ After 2 cycles for patients who achieved < PR
­ After 4 cycles for patients who achieved < CR (IF- neg)
· Dex dose is twice the dose used in phase 2 bortezomib
trials (SUMMIT/CREST)1,2
1Jagannath et al. Br J Haematol. 2004;127:165.
2Richardson et al. N Engl J Med. 2003;348:2609.
Baseline Characteristics (N = 32)
Characteristic
Median age, y (range)
62 (45­84)
Sex, M/F
15/17
Median KPS (range)
90% (50­100)
-microglobulin 4 mg/L
34%
2
Median creatinine mg/dL, median (range)
1 (0.7­2.0)
Salmon-Durie stage III
56%
Myeloma type
IgG
56%
IgA
25%
Light-chain disease
19%
Interim Patient Disposition
Disposition
n
Accrued
42
Evaluable for response
32
Bortezomib alone
10
Bortezomib + dexamethasone
22
Dexamethasone added
22
Cycle 3
13
Cycle 5
9
Cycle 2 Response and Best Overall Response
(N = 32)
Best Confirmed
Bortezomib Alone
Bortezomib ±
Response
Cycle 2
Dexamethasone
Overall
CR, n (%)
1 (3)
2* (6)
nCR, n (%)
3 (9)
6* (19)
PR, n (%)
9 (28)
20 (63)
MR, n (%)
11 (34)
2 (6)
SD, n (%)
7 (22)
1 (3)
PD, n (%)
1 (3)
1 (3)
*Bortezomib alone induced 1 CR and 5 nCR
Addition of Dexamethasone (n = 22)
· Dexamethasone added: 22 patients
­ 13 patients at cycle 3
­ 9 patients at cycle 5
· Additional responses: 15/22 patients
­ Response improved by 2 levels:
· SD to CR: 1
· SD to PR: 4
­ Response improved by 1 level:
· MR to PR: 10
Time to Best Overall Response
CR + nCR + PR (N = 32)
Bortezomib
Bortezomib
+/- Dexamethasone
100
100
88%
90
78%
80
80
)
70
%
)
(
60
60
%(
Rate
50
40%
Median 2
40
40
months
30
Response
Response
20
20
10
0
0
24
6
0
1
2
3
4
5
Cycle
Months
Partial Response
Near Complete Response
Complete Response
Confirmation of Remission:
PET Scan
Plasmacytomas
Pretreatment
After 4 Cycles
Stem Cell Transplantation
Stem cell harvesting with G-CSF in 8 patients
· Median days of harvest: 2
· Median CD 34+ cells: 13.20 (7.19­16.09) x 106/kg
Stem cell transplantation in 6 patients
· Median time to:
­ ANC > 1000: 10 (9­10) days
­ Platelet counts > 100,000/mm3: 17 (11­20) days
Adverse Events Grade 2* (N = 32)
Neuropathy*
16%
Gr 2
Gr 3
6%
Gr 4
Fatigue
9%
Diarrhea
Constipation
Hematologic Toxicities
16%
6%
0
2
4
6
8
10 12 1416 18 202224 26 2830 32
Number of Patients
*Neuropathic pain: 5 patients
Grade 4:
1 x thrombocytopenia
·Grade 2 ­ 3 patients
1 x neutropenia
·Grade 3 ­ 2 patients
Richardson et al. N Engl J Med. 2003;348:2609.
* Adverse events graded per NCI CTC v2
Jagannath et al. Br J Haematol. 2004;127:165.
Adverse Events (N = 32)
· 8 early discontinuations
­ Grade 3 dizziness
1
­ Grade 2 sensory neuropathy
2
­ Grade 3 sensory neuropathy
5
· Neuropathy grade 2-3 in 10 patients
­ At the time of this report, resolution reported in 5
­ Median time to resolution 3 months
(this includes 3 patients with neuropathic pain)
· 1 patient had a PR after cycle 2 and then progressed after
cycle 4 into plasma cell leukemia, came off study, and died
within 30 days
Conclusions
· Bortezomib, alone or in combination with
dexamethasone, is an effective front-line therapy in MM
· Response rate 88%, with a CR + nCR rate of 25%
· Combination with dexamethasone provided added
benefit
· Stem cell harvest was successful and engraftment was
prompt
· Toxicities were manageable
· Occurrence and resolution of peripheral neuropathy
require further study
Acknowledgments
· St Vincent CCC, NY--Jagannath, Mazumder
· Alta Bates CCC, CA--Wolf, Irwin
· Boca Raton--Berliner
· CCC Desert--Camacho
· Mt Sinai--Lutzky
· Cedars Sinai CCC--Durie
· CRAB--Crowley
· Salick Health Care Research Network and data
management

Document Outline