Efficacy and Safety of Three Bortezomib-
Based Combinations in Elderly, Newly
Diagnosed Multiple Myeloma Patients:
Results From All Randomized Patients in
the Community-Based, Phase 3b
UPFRONT Study
Ruben Niesvizky,1 Ian Flinn,2 Robert Rifkin,3 Nashat Gabrail,4 Veena Charu,5
Billy Clowney,6 James Essell,7 Yousuf Gaffar,8 Thomas Warr,9 Rachel
Neuwirth,10 Deyanira Corzo,10 and James Reeves11
1Center of Excellence for Lymphoma and Myeloma, Weill Medical College of Cornell University, New York Presbyterian
Hospital, NY; 2Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; 3Rocky Mountain Cancer
Centers, US Oncology, Denver, CO; 4Gabrail Cancer Center, Canton, OH; 5Pacific Cancer Medical Center, Anaheim, CA;
6Santee Hematology/Oncology, Sumter, SC; 7Sarah Cannon Research Institute and Oncology Hematology Care Inc.,
Cincinnati, OH; 8St Joseph Medical Center, Towson, MD; 9Clinic Cancer Care, Great Falls, MT, USA; 10Millennium
Pharmaceuticals, Inc., Cambridge, MA; 11Sarah Cannon Institute and Florida Cancer Specialists, Fort Myers, FL
1
Background
Elderly multiple myeloma (MM) patients are often ineligible for high-dose therapy
and stem cell transplant (HDTSCT) due to age and co-morbidities
Bortezomib (V)-based therapies have shown activity in newly diagnosed MM in
several phase 2 and 3 clinical trials; however, the efficacy and safety of these
different V-based regimens has not been directly compared
Regimen
Patient population (all previously untreated)
Median PFS
3-year OS rate
VD1
Younger patients (n=240), transplant-eligible
36 months
81%
VTD2
Younger patients (n=236), transplant-eligible
Not reported
86%
VMP3
Elderly patients (n=60), transplant-ineligible
25 months
85% (at 38 months)
VMP4
Elderly patients (n=344), transplant-ineligible
21.7 months
69%
VMP5
Elderly patients (n=260) , transplant-ineligible
34 months
74%
VD, bortezomib, dexamethasone; VTD bortezomib, thalidomide, dexamethasone; VMP, bortezomib,
melphalan, prednisone; PFS, progression-free survival; OS, overall survival
1Harousseau JL, et al. J Clin Oncol 2010;28:46219; 2Cavo M, et al. Lancet 2010;376:207585; 3Mateos MV, et al. Haematologica
2008;93:5605; 4Mateos MV, et al. J Clin Oncol 2010;28:225966; 5Mateos MV, et al. Lancet Oncol 2010;11:93441
2
1
Aims
UPFRONT is a randomized, open-label, multicenter,
phase 3b study conducted in the US community practice
setting, designed to:
compare the efficacy and safety of VD, VTD, and
VMP, in newly diagnosed MM patients ineligible for
HDTSCT
evaluate the use of single-agent V as a
maintenance therapy following VD, VTD, or VMP
induction
3
Endpoints and assessments
Primary endpoint:
PFS
Secondary endpoints included:
Efficacy of VD, VTD, and VMP
Overall response rate (ORR), complete response (CR)/near-CR (nCR),
very good partial response (VGPR), partial response (PR)
· Responses assessed by investigators applying IMWG criteria
OS
Safety and tolerability of VD, VTD, and VMP
Grade 3 adverse events (AEs)
Serious AEs (SAEs)
Peripheral neuropathy (PN)
· AEs graded using NCI-CTCAE version 3.0
4
2
Treatment schema
Induction: eight 21-day cycles
Maintenance:
five 35-day cycles
Cycles 14
Cycles 58
Cycles 913
VD
V: 1.3 mg/m2, days
V: 1.3 mg/m2, days
1,4,8,11
1,4,8,11
D: 20 mg, days
D: 20 mg, days 1,2,4,5
1,2,4,5,8,9,11,12
1:1:1
VTD
ZE
V: 1.6 mg/m2,
V: 1.3 mg/m2, days
V: 1.3 mg/m2, days
days 1,8,15,22
1,4,8,11
1,4,8,11
T: 100 mg, days 121
T: 100 mg, days 121
Rest period:
NDOMI
days 2335
D: 20 mg, days
D: 20 mg, days 1,2,4,5
RA
1,2,4,5,8,9,11,12
VMP
V: 1.3 mg/m2, days 1,4,8,11
M: 9 mg/m2, days 1,2,3,4 of every other cycle
P: 60 mg/m2, days 1,2,3,4 of every other cycle
5
Study design
Key inclusion criteria:
Patients aged 18 years with previously untreated symptomatic MM
Ineligibility for HDTSCT due to age, presence of co-morbid conditions, or
patient preference
Karnofsky Performance Status (KPS) score 50%
Measurable disease requiring systemic therapy
Serum M-protein: IgG or IgM >1 g/dL; IgA or IgD >0.5 g/dL
Urine light chain 200 mg/24hr urine collection
Key exclusion criteria:
Grade 2 PN within 21 days prior to enrollment
Concomitant prophylaxis:
VTD arm: aspirin, full-dose warfarin, or low-molecular weight heparin unless
medically contraindicated1
All groups: prophylaxis for herpes zoster recommended
1
6
Palumbo A, et al. Leukemia 2008;22:41422.
3
Data analyses
Efficacy and safety data were analyzed after a maximum
of 13 treatment cycles.
Safety data were analyzed after 8 induction cycles (I) and 5 V
maintenance cycles (M)
Efficacy data were analyzed after 13 cycles (I+M)
423 patients were evaluable for response
486 patients were included in the safety population
KaplanMeier PFS and OS analyses were performed on
the intent-to-treat population (all randomized patients,
N=502)
PFS and OS data are not yet mature; preliminary data are presented
7
Patient demographics and
baseline disease characteristics
VD
VTD
VMP
(N=168)
(N=167)
(N=167)
Median age, years (range)
74.5 (3991)
73.0 (3888)
72.0 (4286)
75 years, %
51
40
38
80 years, %
24
17
14
Male, %
60
42
54
Race*
White / Black / Other / Not reported, %
78 / 14 / 7 / 1
74 / 19 / 7 / 0
71 / 17 / 11 / <1
Myeloma type**
IgG / IgA / Light chain / Other, %
62 / 25 / 13 / <1
58 / 28 / 13 / 1
63 / 25 / 11 / 1
KPS 5060 / 7080 / 90100, %
11 / 41 / 48
8 / 40 / 52
12 / 45 / 43
ISS stage I / II / III, %
21 / 46 / 33
32 / 36 / 32
26 / 39 / 35
Charlson co-morbidity index 0 / 1 / 2, %
54 / 24 / 22
59 / 26 / 15
54 / 28 / 18
Serum creatinine >1.5 x ULN, %
13
10
11
Median 2-microglobulin, mg/L
4.45
3.90
4.03
*Other includes native Hawai an or other Pacific Islander, Asian, and American Indian or Alaskan native; **Other includes IgD,
IgM, or biclonal disease; Based on patients with available data; ISS, International staging system; ULN, upper limit of normal
8
4
Most common co-morbidities
at baseline (Charlson scale)
VD
VTD
VMP
Co-morbidity, %*
(N=168)
(N=167)
(N=167)
At least one co-morbidity
51
45
48
Excluding mild renal disease
46
41
46
Diabetes mellitus
22
19
23
Renal disease
22
14
9
Chronic pulmonary disease
7
8
9
Cerebrovascular disease
6
6
7
Congestive heart failure
8
4
4
Myocardial infarction
5
6
3
*Based on patients with available data; co-morbidities in 5% of patients across all three treatment arms are shown
9
[This slide may be
removed due to oral Most common concomitant
presentation time
constraints]
medications at baseline
VD
VTD
VMP
Class of concomitant medication, n (%)*
(N=165)
(N=158)
(N=163)
At least one concomitant medication
149 (90)
157 (99)
147 (90)
Anti-coagulants
73 (44)
146 (92)
59 (36)
Narcotics
90 (55)
75 (47)
95 (58)
Anti-emetics
77 (47)
73 (46)
87 (53)
Antibiotics (not biaxin)
76 (46)
73 (46)
73 (45)
Aspirin
48 (29)
102 (65)
39 (24)
Constipation therapies
58 (35)
68 (43)
50 (31)
Diuretics
59 (36)
76 (48)
39 (24)
Bisphosphonates
55 (33)
53 (34)
59 (36)
Anti-virals
56 (34)
45 (28)
53 (33)
Anxiolytics/anti-depressants
47 (28)
46 (29)
34 (21)
Non-narcotic analgesics
43 (26)
33 (21)
47 (29)
Proton pump inhibitors
42 (25)
46 (29)
33 (20)
*Most common concomitant medications taken by 25% of patients across all three treatment arms are shown
10
5
Treatment exposure
VD
VTD
VMP
(N=165)
(N=158)
(N=163)
No. of treatment cycles received,
8 (113)
6 (113)
7 (113)
median (range)
Patients receiving V maintenance,
82 (50)
60 (38)
69 (42)
n (%)
V dose intensity (mean doses
received/doses planned), %
Induction (cycles 18)
71
63
68
Maintenance (cycles 913)
75
81
87
11
Best confirmed response rates during
induction and maintenance
VGPR
100
PR
VGPR
CR+nCR
90
80
(%)
80
73
70
69
60
30
40
category
37
51*
33
50
40
40
7
11
7
30
response
20
36
Best
29
29
10
0
VD (N=146)
VTD (N=133)
VMP (N=144)
*VGPR rate VTD > VD, p=0.0174
12
6
PFS after a median follow-up of 26 months
1.0
0.9
0.8
0.7
patients
0.6
of
0.5
0.4
VD (N=168, 51% PFS events)
0.3
0.2
VTD (N=167, 42% PFS events)
Proportion
0.1
VMP (N=167, 49% PFS events)
0
0
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46
Time (months)
Patients remaining, n
VD
168 147 126 105 90 79 64 50 38 34 29 24 18 15
9
8
6
5
21
VTD
166 136 122 90 79 72 57 46 39 34 30 26 22 18 14 10
9
4
21
VMP
167 147 128 110 95867160 51 40 33251410
9
7
6
4
3
2
PFS was assessed in the ITT population (N=502)
Although median fol ow-up is 26 months, PFS data are preliminary as a significant number of patients are censored
within the first 12 months
1-year PFS estimates were 57.4% (VD), 63.8% (VTD), and 67.3% (VMP)
There was no statistically significant difference in PFS between the three arms
13
OS after a median follow-up of 26 months
1.0
0.9
0.8
0.7
patients
0.6
of
0.5
0.4
VD (N=168, 27% OS events)
0.3
0.2
VTD (N=167, 27% OS events)
Proportion
0.1
VMP (N=167, 25% OS events)
0
0
2 4
6 8 10 1214161820 2224 26 28 30 32 34 36 38 40 42 44 46 48
Time (months)
Patients remaining, n
VD
168 156 143 136 130 123 120 112 102 93 88 78 68 62 49 41 34 27 23 14 9
5
3
VTD
167 145 138 131 125 117 111 104 100 91 85 75 67 53 46 39 32 25 17 11 7
3
1
VMP
167 156 147 138 134 133 126 120 113 102 91 86 76 65 54 46 39 32 27 19 5
3
1
OS was assessed in the ITT population (N=502)
Although median fol ow-up is 26 months, OS data are preliminary as a significant number of patients are censored
within the first 12 months
1-year OS estimates were 87.4% (VD), 86.1% (VTD), and 88.3% (VMP)
2-year OS estimates were 73.7% (VD), 73.6% (VTD), and 77.6% (VMP)
There was no statistically significant difference in OS between the three arms
14
7
Treatment-emergent
grade 3 AEs
VD
VTD
VMP
n (%)
I
M
I
M
I
M
(N=165)
(N=82) (N=158)
(N=60) (N=163)
(N=69)
At least one grade 3 AE
122 (74)
7 (9)
132 (84)
5 (8)
133 (82)
2 (3)
PN*
31 (19)
5 (6)
38 (24)
4 (7)
31 (19)
2 (3)
Fatigue
16 (10)
2 (2)
19 (12)
0
13 (8)
0
Diarrhea
15 (9)
3 (4)
5 (3)
3 (5)
12 (7)
4 (6)
Pneumonia
16 (10)
1 (1)
10 (6)
0
8 (5)
2 (3)
Neutropenia
3 (2)
0
4 (3)
0
29 (18)
0
Thrombocytopenia
4 (2)
0
6 (4)
0
23 (14)
1 (1)
The most common grade 3 AEs reported in 7% of patients during induction and maintenance across all three treatment
arms are shown; The M column represents patients with the first onset of a particular AE during maintenance; *PN includes
neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, neuralgic amyotrophy, and peripheral
sensorimotor neuropathy
15
Serious AEs, discontinuations, deaths,
and second primary malignancies
VD
VTD
VMP
I
M
I
M
I
M
n (%)
(N=165)
(N=82)
(N=158)
(N=60)
(N=163)
(N=69)
At least one SAE
79 (48)
9 (11)
84 (53)
7 (12)
77 (47)
6 (9)
Pneumonia
17 (10)
1 (1)
11 (7)
1 (2)
8 (5)
2 (3)
Dehydration
8 (5)
0
5 (3)
1 (2)
9 (6)
0
Diarrhea
9 (5)
3 (4)
4 (3)
1 (2)
8 (5)
1 (1)
PN*
4 (2)
1 (1)
10 (6)
0
4 (2)
0
DVT/PE
11 (7)
8 (5)
3 (2)
Discontinuation of all
48 (29)
58 (37)
55 (34)
study drugs due to AEs
On-study deaths
11
1
(treatment-related), n
Second primary
0
0
1 (lung neoplasm)
malignancies, n
DVT/PE, deep vein thrombosis/pulmonary embolism; SAEs reported in 4% of patients during induction and maintenance
across all three treatment arms are shown, as wel as other SAEs of particular interest (DVT/PE); The M column represents
patients with the first onset of a particular AE during maintenance; *PN includes neuropathy peripheral, peripheral sensory
neuropathy, peripheral motor neuropathy, neuralgic amyotrophy, and peripheral sensorimotor neuropathy
16
8
Peripheral neuropathy
VD
VTD
VMP
I
M
I
M
I
M
n (%)
(N=165)
(N=82)
(N=158) (N=60)
(N=163) (N=69)
Any grade PN
77 (47)
5 (6)
90 (57)
4 (7)
72 (44)
3 (4)
Grade 3 PN
31 (19)
1 (1)
38 (24)
3 (5)
31 (19)
2 (3)
Any grade PN resulting in
17 (10)
5 (6)
25 (16)
0
28 (17)
1 (1)
discontinuation of all study
drugs
Grade 3 PN resulting in
12 (7)
5 (6)
19 (12)
0
21 (13)
1 (1)
discontinuation of all study
drugs
Median time to PN onset, days
70 (5316)
42 (2245)
63 (2375)
(range)
PN includes neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, neuralgic amyotrophy, and
peripheral sensorimotor neuropathy The M column represents patients with the first onset of a particular AE during maintenance
PN rates were higher for VTD vs. VD and VMP during induction
Compared with induction, the incidence of PN did not increase substantially during maintenance
in all three arms
17
Patient-reported QoL
(mean global health status score by treatment arm)
Induction
Maintenance
58
56
54
52
50
Score 48
46
44
42
VD
VTD
VMP
40
Baseline
Cycle 3
Cycle 5
Cycle 7
Cycle 9
Cycle 11
Cycle 13
Day 1
Day 1
Day 1
Day 1
Day 1
Day 1
Timepoint
In all three treatment arms, there was a trend for decreasing QoL during induction,
followed by an improvement/stabilization in QoL during maintenance
There was a trend for poorer QoL in the VTD vs. VD and VMP arms
18
UPFRONT QoL poster (ASH abstract 1864)
9
Summary and conclusions
VD, VTD, and VMP were active in the treatment of elderly
patients with newly diagnosed MM
VGPR rates were significantly higher for VTD vs. VD after maintenance
PFS and OS appeared similar between the treatment arms (ITT
population) at the current follow-up
Outcomes data are still immature and patients continue to be followed for
progression and survival status
Rates of grade 3 AEs, serious AEs, discontinuations, and PN
due to AEs were highest in the VTD arm
VTD was also associated with poorer overall QoL vs. VD and VMP
Maintenance with single-agent V was well tolerated, with limited
additional toxicity compared with induction
19
Summary and conclusions
This is the first study of VD and VTD in elderly, newly
diagnosed, transplant-ineligible MM patients
Triplet therapy with VTD or VMP appears to offer little advantage over
doublet therapy with VD for improving response rates and survival
outcomes in this patient population
Alternative VMP regimens based on less intensive V dosing
have also demonstrated substantial activity in elderly,
transplant-ineligible MM patients1,2
Weekly V dosing may therefore be preferable in the community-based setting
1Palumbo A, et al. J Clin Oncol 2010;28:51019; 2Bringhen S, et al. Blood 2010;116:474553.
20
10
Acknowledgments
The authors would like to thank all UPFRONT patients and study investigators
~200 UPFRONT study sites
21
11