Bortezomib Therapy Alone and in
Combination With Dexamethasone for
Patients With Previously Untreated
Multiple Myeloma
S. Jagannath,1 B. Durie,1 J. Wolf,1 E. Camacho,1
D. Irwin,1 J. Lutzky,1 M. McKinley,1 E. Gabayan,1
A. Mazumder,1 J. Crowley,2 R. Vescio,1 and D. Schenkein3
1Aptium Oncology Research Network, CA;
2Cancer Research and Biostatistics, WA;
3Millennium Pharmaceuticals, Inc., MA
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, 1115-1123.
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
Baseline Patient Characteristics
Characteristic
N = 48
Median age, y (range)
60 (4084)
Male, %
46
Median KPS, % (range)
90 (50100)
-microglobulin 4 mg/L, %
31
2
Median creatinine, mg/dL (range)
1 (0.72.0)
Durie-Salmon stage III, %
50
Myeloma type, %
IgG
64
IgA
21
Light-chain disease
15
Cycle 2 Response and Best Overall
Response (N = 48)
Bortezomib ±
Best
Bortezomib Alone
Dexamethasone
Confirmed
Cycle 2
Overall
Response
n (%)
n (%)
CR
1 (2)
4 (8)
nCR
4 (8)
5 (10)
ORR
90%
PR
19 (40)
34 (71)
MR
12 (25)
4 (8)
SD
11 (23)
0
PD
1 (2)
1 (2)
MR = minor response; SD = stable disease; PD = progressive disease; ORR = overall response rate
Cumulative Best Response By Cycle
Bortezomib ±
Dexamethasone
100
90
90
PR
)
Bortezomib Alone
79
%
80
nCR
e(
70
CR
60
50
Rat
50
sen 40
o
30
Resp
20
10
0
246
Cycle
Stem Cell Transplantation
Stem cell harvesting with G-CSF or local protocol* in
23 patients
Median number of harvest days (range): 2 (18)
Median CD34+ cells (range): 12.55 × 106/kg
(5.1140.37 × 106/kg)
Stem cell transplantation in 23 patients
Median time to absolute neutrophil count >
1,000/mm3 (range): 11 days (813)
Median time to platelet count > 100,000/mm3
(range): 17 days (1098)
*In 6 patients, stem cells were mobilized with G-CSF and cyclophosphamide.
Data available in 23 of 24 transplanted patients.
2 patients received tandem stem cell transplantation (twice per patient) where data was
included for the first transplantation only; for both patients, prompt hematopoietic recovery
was also observed following the second transplantation.
Progression-Free Survival and Overall
Survival (N=48)
Progression-Free Survival
Overall Survival
Data ending November 23, 2005
Data ending November 23, 2005
100%
100%
80%
80%
60%
60%
40%
40%
20%
20%
Median
12-Month
Events / N in Months
Deaths / N
Estimate
Bortezomib(Velcade)
23 / 48
15 (9,24)
Bortezomib(Velcade)
4 / 48
93% (83,100)
0%
0%
0
6
12
18
24
30
0
6
12
18
24
30
Months After Registration
Months After Registration
Progression-Free Survival
Overall Survival
Median progression-free survival: 15 months (range, 9-24)
Median overall survival: not reached
Estimated survival rate at 12 months: 93%
Stem Cell Transplantation
Stem cell harvesting with G-CSF or local protocol* in
23 patients
Median number of harvest days (range): 2 (18)
Median CD34+ cells (range): 12.55 × 106/kg
(5.1140.37 × 106/kg)
Stem cell transplantation in 23 patients
Median time to absolute neutrophil count >
1,000/mm3 (range): 11 days (813)
Median time to platelet count > 100,000/mm3
(range): 17 days (1098)
*In 6 patients, stem cells were mobilized with G-CSF and cyclophosphamide.
Data available in 23 of 24 transplanted patients.
2 patients received tandem stem cell transplantation (twice per patient) where data was
included for the first transplantation only; for both patients, prompt hematopoietic recovery
was also observed following the second transplantation.
Treatment-Emergent Adverse Events*
Grade 2 (N = 49)
Grade 2
Grade 3
Grade 4
n (%)
n (%)
n (%)
Sensory
12 (24)
6 (12)
0
neuropathy/neuropathic pain
Neutropenia
1 (2)
4 (8)
1 (2)
Diarrhea
1 (2)
3 (6)
0
Fatigue
8 (16)
2 (4)
0
Abdominal pain/cramping
2 (4)
1 (2)
0
Myalgia
1 (2)
1 (2)
0
Anorexia
3 (6)
1 (2)
0
Constipation
8 (16)
0
0
Nausea
6 (12)
0
0
Thrombocytopenia
1 (2)
0
1 (2)
*Includes adverse events reported in 10% of patients or those graded 3 or 4 in severity.
One patient who received <2 cycles of treatment was included in this analysis.
2 patients had concurrent grade 2 or 3 sensory neuropathy and grade 2 or 3 neuropathic pain.
Summary of Dose Modifications
Doses held in 2 patients due to:
Grade 3 neuropathy and grade 3 diarrhea in one
patient
Grade 3 neutropenia in another patient
Dose reductions occurred in 17 patients
Median 25% dose reduction (to 1.0 mg/m2)
Most common reasons for dose reduction were
peripheral neuropathy (n = 9) and concurrent
neuropathy and pain (n = 2)
Discontinuations due to adverse events occurred in 9
patients
Grade 2 dizziness (n = 1)
Grade 3 neuropathy (n = 4)*
Grade 2 neuropathy (n = 4)
*1 patient had concurrent neuropathic pain.
2 patients had concurrent neuropathic pain.
CONCLUSIONS
Bortezomib alone and in combination with
dexamethasone is an effective frontline therapy in
multiple myeloma
Response rate with bortezomib ± dexamethasone
was 90% with a CR + nCR rate of 19%
Estimated 1-year survival rate is 93%
Bortezomib is a feasible option for induction therapy
Successful stem cell harvest and engraftment
Rapid hematopoietic recovery
Adverse events were predictable and manageable