First-line Therapy With Bortezomib
(VELCADE®, Formerly PS-341) in
Patients With Multiple Myeloma
Multi-Institutional Phase II Clinical Trial
Sundar Jagannath,1 Brian G.M. Durie,1 Jeffrey Wolf,1 Elber Camacho,1
David Irwin,1 Jose Lutzky,1 Marti McKinley,1 Eli Gabayan,1
Amitabha Mazumder,1 John Crowley,2 David Schenkein3
1Salick Health Care Research Network, Los Angeles, CA; 2Center for Research &
Biostatistics, Seattle, WA; 3Millennium Pharmaceuticals, Inc., Cambridge, MA
Objectives
Primary Objectives
· Determine response rate 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
· Harvest stem cells after bortezomib with G-CSF
alone
Methods
Patient Population
· Patients with newly diagnosed MM requiring
treatment
· Inclusion criteria
­ No previous chemotherapy
­ Measurable disease
· Exclusion
­ HIV
­ Hemodialysis
­ Plasma cell leukemia
Treatment Plan
· Bortezomib 1.3 mg/m2 2x/week x2 q 3 weeks for
a maximum of 6 cycles
· Dex 40 mg permitted only on the day of and
after each bortezomib dose
­ After 2 cycles for patients who achieve less than
a PR
­ After 4 cycles for patients who achieve less than
a CR (immunofixation negative)
­ Dex dose was twice the dose used in the phase 2
bortezomib trials (SUMMIT/CREST)5,6
· Premedication was allowed according to
physician discretion
Statistical Design
· Initially,19 eligible patients will be accrued
· If 9 or more confirmed responses are observed,
an additional 23 eligible patients will be accrued
for a total of 42 patients
· Current accrual: 31 patients
Patient Demographics (N = 24)
Characteristic
Median age, y (range)
58.8 (45­83)
Sex, M/F
11/13
Median Karnofsky performance score (range)
90 (50­100)
Stage II/III
18 (75%)
Current Best Overall Responses
(n = 24)
Response*
n (%)
CR
2 (8)
NCR
4 (17)
Overall 79%
PR
13 (54)
MR
4 (17)
SD
0 (0)
PD
1 (4)
*Responses based on paraprotein.
· Bortezomib alone induced CR/NCR in 6 patients;
2 of these NCR patients received dexamethasone and response
status remained unchanged
Addition of Dexamethasone (n = 14)
· Dexamethasone was added to the treatment of
­ 8 patients at cycle 3
­ 6 patients at cycle 5
· Additional response after dexamethasone, 8/14
· Response improved by 2 levels:
­SD to PR: 2
· Response improved by 1 level:
­MR to PR: 4
­SD to MR: 2
Time To Best Overall Response
(n = 24)
Best Overall Response*
Cycle 2
Cycle 4
Cycle 6
CR/PR/MR, n (%)
9 (38)
20 (83)
23 (96)
CR/PR, n (%)
7 (29)
17 (71)
19 (79)
*Responses based on paraprotein.
1 patient had PD after cycle 2.
Treatment-Related Adverse Events* (n = 24)
Neuropathic pain
Sensory neuropathy
Fatigue
Diarrhea
Constipation
Maximum grade: any AE
02468
10 12 14 16 18 20 22 24
Number of Patients
Maximum toxicity grade:
1234
*Adverse events graded per NCI CTC v2.
Treatment Related
Adverse Events (n = 24)*
· 5 early discontinuations due to treatment-
related adverse events, and
· 1 death due to sepsis while on Velcade +
Dexamethasone
· The spectrum and severity of adverse events
are very similar to a phase 2 clinical trial of
bortezomib.1 In that trial, dexamethasone 20
mg was given on the day of and day after
bortezomib
1Richardson et al. N Engl J Med. 2003;348:2609.
Ancillary Findings
· Stem cell harvesting
­ Has proceeded without difficulty
­ Successful harvest: 5/5 (100%)
­ 2 patients transplanted with complete hematologic
recovery
Conclusions
· Bortezomib was effective and well tolerated as front-
line therapy in this study
· This phase 2 study has demonstrated a 79%
response rate
· Combination with dexamethasone provides added
benefit in some patients
· Stem cell harvesting and engraftment was feasible
· Development of peripheral neuropathy and resolution
requires further study; monitoring in the clinical
setting is warranted
· Accrual ongoing
Multi-Institutional Phase II Clinical Trial
Confirmation of Remission:
PET Scan
Plasmacytomas
Pretreatment
After 4 Cycles

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